Articles de revues sur le sujet « Art. 55 c. 2 c.p »

Introduction The aim of this study was to evaluate the micro-shear bond strength (μSBS) of different repair systems (Clearfil Repair, iGOS Repair) to restorative materials for CAD/CAM (Cerasmart, Lava Ultimate, InCoris TZI , VITA Suprinity, VITA Mark II, IPS e.max CAD, IPS Empress CAD). Methodology The 140 1.2 mm-thick specimens were prepared from CAD/CAM blocks (n=20) and thermocycled (10,000 cycles, 5–55°C, dwell time 20s). The specimens were randomly divided into two groups according to the repair system: Clearfil Repair (40% phosphoric acid+mixture of Clearfil Porcelain Bond Activator and Clearfil SE Bond Primer+Clearfil SE Bond+CLEARFIL MAJESTY ES-2) and iGOS Repair (40% phosphoric acid+ Multi Primer LIQUID+ iGOS Bond+ iGOS Universal). The composite resins were polymerized. All specimens were stored in distilled water at 37°C for 24 hours. The μSBS test was performed with a micro-shear testing machine (at 1 mm/min). The data were analyzed using two-way ANOVA, Tukey’s multiple comparison tests at a significance level of p<0.05. Each failure modes were examined under a stereomicroscope at×16 magnification. Results The type of CAD/CAM restorative material and repair system showed a significant effect on the μSBS (p<0.05). Specimens repaired with the iGOS Repair system showed the highest μSBS values than the Clearfil Repair system among all tested materials except for the InCoris TZI group (p<0.05). Conclusion All groups, except for the InCoris TZI group, repaired with iGOS Repair system showed higher μSBS than Clearfil Repair. The type of restoration and repair material is important in the success of the fracture repair.

Purpose To compare the receipt of clofarabine plus cytarabine (Clo+Ara-C arm) with cytarabine (Ara-C arm) in patients ≥ 55 years old with refractory or relapsed acute myelogenous leukemia (AML). Patients and Methods Patients were randomly assigned to receive either clofarabine (Clo) 40 mg/m2 or a placebo followed by Ara-C 1 g/m2 for five consecutive days. The primary end point was overall survival (OS). Secondary end points included event-free survival (EFS), 4-month EFS, overall remission rate (ORR; complete remission [CR] plus CR with incomplete peripheral blood count recovery), disease-free survival (DFS), duration of remission (DOR), and safety. Results Among 320 patients with confirmed AML (median age, 67 years), the median OS was 6.6 months in the Clo+Ara-C arm and 6.3 months in the Ara-C arm (hazard ratio [HR], 1.00; 95% CI, 0.78 to 1.28; P = 1.00). The ORR was 46.9% in the Clo+Ara-C arm (35.2% CR) versus 22.9% in the Ara-C arm (17.8% CR; P < .01). EFS (HR: 0.63; 95% CI, 0.49 to 0.80; P < .01) and 4-month EFS (37.7% v 16.6%; P < .01) favored the Clo+Ara-C arm compared with Ara-C arm, respectively. DFS and DOR were similar in both arms. Overall 30-day mortality was 16% and 5% for CLO+Ara-C and Ara-C arms, respectively. In the Clo+Ara-C and Ara-C arms, the most common grade 3 to 4 toxicities were febrile neutropenia (47% v 35%, respectively), hypokalemia (18% v 11%, respectively), thrombocytopenia (16% v 17%, respectively), pneumonia (14% v 10%, respectively), anemia (13% v 0%, respectively), neutropenia (11% v 9%, respectively), increased AST (11% v 2%, respectively), and increased ALT (10% v 3%, respectively). Conclusion Although the primary end point of OS did not differ between arms, Clo+Ara-C significantly improved response rates and EFS. Study follow-up continues, and the role of clofarabine in the treatment of adult patients with AML continues to be investigated.

Abstract Pegylated interferon (Peg-IFN) plus ribavirin is the standard treatment for patients with chronic hepatitis C. In a multicenter open trial, we assessed the efficacy and tolerability of this treatment in 78 HIV negative hemophiliacs (age: 20–64 years) with persistently high transaminase values. Sixty-four were naïve and 14 were relapsers to IFN monotherapy. Cirrhosis was clinically detected in 12 patients (15%). HCV genotype was 1 in 69%, 2a/c in 14%, 3a in 14% and 4 in 3%. Peg-IFN alpha-2b was given subcutaneously at doses of 1.5 mcg/Kg/week for 48 weeks in genotypes 1 and 4 and for 24 weeks in genotypes 2 and 3; oral ribavirin at 800–1200 mg/day based on body weight. Treatment was stopped in patients with polymerase chain reaction positive HCV-RNA at month 6. Results: 11 patients (14%) withdrew for side effects (4) or non-compliance (7). Neutropenia (&lt;500 cells/mmc), decompensated diabetes, ALT flares, and vomiting not responding to antiemetic drugs were reasons for treatment discontinuation. The median fall in hemoglobin levels was 3.1 g/dL. Weight loss (38%), fatigue (33%) and cephalalgia (15%) were frequent side effects. Thirty-two patients (41%) required dose reduction of ribavirin (23, 29%) or Peg-IFN (20, 26%). At the end of the 6-month follow-up, sustained virological response (SVR) was achieved in 43 patients (55%): 40/64 naïve (63%) and 3/14 relapsers (21%, p = 0.007). Five patients (6%), all relapsers to IFN monotherapy, had a virological breakthrough during treatment and 4 (5%) relapsed during the post-treatment follow-up period. SVR was obtained in 86% genotypes 2/3 and 43% genotypes 1/4 (p = 0.001). Predictors of SVR were evaluated by univariate analysis in the 64 naïve patients. SVR was significantly associated with HCV infection type 2 and 3 (86% vs 50% in HCV type 1 and 4; p = 0.008), absence of cirrhosis (97.5% vs 75% in non-responders; p = 0.02) and higher pre-treatment serum ALT levels (111 vs 75 IU/L in non-responders; p = 0.02). SVR rates did not differ in relation to patient’s age, pretreatment HCV viremia, median disease duration and compliance to full-dose treatment. Conclusions: combination therapy with Peg-IFN plus ribavirin is the recommended therapeutic option for hemophiliacs with hepatitis C chronic infection. Relapsers to IFN monotherapy may benefit of re-treatment with Peg-IFN plus ribavirin achieving at least 20% SVR. Genotype 2 and 3 infection is the most significant predictor of SVR.

Among the hundreds of archaeological sites in the lower reaches of the Amur basin, a special place belongs to the stones and rocks with ancient drawings. The rock art of the Lower Amur region has been studied since the sixties of the nineteenth century. Among the discoverers and researchers are the names of local historians and scientists. Systematic academic scientific research of petroglyphs monuments was carried out only 100 years later, in the sixties of the twentieth century, by Soviet archaeologists. The research source base (topography, description, tracing, scientific interpretation and publication of materials) was prepared by a team of employees of the Far Eastern Archaeological Expedition of the Institute of Archeology and Ethnography of the Siberian Branch of the USSR Academy of Sciences under the leadership of A. P. Okladnikov. Pisanitsa on the Sukpai River in the Ussuri River basin is one of the new sites of rock art in the region, it was discovered in the 1980s by archaeologist V. I. Dyakov, an employee of the Institute of History, Archeology and Ethnography of the Peoples of the Far East of the Far Eastern Branch of the Russian Academy of Sciences. The article offers the experience of studying the stylistic diversity of the Lower Amur rock art monuments, namely, the drawings of the Sukpai petroglyph, which predetermines its relevance. The novelty of the study is due to the fact that the article highlights the signs of the Sukpai artistic style, the extent of its distribution among the petroglyphs of the region and adjacent territories. To write the work, a wide range of research methods was used, including the method of analyzing scientific literature, the sources were scientific papers on the topic of the study. The result of the research: a) the distinctive features of the style of plots on the rock of the Sukpai River are highlighted; b) similar images were traced on the stones and rocks of the Sikachi-Alyan-Malyshevo site; c) substantiation of the identification of the Sukpai artistic style among the petroglyphs of the Lower Amur; d) the similarity of the drawings of the sukpai style with the plots of the shamanic thematic direction of the rock art monuments of the adjacent territories of Eastern Siberia, Yakutia, the Upper and Middle Amur Region, and Transbaikalia was traced.

Abstract Abstract 1551 Poster Board I-574 Introduction Hodgkin lymphoma (HL) is a B-cell neoplasm characterized by a minority of neoplastic cells, the so-called Hodgkin and Reed-Sternberg (HRS) cells, which are located within an extensive infiltrate of reactive cells. Aberrant signaling of various receptor tyrosine kinases (RTKs) via autocrine or paracrine mechanisms contributes to the survival and proliferation of HRS cells. Activation of the hepatocyte growth factor (HGF)/c-Met signaling pathway has been implicated in the pathophysiology of many cancers, but its role in HL is poorly investigated. In this study, we investigated the expression of c-Met and HGF in HL patient tissues and studied the cell physiological effects of the HGF/c-Met signaling pathway using a c-Met tyrosine kinase inhibitor SU11274 in HL cell lines. Methods The expression of c-Met and HGF in HL patient tissues was studied by immunohistochemistry on a HL tissue microarray. The c-Met expression level was determined by Western blotting, while HGF mRNA and protein levels were measured by quantitative (q)RT-PCR and ELISA in four HL cell lines, i.e. L428, KMH2, L1236 and U-HO1. The effects of SU11274 treatment on the activity of the HGF/c-Met signaling pathway was determined by detection of phosphorylated downstream targets by Western blotting. Effects on cell growth and cell cycle were determined by 3-(4,5- Dimethylthiazol -2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and by flow cytometry with Propidium iodide (PI), respectively. Results C-Met was detected in HRS cells in 55% (26/47) of HL patient tissues. Expression of HGF was detected in HRS cells in 5 c-Met positive and 2 c-Met negative HL patient tissues. C-Met was highly expressed in L428 compared to three other HL cell lines, whereas HGF was highly expressed in KMH2 and not or only weakly in the other three HL cell lines. Detectable levels of phosphorylated c-Met (p-Met) were observed only in L428 consistent with the high basal expression level of c-Met. Phosphorylation of c-Met, Akt and Erk1/2 were upregulated upon HGF stimulation of L428 cells. This activation could be blocked by inhibiting c-Met activation with SU11274. In functional studies, SU11274 suppressed cell growth in L428, promoted G2/M cell cycle arrest after 24h incubation, and induced tetraploidy after 48h. Washing of the cells after induction of G2/M arrest resulted in normal cell cycle progression indicating that the G2/M cell cycle arrest was reversible. Inhibition of PI3K, MEK1/2 and Erk1/2, three downstream targets of the HGF/c-Met signaling pathway, also induced G2/M cell cycle arrest in L428, indicating that these factors are involved in the G2/M cell cycle arrest induced by SU11274. Conclusion Co-expression of c-Met and HGF in HRS cells was observed in 11% of the HL patient tissues and HGF/c-Met signaling pathway regulates cell growth and cell cycle progression in L428 cells. Disclosures No relevant conflicts of interest to declare.

(1) Background: Thermoplastic materials are not inert and subject to changes in the oral environment, which affect their surface quality. Color stability and topographic characteristics of clear thermoplastic appliances are critical considerations. The study aimed to evaluate the optical changes and surface topography of different thermoplastic materials related to staining beverages and cleaning agents. (2) Methods: Thermoplastic polyethylene terephthalate glycol (PET-G) material specimens were selected for the study: S (Duran, Scheu-Dental GmbH, Iserlohn, Germany), D (Biolon, Dreve Dentamid GmbH, Unna, Germany), and B (Crystal, Bio Art Dental Equipment, Sao Carlos, Brazil). Four different media were involved for immersion: coffee (C) and black tea (T) at 55 °C, Coca-Cola (K) at 5 °C, and distilled water (W) at 22 °C. As for cleaning, chemical options and mechanical brushing were selected (P-powder, T-tablets, and X-brushing). Color changes, and mean surface roughness were measured at 24 h, 48 h, and after 7 days. Statistical analysis was performed. After the testing period, atomic force microscopy (AFM) analyses and SEM images were registered in order to characterize the surface topography. (3) Results: Quantitative color change evaluations revealed a slight change in color after 24 h and an extremely marked change after 48 h, respective 7 days. Mean roughness values are kept below the clinically acceptable limit of 0.20 µm for all samples. Related to mean nanoroughness values Sa, and 3D evaluations of the surface quality, Biolon samples have demonstrated the most constant behavior, while Crystal samples are visibly influenced by water immersion. Related to the cleaning method, the topography of Duran samples was influenced by mechanical brushing. (4) Conclusions: Nanoscale investigations provided high accuracy and more realistic surface quality examinations of the examined samples compared to profilometry. Both SEM and AFM should be used for a more detailed description of the surface topography.

Background Isoflurane and sevoflurane have been shown to elicit myocardial postconditioning, but the effect of desflurane remain unknown. The authors studied the mechanisms involved in desflurane-induced myocardial postconditioning. Methods Contracting isolated human right atrial trabeculae (34 degrees C, stimulation frequency 1 Hz) were exposed to 30-min hypoxia followed by 60-min reoxygenation. Desflurane at 3%, 6%, and 9% was administered during the first 5-min of reoxygenation. Postconditioning with 6% desflurane was studied in the presence of 1 microM calphostin C, a protein kinase C inhibitor; 800 mm 5-hydroxydecanoate, a mitochondrial adenosine triphosphate-sensitive potassium channels antagonist; 1 microM Akt inhibitor; 20 microM PD89058, an extracellular-regulated kinase 1/2 inhibitor; and 1 microM SB 202190, a p38 mitogen-activated protein kinase inhibitor. The force of contraction at the end of the 60-min reoxygenation period was compared (mean +/- SD). The p38 mitogen-activated protein kinase phosphorylation was studied using Western blotting. Results Desflurane at 3% (77 +/- 10% of baseline), 6% (90 +/- 14% of baseline), and 9% (86 +/- 11% of baseline) enhanced the recovery of force after 60 min of reoxygenation as compared with the control group (51 +/- 9% of baseline; P &lt; 0.001). Calphostin C (55 +/- 3% of baseline), 5-hydroxydecanoate (53 +/- 3% of baseline), Akt inhibitor (57 +/- 8% of baseline), PD89058 (64 +/- 6% of baseline), and SB 202190 (61 +/- 3% of baseline) abolished desflurane-induced postconditioning. Western blot analysis showed that 6% desflurane increased p38 mitogen-activated protein kinase phosphorylation. Conclusions In vitro, desflurane postconditioned human atrial myocardium through protein kinase C activation, opening of mitochondrial adenosine triphosphate-sensitive potassium channels, Akt and extracellular-regulated kinase 1/2 activation, and p38 mitogen-activated protein kinase phosphorylation.

9023 Background: c-Met overexpression (OE) and MET amplification (amp) are prognostic of poor outcome for non-small cell lung cancer (NSCLC). Telisotuzumab vedotin (ABBV-399; teliso-v [T]), an anti–c-Met Ab and monomethyl auristatin E drug conjugate, showed efficacy as monotherapy (mono) and combined with erlotinib (T+Er) in a phase 1/1b trial (NCT02099058) in NSCLC patients (pts) with c-Met OE. Here, c-Met OE (by immunohistochemistry [IHC]) and its association with T efficacy were explored. IHC, mRNA, and amp platforms for MET were also compared. Methods: Archival tissue from pts with NSCLC in the phase 1/1b trial was examined. c-Met was assessed centrally by IHC with SP44 Ab (Ventana Medical Systems) and pts with c-Met OE (membrane H-score [H-S] of ≥150) were enrolled. MET mRNA expression was analyzed from total RNA and sequenced on HiSeq 3000 (Illumina). MET amp was analyzed by FISH ( MET/ CEP7 ratio of ≥2) or whole-exome sequencing (copy number ≥2). Efficacy in the T mono every 2 (TQ2W) or 3 (TQ3W) weeks and the T+Er EGFR mutant cohorts was assessed for IHC H-S ≥150 and ≥225. Results: As of Dec 2018, 238 pts with NSCLC were screened centrally for c-Met OE. Of these, 118 pts were enrolled. For screened pts, 76%/37% of nonsquamous (NSQ, n = 201) and 58%/16% of squamous (SQ, n = 32) pts had H-S ≥150/≥225; 75%/41% of NSQ and 55%/16% of SQ NSCLC pts had ≥50% cells with 2+/3+ staining intensity. MET amp was reported for 5 pts, all with high H-S (≥270); there was an association between MET amp and MET RNA levels (n = 4) (t-test p value: 0.0002). See Table for ORR and median PFS by H-S and T treatment. Conclusions: c-Met expression prevalence in NSCLC showed a similar trend as in previous reports. In T+Er-treated pts, ORR was higher for those with c-Met H-S ≥225 than ≥150– < 225, suggesting that biomarker expression may act as an effect size multiplier. Optimization of the c-Met IHC cutoff warrants further investigation. Clinical trial information: NCT02099058. [Table: see text]

The purpose of this study was to test the hypothesis that exercise-induced cardiac adaptations would be attenuated by the free radical scavenger N-2-mercaptopropionyl glycine (MPG). Male Sprague-Dawley rats were divided into four groups ( n = 9–13 per group) for 3–4 wk: sedentary (S), S+MPG (100 mg/kg ip daily), exercised on a treadmill (E) (60 min/day, 5 days/wk, at a speed of 20 m/min up a 6° grade in a 6°C room), or E+MPG given 10 min prior to exercise. Additional rats ( n = 55) were used to determine acute exercise effects on myocardial redox state [nonprotein nonglutathione sulfhydryls (NPNGSH)] and PI3K/Akt signaling pathway activation. Compared with S, NPNGSH levels were 48% lower in E ( P < 0.05) and unchanged in E+MPG ( P > 0.05). MPG also attenuated exercise-induced activation of the signaling proteins Akt and S6. Hearts from the 4-wk groups were weighed, and cardiac function was evaluated using an isolated perfused working heart preparation. Similar increases ( P < 0.05) in both exercised groups were observed for heart weight and heart weight-to-body weight ratio. Cardiac function improved in E vs. S, as indicated by greater ( P < 0.05) external work performed (cardiac output × systolic pressure) and efficiency of external work (work/V̇o2). MPG prevented these exercise-induced functional improvements. Skeletal muscle mitochondria content increased to similar levels in E and E+MPG. This study provides evidence that free radicals do not play an essential role in the development of exercise-induced cardiac hypertrophy; however, they appear to be involved in functional cardiac adaptations, which may be mediated through the PI3K/Akt pathway.

Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus. We analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from The Cancer Genome Atlas (TCGA). Among them, a total of 55 Yale samples including two patient-derived xenografts (PDXs) and 27 TCGA samples have whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples have RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples have whole-genome sequencing (WGS) data. We found recurrent somatic mutations in TP53, MED12, and PTEN genes. Top somatic mutated genes included TP53, ATRX, PTEN, and MEN1 genes. Somatic copy number variation (CNV) analysis identified 8 copy-number gains, including 5p15.33 (TERT), 8q24.21 (C-MYC), and 17p11.2 (MYOCD, MAP2K4) amplifications and 29 copy-number losses. Fusions involving tumor suppressors or oncogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being potentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothripsis. Clinically actionable mutational signatures of homologous-recombination DNA-repair deficiency (HRD) and microsatellite instability (MSI) were identified in 25% (12 of 48) and 2% (1 of 48) of fresh frozen uLMS, respectively. Finally, we found olaparib (PARPi; P = 0.002), GS-626510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and suggest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.

Abstract Endocannabinoid system is a set of ligands, receptors and endogenous enzymes which modulate a variety of physiological effects. There are two well-characterized cannabinoid receptors, CB1 (mainly expressed in Central Nervous System) and CB2 (mainly in hematopoietic cells). Here, we tested the effect of the cannabinoid WIN-55 212-2 in acute myeloid leukemia (AML) in vitro, ex vivo and in vivo and studied the molecular signaling pathways involved in this effect. Moreover, we synthesized a new family of twelve cannabinoids that are specific to CB2 receptor. For their design and synthesis, computational techniques of docking, analytical and spectroscopic techniques such as mass spectrometry (MS) were used. To assess the anti-leukemia effect of the different cannabinoids, we analyzed cell viability by MTT and flow cytometry using six human AML cell lines, primary cells from healthy donors (hematopoietic progenitor cells (HPC) and lymphocytes) and blasts from AML patients. Cannabinoids induced a potent proapoptotic effect on AML cell lines and on primary leukemic cells, which was not observed in normal HPC and lymphocytes from healthy donors. Fragmentation of PARP and activation of caspases 2, 3, 8 and 9 were confirmed by western-blot. Other proteins involved in the effect of cannabinoids were p-AKT, p-ERK 1/2, p-38 and p- JNK. Also studies on p-PERK, p-IRE1 and CHOP confirmed an increased endoplasmic reticulum stress upon exposure to cannabinoids. Mitochondrial damage was analyzed by flow cytometry using TMRE and by MitoSOXTMRed. These assays confirmed a very early mitochondrial damage in leukemic cells which was not observed in normal hematopoietic progenitor cells. Moreover, we analyzed the ceramide levels, a membrane lipid associated with death/survival cell processes by HPLC and immunohistochemistry. Remarkably, we observed significant differences in the amounts of certain subtypes of ceramides in untreated versus treated leukemic cells. The proapoptotic effect of cannabinoids on AML cells was abolished upon co-culture with either CB2 receptor antagonists or with pancaspase inhibitors. Finally, NOD/scid/IL-2R gammae null (NSG) mice were xenotransplanted with HL60 cell line. We confirmed disease infiltration in bone marrow (BM) by BM aspirates and flow cytometry assays. Once the presence of leukemic cells was confirmed, treatment with vehicle, WIN-55 cannabinoid at a dose of 5 mg/kg/day or citarabine (ARA-C) at 50 mg/kg during 5 days was administered. We observed a significantly increased survival among mice treated with WIN-55 cannabinoid as compared to both the control group and the group treated with ARA-C. In addition, we tested in vivo the effect of these compounds on normal hematopoiesis by treating healthy BALB-C mice. We confirmed that cannabinoids did not affect the viability of the different populations of hematopoietic progenitors (LK, GMP, CMP) and, moreover, an increased platelet count was observed in treated mice. Our findings indicate that cannabinoids display a highly selective proapoptotic effect against leukemic cells. Several pathways are involved in this effect, the modification in the ceramide pattern playing a main role. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 190 Introduction: Overexpression of Bcl-2 in Chronic Lymphocytic Leukemia (CLL) is associated with enhanced CLL-cell resistance to spontaneous or chemotherapy-induced apoptosis. The BH3 mimetic protein navitoclax (ABT-263) specifically inhibits Bcl-2, and related proteins Bcl-xL and Bcl-w, and can induce apoptosis of CLL cells in vitro. Phase I evaluation in relapsed/refractory CLL patients demonstrated 35% overall response rate (Roberts, 2012). Dose-limiting thrombocytopenia due to Bcl-xL inhibition was mitigated using a lead-in dosing schedule to allow the bone marrow to achieve a compensatory increase in platelets prior to dose escalation to the MTD of 250 mg. Based on the promising single-agent data, a Phase II trial randomized trial compared the safety, pharmacokinetics, and biologic activity of treatment with navitoclax and rituximab (RTX) versus RTX alone. Methods: Patients with CLL who required initial treatment according to iwCLL criteria (Hallek et al, 2008) were stratified by Binet stage and high-risk cytogenetic features (17p deletion and/or 11q deletion), and randomized 1:1:1 to receive RTX weekly for 8 wks (375 mg/m2 wk 1, 500 mg/m2 wks 2–8) (Arm A), or RTX for 8 wks plus navitoclax daily for 12 wks (250 mg/day following a 7–14 day lead-in period of 100 mg/day) (Arm B), or RTX for 8 wks plus navitoclax daily as in Arm B, but continued treatment with navitoclax until disease progression, relapse, or unacceptable toxicity (Arm C). Arm A to Arm B crossover was permitted. Response rate was assessed by iwCLL CLL response criteria at week 12, and every 12 weeks during follow-up. The study was stopped after the last patient had completed ≥ 12 weeks of treatment and week-12 response assessment. Results: Baseline characteristics and prognostic factors for the 118 randomized patients were generally balanced among the three treatment arms. Median age was 63 years (range 38–94), and 55% were Binet stage B+C. Median baseline lymphocyte count was 53,000 mm3 (range 7,000–552,000/mm3). FISH analyses identified higher than expected rates of deletion of 11q or 17p in the CLL cells of 32% or 28% of patients, respectively. Median time on study was 32 weeks overall (24 wks for Arm A, 33 wks Arm B, and 44 wks Arm C). AEs of Grade 3–4 that were more common (> 5% greater) in a navitoclax-treated arm compared with the RTX arm included thrombocytopenia, neutropenia, leukopenia, anemia, GI symptoms (diarrhea, abdominal pain), chills, fatigue, ALT/AST/bilirubin elevations, and infusion-related reactions (to RTX). Thrombocytopenia, neutropenia, and hepatic enzyme elevations were generally reversible when navitoclax was stopped and/or dose-reduced; however, 12 patients (15%) discontinued navitoclax due to laboratory abnormalities (9 due to ALT elevations). Neutropenia responded to growth factors. One serious event of epistaxis occurred related to the thrombocytopenia. Two deaths occurred on study, one on the RTX-only arm due to a pulmonary embolus and one on Arm B due to hypotension and dyspnea related to a severe RTX infusion reaction. Investigator-assessed objective response (CR and PR) rate was 35% for Arm A, 55% for Arm B (p=0.19 vs A), and 70% for Arm C (p=0.0034 vs A). All responses were PRs except for 2 CRs in Arm C. All responses were confirmed by CT (and BM for CR) ≥ 8 wks after clinical response assessment. While the presence of 17p deletion appeared to result in a lower response rate to RTX alone (Arm A, ORR 18%, 2/11 pts), it did not appear to affect the response to ABT-263 and RTX (Arm B, ORR 73%, 8/11 pts); Arm C, ORR 50%, 5/10 pts. Limited PFS results appeared consistent with the responses by arm, with a longer PFS associated with the longer duration of ABT-263 treatment on Arm C; however, the magnitude of PFS differences could not be precisely quantified due to the limited follow-up and patient number. Preliminary pharmacokinetic analysis did not detect any drug interaction between navitoclax and RTX. Conclusions: Navitoclax in combination with RTX weekly × 8 was generally well-tolerated as initial therapy for CLL patients and demonstrated greater clinical activity than treatment with RTX alone as well as responses in patients with 17p deletion. The preliminary results of this study indicate that a BH3-mimetic inhibitor of Bcl-2 could be highly effective when used in combination with RTX for treatment of patients with CLL. Disclosures: Eradat: Genentech: Research Funding. Off Label Use: BH3 Mimetic Protein Navitoclax (ABT-263). Catalono:Genentech: Consultancy. Kipps:Genentech: Research Funding. Zheng:Genentech: Employment. Yalamanchili:Genentech: Employment. Sahasranaman:Genentech: Employment. Hurst:Genentech: Employment. Ho:Genentech: Employment.

Abstract In order to analyse the incidence of iron overload after allo BMT and assess the role of venesection in preventing complications, we retrospectively analysed 168 consecutive patients undergoing allo BMT at our institution from 1998–2003 surviving at least one year. Iron studies were performed routinely pre-BMT, at D100, one & two years post BMT. Iron overload was defined by at least one of the following criteria i)liver biopsy (n=24), one of : a) dry weight iron concentration >80μmol/g; b) iron index >1.9; c) Perl’s stain grade 3 or 4, ii) CT liver iron >1.0mg/ml (n=13) iii) raised ferritin >1000 μg/L and transferrin saturation >55% on 2 occasions, persisting >6/12 post BMT (n=11), iv) venesection >5g iron (n=1). Using these criteria, iron overload occurred in 49/168 (29%) pts. 12/119 in the non-overloaded group had further investigation but did not meet the criteria; liver biopsy (n=10) or CT (n=2). Elevated ferritin, particularly early post-transplant, did not reliably predict for iron overload, with 55/91 evaluable patients having values >1000μg/L at D100 not fulfilling the criteria for iron overload. There was no difference between overloaded and non-overloaded patients with respect to age or sex. Acute (15/49 vs. 26/113) or chronic liver GVHD (25/46 vs. 47/105) was not different between the two groups (both p>0.05). Only 3 patients were hepatitis B sAg+ or hepatitis C Ab+. The iron overloaded group was more likely to i) have been transplanted for acute leukaemia (29/49 vs. 33/119; p 0.0002) ii) be C282Y heterozygotes (11/46 vs. 10/110, p 0.02) (iii) been transfused more units of red cells (mean 42 vs. 19; p<0.0001) and iv) have persistently abnormal liver function post-transplant, ALT (IU/ml; normal <55) at 1 year 77 vs. 52 and at 2 years 67 vs. 37 (all p<0.05). There was no effect of hetero- or homozygosity for H63D. 63 patients were analysed for the S65C, V59M and Q283P mutations. One patient was heterozygous for the S65C mutation (non-overloaded group). A mean of 12.3 units were venesected in 22 patients (range 2–46), all of whom had received >25 units of red cells. ALT fell significantly (mean pre venesection 189 IU/ml, post 36, p<0.05), as did transferrin saturation (mean pre venesection 68%, post 29%, p<0.05). We conclude that tissue iron overload is common after BMT, that biochemical measures of iron stores (ferritin and transferrin saturation) may be unreliable in this context, particularly in the early post BMT period and that radiological or histological assessment to distinguish hyperferritinaemia due to inflammation from true tissue iron overload may be required. Patients at risk of iron overload (transfusions >25 units, C282Y heterozygotes) should be closely monitored and early venesection therapy instituted to minimise organ damage.

Abstract Objectives To describe relationships between diet satisfaction, ability to eat, and CLD. Methods Data collected from 354 patients with CLD was used for this analysis, including 2 items from the validated Chronic Liver Disease Questionnaire (CLDQ): item 7 “ability to eat as much as you like” (EA), and item 14 “bothered by a limitation of your diet” (SWD). Results were stratified by existing diagnosis (Cirrhosis and all-type Hepatitis) and severity of disease [Childs-Pugh score (CP-A, mild; CP-B, moderate; CP-C, severe)]; AST (abnormal &gt; 40 U/L) and ALT (abnormal &gt; 55 U/L). Ordinal Logistic Regression, with odds and likelihood ratios, modeled disease severity CP A-C; general linear models examined EA and SWD. All models adjusted for age and sex. Results 354 CLD patients were included [mean age 50.4y (±11.2); 51% male; 222 cirrhosis; 145 hepatitis; 135 with abnormal AST; 131 abnormal ALT; 100 had CP score A; 83 CP-B; 38 CP-C] Of those included, 31% (n = 110) reported low EA (EA-L), and 25% (n = 88) reported low SWD (SWD-L). In patients with cirrhosis, 36% (n = 80) reported EA-L, and 33% (n = 73) SWD-L. 30% (n = 43) of patients with hepatitis reported EA-L, and 22% SWD-L. 33% (n = 45) of patients with abnormal AST reported EA-L, 30% (n = 41) SWD-L; 40% (n = 52) of those with abnormal ALT reported EA-L, 35% (n = 46) SWD-L. 50% (n = 19) with CP-C had EA-L, 63% (n = 24) SWD-L. 43% (n = 36) with CP-B had EA-L, 39% (n = 32) SWD-L. 25% (n = 25) with CP-A had EA-L, 17% (n = 17) SWD-L. Worsening CP scores were 22.68x (p = .0004) more likely associated with EA-L; the odds of patients with CP-C reporting EA-L was 3.3x greater compared normal CP. Similarly, worse CP scores were 56.99x (p &lt; .0001) more likely associated with SWD-L; odds of patients with CP-C reporting SWD-L were 16.2x greater compared to normal. EA described 23% of variance in SWD (p &lt; .0001), and SWD explained 25% of the variance in EA (p &lt; .0001). Sex was significantly associated with SWD (0.55 ± 0.2, p &lt; .0001), age was not. Neither were significant for EA. Conclusions EA-L and SWD-L strongly relate to worsening disease severity as documented by CP scores. Diet satisfaction and ability to eat as much as you like should be monitored closely for patients with CLD, especially those with cirrhosis because these symptoms signal loss of lean mass– a health risk, and one that may preclude eligibility for life-saving liver transplantation. Funding Sources NIFA National Needs Fellowship

[1] A. Junaidi and C. Sumirat, “Aplikasi Persediaan Barang PT. CAD Solusindo Menggunakan Metode Waterfall,” Jurnal Sisfokom (Sistem Informasi dan Komputer), vol. 7, no. 1, p. 28, 2018, doi: 10.32736/sisfokom.v7i1.280.[2] N. Apriyani and A. Muhsin, “Analisis Pengendalian Persediaan Bahan Baku Dengan Metode Economic Order Quantity Dan Kanban Pada Pt Adyawinsa Stamping Industries,” Opsi, vol. 10, no. 2, p. 128, 2017, doi: 10.31315/opsi.v10i2.2108.[3] M. Sukamto, “ANALISIS PENGENDALIAN PERSEDIAAN BAHAN BAKU DENGAN METODE FIXED ORDER INTERVAL (FOI) TERHADAP BIAYA TOTAL PERSEDIAAN DAN LABA OPERASI PADA RESTORAN BENEDICT,” Jurnal Mozaik, vol. 9, no. 1, pp. 81–93, 2017.[4] Haslindah, A. S. Iriani, M. Ardi, and Zulkifli, “PENERAPAN MANAJEMEN PERSEDIAAN DALAM MENGANTISPASI KERUGIAN BARANG DAGANGAN DI TOKO MEGA JILBAB,” Banco: Jurnal Manajemen dan Perbankan Syariah, vol. 2, no. 2, pp. 58–68, 2020, doi: 10.35905/banco.v2i2.1811.[5] P. C. P. Dewi, N. T. Herawati, and M. A. Wahyuni, “Analisis Pengendalian Persediaan Dengan Metode (EOQ) Economic Order Quantity Guna Optimalisasi Persediaan Bahan Baku Pengemas Air Mineral,” Jurnal Akuntansi Profesi, vol. 10, no. 2, pp. 54–65, 2019.[6] R. Jappi and D. F. Koan, “PENERAPAN INVENTORY MANAGEMENT DALAM MENINGKATKAN PROFITABILITAS DI TOKO X KUPANG,” Calyptra: Jurnal Ilmiah Mahasiswa Universitas Surabaya , vol. 3, no. 1, pp. 1–16, 2014.[7] T. Lukmana and D. Trivena, “Penerapan Metode EOQ dan ROP (Studi Kasus: PD. BARU),” Jurnal Teknik Informatika dan Sistem Informasi, vol. 1, no. 3, pp. 271–279, 2015.[8] N. Hartih Aeni, Satibi, and G. Pamudji Widodo, “Penerapam Metode Economic Order Quantity Dan Reorder Point Dalam Meningkatkan Efisiensi Persediaan Obat,” Jurnal Manajemen dan Pelayanan Farmasi, vol. 3, no. 4, pp. 249–254, 2013.[9] T. Rafliana and B. R. Suteja, “Penerapan Metode EOQ dan ROP untuk Pengembangan Sistem Informasi Inventory Bengkel MJM berbasis Web,” Jurnal Teknik Informatika dan Sistem Informasi, vol. 4, no. 2, pp. 345–354, 2018.[10] D. Misbachul Umami, M. Fuad Fauzul Mu, and R. Rakhmawati, “ANALISIS EFISIENSI BIAYA PERSEDIAAN MENGGUNAKAN METODE EOQ (ECONOMIC ORDER QUANTITY) PADA PT. XYZ Analysis of Cost Efficiency on Inventory System Using EOQ (Economic Order Quantity) Method in The PT. XYZ,” Jurnal Agroteknologi, vol. 12, no. 1, pp. 64–70, 2018.[11] M. K. Anam, T. Nasution, S. Erlinda, L. Efrizoni, and Susanti, “The Analysis and Optimization of Business Processes for Students in Higher Education Based on Togaf 9 . 2,” Scientific Journal of Informatics, vol. 8, no. 2, pp. 230–243, 2021, doi: 10.15294/sji.v8i1.29952.[12] I. P. C. P. Dewi, I. N. T. Herawati, and I. made A. Wahyuni, “ANALISIS PENGENDALIAN PERSEDIAAN DENGAN METODE (EOQ) ECONOMIC ORDER QUANTITYGUNA OPTIMALISASI PERSEDIAAN BAHAN BAKU PENGEMAS AIR MINERAL,” Jurnal Akuntansi Profesi, vol. 10, no. 2, pp. 55–65, 2019.[13] R. Cahya Pratiwi, C. Iswahyudi, and R. Yuliana Rachmawati, “SISTEM MANAJEMEN PERSEDIAAN BARANG DAGANG MENGGUNAKAN METODE SAFETY STOCK DAN REORDER POINT BERBASIS WEB (STUDI KASUS: ART KEA CENTRO PLAZA AMBARRUKMO YOGYAKARTA),” Jurnal SCRIPT, vol. 7, no. 2, pp. 213–222, 2019.[14] M. Jamaris, H. Saputra, M. K. Anam, K. Andesa, and Rahmaddeni, “Sistem Marketplace Pencarian Lapangan Futsal Menggunakan Metode Haversine Berbasis Android,” JURNAL ILMIAH KOMPUTER GRAFIS, vol. 15, no. 1, pp. 53–65, 2022, doi: 10.51903/pixel.v15i1.712.[15] H. Asnal et al., “Sistem Monitoring Persediaan Stok Onderdil Menggunakan Metode Reorder Point Pada Sani Computer,” 2022.[16] M. K. Anam and R. Anwar, “Penerapan Aplikasi Pendukung Touring Pada Komunitas Motor Berbasis Android,” Edumatic: Jurnal Pendidikan Informatika, vol. 4, no. 1, pp. 1–10, 2020, doi: 10.29408/edumatic.v4i1.1980.[17] M. K. Anam and H. Ulayya, “Implementasi dan Analisa SARDrive Sebagai Media Penyimpanan Cloud,” JUITA: Jurnal Informatika, vol. 8, no. 1, pp. 83–90, 2020, doi: 10.30595/juita.v8i1.5748.

Art, considered in its manifestations, whether through music, singing, painting, dancing, and all the possible expressions it can have, is undoubtedly a beautiful way to enrich the soul, the spirit, and human emotions. In this work, the different forms of understanding art, and the benefits that it can have on people, are exposed. It that art in its multiple manifestations can help control stress, anxiety, and depression. For this purpose, the investigators use bibliographic support to compare academic scenarios, artistic expressions that allow people to improve their emotional, physical, and psychological health. For this purpose, is implemented a bibliographic search to comparing academic scenarios, artistic manifestations that allow people to improve their emotional, physical, and psychological health. On the other hand, it was possible to verify that music performed as a half-hour therapy helps children with catastrophic illnesses, relieving pain. Keywords: art, human emotions, artistic expressions. References [1]E. Panosfky and F. Saxl, MITOLOGÍA CLÁSICA EN EL ARTE MEDIEVAL, Áurea, 2021. [2]A. Casanova, «Arteterapia: A arte como instrumento no trabalho do psicólogo,» Psicologia, Ciéncia e Profissao, vol. 34, nº 1, pp. 142-157, 2014. [3]A. Ballesta, O. Vizcaino and E. Mesas, «El arte como un lenguaje posible en las personas con capacidades diversas, » Arte y Políticas de indentidad, vol. 4, nº junio, pp. 137-152, 2011. [4]C. López, «El arte como forma de realidad, » [Online]. Available: https://d1wqtxts1xzle7.cloudfront.net/64011688/Herbert%20Marcuse%20-%20El%20arte%20como%20forma%20de%20realidad-with-cover-page-v2.pdf?Expires=1629957713&Signature=RnZvL4~kWoJF5i0g-BZySz2YpCZgiTsQrx3khQFL80iZznlDRONCJBRLMFEaNDMoAvyVlP~mafoZFAsQfIU5y3d-bJy7. [Last access: August 27, 2021]. [5]E. Hernández-pacheco, «Comisión de investigaciones paleontológicas y prehistóricas,» Junta para ampliación de estudios e investigaciones científicas, Madrid, 2018. [6]Himmelman, «Lo bucólico en el arte antiguo,» de Instituto Arqueológico Alemán, Madrid, 1973. [7]J. Cervelló, Escritura, lengua y cultura en el antiguo egipto, Barcelona: Universidad autónoma de Barcelona, 2015. [8]P. Bosh-Gimpera, «El arte rupestre en América,» Anales de antropología, vol. 1, nº 1, 1964. [9]V. Córdoba, «La música en la edad media,» [Online]. Available: https://www.timetoast.com/timelines/musica-de-la-edad-media. [Last access: August 28, 2021] [10]Pinterest, «Los instrumentos del renacimiento, » [Online]. Available: https://www.pinterest.com/pin/247698048233408250/. [Last access: August 28, 2021] [11]almomento.mx, «El cambio de la música a la época barroca,» 12 marzo 2021. [Online]. Available: https://almomento.mx/historia-de-la-musica-barroca/. [Last access: August 28, 2021] [12]Pinterest, «Música clásica para estudiar y relajarse, » [Online]. Available: https://www.pinterest.es/pin/355221489342463596/. [Last access: August 28, 2021] [13]F. Suárez and L. Rosales, La ingeniería de las emociones humanas, Quito: AutanaBooks, 2021. [14]F. Suárez, L. Rosales y Á. Lezama, Computación inteligente y estados emocionales, Quito: AutanaBooks, 2020. [15]J. Morey, «Intervención plástica como soporte emocional para niños en el instituto nacional de salud del niño-Hospital del Niño,» Hospital del Niño, 2017. [16]J. P. S. De la Rubia y C. Cabañéz, «Impacto fisiológico de la musicoterapia en la depresión, ansiedad, y bienestar del paciente con demencia tipo Alzheimer. Valoración de la utilización de cuestionarios para cuantificarlo, » European Journal of Investigation in Health, vol. 4, nº 2, pp. 131-140, 2014. [17]J. Tresierra, «Musicoterapia y pediatría,» Revista peruana de pediatría, pp. 53-55, 2005. [18]E. Torres-Ake, G. Lugo-Ake, J. Matos-Villanueva and E. Socorro, «Masaje frente a musicoterapia para reducir el estrés en prematuros de una unidad crítica neonatal, una revisión sistemática,» Rev. Enferm Inst Mex Seguro Soc., vol. 28, nº 1, pp. 49-57, 2020.

Abstract Abstract 1413 Hepatitis virus C (HCV) infection is common in patients with inherited bleeding disorders due to the past use of plasma-derived clotting factor concentrates not treated with virucidal methods. The prognosis of the infection and the outcome of antiviral therapy are related to the stage of liver fibrosis. Since liver biopsy, the gold standard to grade fibrosis, is rarely performed in these patients for cost-benefit reasons, it is important to consider non invasive methods to assess fibrosis such as liver stiffness measurement with transient elastography (TE, Fibroscan®), a technique already validated in non hemophilic patients. We measured TE in 170 patients with inherited bleeding disorders and HCV infection (positive serum HCV-RNA). The main characteristics of these patients are reported in the Table. Steatosis was detected by abdominal ultrasound. Cirrhosis was defined by the presence of irregular liver edge, splenomegaly, dilated portal vein and/or esophageal varices combined either with low platelet count and/or reduced albumin/cholinesterase levels. TE was successfully performed in all but 3 patients, 2 of whom for Body Mass Index (BMI) > 30 kg/m2. Overall, the median value of liver stiffness was 7.2 kPa (interquartile range, IQR: 5.3–11.1) with a median success rate of 100% (IQR: 91–100) and a median IQR value of 1.0 (IQR: 0.7–1.9). HCV genotype or the presence of steatosis did not influence the TE values, whereas higher values were observed in patients with cirrhosis than in those without (median 19.8 kPa, IQR: 14.3–28.1 vs 6.8 kPa, IQR: 5.1–9.1, respectively; p< 0.01). In particular, 18/22 (82%) cirrhotic patients had a liver stiffness value ≥ 12.0 kPa, a cut-off previously identified as associated with severe fibrosis in HCV infected patients. Overall, splenomegaly was present in 51 patients (30%), 16 with cirrhosis and 35 without. In 31/35 (89%) of the latter, TE values were < 12 kPa. Moreover, among patients without cirrhosis, 12 (8%) had TE values ≥ 12 kPa: those patients had ALT and GGT levels significantly higher than patients with TE values < 12 kPa (p<0.05 for both variables). In our cohort TE had a 83% sensitivity, a 95% specificity and a 94% negative predictive value for the detection of severe fibrosis. In the same patients we measured the aspartate aminotransferase-to-platelet ratio index (APRI), a simple non-invasive biochemical marker of liver fibrosis. Median APRI values were significantly higher in patients with cirrhosis than in those without (1.6 vs 0.5, respectively; p<0.01), and a value > 1.5 was observed in 12/22 (55%) patients with cirrhosis. An APRI >1.5 had a 96% specificity and a 93% negative predictive value for the detection of severe fibrosis. Univariate and multivariate linear regression analyses were performed to investigate the relationship between log transformed TE and demographic (age, BMI) or laboratory (ALT, GGT, APRI) variables potentially influencing the TE values. By univariate analysis a linear association was found with age, ALT, GGT, APRI and BMI values (p<0.01 for each). In multivariate analysis APRI, ALT and GGT showed the strongest association with TE, while the statistical significance for BMI and age was marginal. The entire model explained about 50% of the variance of TE (R2= 0.49). Our results confirm that TE is a good tool to assess liver fibrosis also in patients with inherited bleeding disorders and chronic hepatitis C and shows that it can be performed safely in a great proportion of patients with a high success rate. The value of biochemical markers of necroinflammation (such as ALT and GGT) at the time of TE performance may influence the result and should be taken into account in the interpretation of the test. Disclosures: No relevant conflicts of interest to declare.

482 Background: The standard of care for locally advanced SCCA of the AC is 5-fluorouracil (5-FU)/mitomycin C (MMC) with concurrent XRT. C was evaluated with 5-FU in 2 large phase III studies (RTOG 98-11 and ACT II) to establish superiority over 5-FU/MMC. Neither study showed significant differences for disease-free survival (DFS) or overall survival (OS). RTOG 98-11 reported reduced colostomy-free survival (CFS) in the C-induction arm; no differences were noted in the ACT II study. We present our 20-year experience with C for locally advanced SCCA of the AC which has been adopted as the standard unless contraindicated. Methods: A retrospective, single institution analysis for locally advanced SCCA of the AC was completed in patients (pts) that received concurrent 5-FU/C/XRT from 1989-2009. Medical records were reviewed for history of STDs, chronic immunosuppression, stage, dose of XRT, toxicity, clinical response (CR), recurrence, and OS. Multidisciplinary management included surgical, radiation, and medical oncologists. OS, DFS, and CFS were calculated using the K-M method. The log-rank test was used to compare OS among these subgroups. Results: 185 pts were identified (51 M:134 F). The median age was 56 (35-83 y.o.). AJCC stage was I (n = 25); II (n = 76); IIIA (n = 36); and IIIB (n = 48). The median XRT dose was 55 Gy in 30 fractions. 181 pts were evaluable for response; 4 were lost to follow up. Complete CR (cCR) was noted in 169 pts (93%); partial response (n = 12); 6 pts received an APR. After a median follow up of 8.6 years, 14 pts (8%) developed local recurrence; 11 received salvage surgery. 16 pts (9%) developed distant metastases (DM). The 5-yr DFS = 81%, 5-yr OS = 85% and 5-yr CFS was 88%. By univariate analysis, N-stage was a poor prognostic indicator for 5-yr DFS (p = 0.02) and DM (p = 0.046) but not OS or CFS. Increased T-stage correlated with salvage surgery (p = 0.005). Conclusions: Cisplatin-based chemoradiation for locally advanced SCCA of the anal canal resulted in favorable DFS, OS, and CFS compared to historical data and phase III studies. Platinum-based therapy for anal cancer appears to be an acceptable alternative to MMC and should be considered as a standard option for locally advanced disease. No significant financial relationships to disclose.

STEAM-based learning is a global issue in early-childhood education practice. STEAM content becomes an integrative thematic approach as the main pillar of learning in kindergarten. This study aims to develop a conceptual and practical approach in the implementation of children's education by applying a modification from STEAM Learning to R-SLAMET. The research used a qualitative case study method with data collection through focus group discussions (FGD), involving early-childhood educator's research participants (n = 35), interviews, observation, document analysis such as videos, photos and portfolios. The study found several ideal categories through the use of narrative data analysis techniques. The findings show that educators gain an understanding of the change in learning orientation from competency indicators to play-based learning. Developing thematic play activities into continuum playing scenarios. STEAM learning content modification (Science, Technology, Engineering, Art and Math) to R-SLAMETS content (Religion, Science, Literacy, Art, Math, Engineering, Technology and Social study) in daily class activity. Children activities with R-SLAMETS content can be developed based on an integrative learning flow that empowers loose part media with local materials learning resources. Keyword: STEAM to R-SLAMETS, Early Childhood Education, Integrative Thematic Learning References Ali, E., Kaitlyn M, C., Hussain, A., & Akhtar, Z. (2018). the Effects of Play-Based Learning on Early Childhood Education and Development. Journal of Evolution of Medical and Dental Sciences, 7(43), 4682–4685. https://doi.org/10.14260/jemds/2018/1044 Ata Aktürk, A., & Demircan, O. (2017). A Review of Studies on STEM and STEAM Education in Early Childhood. Journal of Kırşehir Education Faculty, 18(2), 757–776. Azizah, W. A., Sarwi, S., & Ellianawati, E. (2020). Implementation of Project -Based Learning Model (PjBL) Using STREAM-Based Approach in Elementary Schools. Journal of Primary Education, 9(3), 238–247. https://doi.org/10.15294/jpe.v9i3.39950 Badmus, O. (2018). Evolution of STEM, STEAM and STREAM Education in Africa: The Implication of the Knowledge Gap. In Contemporary Issues in Science, Technology, Engineering, Arts and Mathematics Teacher Education in Nigeria. Björklund, C., & Ahlskog-Björkman, E. (2017). Approaches to teaching in thematic work: early childhood teachers’ integration of mathematics and art. International Journal of Early Years Education, 25(2), 98–111. https://doi.org/10.1080/09669760.2017.1287061 Broadhead, P. (2003). Early Years Play and Learning. In Early Years Play and Learning. https://doi.org/10.4324/9780203465257 Canning, N. (2010). The influence of the outdoor environment: Den-making in three different contexts. European Early Childhood Education Research Journal, 18(4), 555–566. https://doi.org/10.1080/1350293X.2010.525961 Clapp, E. P., Solis, S. L., Ho, C. K. N., & Sachdeva, A. R. (2019). Complicating STEAM: A Critical Look at the Arts in the STEAM Agenda. Encyclopedia of Educational Innovation, 1–4. https://doi.org/10.1007/978-981-13-2262-4_54-1 Colucci, L., Burnard, P., Cooke, C., Davies, R., Gray, D., & Trowsdale, J. (2017). Reviewing the potential and challenges of developing STEAM education through creative pedagogies for 21st learning: how can school curricula be broadened towards a more responsive, dynamic, and inclusive form of education? BERA Research Commission, August, 1–105. https://doi.org/10.13140/RG.2.2.22452.76161 Conradty, C., & Bogner, F. X. (2018). From STEM to STEAM: How to Monitor Creativity. Creativity Research Journal, 30(3), 233–240. https://doi.org/10.1080/10400419.2018.1488195 Conradty, C., & Bogner, F. X. (2019). From STEM to STEAM: Cracking the Code? How Creativity & Motivation Interacts with Inquiry-based Learning. Creativity Research Journal, 31(3), 284–295. https://doi.org/10.1080/10400419.2019.1641678 Cook, K. L., & Bush, S. B. (2018). Design thinking in integrated STEAM learning: Surveying the landscape and exploring exemplars in elementary grades. School Science and Mathematics, 118(3–4), 93–103. https://doi.org/10.1111/ssm.12268 Costantino, T. (2018). STEAM by another name: Transdisciplinary practice in art and design education. Arts Education Policy Review, 119(2), 100–106. https://doi.org/10.1080/10632913.2017.1292973 Danniels, E., & Pyle, A. (2018). Defining Play-based Learning. In Encyclopedia on Early Childhood Development (Play-Based, Issue February, pp. 1–5). OISE University of Toronto. DeJarnette, N. K. (2018). Implementing STEAM in the Early Childhood Classroom. European Journal of STEM Education, 3(3), 1–9. https://doi.org/10.20897/ejsteme/3878 Dell’Erba, M. (2019). Policy Considerations for STEAM Education. Policy Brief, 1–10. Doyle, K. (2019). The languages and literacies of the STEAM content areas. Literacy Learning: The Middle Years, 27(1), 38–50. http://proxy.libraries.smu.edu/login?url=http://search.ebscohost.com/login.aspx?direct=true&db=eue&AN=133954204&site=ehost-live&scope=site Edwards, S. (2017). Play-based learning and intentional teaching: Forever different? Australasian Journal of Early Childhood, 42(2), 4–11. https://doi.org/10.23965/ajec.42.2.01 Faas, S., Wu, S.-C., & Geiger, S. (2017). The Importance of Play in Early Childhood Education: A Critical Perspective on Current Policies and Practices in Germany and Hong Kong. Global Education Review, 4(2), 75–91. Fesseha, E., & Pyle, A. (2016). Conceptualising play-based learning from kindergarten teachers’ perspectives. International Journal of Early Years Education, 24(3), 361–377. https://doi.org/10.1080/09669760.2016.1174105 Finch, C. R., Frantz, N. R., Mooney, M., & Aneke, N. O. (1997). Designing the Thematic Curriculum: An All Aspects Approach MDS-956. 97. Gess, A. H. (2019). STEAM Education. STEAM Education, November, 2011–2014. https://doi.org/10.1007/978-3-030-04003-1 Gronlund, G. (n.d.). “ Addressing Standards through Play-Based Learning in Preschool and Kindergarten .” Gronlund, G. (2015). Planning for Play-Based Curriculum Based on Individualized Goals to Help Each Child Thrive in Preschool and Kindergarten Gaye Gronlund. Gull, C., Bogunovich, J., Goldstein, S. L., & Rosengarten, T. (2019). Definitions of Loose Parts in Early Childhood Outdoor Classrooms: A Scoping Review. The International Journal of Early Childhood Education, 6(3), 37–52. Hapidin, Pujianti, Y., Hartati, S., Nurani, Y., & Dhieni, N. (2020). The continuous professional development for early childhood teachers through lesson study in implementing play based curriculum (case study in Jakarta, Indonesia). International Journal of Innovation, Creativity and Change, 12(10), 17–25. Hennessey, P. (2016). Full – Day Kindergarten Play-Based Learning : Promoting a Common Understanding. Education and Early Childhood Development, April, 1–76. gov.nl.ca/edu Henriksen, D. (2017). Creating STEAM with Design Thinking: Beyond STEM and Arts Integration. Steam, 3(1), 1–11. https://doi.org/10.5642/steam.20170301.11 Inglese, P., Barbera, G., La Mantia, T., On, P., Presentation, T., Reid, R., Vasa, S. F., Maag, J. W., Wright, G., Irsyadi, F. Y. Al, Nugroho, Y. S., Cutter-Mackenzie, A., Edwards, S., Moore, D., Boyd, W., Miller, E., Almon, J., Cramer, S. C., Wilkes-Gillan, S., … Halperin, J. M. (2014). Young Children’s Play and Environmental Education in Early Childhood Education. PLoS ONE, 2(3), 9–25. https://doi.org/10.1586/ern.12.106 Jacman, H. (2012). Early Education Curriculum. Pedagogical Development Unit, FEBRUARY 2011, 163. https://www.eursc.eu/Syllabuses/2011-01-D-15-en-4.pdf Jay, J. A., & Knaus, M. (2018). Embedding play-based learning into junior primary (Year 1 and 2) Curriculum in WA. Australian Journal of Teacher Education, 43(1), 112–126. https://doi.org/10.14221/ajte.2018v43n1.7 Kennedy, A., & Barblett, L. (2010). Supporting the Early Years Learning Framework. Research in Practise Series, 17(3), 1–12. Keung, C. P. C., & Cheung, A. C. K. (2019). Towards Holistic Supporting of Play-Based Learning Implementation in Kindergartens: A Mixed Method Study. Early Childhood Education Journal, 47(5), 627–640. https://doi.org/10.1007/s10643-019-00956-2 Keung, C. P. C., & Fung, C. K. H. (2020). Exploring kindergarten teachers’ pedagogical content knowledge in the development of play-based learning. Journal of Education for Teaching, 46(2), 244–247. https://doi.org/10.1080/02607476.2020.1724656 Krogh, S., & Morehouse, P. (2014). The Early Childhood Curriculum : Inquiry Learning Through Integration. Liao, C. (2016). From Interdisciplinary to Transdisciplinary: An Arts-Integrated Approach to STEAM Education. Art Education, 69(6), 44–49. https://doi.org/10.1080/00043125.2016.1224873 Lillard, A. S., Lerner, M. D., Hopkins, E. J., Dore, R. A., Smith, E. D., & Palmquist, C. M. (2013). The impact of pretend play on children’s development: A review of the evidence. Psychological Bulletin, 139(1), 1–34. https://doi.org/10.1037/a0029321 Maxwell, L. E., Mitchell, M. R., & Evans, G. W. (2008). Effects of Play Equipment and Loose Parts on Preschool Children’s Outdoor Play Behavior: An Observational Study and Design Intervention. Children, Youth and Environments, 18(2), 37–63. McLaughlin, T., & Cherrington, S. (2018). Creating a rich curriculum through intentional teaching. Early Childhood Folio, 22(1), 33. https://doi.org/10.18296/ecf.0050 Mengmeng, Z., Xiantong, Y., & Xinghua, W. (2019). Construction of STEAM Curriculum Model and Case Design in Kindergarten. American Journal of Educational Research, 7(7), 485–490. https://doi.org/10.12691/education-7-7-8 Milara, I. S., Pitkänen, K., Laru, J., Iwata, M., Orduña, M. C., & Riekki, J. (2020). STEAM in Oulu: Scaffolding the development of a Community of Practice for local educators around STEAM and digital fabrication. International Journal of Child-Computer Interaction, 26, 100197. https://doi.org/10.1016/j.ijcci.2020.100197 Moomaw, S. (2012). STEM Begins in the Early Years. School Science and Mathematics, 112(2), 57–58. https://doi.org/10.1111/j.1949-8594.2011.00119.x Peng, Q. (2017). Study on Three Positions Framing Kindergarten Play-Based Curriculum in China: Through Analyses of the Attitudes of Teachers to Early Linguistic Education. Studies in English Language Teaching, 5(3), 543. https://doi.org/10.22158/selt.v5n3p543 Pyle, A., & Bigelow, A. (2015). Play in Kindergarten: An Interview and Observational Study in Three Canadian Classrooms. Early Childhood Education Journal, 43(5), 385–393. https://doi.org/10.1007/s10643-014-0666-1 Pyle, A., & Danniels, E. (2017). A Continuum of Play-Based Learning: The Role of the Teacher in Play-Based Pedagogy and the Fear of Hijacking Play. Early Education and Development, 28(3), 274–289. https://doi.org/10.1080/10409289.2016.1220771 Quigley, C. F., Herro, D., & Jamil, F. M. (2017). Developing a Conceptual Model of STEAM Teaching Practices. School Science and Mathematics, 117(1–2), 1–12. https://doi.org/10.1111/ssm.12201 Ridgers, N. D., Knowles, Z. R., & Sayers, J. (2012). Encouraging play in the natural environment: A child-focused case study of Forest School. Children’s Geographies, 10(1), 49–65. https://doi.org/10.1080/14733285.2011.638176 Ridwan, A., Rahmawati, Y., & Hadinugrahaningsih, T. (2017). Steam Integration in Chemistry Learning for Developing 21st Century Skills. MIER Journail of Educational Studies, Trends & Practices, 7(2), 184–194. Rolling, J. H. (2016). Reinventing the STEAM Engine for Art + Design Education. Art Education, 69(4), 4–7. https://doi.org/10.1080/00043125.2016.1176848 Sancar-Tokmak, H. (2015). The effect of curriculum-generated play instruction on the mathematics teaching efficacies of early childhood education pre-service teachers. European Early Childhood Education Research Journal, 23(1), 5–20. https://doi.org/10.1080/1350293X.2013.788315 Sawangmek, S. (2019). Trends and Issues on STEM and STEAM Education in Early Childhood. Képzés És Gyakorlat, 17(2019/3-4), 97–106. https://doi.org/10.17165/tp.2019.3-4.8 Science, A. I. (n.d.). STEM Project-Based Learning. Spencer, R., Joshi, N., Branje, K., Lee McIsaac, J., Cawley, J., Rehman, L., FL Kirk, S., & Stone, M. (2019). Educator perceptions on the benefits and challenges of loose parts play in the outdoor environments of childcare centres. AIMS Public Health, 6(4), 461–476. https://doi.org/10.3934/publichealth.2019.4.461 Taylor, J., Bond, E., & Woods, M. (2018). A Multidisciplinary and Holistic Introduction. Varun A. (2014). Thematic Approach for Effective Communication in Early Childhood Education Thematic Approach for effective communication in ECCE. International Journal of Education and Psychological Research (IJEPR), 3(3), 49–51. https://www.researchgate.net/publication/289868193 Wang, X., Xu, W., & Guo, L. (2018). The status quo and ways of STEAM education promoting China’s future social sustainable development. Sustainability (Switzerland), 10(12). https://doi.org/10.3390/su10124417 Whitebread, D. D. (2012). The Importance of Play. Toy Industries of Europe, April, 1–55. https://doi.org/10.5455/msm.2015.27.438-441 Wong, S. M., Wang, Z., & Cheng, D. (2011). A play-based curriculum: Hong Kong children’s perception of play and non-play. International Journal of Learning, 17(10), 165–180. https://doi.org/10.18848/1447-9494/cgp/v17i10/47298 Zosh, J. M., Hopkins, E. J., Jensen, H., Liu, C., Neale, D., Hirsh-Pasek, K., Whitebread, Solis, S. L., & David. (2017). Learning through play : a review of the evidence (Issue November). The LEGO Foundation.

Abstract Background Children with perinatally acquired human immunodeficiency virus (HIV; PHIVs) face a lifelong cumulative exposure to HIV and antiretroviral therapy (ART). The relationship between gut integrity, microbial translocation, and inflammation in PHIV is poorly understood. Methods This is a cross-sectional study in 57 PHIVs, 59 HIV-exposed but uninfected children, and 56 HIV-unexposed and -uninfected children aged 2–10 years old in Uganda. PHIVs were on stable ART with HIV-1 RNA &lt;400 copies/mL. We measured markers of systemic inflammation, monocyte activation, and gut integrity. Kruskal-Wallis tests were used to compare markers by group and the Spearman correlation was used to assess correlations between biomarkers. Results The mean age of all participants was 7 years and 55% were girls. Among PHIVs, the mean CD4 % was 34%, 93% had a viral load ≤20 copies/mL, and 79% were on a nonnucleoside reverse transcriptase inhibitor regimen. Soluble cluster of differentiation 14 (sCD14), beta-D-glucan (BDG), and zonulin were higher in the PHIV group (P ≤ .01). Intestinal fatty acid binding protein (I-FABP) and lipopolysaccharide binding protein (LBP) did not differ between groups (P &gt; .05). Among PHIVs who were breastfed, levels of sCD163 and interleukin 6 (IL6) were higher than levels in PHIV who were not breastfed (P &lt; .05). Additionally, in PHIVs with a history of breastfeeding, sCD14, BDG, LBP, zonulin, and I-FABP correlated with several markers of systemic inflammation, including high-sensitivity C-reactive protein, IL6, d-dimer, and systemic tumor necrosis factor receptors I and II (P ≤ .05). Conclusions Despite viral suppression, PHIVs have evidence of altered gut permeability and fungal translocation. Intestinal damage and the resultant bacterial and fungal translocations in PHIVs may play a role in the persistent inflammation that leads to many end-organ diseases in adults. Despite viral suppression, children with perinatally acquired human immunodeficiency virus (HIV) in Uganda have evidence of alterations in intestinal permeability and fungal translocation, compared to HIV-exposed but uninfected and HIV-unexposed children, which may play a role in HIV-associated chronic inflammation.

Abstract The Tumor Necrosis Factor (TNF) family member TNF-Related Apoptosis Inducing Ligand (TRAIL) was originally reported to induce apoptosis in many tumor cells but not in normal cells in vivo and thus represents a promising anticancer cytokine. The in vitro cytotoxic response of acute myelogenous leukemia (AML) cell lines to recombinant TRAIL varies from good to moderate, however, a number of in vitro studies have convincingly demonstrated that AML primary cells are resistant to the proapoptotic activity of TRAIL used as a single agent. To potentiate the response of AML cells to TRAIL cytotoxicity, we have adopted a strategy of combining perifosine, a novel Akt inhibitor, with recombinant TRAIL. The rationale for using such a combination is that perifosine was recently described to increase TRAIL-R2 receptor expression and decrease cellular FLICEinhibitory (c-FLIP, an inhibitor of caspase-8 activation) protein in human lung cancer cells. Both perifosine and TRAIL, when used alone, induced cell death by apoptosis in THP- 1 AML cells, which normally express constitutively active Akt and nonfunctional p53. Perifosine treatment, at concentrations well below the IC50 (0.5 μM), dephosphorylated Akt on Ser473 and increased TRAIL-R2 levels, as demonstrated by flow cytometry, western blot, and RT-PCR. Perifosine also downmodulated cFLIP-L and XIAP levels. However, perifosine did not affect expression of TRAIL-R1 and TRAIL-R4 receptors, or of other proteins which are critical for TRAIL-mediated proapoptotic signaling, including FADD and Mcl-1. Perifosine and TRAIL strongly synergized to induce cytotoxicity as suggested by calculation of the combination index (CI range: 0.15–0.37). The combined treatment resulted in upregulation of caspase-8 activity and apoptosis which was markedly reduced by a selective caspase-8 inhibitor (Z-IETD-FMK). While cFLIP-L and XIAP downregulation was dependent on inhibition of NF-κB activity caused by perifosine, upregulation of TRAIL-R2 expression was dependent on generation of reactive oxygen species (ROS) by perifosine which in turn sequentially activated protein kinase C (PKC)α, JNK2, and c-Jun. A ROS scavenger (N-acetylcysteine), siRNA downregulation of either PKCα or c-Jun, or a JNK1/2 selective pharmacological inhibitor (SP600125), all markedly impaired perifosine-dependent TRAIL-R2 upregulation. Perifosine synergized with TRAIL by inducing apoptosis exclusively in primary AML cells displaying constitutive activation of the Akt pathway. Also in primary AML blasts, perifosine upregulated TRAIL-R2 levels, downmodulated the expression of both c-FLIP and XIAP, and increased Ser 63 p-c-Jun levels, without affecting the expression of FADD. Remarkably, perifosine increased p-JNK2 levels and TRAIL-R2 expression in primary AML patient blasts (CD34+, CD38Low/Neg, CD123+) enriched in putative leukemic stem cells. Perifosine and TRAIL combined treatment was effective in inducing apoptosis (55–60%) in this immature blast population, as documented by a quadruple staining flow cytometric technique for CD34+, CD38Low/Neg, CD123+, Annexin V+ blast cells. The combined treatment negatively affected the clonogenic activity of CD34+ cells from AML patients with Akt activation. In contrast, CD34+ cells from healthy donors and AML patients without Akt activation were resistant to perifosine plus recombinant TRAIL treatment. Our findings suggest that a combination consisting of perifosine plus recombinant TRAIL might offer a novel therapeutic strategy for AML displaying enhanced Akt signaling by overcoming critical mechanisms of apoptosis resistance. Moreover, this kind of combination therapy could be effective also in AML cases exhibiting nonfunctional p53 or low levels of p53.

270 Background: Sorafenib is the standard first line treatment for advanced HCC and showed a median time to progression (TTP) of 5.5 months and an overall response rate (ORR) of 2% in the phase III SHARP trial. FOLFOX has shown modest activity in HCC with a progression free survival (PFS) of 2.9 months and ORR of 8% in a phase III trial. In this single-arm, multicenter phase 2 and biomarker study, sorafenib plus FOLFOX was evaluated in the first line treatment of advanced HCC. Methods: Patients with histologically proven advanced HCC, Child Pugh A liver function, and no prior systemic therapies received sorafenib 400mg orally twice daily during a 2-week lead-in, followed by concurrent modified FOLFOX (5-FUCI 1200mg/m2/day for 46 hours and LV 400mg/m2 bolus, Oxaliplatin 85mg/m2) on day 1 and 15 of each 28-day cycle. The primary endpoint was TTP, calculated from date of study entry to date of radiological or clinical disease progression. Serial plasma anti-angiogenic and anti-inflammatory biomarkers were evaluated. Results: The study enrolled 40 patients with advanced HCC: median age, 65 years; male 85%; Child Pugh A5, 70%; BCLC stage C, 95%; HCC etiology, HCV 40%, HBV 13%, alcohol 13%. Grade 3/4 adverse events were notable for AST (23%), ALT (15%), bilirubin (10%), diarrhea (10%), anemia (10%), hypertension (5%), hand-foot syndrome (5%), and thrombocytopenia (5%). Dose reductions for sorafenib and FOLFOX were done in 73% and 65% of patients, respectively. The median TTP was 8.8 months (95%CI, 6.5-11.2). The ORR was 18%, and the stable disease rate was 55%. Among 36 patients with a baseline AFP ≥ 5 ng/mL, 10 (28%) had a ≥ 50% drop in AFP. Low baseline plasma levels of sVEGFR1, VEGF-C, and bFGF and high levels of s-cMET and IL-12 tended to associate with longer TTP (p < 0.10). Decreased s-cMET at day 15 and decreased s-cMET and IL-2 at day 43 were associated with longer TTP (p < 0.05). Conclusions: Sorafenib+FOLFOX demonstrated encouraging clinical efficacy with moderate toxicity in the first line treatment of advanced HCC. Initial biomarker evaluation suggested a correlation between TTP and baseline angiogenic markers as well as changes in IL-2 and s-cMET. Complete biomarker analysis will be presented at the meeting. Clinical trial information: NCT01775501.

The ability to tell stories needs to be trained in early childhood to learn to express their thoughts, needs, and emotions. The purpose of the study was to analyze the initial ability of storytelling that is owned by children aged 5-6 years so that it can be taken into consideration in determining the learning media to be made. The place of the study was conducted at Al Iman Kindergarten in East Jakarta from January - December 2016. The research method used was quantitative by using a storytelling ability test that was distinguished by language and non-language aspects. Data analysis techniques are carried out using descriptive statistics. The results of the research are indicators of storytelling abilities derived from language and non-language aspects. Based on the results of the storytelling ability test obtained if most children are still not good in the language and non-language aspects. Recommendations for further research are expected to develop learning media that train children’s storytelling skills for the better. References: Berkowitz, D. (2011). Oral storytelling: Building community through dialogue, engagement, and problem-solving. YC Young Children, 66(2), 36-41. https://eric.ed.gov/?id=EJ930387 Djaali & Muljono, (2008). Pengukuran dalam bidang pendidikan. Jakarta: Grasindo. Fekonja-Peklaj, U., Marjanovič-Umek, L., & Kranjc, S. (2010). Children’s storytelling: The effect of preschool and family environment. European Early Childhood Education Research Journal, 18(1), 55–73.doi:10.1080/13502930903520058 Kervin, L. & Mantei, J. (2016). Digital storytelling: Capturing children’s participation in preschool activities. Issues in Educational Research, 26(2), http://www.iier.org.au/iier26/kervin.pdf Lenox, M. F. (2000). Storytelling for young children in a multicultural world. Early Childhood Education Journal, 28(2), 97–103. doi:10.1023/a:1009599320835 Maidar G. A. & Mukti U.S. (1988). Pembinaan kemampuan berbicara. Jakarta: Erlangga. Miller, S. & Pennycuff. (2008). The power of story: Using storytelling to improve literacy learning. Journal of Cross-Disciplinary Perspectives in Education, 1(1), 36 – 43. http://wmpeople.wm.edu/asset/index/mxtsch/storytelling Nurgiyantoro, B. (2010). Penilaian pembelajaran bahasa berbasis kompetensi. Yogyakarta: BPFE. Pekdoğan, S. (2016). Investigation of the effects of story-based social skills training program on the social skill development of 5-6-year-old children. Education and Science, 41, 183, 305-318. https://eric.ed.gov/?id=ED573653 Schneider, P., Rivard, R., & Debrueil, B. (2011). Does colour affect the quality or quantity of children’s stories elicited by pictures?. Child Language Teaching and Therapy, 27, 2-3. https://rehabilitation.ualberta.ca//media/rehabili-tation/faculty-site/departments/csd/documents/enni/bw-colour-final-version.pdf Setiati, L., Sunarto, P. & Setiawan, P. (2011). Komunikasi gambar bercerita pada buku belajar baca anak taman kanak-kanak. ITB J. Vis. Art & Des, 5(1), http://download.portalgaruda.org/article.php?article=312143&val=7392&title=Komunikasi%20Gambar%20Bercerita%20 pada%20Buku%20Belajar%20Baca%20Anak%20Taman%20Kanak-Kanak Silva, M., Strasser, K., & Cain, K. (2014). Early narrative skills in Chilean preschool: Questions scaffold the production of coherent narratives. Early Childhood Research Quarterly, 29, 205–213 http://repositorio.uchile.cl/bitstream/han-dle/2250/124436/Early-narrative-skillsin-Chilean-preschool-Questions-scaffoldthe-production-of-coherent-narratives.pdf?sequence=1 Stadler, M. A., & Ward, G. C. (2006). Supporting the Narrative Development of Young Children. Early Childhood Education Journal, 33(2), 73–80. doi:10.1007/s10643-005-0024-4 Tayler, C. (2015). Learning in early childhood: Experiences, relationships and ‘learning to be.’ European Journal of Education. 50(2). http://onlinelibrary.wiley.com/doi/10.1111/ejed.12117/full Whorrall, J., & Cabell, S. Q. (2015). Supporting Children’s Oral Language Development in the Preschool Classroom. Early Childhood Education Journal, 44(4), 335–341. doi:10.1007/s10643-015-0719-0 Willis, C. A., & Schiller, P. (2011). Preschoolers’ social skills steer life success. YC young children, 66(1), 42-49. CCCNS NoG-090-Wil/YC. Wright, C., Diener, M. L., & Kemp, J. L. (2013). Storytelling dramas as a community building activity in an early childhood classroom. Early Childhood Education Journal, 41, 197–210. doi: http://dx.doi.org/10.4135/9781483340333.n391

Background: This study was conducted to determine the effects of vitamin D supplementation on some of the gene expressions related to insulin and lipid metabolism in diabetic hemodialysis (HD) patients. Methods: A double-blind, randomized, placebo-controlled clinical trial was carried out in 55 patients with diabetic HD. The current project used two groups in which each subject received vitamin D supplements (50,000 IU, n=28) or placebo (50,000 IU, n=27) every 2 weeks for 12 weeks. Gene expression analyses (RT-PCR) were included to obtain the rate of gene expression of the related insulin and lipid metabolism genes in peripheral blood mononuclear cells (PBMCs) of patients with diabetic HD. Results: Our data revealed that consumption of vitamin D supplementation enables to overexpress the peroxisome proliferation-activated receptor gamma (PPAR-γ) (P=0.001), AKT (P=0.04), PI3K (P=0.02), insulin receptor substrate-1 (IRS1) (P0.008) and glucose transporter type 4 (GLUT-4) (P=0.01) and downregulate the expression of protein kinase C (PKC) (P=0.001) in patients with diabetic HD than control group following the 12-week intervention. In addition, vitamin D supplementation downregulated low-density lipoprotein receptor (LDLR) (P=0.03) expression in the subjects with diabetic HD than the control group. Vitamin D supplementation did not show any effects on the expression of pyruvate dehydrogenase kinase 1 (PDK1) (P=0.37), IRS2 (P=0.90) and lipoprotein (a) [Lp(a)] (P=0.05). Conclusions: Our findings confirmed that diabetic HD subjects who received the vitamin D supplementation (for 12 weeks), showed a significant overexpression in the PPAR-γ, AKT, PI3K, IRS1 and GLUT4 genes, and also showed a significant downregulation in the PKC and LDLR genes. Moreover, no effects on PDK1, IRS2 and Lp(a) expression were observed.

To identify in vivo the specific alpha-adrenergic receptor mediating direct neural control of chloride transport in the rat S1 proximal convoluted tubule (PCT), the major effector site of neural regulation, microperfusion was employed in conjunction with the alpha 1- and alpha 2-adrenergic receptor antagonists, prazosin and rauwolscine. Using a glomerular ultrafiltrate-like perfusate, prazosin markedly inhibited chloride transport by -42% (302 +/- 10 to 176 +/- 5 peq.mm-1.min-1, P < 0.0001). Using a sodium chloride perfusate, which measures the active component of chloride absorption (J(Cl)act) (control, 153 peq.mm-1.min-1) plus a constant passive (479 peq.mm-1.min-1) component, both prazosin and acute renal denervation reduced J(Cl)act by -38% and -44% (-58 and -67 peq.mm-1.min-1, each P < 0.05). In contrast, rauwolscine caused no significant change in J(Cl)act using either perfusate. Prazosin regulates chloride transport via protein kinase C (PKC), since preactivation of PKC by phorbol abolished inhibitory impact of prazosin. Inhibition of J(Cl)act by prazosin (-58 peq.mm-1.min-1) was fully additive to either the stimulation or inhibition (losartan) of angiotensin II (55 or -49 peq.mm-1.min-1), which uses the adenosine 3',5'-cyclic monophosphate (cAMP) second messenger system [observed changes, not significantly different from 0 and -99 peq.mm-1.min-1; expected changes, not significantly different from 0 and -107 peq.mm-1.min-1]. In conclusion, neural control of S1 PCT chloride absorption in vivo is mediated by alpha 1-adrenergic receptors, which can selectively regulate J(Cl)act by altering PKC activity, independently of the cAMP second messenger system.

534 Background: mTOR plays a critical role in promoting tumor cell growth. In preclinical studies, the anti-tumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated by IGF-1R. We designed a phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT) and pharmacodynamic effects of the IGF-1R antibody IMC-A12 in combination with temsirolimus (tem) in patients (pts) with metastatic breast cancer (MBC) where mTOR is frequently activated. Methods: A 3+3 phase I design was chosen. Tem and IMC-A12 were administered IV days (d) 1, 8, 15, and 22 of a 4-week cycle in pts with MBC refractory to standard therapies. Tumor response was evaluated by RECIST. Adverse events (AE) were reported using CTC v3.0. Serum IGF 1 and C-peptide levels on d2 (24h post infusion) and d8 prior to drug infusion were compared to baseline (BL) using paired t-test. Results: Of 26 pts enrolled, 4 did not complete cycle 1 due to progression (3) or co-morbid condition (1). MTD was determined from remaining 22 pts aged 34-72 (median 48) years with ECOG PS 0 (55%) or 1 (45%). 86% had ER+ cancer. Median number of regimens for MBC was 4. Two DLTs at the starting DL (DL 1) necessitated dose de-escalation of tem to 20mg (DL-1), then to 15 mg (DL-2) which was tolerable (Table). Subsequent dose escalation of IMC-A12 led to DLTs in 0 of 6 in DL-2A and 2 of 3 pts in DL-2B. The MTD was defined as DL-2A. Other AEs included gr 1/2 fatigue, neutropenia, anemia, and hyperglycemia. No CR or PR, but 4 SD lasting ≥ 4 months were observed. At DL-2, -2A and -2B, serum IGF 1 levels were significantly elevated on d2 (p <0.002) and d8 compared to BL (p <0.001), but C-peptide levels were not found to differ from BL. Conclusions: The MTD for the combination of IMC-A12 and tem in pts with MBC is lower than that observed for single agents alone. A phase II study is ongoing in MBC. The study is supported in part by ASCO CDA, Komen Craft to CXM, N01-CM62205 and N01-CM-2011-00071. [Table: see text]

BackgroundWhile immune checkpoint blockade is regarded as standard of care for treatment of non-small cell lung cancer (NSCLC), up to 50% of patients with metastatic NSCLC do not achieve an optimal response.1–3 Previous work by our group and others in adoptive cell therapy (ACT) of metastatic melanoma (MM) has shown that infusion of a CD8+-rich TIL product significantly improved clinical outcomes, yet traditional IL-2 expansion methods have resulted in a predominantly CD4+ NSCLC TIL expansion product.7–12 This preclinical study explores the feasibility of producing a tumor-specific, CD8+-enriched NSCLC TIL product for ACT with an improved culture method.MethodsTIL from resected NSCLC tumors were cultured using 1) the traditional method using IL-2 alone in 24-well plates (TIL 1.0) or 2) IL-2 in combination with agonistic antibodies against CD3 and 4-1BB (Urelumab) in a G-Rex flask (TIL 3.0). Expanded TIL were phenotyped using flow cytometry for CD4 and CD8 subset assessment and the CDR3-beta variable region of the T-cell receptor (TCR) involved in antigen binding was sequenced to assess the T-cell repertoire.ResultsIn a shorter manufacturing time (median of 14 days vs 27.5 days), TIL 3.0 expanded on average 5.3-times more NSCLC TIL (95% CI= 4.3–6.2, p<0.0001) and achieved a higher expansion success rate than the traditional TIL 1.0 method (100% vs 62.5%, respectively, p<0.0001). Additionally, TIL 3.0 greatly enriched for CD3+CD8+ TIL (81.8% vs 36.9%, p=0.001) and expanded a larger breadth of clonotypes (p=0.039) which shared greater homology with the total clonotypes found in the repertoire of the resected tumor (p=0.0007), and contained a greater fraction of the clones found at high frequency in the tumor (p<0.00001). TIL 3.0 also retained a higher proportion of putative tumor-specific TCR when compared to TIL 1.0 (p=0.0039), defined based on exclusion of known viral-specific TCR and other TCR found in the paired uninvolved lung tissue.ConclusionsThis study reports the feasibility of using the TIL 3.0 methodology to robustly expand a CD8+ T-cell repertoire which maintains the respective clonal hierarchy in NSCLC tumors and enriches for putative tumor-specific TIL clones. The robustness and speed of the new process may facilitate testing and implementing effective TIL ACT in NSCLC.ReferencesGaron EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372(21):2018–28.Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373(17):1627–39.Gettinger S, Horn L, Jackman D, Spigel D, Antonia S, Hellmann M, et al. Five-Year Follow-Up of Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: Results from the CA209–003 Study. J Clin Oncol 2018;36(17):1675–84.Melioli G, Ratto G, Guastella M, Meta M, Biassoni R, Semino C, et al. Isolation and in vitro expansion of lymphocytes infiltrating non-small cell lung carcinoma: functional and molecular characterisation for their use in adoptive immunotherapy. Eur J Cancer 1994;30A(1):97–102.McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351(6280):1463–9.Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011;17(13):4550–7.Besser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzhaki O, Hershkovitz L, et al. Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res 2010;16(9):2646–55.Pilon-Thomas S, Kuhn L, Ellwanger S, Janssen W, Royster E, Marzban S, et al. Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma. J Immunother 2012;35(8):615–20.Radvanyi LG, Bernatchez C, Zhang M, Fox PS, Miller P, Chacon J, et al. Specific Lymphocyte Subsets Predict Response to Adoptive Cell Therapy Using Expanded Autologous Tumor-Infiltrating Lymphocytes in Metastatic Melanoma Patients. Clinical Cancer Research 2012;18(24):6758–70.Forget MA, Haymaker C, Hess KR, Meng YJ, Creasy C, Karpinets T, et al. Prospective Analysis of Adoptive TIL Therapy in Patients with Metastatic Melanoma: Response, Impact of Anti-CTLA4, and Biomarkers to Predict Clinical Outcome. Clin Cancer Res 2018;24(18):4416–28.Ben-Avi R, Farhi R, Ben-Nun A, Gorodner M, Greenberg E, Markel G, et al. Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients. Cancer Immunol Immunother 2018;67(8):1221–30.Ma Y, Ou J, Lin T, Chen L, Wang J, Qiao D, et al. Phenotypic analysis of tumor-infiltrating lymphocytes from non-small cell lung cancer and their potential application for adoptive cell therapy. Immunopharmacol Immunotoxicol 2020;42(4):319–29Ethics ApprovalThis study was performed on NSCLC tumor tissue resected from 16 patients enrolled, following informed consent, in the ImmunogenomiC prOfiling of early-stage NSCLC (ICON) project. This study was approved by the University of Texas MD Anderson Cancer Center‘s Institutional Review Board (protocol number PA15-1112_MODCR001).

Abstract Antiviral therapy (AVT) with interferon +/− ribavirin can induce neoplastic regression without chemotherapy (CT) in low-grade non-Hodgkin’s lymphomas (in particular, immunocytomas and nodal/extranodal marginal lymphomas) with associated HCV infection (HCV+). High grade, diffuse large B-cell non- Hodgkin’s lymphomas (DLBCL) are HCV+ in about 12% of cases in Italian population. These patients show peculiar clinical characteristics, such as older age, liver damage, presence of monoclonal gammopathy (often with no clinically relevant cryoglobulinemic and/or rheumatoid activity), increased rate of autoimmune disorders and extranodal localizations. Their clinical outcome, however, is generally considered not significantly different, in terms of response rate, progression free survival (PFS) and overall survival (OS), from that of subjects with HCV negative (HCV−) DLBCL when treated with standard or even high dose CT and if significant signs of liver dysfunction are absent. In the present study we aimed to determine the possible role of AVT, performed after a standard CT treatment, in HCV+ DLBCL. We evaluated 40 HCV+ DLBCL patients (male/female ratio 25/15; median age 63 years, range 39–71) who received AVT after first complete (27 patients) or partial (13 patients) remission was achieved by frontline standard CT. Classic or modified CHOP+/− rituximab regimens were generally employed. Twenty-two patients (55%) showed a higher (3–4) IPI score and twenty patients (50%) evidenced increased ALT/AST values. A favourable HCV genotype (type 2–3) and a low viral load (&lt; 600.000 copies) were observed in 19 (47.5%) and 15 (37.5%) patients, respectively. In the large majoriry of cases AVT consisted of peg-interferon 1 mg/kg (1.5 mg/kg for genotype 1) s.c. once-a-week, plus ribavirin 1000/1200 mg/d p.o., according to body-weight &lt; or &gt; 70/kg. A small number of patients received interferon-alpha with or without ribavirin. The planned duration of AVT ranged from 3 to 12 months and was modulated according to viral genotype and molecular response (genotype 2: 3 months, if viral clearance obtained after 1 month, otherwise continued for 6 months; other genotypes: 3 months of treatment with following suspension if viral clearance not obtained, otherwise continued for 12 months). Sequential treatment (CT followed by AVT) was generally well tolerated. Six patients, however, interrupted AVT before three months, mainly because of general malaise or myelotoxicity. HCV clearance was obtained in 22 patients (55%). A case-control comparison was made with a similar cohort of 40 HCV+ DBLCL patients, who did not receive AVT, matched for age, sex, IPI score, liver function, type of prior CT and response, viral load and HCV genotype. Three-year PFS was not statistically different between the two groups (52.5% vs 57.5%, p n.s.), while a trend in favour of AVT treated patients was observed in terms of three-year OS (67.5%% vs 57.5%, p=0.055). A weak correlation between viral clearance and longer OS duration was also observed (p=0.048). Interestingly, during the follow up period, severe hepatic failure developed in 5 (12.5%) out of patients who had not received AVT and in only one (2.5%) of those treated with AVT. Seventy-nine percent of relapsed patients not treated with AVT received salvage CT, compared to 100% of AVT treated patients. Our currently available data indicate that a sequential treatment with CT followed by AVT is feasible in HCV+ DLBCL and may induce complete virus clearance in more than half of these patients. We hypothesize that a better control of the viral infection, rather than a direct or indirect antineoplastic activity of AVT, could have positive effects on the clinical outcome of patients with HCV+ DLBCL and, possibly, on their survival, i.e. by allowing the possibility of further salvage therapies and reducing that of hepatic failure.

Publicamos una pequeña serie de monedas, relacionadas con las piezas conocidas inicialmente como de ejemplares “tipo Auriol”. Se trata de varias imitaciones greco-massaliotas, relacionadas con el ciclo numismático griego del Occidente mediterráneo. La importante novedad de las mismas se fundamenta en el lugar de hallazgo, pues este se ha producido en una zona interior de la Península Ibérica, donde hasta el momento no se había documentado el descubrimiento de numismas de este tipo. Palabras clave: moneda, imitaciones, edetanosTopónimos: Massalia, Emporion, AuriolPeriodo: Edetanos ABSTRACTThe text presents a small series of coins, similar to those initially known as "Auriol type". These are various Greek-Massalian imitations, related to the Greek numismatic cycle of the Western Mediterranean. What makes these coins particularly interesting is their place of discovery, since they were found in an inland area of the Iberian Peninsula, where the appearance of specimens of this type had not previously been documented. Keywords: coin, imitations, AuriolPlace names: Massalia, Emporion,Period: edetans REFERENCIASAmorós, J. V. (1934), Les monedes emporitanes anteriors a les dracmes, Barcelona, Gabinet Numismàtic de Catalunya.Arévalo González, A. (2002), “La moneda griega foránea en la Península Ibérica”, en Actas del X Congreso Nacional de Numismática, Madrid, Museo Casa de la Moneda, pp. 1-15.Babelon, E. C. F. (1901), Traité des monnaies grecques et romaine, vol. 1, Paris, Ernest Leroux Editeur.Benezet, J., Delhoeste, J. Lentillon, J.-P. (2003), “Une monnaie du “type d´Auriol” dans la plaine roussillonnaise”, Cahiers Numismatiques, 158, pp. 5-8.Blancard, M. (1870-1871), “Iconographie des monnaies du trésor d´Auriol acquises par le cabinet des médailles de Marseille”, en Mémoires del´Académie des Sciences, Belles-Lettre et Arts de Maseille, Marseille, Barlatier-Feissat Pére et fils, pp. 17-33.Blanchet, A. (1905), Traité des monnaies gauloises, vol. 1, Paris, Ernest Leroux Editeur.Campo Díaz, M. (1987), “Circulación de monedas massaliotas en la Península Ibérica (s. V-IV a. C.)”, en Mélanges offerts au docteur J. B. Colbert de Beaulieu, Paris, Leópard d`or, pp. 175-187.— (1997), “La moneda griega y su influencia en el contexto indígena”, en Historia monetaria de Hispania antigua, Madrid, Jesús Vico, pp. 19-49.— (2002), “Las emisiones de Emporion y su difusión en el entorno ibérico”, La monetazione dei Focei in Occidente, Atti dell´XI Convegno del Centro Internazionale di studi Numismatici, Roma, Istituto italiano di Numismatica, pp. 139-165.— (2003), “Les primeres imatges gregues: l´inici de les fraccionàries d´Emporion”, en VII Curs d´Història Monetaria d´Hispània. Les imatges monètaries: llenguatge i significat, Barcelona, Museu Nacional d´Art de Catalunya, pp. 25-45. Campo Díaz, M. y Sanmartí, E. (1994), “Nuevos datos para ña cronología de las monedas fraccionarias de Emporion: revisión del tesoro Neapolis-1926”, Huelva Arqueológica, 13, pp. 153-172.Chevillon, J. A. (2002), “Les monnaies archaïques d´Emporion dans le trésor d´Auriol”, Bulletin de la Société Française de Numismatique, 57, pp. 30-33.Chevillon, J. A., Bertaud, O. y Guernier, R. (2008), “Nouvelles données relatives au monnayage archaïque massaliète”, Revue Numismatique, 164, pp. 209-244.Chevillon, J. A. Ripollès, P. P. (2014), “The Greeck Far West: un exceptional adaptation of a design from Asia Menor with bull und lion foreparts”, Journal of the Numismatic Association of Australia, 25, pp. 44-46.Chevillon, J. A., Ripollès, P. P. y López, C. (2013), “Les têtes de taureau dans le mnnayage postarchaïque empuritain du V siècle av. J. C.”, OMNI. Revue Numismatique, 6, pp. 10-14. De Saucy, F., De Berthélemy, A. y Hucher, E. (1875), “Examen détaillée du trésor d´Auriol (Bouches-du-Rhone)”, en Mélanges de Numismatique 1, Paris, Le Mans, pp. 12-44.Furtwängler, A. E. (1971), “Remarques sur les plus anciennes monnaies frapées en Espagne”, Schweizer Münzblätter, 81, pp. 13-21.— (1978), Monnaies grecques en Gaule. Le trésor d´Auriol et le monnayage de Massalia 525/520-460 av. J. C., Fribourg.— (2002), “Monnaies grecques en Gaule: nouvelles trouvalles (6ème-5 ème s. av. J.-C.)”, en La monetazione dei Focei in Occidente. Atti dell`XI Convegno del Centro Internazionale di Studi Numismatici, Rome, Istituto italiano di Numismatica, pp. 93-11.García-Bellido, M. P. (1993), Las cecas libio-fenicias, Ibiza, Museu Arqueologic d´Eivissa e Formentera.— (1998), “La moneda griega de Iberia”, en Los griegos en España, Madrid, Ministerio de Cultura, pp. 158-178. — (2017), “Las copias de la moneda Tipo Auriol en el Golfo de León: foceos y nativos”, Gaceta Numismática, 194, pp. 3-14.Gozalbes Cravioto, E. (2014), “La economía monetaria en la provincia de Cuenca en la antigüedad”, E. Gozalbes Cravioto, J. A. Hernández Rubio y J. A. Almonacid Clavería (coords.), Cuenca: historia en sus monedas, Cuenca, Universidad de Castilla-La Mancha, pp. 55-84.— (2017a), “La ceca de Ikalesken y el problema de su localización”, Gaceta Numismática, 193, pp. 3-19.— (2017b), “Una pieza de Urkesken y la localización de la ceca”, Gaceta Numismática, 193, pp. 21-30.Gozalbes Fernández de Palencia, M. y Ripollès, P. P. (2002), “Nuevos hallazgos de monedas foráneas en el territorio de Arse-Saguntum”, en P. P. Ripollès y M. M. Llorens, Arse-Saguntum. Historia monetaria de la ciudad y su territorio, Sagunto, Fundación Bancaja, pp. 528-533.Gozalbes García, H. y Gozalbes Cravioto, E. (2017), “Une obole massaliote datant du Ve siècle av. J. C. sur le territoire de Cuenca (Espagne)”, Bulletin de la Société Française de Numismatique, 72.2, pp. 52-56.Guadán, A. M. (1968), Las monedas de plata de Emporion y Rhode vol. I, Barcelona, Ayuntamiento de Barcelona.— (1970), Las monedas de plata de Emporion y Rhode, vol. II, Barcelona, Ayuntamiento de Barcelona.Lambert, E. (1864), Essai sur la numismatique gauloise du Nord-Ouest de la France, Paris, Derache.Maurel, G. (2013), Corpus des monnaies de Marseille et Provence, Languedoc oriental et vallée du Rhone (520-20 av. notre ère), Montpellier, Omni, 2013.Omos, R. (1995), “Usos de la moneda en la Hispania prerromana y problemas de lectura iconográfica”, en M. P. García-Bellido y R. M. Centeno (eds.), La moneda hispánica. Ciudad y territorio, Madrid, Consejo Superior de Investigaciones Científicas, pp. 41-52.Planas Palau, A. y Martí Mañanes, A. (1991), Las monedas de otras cecas encontradas en Ibiza, Ibiza, Puig Castellar. Ripollès, P. P. (1982), La circulación monetaria en la Tarraconense mediterránea, Valencia, Federico Domenech. — (1985), “Las monedas del tesoro de Morella, conservadas en la B. N de París”, Acta Numismàtica, 19, (1985), pp. 47-64.— (1989), “Fracciones ampuritanas. Estado de la investigación”, Archivo de Prehistoria Levantina, 19,pp. 303-317.— (2005), “Las acuñaciones antiguas de la península Ibérica: dependencias e innovaciones”, en C. Alfaro, C. Marcos y P. Otero (coords.), Actas del XIII Congreso Internacional de Numismática, vol. 1, Madrid, Ministerio de Cultura, pp. 187-208.— (2011), “Cuando la plata se convierte en moneda: Iberia oriental”, en Barter, Money and Coinage in the Ancienr Mediterranean (10th-1st Centuries B.C.). Actas del IV Encuentro Peninsular de Numismátic Antigua, Madrid, Consejo Superior de Investigaciones Científicas, pp. 213-226.— (2013), “Ancient Iberian Coinage”, Documentos Digitales de Arqueología, 2, pp. 1-55.— (2015), “Los divisores ampuritanos con cabeza de carnero y puntos en el campo”, OMNI. Revue Numismatique, 9, pp. 13-16.Ripollès, P. P. Chevillon, J. A. (2013), “The Archaic coinage of Emporion”, The Numismatic Chronicle, 173, pp. 1-21.Ripollès, P. P. y Llorens, M. M. (2002), Arse-Saguntum. Historia monetaria de la ciudad y su territorio, Sagunto, Fundación Bancaja.Rodríguez Casanova, I. (2014), “El tesoro de Valeria: nuevas aportaciones sesenta años después”, en E. Gozalbes, J. A. Hernández Rubio y J. A. Almonacid (coords.), Cuenca: la Historia en sus monedas, Cuenca, Universidad de Castilla-La Mancha, pp. 85-106.Savès, G. (1976), Les monnaies gauloises à la croix, Toulouse, Privat, 1976.Villaronga, L. (1987), “Les oboles massaliotes à la roue et leurs imitations dans la Péninsule Ibérique”, en Mélanges offerts au docteur J. B. Colbert de Beaulieu, Paris, Leópard d`or, 1987, pp. 769-777.— (1995), “L´emissió emporitana amb cap de be i revers de creu puntejada de la segona meitat del segle V a.C.”, Acta Numismática, 25, (1995), pp. 17-33.— (1997), Monedes de plata emporitanes dels secles V-VI a. C., Barcelona, Leandre, 1997.— (2003), “La troballa de l´Emporà”, Acta Numismàtica, 33, pp. 15-46.Villaronga, L. Benages, J. (2011), Ancient Coinage of the Iberian Peninsula. Greek, Punic, Iberian, Roman, Barcelona, Societat Catalana d´Estudis Numismàtics, 2011 (citado como ACIP).

Iris tectorum Maxim, a very popular Chinese traditional medicinal perennial herb belonging to the Iridaceae family, is widely grown as a year-round ornamental in China. During May to August 2014, as part of a survey for tospoviruses (family Bunyaviridae) in flue-cured tobacco, symptoms suspected to be caused by tospoviruses were observed on I. tectorum around farmers' fields in Kunming, Yunnan province. Symptoms were chlorotic spots on younger leaves and necrosis on older leaves. Since Tomato spotted wilt virus (TSWV) and Tomato zonate spot virus (TZSV) are two common tospoviruses in flue-cured tobacco fields in Yunnan, ELISA with monoclonal TSWV antibody (provided by J. X. Wu, Zhejiang University, China) and polyclonal TZSV antiserum (provided by J. H. Dong, Yunnan Academy of Agriculture Science, China) was performed to identify the presence of virus. Positive extinction values (ODλ405nm 0.835 ± 0.121 and 1.024 ± 0.193, as compared with the negative 0.153 ± 0.076 and the positive control 0.510 ± 0.109 at a confidence interval of P ≤ 0.05) were obtained from two symptomatic samples with TZSV antibody but not with TSWV. The absence of TSWV was confirmed with a commercially available immune-strip (Agdia, Elkhart, IN), following the manufacturer's instructions. To further verify the causal agent of these symptoms, total RNA was isolated from two symptomatic and one asymptomatic samples and reverse transcribed using degenerate primer J13 (1). These cDNAs were then used as a template in a universal PCR assay using specific primers TZSVNF (5′-ATGTCTAACGTCCGGAGTTTAACAC-3′) and TZSVNR (5′-TTAAAAAGACAGATCATTGCTG-3′), which amplify the complete nucleocapsid (N) protein. The PCR was carried out for denaturation at 94°C for 3 min, and subsequently 30 cycles were carried out, with each cycle consisting of 94°C for 45 s, 55°C for 45 s, and 72°C for 1 min, followed by a final extension step at 72°C for 10 min. An 0.8-Kb DNA fragment was amplified from symptomatic samples and cloned into a pGEM-T Easy (Promega, Madison, WI) vector. Three clones of each sample were selected and sequenced. BLAST analysis of the obtained sequences (Accession Nos. KM452916 and KM452917) revealed that the N sequences of these isolates have 96 to 99% nucleotide identity and 99 to 100% amino acid identity with the deposit TZSV sequence in NCBI from Yunnan (JN116580 to JN116583 and EF552433) (2). These combined results provide further confirmation of TZSV infection. It is known that perennial herb or ornamental plants may act as reservoirs for tospoviruses that can infect cultivated crops because tospoviruses have a very broad host range. Therefore, elaborate inspections for tospoviruses and appropriate management strategies to limit virus spread are necessary for production of crops. To our knowledge, this is the first report of TZSV in I. tectorum Maxim. References: (1) I. Cortez et al. Arch Virol. 146:265, 2001. (2) J. Dong et al. Arch Virol. 153:855, 2008.

Withania somnifera (family solanaceae) commonly known as ashwagandha and Indian ginseng, originated in India is one of the most powerful medicinal plants for more than 3,000 years (1). It is commercially cultivated for its roots, a natural rich source of glycowithanolides, tannins, potassium nitrate, etc., which are an anti-inflammatory, anti-tumor, anti-oxidant, anti-ulcer, and regulator of the nervous system and sleep (2). During the monsoon of July 2011, black spots on the leaves of infected plants were observed in the ashwagandha growing Lucknow, Raibareilly, and adjoining areas of Uttar Pradesh province with 10 to 20% disease incidence. Early stage of disease were characterized by the presence of light chlorotic spots on both sides of old leaves that later turned into dark black spots resulting in early defoliation. About 27 samples were collected from different locations of the fields for isolation of the causal organism and microscopic studies. Infected leaves were cut into small pieces, surface sterilized with 1% sodium hypochlorite for 1 min, rinsed thrice with sterilized distilled water, and placed onto potato dextrose agar (PDA) plates. After 21 days of dark incubation at 25°C, 8- to 10-mm grayish-brown colonies were observed. Microscopic studies at early and mature stages of infection showed production of conidia in conidiophores. Conidiophores were mostly 5 to 9, few dense pale brown, simple unbranched, septate, geniculate and 14 to 55 × 3 to 5.5 μm. Conidia were subhyline, obclavate to cylindrical, some were straight to slightly curved, multiseptate, base long obconic to long obconically truncate, and 12 to 85 × 3.5 to 5 μm. On the basis of cultural and morphological studies, the pathogen was identified as Pseudocercospora fuligena (3). The pathogen identity was further confirmed at molecular level using universal primers ITS1/ITS4 through PCR (4). An amplification of the expected size (~550 bp) was generated, eluted from agarose gel by QIAquick gel extraction kit (Qiagen), cloned into pGEM-T Easy vector (Promega), sequenced, and deposited in GenBank (Accession No. KF881898). NCBI BLASTn showed 99% identity with P. fuligena (GU214675) strain CPC 12296, isolated from Lycopersicon sp. Pathogenicity test was carried out on 10 plants of W. somnifera cv. Poshita through two approaches, one using mycelia from culture and another using spore suspension from naturally infected leaves. In the first approach, fungal mycelia were applied onto the healthy ashwagandha leaves, whereas in the second approach, infected leaves were washed with distilled water and spore suspension of 106 spores/ml was sprayed on healthy plants. Plants sprayed with sterilized distilled water served as controls. Inoculated plants were placed in a growth chamber at 28°C under 90% humidity for 3 days. After, pots were placed in the glasshouse at 27 ± 2°C with 70 to 80% humidity for 21 days. Initial symptoms appeared on the 7th day while typical symptoms appeared on all the inoculated plants after 12 to 17 days. Control plants remained free of infection. Re-isolation of the pathogen on PDA fulfilled Koch's postulates. Black leaf mold caused by P. fuligena has been reported on tomato (5). This is the first report of black leaf mould caused by P. fuligena on W. somnifera from India. P. fuligena has the potential to reduce yield of W. somnifera. References: (1) Anonymous. Alt. Med Rev. 9:211, 2004. (2) B. D. Basu and K. R. Kirtikar. Indian Medicinal Plants: Plates, vol. 1-4. Bishen Singh Mahendra Pal Singh, Dehradun, India, 1991. (3) T. C. Wang et al. Plant Dis. 79:661, 1995. (4) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, CA, 1990. (5) S. Yamada. Ann. Phytopathol. Soc. Jpn. 15:13, 1951.

Background:Some infectious agents may act as inducers of autoimmune conditions1. Despite SARS-CoV-2 infection can induce autoimmune phenomena in infected people2, individual risk factors or underlining mechanisms leading to loss of immunological tolerance are still unknown.Objectives:To assess the rate of development of autoantibodies in convalescent SARS-CoV-2 patients and their relation on infection clinical course and disease parameters.Methods:One-hundred and nine convalescent SARS-CoV-2 patients were studied and underwent multidisciplinary assessment in a Day Hospital clinical setting. For each patient, demographic, clinical and immunological data were collected and, at study entry, autoimmune profile [antinuclear antibodies (ANAs), antibodies reacting with extractable nuclear antigens (anti-ENA), antineutrophil cytoplasmic antibodies (ANCAs), Lupus anticoagulant (LA), anticardiolipin antibodies (aCL) IgM and IgG, anti-β2 glycoprotein I (anti-β2GPI) IgM and IgG] was assessed by Fluorescent immunoassay. Moreover, IL-6 plasma levels were assessed by ELISA (ELLA).Results:After a median time from hospitalization for SARS-CoV-2 infection of 53.3 ± 0.9 days, 55(50.5%) SARS-CoV-2 convalescent patients showed the positivity (ABpos) of at least one autoantibody. In particular, 31(28.4%) were positive for LA, 11(10.1%) for IgM-RF, 8(7.3%) for ANA and 6(5.5.%) for IgG-aCL whilst less than 2% showed other autoantibody positivities (IgM-aCL, IgG-anti-β2GPI, ENA, ACPA, c-ANCA, Scl70 and RNP). Analyzing the patient-related characteristics associated with the development of autoimmunity, convalescent male patients were more likely characterized by the development of antiphospholipid antibodies (aPL) (37.3%) than female (16.7%; p=0.02). Considering the disease-related characteristics, convalescent SARS-CoV-2 patients who experienced severe pneumonia (i.e., oxygen support need) during hospitalization, more likely received IL-6R-inhibitor administration (47.3%) and developed more than one autoantibody (87.5%) (aPL + another AB) than convalescent SARS-CoV-2 patients who did not need oxygen support [(12.5%; p=0.02) (OR95%IC: 9.5(1.4-109.1)] or IL-6R-inihibitor (1.9%; p<0.001). Finally, assessing cytokines plasma levels in convalescent SARS-CoV-2 patients stratified based on the development of autoantibodies we found that, despite a significant reduction of IL-6 plasma levels from hospitalization, convalescent SARS-CoV-2 patients who developed autoantibody positivity had higher IL-6 plasma levels (8.5 ± 2.5 pg/ml) than convalescent SARS-CoV-2 ABnegpatients (5.6 ± 1.5 pg/ml; p=0.07), mostly if considered autoantibodies other than aPL (15.4 ± 7.7 pg/ml)(p=0.01).Conclusion:Loss of self-tolerance is a common phenomenon in the medium-term follow-up of SARS-CoV-2 convalescent patients whose occurrence is dependent by a severe disease course and by an aberrant host inflammatory response. Long-term follow-up will reveal AB persistency and their clinical impact.References:[1]Barzilai O, et al. Current Opinion in Rheumatology 2007.[2]Zhou Y, et al. Clin Transl Sci. 2020.Disclosure of Interests:None declared

225 Background: Recently, the CHAARTED and STAMPEDE studies showed a survival benefit for docetaxel when started with androgen deprivation therapy (ADT) in men with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC). While GETUG-AFU 15 failed to demonstrate a survival benefit of early chemotherapy. New biomarker for select the candidate for early chemotherapy in mHSPC is warranted. The objective of this study is to evaluate the bone scan index (BSI) using computer-aided diagnosis system for bone scans for predictive factor in patients receiving ADT as first-line hormone therapy for mHSPC. Methods: We identified consecutive 85 mHSPC patients treated with maximum androgen blockade (MAB) as first-line hormone therapy. We analyzed the correlations between progression-free survival (PFS) of MAB and clinicopathological characteristics, including patients’ age, initial PSA levels, Gleason scores, clinical TNM stage, hemoglobin (Hb), lactase dehydrogenase (LDH), c-reactive protein (CRP), and bone scan index (BSI). Statistical analyses were assessed using cox proportional hazards regression models. Results: The median patients’ age was 73 and the median follow-up duration was 11.3months. The median initial PSA value was 270 ng/ml. Median BSI was 2.7 % (range: 0.0-14.6). Clinical or PSA progression occurred in 55 (64.7%) patients. The median time to progression was 12.9 months. In multivariate analysis, three significant risk factors for PFS were identified; patients’ age ( > 73 years old vs ≤ 73; HR 0.53, p = 0.038), initial PSA levels ( > 270 ng/mL vs ≤ 270; HR 0.53, p = 0.038), and BSI ( > 2.7 vs ≤ 2.7; HR 3.0, p < 0.000). We stratified the patients into two cohorts with low risk (0-1 risk factor present) and high risk (2-3 risk factors present). We found a significant difference in PFS among risk groups (median PFS 15.3 months vs 8.5, p < 0.000). Conclusions: Patients’ age, initial PSA levels, and bone scan index were the significant predictive factors for MAB as first-line hormone therapy in patients with mHSPC. These findings might support the decision-making of induction of early chemotherapy for mHSPC.

The basidiomycete Heterobasidion annosum (Fr.) Bref. (=Fomes annosus (Fr.) Cooke), one of the most important pathogens in coniferous forests in Europe, Asia, and North America, causes root and butt rot. H. annosum was first recorded on Pinus pinaster Ait. (commonly known as Maritime pine) in France and Great Britain in 1961 (4) and Portugal in 1986 (2). P. pinaster is the most widespread conifer in Spain, with more than 700,000 and 600,000 ha in pure and mixed stands, respectively. Over the last few years, P. pinaster decline was observed in several stands in the center of the Iberian Peninsula. Unusual crown transparency, small needles, foliage discoloration, and early tree death are characteristic decline symptoms associated with the high mortality rate on this species. In June of 2010, 11 trees (40 to 60 years old) with a different degree of decline were felled in two zones (42°2′41″N, 3°18′14″W, elevation 1,096 m and 41°55′40″N, 3°12′3″W, elevation 1,128 m) and cut into sections (stump height, breast height, and near the top). Wood slices were removed from each section and taken to the laboratory. Samples were placed in moist chambers with optimal conditions of humidity and temperature to enhance pathogen growth. After 20 days of incubation in darkness at 25°C, H. annosum (anamorph Spiniger meineckellum [A. Olson] Stalpers) occurred on most of these slices. Conidiophores with subglobose to pyriform conidia (5.8 × 4.2 μm) were observed with a compound microscope. The fungus was isolated to extract DNA by disruption of the mycelium followed by washes with phenol/chloroform/isoamyl alcohol solution (25:24:1). DNA was precipitated with 20% polyethylene glycol solution. PCR was carried out according to the instructions of the manufacturer of Dynazyme II DNA polymerase (Finnzymes Ltd, Espoo, Finland) with ITS primers, 1F (5′-CTTGGTCATTTAGAGGAAGTAA-3′) and 4 (5′-TCCTCCGCTTATTGATATGC-3′). After DNA purification, samples were sequenced (SECUGEN, Madrid, Spain) and aligned and corrected with Geneious Pro 5.3 to obtain the consensus sequences. Resulting DNA sequences of two isolates were deposited in GenBank (Nos. FR850494 and FR850495), and compared with a Blastn search at GenBank showing 100% identity and 100% coverage with H. annosum sensu stricto, former ISG-P (intersterility group of pines). For pathogenicity tests, 10 seedlings (2 year old) were inoculated with autoclaved P. pinaster wood chips colonized by H. annosum, and 10 control seedlings were inoculated with noncolonized wood chips. Inoculums were prepared by growing H. annosum on 4-mm-diameter wood chips placed on potato dextrose agar media for 3 weeks. The wood chips were put inside an oblique incision made at 6 cm above the soil line and wrapped with Parafilm. After 8 weeks in a growth chamber at 22.5°C with a 14-h photoperiod, the inoculated seedlings showed typical symptoms and 3 seedlings of 10 were dead. H. annosum was previously recorded on P. sylvestris in central Spain (1), causing needle drop, swelling at the stump height, and presence of dead trees by circular areas. This pathogen was also reported on P. nigra in northeastern Spain, associated with defoliation and mortality (3). To our knowledge, this is the first record of H. annosum on P. pinaster in Spain. References: (1) J. Benito-Martínez. An. Jardín Bot. Madrid 3:23, 1943. (2) N. Neves et al. EPPO Bull. 16:505, 1986. (3) J. Oliva et al. Bol. Sanidad Vegetal. Plagas. 34:415, 2008. (4) P. Spaulding. US Dep. Agric. Agric. Handb. 197:100, 1961.

BackgroundAdoptive cell therapies (ACT) directed against the products of somatic mutations in cancer cells can lead to long lasting clinical responses. We focused on ACT against shared p53 mutations to be used to potentially treat a broad range of patients with common cancers. We have built a library of anti-mutant p53 T cell receptors (TCRs) to be used for the treatment of patients with epithelial cancers in the autologous setting and as ‘off-the-shelf’ reagents for patients sharing the same p53 mutation and HLA.MethodsTumor infiltrating lymphocytes (TILs) were screened for recognition of p53 mutations and were expanded as previously described (1). For treatment of patient 4349 with metastatic breast cancer, the patient‘s peripheral blood T cells were retrovirally engineered to express the allogeneic anti-p53 R175H TCR.ResultsWe identified TILs recognizing ‘hotspot’ p53 mutations, such as R175H, Y220C, and R273C as well as less frequent but recurrent mutations, such as L111R, C135Y, and Q331H (table 1). First, we adoptively transferred TILs that included T cells reactive to a p53 mutation in an autologous manner for the treatment of patients with metastatic epithelial cancers (n=12). Except for the two patients who exhibited an objective response (RECIST), most of the patients did not respond to the therapy, possibly due to low frequencies of anti-mutant p53 cells in the infusion product, exhausted phenotype, and/or poor persistence (table 2). To overcome these barriers to TIL treatment, we retrovirally transduced autologous peripheral blood T cells to express an allogeneic anti-mutant p53 TCR. We engineered the HLA-A*02:01-restricted anti-p53 R175H TCR into patient 4349’s lymphocytes (transduction efficiency of 64%) and saw less expression of exhaustion markers relative to the TIL infusion products (table 2). This patient with metastatic breast cancer was refractory to the six prior chemotherapy regimens. After the transfer of 5.3e10 cells, the patient experienced an objective partial response, showing regression by 55% of skin and mediastinal lesions for 7 months. The persistence of the infused T cells was higher than the other patients who received the TIL treatment (table 2).Abstract 152 Table 1Anti-mutant p53 TCR library1 N=51,782 solid tumors (http://p53.fr/)2 Phenotype frequency (http://www.allelefrequencies.net/)3 Malekzadeh et al. J Clin Invest, 2019. 129(3): p. 1109–1114.4 Lo et al, Cancer Immunol Res, 2019. 7(4): p. 534–543Abstract 152 Table 2Patients who received mutant p53-reactive cell products1 TCRB sequencing (Adaptive Biotechnology)2 Flow cytometry against the murine TCR β constant region3 Lo et al, Cancer Immunol Res, 2019. 7(4): p. 534–543.NA not available, NR no response, PR partial response, PD progressive disease, SD stable disease, TX treatmentConclusionsThe library of anti-mutant p53 TCRs we have generated can potentially be used to treat ~6% of all cancer patients. We are pursuing the adoptive transfer of TILs against mutant p53 naturally occurring in the tumor or TCR-engineered cells using ‘off-the-shelf’ receptors against mutant p53.Ethics ApprovalThis study was approved by the Institutional Review Board (IRB) of the NCI, and the approval numbers are as follows:Protocol 10-C-0166 (TIL treatment); Protocol 18-C-0049 (allogeneic TCR engineered T cell therapy)ReferenceLo, W., et al., Immunologic Recognition of a Shared p53 Mutated Neoantigen in a Patient with Metastatic Colorectal Cancer. Cancer Immunol Res, 2019. 7(4): p. 534–543.

Abstract A study of the dienophilic properties of F3CP = C(H)F (1) and F3CP = C (D)F (4) has been performed by using Me3SnP(CF3)CF2H (2) and Me3SnP(CF3)CF2D (3), respectively, as precur­ sors for the in situ generation of 1 and 4 in the presence of 2 ,3-dim ethyl-1,3-butadiene, 1,3-cyclohexadiene or 9,10-dimethylanthracene. Slow elimination of Me3SnF occurs at 55 °C yielding the cycloadducts of 1 and 4, respectively, within 5 or 7 days. Polymerization is observed as the main stabilizing reaction of 1 and 4, thus reducing the yields o f the [2+4]-cycloadducts 5 to 9 to about 20%. They are formed as mixtures o f diastereomers in the ratio a:b ≈ 90:10. In the preferred isomer a according to NMR data CF3 and F have anti positions. Since NMDO calculations yield energy barriers of about 40 kcal/mol for E/Z isomerization, and literature values for inversion barriers of trialkyl phosphanes are of the same magnitude, the formation of isomers most likely has to be explained by a nonconcerted mechanism of the [2 + 4]-cycloaddition.

Rare variants in the γ-globin (HBG2 and HBG1) promoters cause sustained postnatal expression of fetal hemoglobin (HbF, α2γ2) in red blood cells (RBCs). This benign condition is termed hereditary persistence of fetal hemoglobin (HPFH). Individuals with HPFH variants are protected from β-hemoglobinopathies including sickle cell disease and β-thalassemia. Our group and others have used CRIPSR/Cas9-mediated non-homologous end joining to generate HPFH-like insertion-deletion (indel) mutations in the γ-globin promoter. However, simultaneous double-stranded breaks (DSBs) in the tandem duplicated γ-globin genes can result in loss or inversion of the intervening genetic material and/or chromosomal rearrangements. More generally, Cas9-associated DSBs can elicit a cytotoxic DNA repair response leading to cell death or evoke p53 loss with malignant transformation. Base editor (BE) proteins represent a promising approach to install precise nucleotide substitutions without DSBs. Adenosine base editors (ABEs), consisting of catalytically impaired Cas9 fused to a modified adenosine deaminase, create targeted A:T-to-G:C mutations. Here we describe the use of ABEs to recapitulate naturally occurring HPFH variants in hematopoietic stem cells (HSCs). We electroporated ABE7.10-single guide (sg) RNA ribonucleoprotein (RNP) complex into mobilized peripheral blood CD34+ hematopoietic stem and progenitor cells (HSPCs) to recreate 3 different HPFH variants in the HBG1/2 promoters (-198 T&gt;C, -175 T&gt;C and -113 A&gt;G). Measured editing frequency was maximal on day 10 after electroporation and transferred to erythroid differentiation media. 20% editing efficiency was observed for the -198 site, 58% for -175 and 50% for -113. Indel frequencies were &lt;2% at each of the three sites, reflecting a low rate of DSBs. Fetal hemoglobin levels in erythroid cells generated in vitro from A base-edited CD34+ HSPCs were 26±4% (-198 T&gt;C), 60±10% (-175 T&gt;C), and 42±7% (-113 A&gt;G) versus14±2% in unedited control cells. Base editing at the -175 site in sickle cell disease (SCD) donor CD34+ HSPCs resulted in the induction of HbF to 55% in erythroid progeny compared to 6% in controls. After exposure to hypoxia (2% oxygen), reticulocytes generated from -175 T&gt;C-edited CD34+ HSPCs exhibited sickling rates of 24%, compared to 52% in controls. Thus, creation of this variant, which generates a de novo binding site for the transcriptional activator TAL1, reactivates erythroid cell HbF to levels that inhibit sickle hemoglobin polymerization and cell sickling. To assess base editing in HSCs, we used ABE RNP to modify the -175 site in SCD donor CD34+ HSPCs, followed by transplantation into NBSGW mice. The editing frequency in CD34+ HSPCs before transplantation was ~30% and declined to approximately 20% in bone marrow-repopulating donor cells at 16 weeks post-transplantation. Editing frequencies were similar in CD34+ donor cell-derived myeloid, erythroid, and B cells, indicating that hematopoietic differentiation was not altered. Bone marrow erythroblasts derived from base-edited and control CD34+ HSPCs exhibited similar maturation profiles and enucleation. Erythroblasts generated in vivo from SCD patient HSPCs exhibited 32±2% HbF compared to unedited controls (4±1%) (n=4, P&gt;0.0001). Our studies provide proof of concept that adenosine base editors can be used therapeutically for β-hemoglobinopathies. Specifically, generation of the -175 T&gt;C HPFH mutation in patient HSCs followed by autologous transplantation represents a new therapeutic approach for SCD and β-thalassemia. Disclosures Yen: Beam Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Sharma:Spotlight Therapeutics: Consultancy; Magenta Therapeutics: Other: Research Collaboration; CRISPR Therapeutics, Vertex Pharmaceuticals, Novartis: Other: Clinical Trial PI. Liu:Pairwise Plants: Consultancy, Patents & Royalties; Editas Medicine: Consultancy, Patents & Royalties; Beam Therapeutics: Consultancy, Patents & Royalties; Prime Medicine: Consultancy, Patents & Royalties. Weiss:Beam Therapeuticcs: Consultancy, Current equity holder in private company; Esperion Therapeutics: Consultancy, Current equity holder in private company; Novartis: Consultancy, Current equity holder in private company; Cellarity Inc.: Consultancy, Current equity holder in private company; Rubius Inc.: Consultancy, Current equity holder in private company.

Background:Over the past few years new international criteria have been proposed for the classification of primary Sjögren’s syndrome (pSS) from the American College of Rheumatology (ACR) in 2012 and the ACR with European League Against Rheumatism (ACR/EULAR) in 2016 [1, 2]. In real practice in Russia we use Russian criteria (2001).Objectives:To estimate ACR (2012) and ACR/EULAR (2016) criteria in Russian cohort of patients with pSS patients fulfilling Russian criteria (2001).Methods:From 2016 to 2019 we examined 110 patients (109 female, 1 male) with newly diagnosed pSS fulfilling Russian criteria with the mean age 50,2±14 years (min 18; max 82). Russian criteria for pSS: I) keratoconjunctivitis sicca (stimulated Schirmer’s test <10 mm/5 min or fluorescein staining of the cornea or tear break-up time < 10 sec); II) sialadenitis (sialectasia on parotid sialography (obligatory) +/- stimulated saliva flow test<2,5 ml/ 5min +/- labial salivary gland biopsy with focus score (FS) of ≥2 foci/4mm2); III) positive antinuclear antibody (ANA) or positive ANA with rheumatoid factor (RF) or anti-SSA (anti-Ro) or/and SSB (anti-La). According it pSS is verified if the first two criteria and at least one of the immunological criteria are presented. We evaluated clinical, laboratory and instrumental features (table 1).Table 1.Characteristics of Russian cohort of patients with primary Sjögren’s syndrome (n = 110)ParametersPatients (n / %)ocular dryness76 (69%)oral dryness88 (80%)anti-SSA (anti-Ro) positive (>25 IU/ml)93 (84.5%)anti-SSB (anti-La) positive (>25 IU/ml)57 (51.8%)RF positive >2UNL (>30 IU/ml)68 (61.8%)ANA ≥1:320110 (100%)(stimulated) Schirmer’s test (≤5 mm/5 minutes)55 (50%)stimulated SFT <2,5ml/5 min77 (70%)OSS ≥528 (25.4%)OSS ≥343 (39%)FS ≥ 1foci/4 mm299 (90%)Sialectasia on parotid sialography110 (100%)In our cohort according to Russian criteria (2001) 94 patients (86%) fulfilled ACR (2012) criteria, 86 (78%) - ACR/EULAR (2016) criteria.Results:In our cohort, 20-30% of patients, according to Russian criteria did not complain of oral or ocular dryness. In 61% of patients, mild eye damage was detected (OSS<3-5), and in half of the cases, the stimulated Schirmer’s test was more than 5.0 mm, but less than 10 mm/5 minutes, while 69% of patients complained of dry eyes. Most patients (84.5%) had positive anti-Ro, just over half (51.8%) had anti-La. All patients had sialectasia of various stages on parotid sialography. Less than 1 FS was detected in 10% of patients.Conclusion:Using Russian criteria (2001), we can identify pSS at an early stage. Our criteria inclusion complex examination in which an immunological sign must be present to confirm the diagnosis. Patients with pSS according to ACR (2012) and/or ACR/EULAR (2016) criteria seem to be diagnosed without specific antibodies and on the more progressive disease stages.References:[1]SC Shiboski, CH Shiboski, LA Criswell, AN Baer, S Challacombe, H Lanfranchi, M Schiødt, H Umehara, F Vivino, Y Zhao, Y Dong, D Greenspan, AM Heidenreich, P Helin, B Kirkham, K Kitagawa, G Larkin, M Li, T Lietman, J Lindegaard, N McNamara, K Sack, P Shirlaw, S Sugai, C Vollenweider, J Whitcher, A Wu, S Zhang, W Zhang, JS Greenspan, and TE Daniels for the Sjögren’s International Collaborative Clinical Alliance (SICCA) Research Groups. American College of Rheumatology Classification Criteria for Sjögren’s Syndrome: A Data-Driven, Expert Consensus Approach in the SICCA Cohort.[2]Caroline H. Shiboski,1 Stephen C. Shiboski,1 Raphae `le Seror,2 Lindsey A. Criswell,1 Marc Labetoulle,2 Thomas M. Lietman,1 Astrid Rasmussen,3 Hal Scofield,4 Claudio Vitali,5 Simon J. Bowman,6 Xavier Mariette,2 and the International Sjogren’s Syndrome Criteria Working Group. 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjogren’s Syndrome. ARTHRITIS & RHEUMATOLOGY Vol. 00, No. 00, Month 2016, pp 00–00 DOI 10.1002/art.39859.Disclosure of Interests: :None declared

Introduction Chimeric antigen receptor (CAR) T-cells can induce a rapid disease response but are frequently associated with immunologic toxicities. In addition to cytokine release syndrome (CRS), macrophage activation syndrome-like manifestations (MAS-L), characterized by uncontrolled immune activation, have been described (Shah et al, 2020). Traditional MAS definitions are challenging to apply in patients receiving CAR T cells, due to overlapping signs and symptoms with lymphodepletion and CRS. Therefore, we sought to develop novel criteria to characterize MAS-L following CAR T cells and used these criteria to identify risk factors for developing MAS-L. Methods We conducted a retrospective review of 55 patients who received B cell maturation antigen-directed CAR T cells for multiple myeloma from 11/1/17 - 5/1/20. Based on the labs readily available in our patient population, we defined MAS-L using the following criteria: 1) rate of ferritin rise ³ 100 mg/L/hour within a 24 hour period and2) minimum fibrinogen &lt; 150 mg/dL or maximum LDH &gt; 2 times the upper limit of normal. In developing these simplified criteria, we considered multiple laboratory markers of inflammation (ferritin, LDH, soluble interleukin receptor-2, natural killer cell activity) and end organ damage. Infection was defined as any culture positivity, febrile neutropenia, or clinical suspicion such that a new antimicrobial was started in the 30 days prior to CAR T cells. Wilcoxon rank-sums and Fisher's exact test were used to compare continuous and categorical variables, respectively. Overall (OS) and progression-free survival (PFS) were compared using log-rank tests. Results Of the 55 patients, 12 (21.8%) met the above criteria for MAS-L with similar disease trajectories. Following CAR T cells, all 12 patients first developed CRS, characterized by an elevated C-reactive protein (CRP) and administration of tocilizumab, and subsequently developed MAS-L, characterized by decrease in fibrinogen and rapid rise of ferritin and LDH (Figure 1). Compared to the 45 patients who did not develop MAS-L, patients with MAS-L had similar baseline patient and disease characteristics (Table 1); however, a significantly higher proportion of patients with MAS-L had an infection prior to receiving CAR T cells (75% vs 9.3%, p &lt; 0.001.) Patients with MAS-L also had higher peak ferritin (median 20,707 vs 573 ug/L, p &lt; 0.001), D-dimer (14,000 vs 3,010 ng/mL, p &lt; 0.001), aspartate aminotransferase (AST; 153 vs 48 U/L:, p &lt; 0.001) and a trend towards higher alanine aminotransferase (ALT; 76 vs 50 U/L, p = 0.08). In contrast, patients with MAS-L had a lower peak C-reactive protein (CRP; 29.8 vs 60 mg/L, p = 0.03). Compared to patients who did not develop MAS-L, a similar proportion of MAS-L patients developed any CRS (100% vs 84%, p = 0.33) and ³ grade 2 CRS (50% vs 50%, p = 1). Neurotoxicity was more common in patients with MAS-L (42% vs 14%, p = 0.05). A greater proportion of patients with MAS-L received tocilizumab (100% vs 70%, p = 0.05), systemic steroids (92% vs 27%, p &lt; 0.001), and anakinra (83% vs 2.3%, p &lt; 0.001). Anakinra was given per clinician discretion and not per study protocol. Following CAR T cell therapy, patients with MAS-L had longer hospitalizations (21 vs 19 days, p = 0.009) and a greater proportion required ICU-level care (27% vs 2%, p = 0.02). OS and PFS between the two groups were similar (p = 0.15 and 0.63, respectively), with a 1-year OS of 65.2% vs 90.6% and PFS of 35.4% vs 54.7% for patients with vs without MAS-L, respectively. In univariate logistic regression of baseline patient factors, disease characteristics, and ferritin, CRP, and D-dimer prior to receiving CAR T cells, only a history of documented infection in the 30 days prior to CAR T cells predicted MAS-L development (Hazard Ratio 29.2, 95% CI 5.54 - 154, p &lt; 0.001). Conclusions In this analysis, we developed novel criteria for defining MAS-L following CAR T cell therapy and used these criteria to define the unique laboratory profile and clinical trajectory of patients with MAS-L. We also identify pre-existing infection as a strong risk factor for MAS-L development. Although patients with MAS-L frequently require prolonged monitoring, this immunologic toxicity can be mitigated with steroids, anakinra, and supportive care, and patients ultimately have similar survival compared to patients without MAS-L. Larger studies are needed to prospectively validate these novel criteria. Disclosures Wolf: Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martin:Sanofi, Amgen, Seattle Genetics, JNJ - Janssen: Research Funding; Legend Biotech: Consultancy. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Wong:Bristol Myers Squibb: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Janssen: Research Funding; Roche: Research Funding; Fortis: Research Funding; GSK: Research Funding.

Abstract Basis. Abnormalities in chromosome 8 (8p-/8q+) are observed in 2-5% of CLL patients. Microarray studies have revealed up to 30-40% of 8 alterations in del(17p) patients and an independent association with poor outcome. Large series assessing CLL patients with 8p-/8q+ are scarce. Aims. 1. To describe the frequency of 8q gains (8q+) and 8p losses (8p-) in CLL patients with del(17p); 2. To compare cytogenetic and clinical characteristics between patients with 8p-/8q+ (Alt-chr8) and those with normal chromosome 8 (N-chr8); 3. To assess their prognostic value. Patients and methods. From 2,249 patients included in the Spanish CLL database, 75 del(17p) cases were selected. Gains of MYC (8q24) and losses of LPL (8p22) were studied by FISH. Clinical and cytogenetic data of Alt-chr8 and N-chr8 were compared. Results. 8p- and/or 8q+ were found in 21/75 patients (28%). In the Alt-chr8 group, 8q+ was more frequent than 8p- (71% vs. 52%) and 29% showed concomitance of both abnormalities, suggesting the presence of i(8q). Six different FISH patterns were identified, some of them coexisting in the same patient (Table 1). Conventional cytogenetics data were available in 47 cases (15 Alt-chr8 and 32 N-chr8). Alt-chr8 group showed a higher median number of alterations and frequency of complex karyotypes (P=0.048 and P=0.013). In the Alt-chr8 group, the karyotype revealed 8p-/8q+ in 3 patients and in 9 cases with abnormal karyotype, the presence of marker chromosomes, added material and/or cryptic alterations would explain the FISH results (Table 1). From 66 cases, routine FISH data (13q, 12 and 11q) were available and no significant differences were detected among Alt-chr8 and N-chr8, as with other clinical and analytical parameters at diagnosis. Of note, shorter Overall Survival (OS) was observed for Alt-chr8, although differences were only significant for patients with 8p- (P=0.012, Figure 1). Interestingly, for 3 patients of Alt-chr8 group, previous non-del(17p) samples already presented 8p-/8q+. Conclusions. 1. In CLL patients with del(17p), detection of 8p- and/or 8q+ is associated with an increased karyotypic complexity and a worse outcome; 2. 8p-/8q+ could act as a primary event that trigger del(17p). More cases are required to confirm this hypothesis. Acknowledgments.PI11/01621; RD12/0036/0044, RD12/0036/0069; 2014/SGR585; Fundació La Caixa. Table 1. Karyotypes and FISH results of patients with del(17p) and Alt-chr8. Conventional Cytogenetics FISH ID Karyotype % del(17p) Chromosome 8 alteration % Pattern* 1 46,XX,del(8)(p21),add(10)(q26),add(17)(p13),+2ac[5]/47,XX,+12,add(17)(p13),del(18)(q21),add(22)(q13)[3] 80 20 1O2G 8p- 2 - 95 75 3 46,XX,add(6)(q24),add(14)(q32,3),i(17)(q10)[6]/46,XX[8] 95 75 4 - 76 50 5 45,XY,-5,-9,-15,add(17)(p13),+18,-21,+2mar[13]/46,XY[37] 70 17 6 46,X,der(X),add(8)(p23),del(13)(q12q22),add(17)(p13)[11]/46,XX[13] 10 32 1O3G 8p- and 8q+ 7 - 95 64 8 45,XY,add(3)(q29),del(4)(q26q35),der(7)(1p36-1p32::7p22-7q32::15q22-15q26), -8,der(9),del(13)(q21q34),-15,-17,-18,+19,add(19)(p13),+2mar,+ac[17]/46,XY[3] 78 34/21 1O3G/2O3G 9 44,X,-X,-6,der(13;15)(q10;q10),add(17)(p13),-20,+mar[13]/46,XX[7] 95 10/23 1O3G/1O2G 10 - 95 66/31 11 45,XY,add(6)(q22),del(11)(q11q22),-17[15]/44,XY,add(6)(q22),del(11)(q11q22),-17,-20,-22,+mar[2] 87 40/24 12 46,XX,del(13)(q14q21)[2]/45,X,-X,del(13)(q14q21)[3]/45,XX,add(3)(q27), t(9;10)(q21;q22),+12,der(12)t(12;17)(q11;p11),del(13)(q14q21),-14,-17[7]/46,XX[8] 70 62 2O3G 8q+ 13 46,XY[30] 14 88 14 46,XY[13] 80 82 15 47,XY,+12[8]/46,XY,add(1)(p34),add(2)(q34),t(11;22)(p14;q11),+12,-22[15]/46,XY[11] 75 18 16 43,X,-X,del(2)(p15),+4,-7,add(11)(q21),-12,-13,add(14)(q32),add(17)(p11)[6]/46,XX[9] 19 14 17 45,XY,del(6)(q?),-9,add(14)(q32),-22,+mar[9]/ 46,XY,del(6)(q?),add(17)(p13),add(19)(q13)[21] 55 23 18 45,XY,add(6)(p11),-22[13]/46,XY,i(17)(q10)[5]/46,XY[16] 16 57 19 - 70 66 2O4G 20 - 90 81 2OnG 21 46,XY[11] 43 60 4O4G Tetraploid *O: LPL signal in orange, G: MYC signal in green. Figure 1. Kaplan Meier plots for OS and (A) 8p- and/or 8q+, (B) 8p- or (C) 8q+. Figure 1. Kaplan Meier plots for OS and (A) 8p- and/or 8q+, (B) 8p- or (C) 8q+. Disclosures No relevant conflicts of interest to declare.

Abstract Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease affecting at least a quarter of the world’s population. NAFLD is commonly associated with other metabolic conditions such as insulin resistance, type 2 diabetes, obesity, and dyslipidemia. Given the liver’s prominent role in regulating glucose and lipid homeostasis, we hypothesized that subjects with NAFLD have a distinct profile of blood analytes. This investigation examines the association between NAFLD and circulating markers of glucose and lipid metabolism in order to identify a NAFLD-specific metabolite panel that can be used as a predictive biomarker in future studies. We are performing a cross-sectional study in 500 subjects to identify genetic and hormonal factors that correlate with the presence of NAFLD. This abstract reports a preliminary analysis of the results from the first 45 subjects enrolled. Fasting blood samples were collected from 31 subjects with NAFLD and 14 subjects with other metabolic diseases (‘Other’) and without radiologic evidence of NAFLD. The following analytes were measured: serum alanine aminotransferase (ALT), total cholesterol, direct-LDL, HDL, triglycerides, ApoB, small dense LDL-C (sdLDL), VLDL, Lp(a), cholesterol absorption/production markers (beta-sitosterol, campesterol, lathosterol, and desmosterol), glucose, insulin, hemoglobin A1C, adiponectin, hs-CRP, and fatty acids (saturated and unsaturated). Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from glucose and insulin levels, and fatty acids were batched together by structural similarity and reported as indices. The groups were compared using multiple t-tests or the Kolmogorov-Smirnov test when data were non-parametric. The NAFLD group had a mean age 48.4 ± 12.9 yrs and BMI 32.9 ± 6.6 kg/m2. These participants were 61% female and 58% had dyslipidemia, 25% pre-diabetes, and 25% type 2 diabetes. The Other group had a mean age 49.9 ± 12.9 yrs and BMI 39.1 ± 15.6 kg/m2. They were 64% female and 57% had dyslipidemia, 14% pre-diabetes, and 21% type 2 diabetes. ALT was higher in the NAFLD group (55 ± 40 vs 27 ± 22 IU/L, P&lt;0.001). Intriguingly, the saturated fatty acid index was elevated in the NAFLD group (32.5 ± 1.9 vs 30.1 ± 2.2 %, P&lt;0.05), and the omega-6 fatty acid index was elevated in the Other group (42.9 ± 3.7 vs 38.5 ± 4.7 %, P&lt;0.05). These changes led to an unsaturated/saturated fatty acid ratio that was significantly lower in the NAFLD group (2.0 ± 0.1 vs 2.3 ± 0.2, P&lt;0.01). There were no other significant differences in the blood metabolites and hormones. In this small sample comparing subjects with metabolic disease with and without NAFLD, levels of ALT and the ratio of circulating unsaturated/saturated fatty acids are distinguishing features of NAFLD. These may be helpful measures to identify subjects with metabolic disease that require further evaluation for NAFLD.

Functional TLR4 expression has been linked to HCC development. TLR4 may serve an important role in HCC development by promoting the malignant transformation of epithelial cells and tumor growth. The consequences might be dependent on the complex signaling networks triggered by TLR4 activation and the tumor microenvironment. The study included 90 consecutive subjects classified into 3 group their age from 40 to 70 years old. Group (I): HCC patients on top of chronic HCV infection. they were 45 patients 30 male and 15 females, their age ranged from 45 to 55 who were subdivided into 3 subgroups according to Barcelona clinic liver cancer (BCLC): Group (Ia): included 8 HCC patients in early stage. (stage A). Group (Ib): included 12 HCC patients in intermediate stage (stage B). Group (Ic): included 25 HCC patients in advanced stage. (stage C). Group (II): 30 Cirrhotic patients with chronic HCV, 21 male and 9 females, their age ranged from 50 to 60. This group was subdivided into 2 subgroups according to Child–Pugh score Group (IIa): included 8 Child–Pugh A. Group (IIb): included 22 Child–Pugh B and C. Group (III): controlled group included 15 normal subjects. 10 male and 5 females, their age ranged from 45 to 60. They were selected to match patients’ groups in demographic and socioeconomic standards. In our study where 15 persons are control showed lower level in TLR4 with mean 1.0±0.2, however 30 patients with HCV and other 45 patients with HCC showed higher level in TLR with mean 2.27±0.6 and 4.2±1.06 respectively. In our study there is statistically significant difference in serum TLR4 level between group (Ia) (2.25±0.5) and other subgroups which shows more increase in serum level of TLR4 in Group IB (3.2-1.06) than Group IA. Also shows more increase in serum level of TLR4 in Group IC (4.0±2.0) than Group IA and IB In our study HCC group showed higher level of LPS with mean 4.5±1.26 however lower in HCV group with mean 2.9-1.0 and least in control group with mean 1.1±0.4 In our study there is statistically significant difference in serum LPS level between group (IA) with mean 3.0±0.5 and other subgroups which shows more increase in serum level of LPS in Group IB with mean 4.4-1.0 than Group IA. Also shows more increase in serum level of LPS in Group IC with mean 4.0±1.76 than Group IA and IB In our study there is statistically significant difference in serum LPS level between group (IIB) and group (IIA) which shows more increase in serum level of TLR4 in Group IIB with mean 2.7±1.1 than Group IIA with mean 2.20±0.2 In our study there is statistically insignificant difference of the mean value ± SD of sex as regard to LPS and TLR expression (t = 1.2, p = 0.22). (t = 0.16, p = 0.87) respectively.In our study there is statistically significant positive correlation between ALT, AST, Platelets, alpha fetoprotein and LPS as regard to TLR4 expression in group II more in IIB,C than IA . but insignificant of the mean value ± SD of other parameters. In our study there is statistically significant difference of the mean value ± SD of ALT, AST, Platelets, alpha fetoprotein and TLR4 as regard to LPS expression in group I more in IB, C than IA. but insignificant of the mean value ± SD of other parameters.In our study there is statistically significant difference of the mean value ± SD of ALT, AST, Platelets and TLR4 as regard to LPS expression in group II more in IIB than IIA. but insignificant of the mean value ± SD of other parameters. Conclusion: TLR4 and LPS measurement should be carried for all patient with HCV Who are at risk for HCC with close monitoring. Conduct a study on a Gut microbiota as therapeutic targets for HCC.

Introduction/ aim. Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease of a broad histological spectrum, characterized by the accumulation of triglycerides in more than 5% of hepatocytes in the absence of consuming alcohol in quantities harmful to the liver. The aim of our study was to determine the importance of anthropometric and laboratory parameters as well as metabolic syndrome (MS) for the diagnosis of NAFLD and to estimate their influence on the degree of liver steatosis as evaluated by ultrasound (US). Methods. The study included 86 participants, 55 of whom had fatty liver diagnosed by ultrasound and they comprised the study group. The control group consisted of 31 control subjects. During the course of hospitalization at the Clinic of Gastroenterology and Hepatology, Clinical Centre Nis, the patients had their anamnesis taken, and anthropometric measurements as well as biochemical blood analyses and abdominal ultrasound were performed. Results. The patients with NAFLD had statistically higher values of body mass index (BMI), waist circumference (WC), systolic (SBP) and diastolic blood pressure (DBP), levels of alanin and aspartate aminotransferase (ALT, AST), gamma-glutamyl transpeptidase (GGT) (p<0.001), low-density lipoprotein cholesterole (LDL), total bilirubin (TBIL) (p<0.05), total cholesterol (p<0.01), triglycerides (TGL), urates, C-reactive protein (CRP), ferritin, fibrinogenes, fasting blood glucose (FBG), insulin and Homeostasis Model Assessment (HOMA-IR) (p<0.001), whereas the levels of high-density lipoprotein cholesterol (HDL) were higher in the control group (p<0.05). In the NAFLD group, there were statistically significantly more patients with hypertension (72.73% vs. 12.90%, p<0.001) and type 2 diabetes mellitus (DM) (47.27%). Metabolic syndrome was determined in 48 (87.27%) patients of the study group. An equal number of patients, 16 of them (29.09%), had 3, 4 and 5 components of MS. In the NAFLD group there were 17 overweight (30.91%) (BMI from 25 kg/m2 to 29.9 kg/m2) and 38 (69.09%) obese patients. (BMI ? 30.0 kg/m2). The largest number of patients in the obesity group, 22 (40.00%) of them, had the first degree obesity (BMI from 30 kg/m2 to 34.99 kg/m2). The largest number of the NAFLD group patients - 23 (41.82%), had an ultrasound finding of grade 3 fatty liver, 20 patients (36.36%) had grade 2 and 12 (21.82%) grade 1 fatty liver. Kruskal-Wallis test and ANOVA analysis showed statistically significant differences between groups with different US grade for insulin, LDL-cholesterol, WC, BMI (p<0.05), as well as HOMA-IR and body weight (BW) (p<0.01). Metabolic syndrome was statistically more present in patients with US finding grades 2 and 3 (p<0.01) in relation to grade 1 US finding, as well as obesity, hypertension and DM type 2 (p<0.05). Conclusion. The results of our study have confirmed that a high percentage of patients with high risk factors (DM, MS, dyslipidemia, hypertension) have NAFLD.

Композиты на основе полианилина и CuCl2·2H2O/ZrOCl2·8H2O, в качестве модифицирующих добавок получены методом химической полимеризации без добавления кислоты. Особенности электронной структуры и химических связей образцов исследованы методами ИК спектроскопии и спектроскопии рентгеновского поглощения. Микроструктура поверхности композитов исследовалась методом сканирующей электронной микроскопии. Полианилин в состав композитов входит в частично окисленной форме, степень окисления полимера зависит от типа модифицирующей добавки. Добавление CuCl2·2H2O/ZrOCl2·8H2O в процессе синтеза увеличивает электропроводность образцов ЛИТЕРАТУРА1. Ćirić-Marjanović G. Recent advances in polyaniline research: Polymerization mechanisms,structural aspects, properties and applications // Synthetic Metals, 2013, v. 177, pp. 1-47. DOI: https://doi.org/10.1016/j.synthmet.2013.06.0042. Боева Ж. А., Сергеев В. Г. Полианилин: синтез, свойства и применение // Высокомолекулярныесоединения. Серия С, 2014, т. 56(1), с. 153–164. DOI: https://doi.org/10.7868/S23081147140100383. Benabdellah A., Ilikti H., Belarbi H., Fettouhi B., Ait Amer A., Hatti M. Effects of the synthesis temperatureon electrical properties of polyaniline and their electrochemical characteristics onto silver ca vitymicroelectrode Ag/C-EM // Int. J. Electrochem. Sci., 2011, v. 6, pp.1747 – 1759.4. Kelly F. M., Meunier L., Cochrane C., Koncar V. Polyaniline application as solid state electrochromicin a fl exible textile display // Displays, 2013, v. 34 (1),pp. 1–7. DOI: https://doi.org/10.1016/j.displa.2012.10.0015. Lobotka P., Kunzo P., Kovacova E., Vavra I., Krizanova Z., Smatko V., Stejskal J., Konyushenko E. N.,Omastova M., Spitalsky Z., Micusik M., Krup I. Thin polyaniline and polyaniline/carbon nanocompositefi lms for gas sensing // Thin Solid Films, v. 519 (12, 1), pp. 4123–4127. DOI: https://doi.org/10.1016/j.tsf.2011.01.1776. Wang H., Linc J., Shen Z.X. Polyaniline (PANi) based electrode materials for energy storage and conversion// Journal of Science: Advanced Materials and Devices, 2016, v. 1 (3), pp. 225–255. DOI: https://doi.org/10.1016/j.jsamd.2016.08.0017. Иванова Н. М., Соболева Е. А., Висурханова Я. А., Кирилюс И. В. Электрокаталитическаяактивность полианилин-медных композитов в электрогидрировании p-нитроанилина // Электрохимия, 2015, т. 51 (2), с. 197–204. DOI: https://doi.org/10.7868/S042485701502005X8. Матнишян А. А., Ахназарян Т. Л., Абагян Г. В., Бадалян Г. Р., Петросян С. И., Кравцова В. Д. Синтези исследование нанокомпозитов полианилина с окислами металлов // ФТТ, 2011, т. 53 (8), с. 1640–1 6 4 4 . D O I : https://doi.org/10.1134/S10637834110801789. Zhu Y., He H., Wan M., Jiang L. Rose-like microstructures of polyaniline by using a simplifi ed tem-plate-free method under a high relative humidity // Macromol. Rapid Commun., 2008, v. 29 (21), pp. 1705–1710. DOI: https://doi.org/10.1002/marc.20080029410. Konyushenko E.N., Stejskal J., Šeděnková I., Trchová M., Sapurina I., Cieslar M., Prokeš J. Polyanilinenanotubes: conditions of formation // Polym. Int, 2006, v. 55, pp. 31–39. DOI: https://doi.org/10.1002/pi.189911. Trchová M., Šeděnková I., Konyushenko E. N., Stejskal J., Holler P., Ćirić-Marjanović G. Evolution ofpolyaniline nanotubes: The oxidation of aniline in water // J. Phys. Chem. B, 2006, v. 110(19), pp. 9461–9468. DOI: https://doi.org/10.1021/jp057528g12. Bhadra S., Khastgir D. Extrinsic and intrinsic structural change during heat treatment of polyaniline// Polymer Degradation and Stability, 2008, v. 93 (6), pp. 1094–1099. DOI: https://doi.org/10.1016/j.polymdegradstab.2008.03.01313. Yalovega G. E., Myasoedova T. N., Shmatko V. A., Brzhezinskaya M. M., Popov Y. V. Infl uenceof Cu/Sn mixture on the shape and structure of crystallites in copper-containing fi lms: Morphological andX-ray spectroscopy studies // Applied Surface Science, 2016, v. 372, pp. 93–99. DOI: https://doi.org/10.1016/j.apsusc.2016.02.24514. Domashevskaya E. P., Hadia N. M. A., Ryabtsev S. V., Seredin P. V. Structure and photoluminescenceproperties of SnO2 nanowires synthesized from SnO powder // Kondensirovannye sredy i mezhfaznyegranitsy [Condensed Matter and Interphases], 2009,v. 11(1), С. 5–915. Baibarac M., Baltog I., Lefrant S., Mevellec J. Y., Chauvet O. Polyaniline and carbon nanotubes basedcomposites containing whole units and fragments of nanotubes // Chem. Mater., 2003, v. 15, pp. 4149–4156.DOI: https://doi.org/10.1021/cm021287x16. Окотруб А. В., Асанов И. П., Галкин П. С., Булушева Л. Г., Чехова Г. Н., Куреня А. Г., Шубин Ю. В.Композиты на основе полианилина и ориентированных углеродных нанотрубок // Высокомолекулярные соединения Серия Б, 2010, т. 52 (2), с. 351–359.17. Wang S., Tan Z., Li Y., Suna L., Zhang T. Synthesis, characterization and thermal analysis ofpolyaniline/ZrO2 composites // Thermochimica Acta, 2006, v. 441, pp. 191–194. DOI: https://doi.org/10.1016/j.tca.2005.05.02018. Ullah R., Bowmaker G.A., Laslau C., Waterhouse G. I. N., Zujovic Z. D., Ali K., Shah A.-U.-H. A.,Travas-Sejdic J. Synthesis of polyaniline by using CuCl2 as oxidizing agent // Synthetic Metals, 2014, v. 198,pp. 203–211. DOI: https://doi.org/10.1016/j.synthmet.2014.10.00519. Izumi C. M., Constantino V. R., Temperini M. L. Spectroscopic characterization of polyaniline formedby using copper(II) in homogeneous and MCM-41 molecular sieve media // J. Phys. Chem. B, 2005, v. 109,pp. 22131–22140. DOI: https://doi.org/10.1021/jp051630w20. Magnuson M., Guo J.-H., Butorin S.M., Agui A., Sеthe C., Nordgren J. The electronic structure of polyanilineand doped phases studied by soft x-ray absorption and emission spectroscopies // J. Chem. Phys.,1999, v. 111, pp. 4756–4761. DOI: https://doi.org/10.1063/1.47923821. Домашевская Э. П., Cторожилов С.А., Турищев С. Ю., Кашкаров В. М., Терехов В. А., Стогней О. В., Калинин Ю. Е., Ситников А. В., Молодцов С. Л. XANES- И USXES-исследования межатомн ы х в з а и м од е й ст в и й в н а н о ко м п о з и т а х (Co41Fe39B20)x(SiO2)1–x // ФТТ, 2008, т. 50 (1), с. 135–141.22. Gaur A., Klysubun W., Sonic B., Shrivastav D., Prasad J., Srivastava K. Identifi cation of different coordinationgeometries by XAFS in copper(II) complexes with trimesic acid // Journal of Molecular Structure,2016, v. 1121, pp. 119–127. DOI: https://doi.org/10.1016/j.molstruc.2016.05.06623. Fulton J. L., Hoffmann M. M., Darab J. G., Palmer B. J. Copper(I) and сopper(II) сoordinationstructure under hydrothermal conditions at 325 °C: an X-ray absorption fine structure and moleculardynamics study // J. Phys. Chem. A., 2000, v. 104, pp. 11651–11663. DOI: https://doi.org/10.1021/jp001949a24. Porto A. O., Pernaut J. M., Daniel H., Schilling P. J., Martins M. C. Alves X-ray absorption spectroscopyof iron-doped conducting polymers // Synthetic Metals, 1999, v. 104, pp. 89–94. DOI: https://doi.org/10.1016/S0379-6779(99)00025-925. Zhang Y., Addison O., Gostin P. F., Morrell A., Cook A. J. M. C., Liens A., Wu J., Ignatyev K., Stoica M.,Davenport A. In-situ synchrotron X-ray characterization of corrosion products in Zr artifi cial pits in simulatedphysiological solutions // J. Electrochem. Soc, 2017, v. 164(14), pp. 1003–1012. DOI: https://doi.org/10.1149/2.0671714jes

e3293014Current Brazilian legislation defines the gifted as those who have high ability and high involvement in areas of human knowledge (intellectual, leadership, psychomotor, arts, and creativity), whether in isolation or in combined areas. The law nº 9.394/1996, integrates these students to the public of Special Education and assures them education appropriate to their needs, the possibility of acceleration of studies, specialized educational assistance, and special education for work. However, the estimates indicate that a large number of these students are unassisted, without them being at least identified by the educational systems. The historical recovery of the legal guidelines that guided and guide the educational service of the gifted in Brazil reveals that the national legislation was preceded by isolated pedagogical practices, which began in the first half of the twentieth century. Initiatives in favor of the gifted have gained strength after the law nº 5.692/1971 explicitly mention this pupil. At that time, the Federal Council of Education issued opinions aimed at meeting the needs of this public, but the expansion of care has occurred in a gradual and modest way, so that, despite a series of legal documents issued in the last decades, the gifted remain with their potentialities and needs ignored.ResumoA legislação brasileira atual define os estudantes com altas habilidades/superdotação como aqueles que possuem alta potencialidade e elevado envolvimento em áreas do conhecimento humano (intelectual, de liderança, psicomotora, de artes e criatividade), seja isoladamente, seja em áreas combinadas. A Lei nº 9.394/1996 integra esses discentes ao público da Educação Especial e assegura-lhes ensino adequado às suas necessidades, possibilidade de aceleração de estudos, atendimento educacional especializado e educação especial para o trabalho. No entanto, as estimativas apontam que grande parcela desses estudantes se encontra desassistida, sem que eles sejam, ao menos, identificados pelos sistemas de ensino. O resgate histórico das diretrizes legais que orientaram e orientam o atendimento educacional dos estudantes com altas habilidades/superdotação, no Brasil, objetivo deste ensaio teórico, revela que a legislação nacional foi antecedida por práticas pedagógicas isoladas, as quais tiveram início na primeira metade do século XX. As iniciativas em favor desse alunado ganharam força após a Lei nº 5.692/1971, sem mencioná-los, explicitamente. Nessa época, o Conselho Federal de Educação emitiu pareceres voltados à atenção das necessidades desse público, mas a ampliação do atendimento tem ocorrido de modo gradativo e modesto, de maneira que, a despeito de uma série de documentos legais expedidos nas últimas décadas, tais estudantes permanecem com suas potencialidades e necessidades ignoradas.ResumenLa legislación brasileña actual define a los superdotados como aquellos que poseen alta potencialidad y alto involucramiento en áreas del conocimiento humano (intelectual, liderazgo, psicomotora, artes y creatividad), sea aisladamente o en áreas combinadas. La Ley nº 9.394/1996, integra estos discentes al público de la Educación Especial y les asegura una enseñanza adecuada a sus necesidades, posibilidad de aceleración de estudios, atención educativa especializada y educación especial para el trabajo. Sin embargo, las estimaciones apuntan que una gran parte de estos estudiantes se encuentra desasistida, sin que ellos, al menos, sean identificados por los sistemas de enseñanza. El rescate histórico de las directrices legales que orientaron y orientan la atención educativa de los superdotados en Brasil revela que la legislación nacional fue precedida por prácticas pedagógicas aisladas, las cuales comenzaron en la primera mitad del siglo XX. Las iniciativas en favor de los superdotados ganaron fuerza después de la Ley nº 5.692/1971 mencionar, explícitamente, ese alunado. En esa época, el Consejo Federal de Educación emitió opiniones orientadas a la atención de las necesidades de ese público, pero la ampliación de la atención ha ocurrido de modo gradual y modesto, de manera que, a pesar de una serie de documentos legales expedidos en las últimas décadas, los superdotados permanecen con sus potencialidades y necesidades ignoradas.Palavras-chave: Educação especial, Diretrizes da educação, Superdotação.Keywords: Special education, Education guidelines, Giftedness.Palabra clave: Educación especial, Pautas educativas, Superdotación.ReferencesALMEIDA, L. S.; ARAÚJO, A. M.; SAINZ-GÓMES, M.; PRIETO, M. D. Challenges in the identification of giftedness: Issues related to psychological assessment. Anales de psicologia, v. 32, n. 3, p. 621-627, 2016.ALMEIDA, M. A.; CAPELLINI, V. L. M. F. Alunos talentosos: possíveis superdotados não notados. Educação, Porto Alegre, v. 55, n. 1, p. 45-64, 2005.ALVARENGA, R. Entrevista virtual com Helena Antipoff: a psicóloga de Minas Gerais. Belo Horizonte: Minas Gerais, 2014.ANTIPOFF, C. A. Uma proposta original na educação de bem-dotados: ADAV – Associação Milton Campos para Desenvolvimento e Assistência de Vocações de Bem Dotados em sua primeira década de funcionamento: 1973-1983. 2010. 239f. Dissertação (Mestrado em Educação) – Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil, 2010.BRASIL. Decreto nº 1.426, de 12 de Setembro de 1854. Coleção de Leis do Império do Brasil - 1854, 1, pt I, p. 295 (Publicação Original). Disponível em: http://www2.camara.leg.br/legin/fed/decret/1824-1899/decreto-1428-12-setembro-1854-508506-publicacaooriginal-1-pe.html. Acesso em: 21 set. 2015.BRASIL. Lei n. 4.024, de 20 de dezembro de 1961. Fixa as Diretrizes e Bases da Educação Nacional. Disponível em: http://wwwp.fc.unesp.br/~lizanata/LDB%204024-61.pdf. Acesso em: 05 out. 2015.BRASIL. Lei n. 5.692, de 11 de agosto de 1971. Fixa Diretrizes e Bases para o ensino de 1° e 2º graus, e dá outras providências. Disponível em: http://www.planalto.gov.br/ccivil_03/Leis/L5692.htm. Acesso em: 05 out. 2015.BRASIL. Constituição da República Federativa do Brasil,1988. Disponível em: http://www.planalto.gov.br/ccivil_03/Constituicao/Constituicao.htm. Acesso em: 16 fev. 2019.BRASIL. Lei nº 8.069, de 13 de julho de 1990. Estatuto da Criança e do Adolescente. Disponível em: http://www.planalto.gov.br/ccivil_03/LEIS/L8069.htm. Acesso em: 16 fev. 2019.BRASIL. Ministério da Educação. Diretrizes gerais para o atendimento educacional aos alunos portadores de altas habilidades/superdotação e talentos. Brasília, DF: MEC/SEESP, 1995.BRASIL. Lei n. 9.394, de 20 de dezembro de 1996. Estabelece as diretrizes e bases da educação nacional. Disponível em: http://www2.camara.leg.br/legin/fed/lei/1996/lei-9394-20-dezembro-1996-362578-publicacaooriginal-1-pl.html. Acesso em: 07 out. 2015.BRASIL. Resolução CNE/CEB nº 2, de 11 de setembro de 2001. Institui Diretrizes Nacionais para a Educação Especial na Educação Básica. Disponível em: http://portal.mec.gov.br/cne/arquivos/pdf/CEB0201.pdf. Acesso em: 13 out. 2015.BRASIL. Ministério da Educação. Documento Orientador: Execução da Ação. Núcleos de Atividades de Altas Habilidades/Superdotação. Brasília, DF: MEC/SEESP. 2006.BRASIL. Ministério da Educação. Política Nacional de Educação Especial na Perspectiva da Educação Inclusiva, 2008. Disponível em: http://portal.mec.gov.br/arquivos/pdf/politicaeducespecial.pdf. Acesso em: 07 jan. 2015.BRASIL. Decreto nº 6.949, de 25 de agosto de 2009a. Promulga a Convenção Internacional sobre os Direitos das Pessoas com Deficiência e seu Protocolo Facultativo, assinados em Nova York, em 30 de março de 2007. Disponível em: http://www.planalto.gov.br/ccivil_03/_ato2007-2010/2009/decreto/d6949.htm. Acesso em: 20 fev. 2019.BRASIL. Resolução CNE/CEB nº 4, de 02 de outubro de 2009b. Institui Diretrizes Operacionais para o Atendimento Educacional Especializado na Educação Básica, modalidade Educação Especial. Disponível em: http://portal.mec.gov.br/dmdocuments/rceb004_09.pdf. Acesso em: 16 fev. 2019.BRASIL. Ministério da Educação. Secretaria de Educação Especial. Marcos Político-Legais da Educação Especial na Perspectiva da Educação Inclusiva/Secretaria de Educação Especial. Brasília: Secretaria de Educação Especial. 73 p. 2010. Disponível em http://pfdc.pgr.mpf.mp.br/atuacao-e-conteudos-de-apoio/publicacoes/educacao/marcos-politico-legais.pdf. Acesso em: 16 out. 2015.BRASIL. Decreto nº 7.611, de 17 de novembro de 2011. Dispõe sobre a educação especial, o atendimento educacional especializado e dá outras providências. Disponível em http://www.planalto.gov.br/ccivil_03/_ato2011-2014/2011/decreto/d7611.htm. Acesso em: 17 out. 2015.BRASIL. Lei nº 12.764, de 27 de dezembro de 2012. Institui a Política Nacional de Proteção dos Direitos da Pessoa com Transtorno do Espectro Autista; e altera o § 3o do art. 98 da Lei no 8.112, de 11 de dezembro de 1990. Disponível em: http://www.planalto.gov.br/CCivil_03/_Ato2011-2014/2012/Lei/L12764.htm. Acesso em: 17 fev. 2019.BRASIL. Lei n. 12.796, de 4 de abril de 2013. Altera a Lei no 9.394, de 20 de dezembro de 1996, que estabelece as diretrizes e bases da educação nacional, para dispor sobre a formação dos profissionais da educação e dar outras providências. Disponível em: https://www.planalto.gov.br/ccivil_03/_ato2011-2014/2013/lei/l12796.htm. Acesso em: 17 out. 2015.BRASIL. Lei nº 13.146, de 6 de julho de 2015a. Institui a Lei Brasileira de Inclusão da Pessoa com Deficiência (Estatuto da Pessoa com Deficiência). Disponível em: http://www.planalto.gov.br/ccivil_03/_Ato2015-2018/2015/Lei/L13146.htm. Acesso em: 17 fev. 2019.BRASIL. Lei nº 13.234, de 29 de dezembro de 2015b. Altera a Lei no 9.394, de 20 de dezembro de 1996 (Lei de Diretrizes e Bases da Educação Nacional), para dispor sobre a identificação, o cadastramento e o atendimento, na educação básica e na educação superior, de alunos com altas habilidades ou superdotação. Disponível em: http://www.planalto.gov.br/ccivil_03/_Ato2015-2018/2015/Lei/L13234.htm. Acesso em: 16 fev. 2019.BRASIL. Lei nº 13.632, de 06 de março de 2018. Altera a Lei nº 9.394, de 20 de dezembro de 1996 (Lei de Diretrizes e Bases da Educação Nacional), para dispor sobre educação e aprendizagem ao longo da vida. Disponível em: http://www.planalto.gov.br/ccivil_03/_Ato2015-2018/2018/Lei/L13632.htm. Acesso em: 16 fev. 2019.CAMPOS, R. H. F. Helena Antipoff: razão e sensibilidade na psicologia e na educação. Estudos Avançados, São Paulo, v. 17, n. 49, p. 209-223, 2003.CARVALHO, E. N. S. Educação especial e inclusiva no ordenamento jurídico brasileiro. Revista Educação Especial, Santa Maria, v. 26, n. 46, p. 261-276, 2013.CUPERTINO, C. M. B. (org.). Um olhar para as altas habilidades: construindo caminhos. Secretaria da Educação. São Paulo: FDE, 2008.DELOU, C. M. C. Políticas públicas para a educação de superdotados no Brasil. In: REUNIÃO ANUAL DA SOCIEDADE BRASILEIRA PARA O PROGRESSO DA CIÊNCIA, 57, 2005, Fortaleza. Anais... Fortaleza: UECE, 2005. Disponível em: http://www.educacao.pr.gov.br/desvio.html. Acesso em: 31 ago. 2020.DELOU, C. M. C. Educação do Aluno com Altas Habilidades/Superdotação: Legislação e Políticas Educacionais para a Inclusão. In: FLEITH, D. S. (org.). A construção de práticas educacionais para alunos com altas habilidades/superdotação. Volume 1: orientação a professores. Brasília: Ministério da Educação, Secretaria de Educação Especial, 2007. p. 25-39.DOMINGUES, S. O conceito de excepcional na obra de Helena Antipoff: diagnóstico, intervenções, e suas relações com a educação inclusiva. 2011. 193f. Dissertação (Mestrado em Educação) – Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil, 2011.EURYDICE (Unidade Portuguesa). Educação de sobredotados na Europa. Lisboa: Gabinete de Estatística e Planejamento da Educação, 2008.FLEITH, D. S. et al. Educação do aluno sobredotado no Brasil e em Portugal: uma análise comparativa. Revista Lusófona de Educação, n. 16, p. 75-88, 2010.FLEITH, D. S.; ALENCAR, E. M. L. S. Implementing the Schoolwide Enrichment Model in Brazil. Gifted Education International, v. 26, n. 2/3, p. 169-177, 2010.FREEMAN, J. Um estudo comparativo de 35 anos com crianças identificadas como superdotadas, não identificadas como superdotadas e com habilidades médias. Revista Educação Especial, Santa Maria, v. 27, n. 50, p. 563-581, set./dez. 2014.GAMA, M. C. S. S. Educação de Superdotados: teoria e prática. São Paulo: EPU, 2006.GAMA, M. C. S. S. Superdotação: Problema ou Riqueza Nacional? In: FLEITH, D. S.; ALENCAR, E. M. L. S. (org.). Superdotação: trajetória de desenvolvimento e realizações Curitiba: Juruá, 2013. p. 175-192.GUENTHER, Z. C. Capacidade e Talento: um programa para a Escola. São Paulo: EPU, 2006.GUENTHER, Z. C. Caminhos para desenvolver potencial e talento. Lavras: Ed, UFLA, 2011.INCLUSIÓN INTERNACIONAL. Instituto Universitario de Integración en la Comunidad (INICO). Mejor educación para todos: cuando se nos incluya también - un informe mundial. Salamanca, Espanha: Universidad de Salamanca; Instituto Universitario de Integración en la Comunidad, 2009. Disponível em: http://inclusion-international.org/wp-content/uploads/2009/07/Mejor-Educacion-para-Todos_Un-Informe-Mundial_Octubre-2009.pdf. Acesso em: 17 out. 2015.INEP – Instituto Nacional de Estudos e Pesquisas Educacionais Anísio Teixeira. Sinopses Estatísticas da Educação Básica, 2017. Disponível em: http://portal.inep.gov.br/web/guest/sinopses-estatisticas-da-educacao-basica. Acesso em: 21 abr. 2018.JANNUZZI, G. M. A educação do deficiente no Brasil: dos primórdios ao início do século XXI. 2. ed. Campinas: Autores Associados, 2006.KASEFF, L. Notas à margem da educação dos super-normais. Revista Nacional de Educação. v. 4, p. 17-19, 1933.KASSAR, M. C. M.; REBELO, A. S.; OLIVEIRA, R. T. C. Embates e disputas na política nacional de Educação Especial brasileira. Educ. Pesqui., São Paulo, v. 45, p. 1-19, 2019. Disponível em: http://dx.doi.org/10.1590/S1678-4634201945217170. Acesso em: 24 jul. 2020.MAIA-PINTO, R. R.; FLEITH, D. S. Aceleração de ensino na educação infantil: estudo de caso de um aluno superdotado. In: FLEITH, D. S.; ALENCAR; E. M. L. S. (org.). Superdotação: trajetória de desenvolvimento e realizações. Curitiba: Juruá, 2013. p. 143-154.MARLAND JUNIOR, S. P. Education of the gifted and talented - Volume 1: Report to the Congress of the United States. Washington, D.C.: U.S. Government Printing Office, 1971. Disponível em: http://eric.ed.gov/?id=ED056243. Acesso em: 16 fev. 2019.MATOS, B. C.; MACIEL, C. E. Políticas Educacionais do Brasil e Estados Unidos para o atendimento de alunos com Altas Habilidades/Superdotação. Revista Brasileira de Educação Especial, Marília, v. 22, n. 2, p. 175-188, 2016.MIRANDA, A. A. B. Educação Especial no Brasil: Desenvolvimento Histórico. Cadernos de História da Educação, v. 7, p. 29-44, 2008.MIRANDA, L. C.; ALMEIDA, L. S. A investigação em Portugal em torno da sobredotação e da excelência: Análise a partir de teses de mestrado e doutoramento. Sobredotação, n. 11, p. 89-102, 2010.MIRANDA, L. C.; ARAÚJO, A. M.; ALMEIDA, L. S. Identification of gifted students by teachers: reliability and validity of the cognitive abilities and learning scale. Revista de Investigación y Divulgación en Psicología y Logopedia, v. 3, n. 2, p. 14-18, 2013.NASCIMENTO, F. P.; BARROS, M. S. F. O sistema capitalista a partir da década de 1990 e suas implicações na educação escolar brasileira. Revista Ibero-Americana de Estudos em Educação, Araraquara, v. 13, n. 4, p. 1779-1791, out./dez., 2018. Disponível em: https://doi.org/10.21723/riaee.unesp.v13.n4.out/dez.2018.9815. Acesso em: 22 jul. 2020.NOVAES, M. H. Desenvolvimento psicológico do superdotado. São Paulo: Atlas, 1979.ONU. Transformando Nosso Mundo: a Agenda 2030 para o Desenvolvimento Sustentável. Traduzido pelo Centro de Informação das Nações Unidas para o Brasil e revisado pela Coordenadoria-Geral de Desenvolvimento Sustentável do Ministério das Relações Exteriores do Brasil, 2016. Disponível em: http://www.br.undp.org/content/dam/brazil/docs/agenda2030/undp-br-Agenda2030-completo-pt-br-2016.pdf. Acesso em: 17 fev. 2019.OUROFINO, V. T. A. T.; GUIMARÃES, T. G. Características Intelectuais, Emocionais e Sociais do Aluno com Altas Habilidades/Superdotação. In: FLEITH, D. S. (org.). A construção de práticas educacionais para alunos com altas habilidades/superdotação. Volume 1: orientação a professores. Brasília, DF: MEC/SEESP, 2007. p. 53-64.PÉREZ, S. G. P. B.; FREITAS, S. N. Encaminhamentos pedagógicos com alunos com Altas Habilidades/Superdotação na Educação Básica: o cenário brasileiro. Educar em Revista, v. 41, p. 109-124, 2011.RENZULLI, J. S. O que é esta coisa chamada superdotação e como a desenvolvemos? Uma retrospectiva de vinte e cinco anos. Educação. Porto Alegre, ano 27, v. 52, n. 1, p.75-131, jan./abr. 2004.RODRIGUES, D.; NOGUEIRA, J. Educação Especial e Inclusiva em Portugal: fatos e opções. Revista Brasileira de Educação Especial, Marília, v. 17, n. 1, p. 3-20, jan./abr. 2011.ROTHER, E. T. Revisão Sistemática X Revisão Narrativa. Acta Paulista de Enfermagem, São Paulo, v. 20, n. 2, abr./jun. 2007.SÁNCHEZ ANEAS, A. Altas capacidades intelectuales: sobredotación y talentos: Detección, evalución, diagnóstico e intervención educativa y familiar. Formación Alcalá: Alcalá la Real, 2013.SANTOS, R.; GUENTHER, Z. C.; ZANIOLO, L. O. Efeitos da legislação para a educação de dotados e talentosos: o que dizem os gestores escolares. Revista on line de Política e Gestão Educacional, v. 20, n. 03, p. 643-667, 2016.SIGOLO, A. R. L.; GUERREIRO, E. M. B. R.; CRUZ, R. A. S. Políticas educacionais para a educação especial no Brasil: uma breve contextualização histórica. Práxis Educativa, Ponta Grossa, v. 4, n. 2, p. 173-194, 2010.SILVA, C. R. Nas ondas de uma rádio: a educação como panaceia no discurso de quem diz fazer um Brasil melhor. Revista Espaço Acadêmico, v. 165, p. 30-40, 2015.UNESCO. Declaração Mundial sobre Educação para Todos: satisfação das necessidades básicas de aprendizagem, Jontiem, Tailândia, 1990. Disponível em: http://unesdoc.unesco.org/images/0008/000862/086291por.pdf. Acesso em: 06 out. 2015.UNESCO. Declaração de Salamanca e Enquadramento na Área das Necessidades Educativas Especiais, Salamanca, Espanha, 1994. Disponível em: http://www.madeira-edu.pt/LinkClick.aspx?fileticket=7fr0EPRPiY4%3Dtabid=304mid=1656. Acesso em: 06 out. 2015.VIANA, T. V. O saber intenso, criativo e voraz: pessoas com altas habilidades/superdotação. In: MAGALHÃES, R. C. B. P. Educação inclusiva e escolarização: política e formação docente. Brasília: Liber Livro, 2011. p. 157-179.VOSGERAU, D. S. A. R.; ROMANOWSKI, J. P. Estudos de revisão: implicações conceituais e metodológicas. Revista Diálogo Educacional, Curitiba, v. 14, n. 41, p. 165-189, jan./abr. 2014.WERMUTH, M. A. D.; NIELSSON, J. G. Ultraliberalismo, evangelicalismo político e misoginia: a força triunfante do patriarcalismo na sociedade brasileira pós-impeachment. Revista Eletrônica do Curso de Direito, v. 13, n. 2, 2018.

Одним из перспективных направлений альтернативной энергетики является использование возобновляемой энергии биомассы, в первую очередь отходов агропромышленного комплекса, с получением биогаза. Биогаз представляет собой климатически нейтральный возобновляемый источник энергии, который имеет ряд преимуществ с точки зрения вклада в декарбонизацию по сравнению с другими видами «зеленой» энергетики. Последние десятилетия одним из признанных лидеров в области развития биогазовой технологии и биоэнергетики является Европа. История развития этой отрасли альтернативной энергии переживала периоды бурного роста, интенсивного развития и завоевания европейского рынка, однако в последние годы отрасль испытывает серьезные проблемы, описанные на примере Германии. С учетом этих проблем анаэробные технологии очистки сточных вод, также получающие биогаз в качестве вторичного продукта, выглядят предпочтительной альтернативой технологиям переработки органических отходов сельского хозяйства и энергетической биомассы, поскольку лишены присутствия вторичного спутника метаногенного сбраживания отходов – органической фракции, создающей основные экологические проблемы и снижающей экономическую эффективность процесса. Республика Татарстан является одним из лидеров в Российской Федерации по переработке молока, а этот процесс вызывает образование большого количества концентрированных сточных вод. В связи с этим представляло интерес оценить эколого-экономическую эффективность технологии биологической анаэробно-аэробной очистки сточных вод молокоперерабатывающего предприятия, работающего на территории Республики Татарстан. Представлена методика и исходные данные для расчета. Показано, что при очистке по усовершенствованной анаэробно-аэробной технологии годовой эколого-экономический эффект на действующем предприятии может составить 147 тысяч рублей. Представлены результаты расчета количества альтернативного климатически нейтрального источника энергии – биогаза. При внедрении усовершенствованной анаэробно-аэробной очистки сточных вод на действующем предприятии объем биогаза может составить до 104 тыс. м3 условного газообразного топлива, а в масштабах Республики Татарстан – до 8.3 млн. м3 условного топлива в год. Расчет коэффициента воспроизводства энергии показал его достаточно высокое значение (около 18.4) при реализации разработанных усовершенствований, что указывает на экономическую привлекательность анаэробно-аэробной очистки сточных вод предприятия по переработке молока с получением биогаза. Библиографические ссылки 1. Баланов П.Е., Смотраева И.В., Иванченко О.Б., Хабибуллин Р.Э. Биотехнология и биоэнергетика в решении вопросов экологии // Вестник Казанского технологического университета. 2015. Т. 18, № 5. C. 229‒232.2. Будущее биогаза в Европе. Часть 1. Декарбонизация htpps://blog.nordicecocentre.com/2020/04/15/будущее-биогаза-в-европе-часть-1-декар (дата обращения 20.02.2022).3. Временная методика определения предотвращенного экологического ущерба. М., 1999. 41 с.4. Гоголева Н.А., Белькова С.В. Анализ использования биогаза в качестве альтернативного топлива на предприятии пищевой промышленности // Актуальные вопросы энергетики. 2020. Т. 2, №1. С. 126‒131. doi: 10.25206/2686-6935-2020-2-1-126-1315. Методика определения предотвращенного экологического ущерба. М., 1999. 32 с.6. Реестр перерабатывающих предприятий Республики Татарстан. https://www.dairynews.ru/news/v-top-100-zavodov-po-kolichestvu-lidiruet-tatarsta.html (дата обращения 20.02.2022).7. Рекус И.Г., Шорина О.С. Основы экологии и рационального природопользования. М.: Изд-во МГУП, 2001. 146 с.8. Фиапшев А.Г., Темукуев Т.Б., Кильчукова О.Х., Хамоков М.М. Энергетическое обоснование использования биогаза // Известия Горского государственного аграрного университета. 2014. Т. 51, № 4. С. 207‒211.9. Хабибуллин Р.Э., Петров А.М., Князев И.В. Анализ энергетической эффективности анаэробно-аэробной технологии очистки сточных вод молочного производства // Вестник Казанского технологического университета. 2014. Т. 17,№1. С. 232‒234.10. Хабибуллин Р.Э., Петров А.М., Князев И.В., Крапивина Н.Ю. Влияние разделения фаз на эффективность процесса очистки сточных вод молочного производства // Георесурсы. 2011. Т. 41, №5. С. 22‒26.11. Хабибуллин Р.Э., Князев И.В., Хасанова Э.Ф., Петров А.М. Энергетический потенциал сточных вод пищевых производств Республики Татарстан в процессе их анаэробной очистки // ЕвразияБио-2010 / Сборник трудов II международного конгресса. М., 2010. С. 201‒203.12. Ahmad T., Aadil R.M., Ahmed H., Rahman U., Soares B.C.V., Souza S.L.Q., Cruz A.G. Treatment and utilization of dairy industrial waste: A review // Trends in food scienceand technology. 2019. Vol. 88. P. 361‒372. doi:10.1016/j.tifs.2019.04.00313. Demirel B., Yenigun O., Onay T.T. Anaerobic treatment of dairy wastewaters: A review // Process biochemistry. 2005. Vol. 40, №8. P. 2583‒2595. doi:10.1016/j.procbio.2004.12.01514. Demuynck M. Biogas plants in Europe: A practical handbook. Springer, 2007. 361 p.15. Göblös S., Portöro P., Bordás D., Kálmán M., Kiss I. Comparison of the effectivities of two-phase and single-phase anaerobic sequencing batch reactors during dairy wastewater treatment // Renewable energy. 2008. Vol. 33, №5. P. 960‒965.doi: 10.1016/j.renene.2007.06.00616. Slavov A.K. General characteristics and treatment possibilities of dairy wastewaters – a review // Food technology and biotechnology. 2017. Vol. 55, №1. P. 14‒28. doi: 10.17113/ftb.55.01.17.452017. Rajeshwari K.V., Balakrishnan M., Kansal A., Lata K., Kishore V.V.N. State-of-the-art of anaerobic digestion technology for industrial wastewater treatment // renewable and sustainable energy reviews. 2000. Vol. 4, №2. P. 135‒156. https://doi.org/10.1016/S1364-0321(99)00014-318. Tocchi C., Federici E., Scargetta S., D’Annibale A., Petruccioli M. Dairy wastewater polluting load and treatment performances of an industrial three-cascade-reactor plant // Process biochemistry. 2013. Vol. 48, №5‒6. P. 941-944. doi:10.1016/j.procbio.2013.04.00919. Weiland P. Production and energetic use of biogas from energy crops and wastes in Germany // Applied biochemistry and biotechnology. 2003. Vol. 109, №1‒3. P. 263‒274. doi: 10.1385/abab:109:1-3:263.20. Zhao K., Wu Y.W., Young S., Chen X.J. Biological treatment of dairy wastewater: A mini review // Journal of environmental informatics letters. 2020. Vol. 4. P. 22‒31. doi:10.3808/jeil.202000036

Abstract Introduction: Acute myeloid leukemia (AML) arises in the bone marrow microenvironment (BME), where cell-cell and cell-matrix adhesion promote AML survival. There is increased incidence of AML in older adults and age-related changes in the BME such as the senescence associated secretory phenotype (SASP) may promote myeloid disorders and cancer. Our objective is to further elucidate the influence of the BME on AML pathobiology. Methods: Using flow cytometry, we prospectively characterized 17 cell adhesion receptors expressed on AML blasts derived from 106 patient blood and bone marrow samples on an IRB approved protocol. For 55 patients, we correlated expression of these individual adhesion receptors with age, cytogenetics, complete remission (CR), relapse free survival (RFS) and overall survival (OS). We correlated expression of adhesion receptors with basal levels of DNA damage in AML blasts, as measured by phosphorylation of histone H2AX (γ-H2AX) by flow cytometry. mRNA microarray gene expression profiling (GEP) on 30 patients, we examined for age-associated differences in the gene expression of cell-cell and cell-matrix adhesion proteins. For 6 patients, we evaluated for changes in GEP that occur in AML blasts with adhesion to plates coated with alternative spliced fibronectin peptide CH296, RetronectinTM (RN) vs. bovine serum albumin (BSA) control. Results: We found a significant positive correlation between L-selectin cell surface expressed protein levels with advancing age (Spearman r = 0.35, p = 0.009) (Figure 1). The response to treatment (CR/CRi) rate, but not RFS, increased with greater surface expression of the following adhesion proteins: CD11a (αL), CD29 (β1), CD44, CD49a (α1) and CD49e (α5). OS improved with greater cell surface expressed protein levels of CD11a (αL) and CD29 (β1). There was a significant negative correlation in L-selectin mRNA levels with basal DNA damage in AML blasts, as measured by γ-H2AX (Spearman r = -0.6, p = 0.005). To further investigate the relationship between L-selection expression and DNA damage in AML, we cultured AML blasts on an L-selectin ligand, P-selectin glycoprotein-1 (PSGL-1) vs. BSA control. We observed increased blast survival and reduced apoptosis when adherent on PSGL-1 compared to BSA after treatment with cytarabine arabinoside (Ara-C) in 4/15 (27%) of samples tested (Figure 2). Ingenuity Pathway Analysis (IPA) results on the gene expression data showed age-associated changes in the expression of L-selectin and cell-matrix proteins involved in the SASP, such as tissue inhibitor of metalloproteinases (TIMP). Adhesion of AML blasts to RN vs. BSA control resulted in up-regulation of genes involved in protein ubiquitination and the PI3K/AKT, nuclear factor-kappa beta (NF-kβ) and IL-8 signaling pathways. Conclusions: Age-related changes in the expression of L-selectin, cell-cell and cell-matrix proteins in AML blasts appear to influence DNA damage signaling/response (DDR), promote Ara-C resistance, and influence patient response to treatment and survival. Adhesion of AML blasts to the BME results in up-regulation of cell survival pathways that confer resistance to apoptosis and maintenance of the SASP. Our results support disruption of L-selectin and other BME-mediated interactions as potential targets to enhance cytotoxicity to chemotherapy and improve age-specific outcomes in AML. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Becker: Invivoscribe: Honoraria; CVS Caremark: Other: Accordant Health Services Medical Advisory Board; Millennium: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Glycomimetics: Research Funding; Pfizer: Other: Scientific Steering Committee for a post marketing study; JW Pharmaceutical: Research Funding.

Las ciudades mesopotámicas estaban amuralladas desde sus orígenes. Muralla y ciudad, símbolo de civilización, eran dos conceptos inseparables. Por mandato de los dioses, el rey era el responsable de la fundación de las ciudades y de la construcción de sus sistemas de defensa, que fueron evolucionando como respuesta a los cambios producidos en el arte de la guerra en el Próximo Oriente antiguo. En este artículo se analiza, en particular, la documentación arqueológica y textual de dos modelos de ciudad fortificada: Mari (III-II milenio a. C.), en el norte, y Babilonia (II-I milenio a. C.), en el sur. Se realiza una nueva propuesta de interpretación del recinto defensivo interior de Babilonia. Palabras clave: Ciudades mesopotámicas, fortificacionesTopónimos: Habuba Kabira, Mari, BabiloniaPeríodo: IV-I milenio a. C. ABSTRACTMesopotamian cities were walled from their origins. Wall and city, a symbol of civilisation, were two inseparable concepts. By mandate of the gods, the king was responsible for the foundation of the cities and the construction of their defence systems, which evolved in response to changes in the art of warfare in the ancient Near East. This article analyses, in particular, the archaeological and textual documentation of two models of fortified cities: Mari (3rd-2nd millennium B.C.), in the north, and Babylon (2nd-1st millennium B.C.), in the south. A new approach to the interpretation of the inner wall of Babylon is proposed. Keywords: Mesopotamian cities, fortificationsPlace names: Habuba Kabira, Mari, BabylonPeriod: IVth-Ist millennium B. C. REFERENCIASAbrahami, Ph. (1997), L’armée à Mari, tesis doctoral, Université de Paris I (inédita).al-Rawi, F.N.H. (1985), “Nabopolassar’s Restoration Work on the Wall Imgur-Enlil at Babylon”, Iraq, 47, pp. 1-9.Aurenche, O. (dir.) (1977), Dictionnaire illustré multilingue de l’architecture du Proche Orient Ancien, Lyon, MOM.Azara, P. (dir.) (2000), La fundación de la ciudad. Mesopotamia, Grecia y Roma, Barcelona, CCCB.Battini, L. (1996), “Un exemple de propagande néoassyrienne: les défenses de Dur-Sharrukin”, CMAO, 6, pp. 215-234.— (1997), “Les sytèmes défensifs à Babylone”, Akkadica, 104-105, pp. 24-55.Becker, H., van Ess, M., Fassbinder, J. (2019), “Uruk: Urban Structures in Magnetic and Satellite Images”, en Uruk. First City of the Ancient World, Los Angeles, Getty Museum.Burke, A. A. (2008), “Walled up to Heaven”. The Evolution of Middle Bronze Age Fortifications Strategies in the Levant, Winona Lake, Eisenbrauns.Butterlin, P. (2016), “Villes de Mésopotamie, D’Uruk à Babylone”, en L’histoire commence en Mésopotamie, París, Louvre, pp. 166-171.— (2020), “Mari, une ville circulaire ordinaire?”, en Circular Cities of Early Bronze Age Syria, Turnhout, Breplos, pp. 265-273.Chavalas, M. (ed.) (2006), Historical Sources in Translation. The Ancient Near East, Malden, Blackwell.Childe, V. G. (1992), Los orígenes de la civilización, México DF, FCE (1ª edición de 1936).Collon, D. (2008), “Le développement de l’arc en Mésopotamie”, en Les armées du Proche-Orient ancien (IIIe et Ier mil. av. J.-C.), Oxford, BAR.Durand, J. M. (1997), Les documents épistolaires du palais de Mari, tome I, Paris, Éditions du Cerf.— (1998), Les documents épistolaires du palais de Mari, tome II, Paris, Éditions du Cerf.George, A. R. (1992), Babylonian Topographical Texts, Leuven, Peeters.Herzog, Z. (1997), “Fortifications”, en The Oxford Encyclopedia of Archaeology in the Near East, New York-Oxford, Oxford University Press, pp. 319-326.Hnaihen, K. H. (2020), The Defensive Brick Architecture in Mesopotamia from the end of Early Bronze Age to th end of Early Iron Age, tesis doctoral, Universidad de Almería (inédita).Houben, H. y Guillaud, H. (2006), Traité de construction en terre, Marseille, Éditions Parenthèses.Kenyon, K. M. (1963), Arqueología en Tierra Santa, Barcelona, Ediciones Garriga.Lackenbacher, S. (2001), “Fondations assyriennes”, en Mites de fundació de ciutats al món antic (Mesopotàmia, Grècia i Roma), Barcelona, MAC, pp. 69-74.Liverani, M. (2006), Uruk. La primera ciudad, Barcelona, Edicions Bellaterra.— (2014), Imaginar Babel. Dos siglos de estudios sobre la ciudad oriental antigua, Barcelona, Edicions Bellaterra.Ludwig (1980), “Mass, Sitte und Technik des Bauens in Habuba-Kabira Süd”, en Le Moyen Euphrate, zone de contactes et d’échanges, Leyden, Brill, pp. 63-74.Margueron, J. C. (2000), “Nacimiento y fundación de ciudades en Mesopotamia”, en La fundación de la ciudad. Mesopotamia, Grecia y Roma, Barcelona, CCCB, pp. 33-48.— (2004), Mari. Métropole de l’Euphrate au IIIe et au Début du IIe millénaire av. J.-C., Paris, Picard-ERC.— (2009), “La fondation de Mari. Première aproche d’une technologie de fondation”, Estudos Orientais, 10, pp. 13-33.— (2011), “Aux origines de l’architecture militaire en Mésopotamie”, en Stratégies de défense, de conquête ou de victoire en Méditerranée des textes aux architectures et à l’aménagement, Tlemcen, pp. 11-45.— (2012), “Du village à la ville: continuité ou rupture?”, en Du village néolithique à la ville syro-mésopotamienne, Ferrol, PAMES-UDC, pp. 67-97.— (2013), Cités invisibles. La naissance de l’urbanisme au Proche-Orient ancien, París, Paul Geuthner— (2014), Mari. Capital of Northern Mesopotamia in the Third Millennium, Oxford-Philadelphia, Oxbow Books.Mazar, A. (1995), “The Fortification of Cities in the Ancient Near East”, en Civilizations of the Ancient Near East, volumes III-IV, Peabody, Hendrickson Publishers, pp. 1523-1537.Mielke, D. P. (2012), “Fortifications and Fortification Strategies of Mega-Cities in the Ancient Near East”, en Mega-cities Mega-sites, the Archaeology of Consumption Disposal, Landscape, Transport Communication, 7th ICAANE vol. 1, Wiesbaden, Harrassowitz Verlag, pp. 74-91.Montero Fenollós, J. L. (2004), “Revisando a Gordon Childe, el concepto de Revolución Metalúrgica en los albores de la historia de Mesopotamia”, en Miscelánea en homenaje a Emiliano Aguirre, Alcalá de Henares, Museo Arqueológico Regional, pp. 312-319.— (2017), “Bronze Metallurgy in the Times of Earliest Cities. New Data on the City I of Mari”, Ash-Sharq, 1, pp. 48-54.— (2019), “La frontera noroccidental del reino de Mari a comienzos del II milenio a. C. a la luz de los textos y la arqueología. Reflexiones sobre la localización de Dur-Yahdun-Lim”, Claroscuro, 18, pp. 1-21.Nadali, D. (2007), “Ashurbanipal against Elam. Figurative Patterns and Architectural Location of Elamite Wars”, Historiae, 4, pp. 57-91Nigro, L. (2015), “Tell es-Sultan 2015. A Pilot Project for Archaeology in Palestine”, Near Eastern Archaeology, 79, pp. 4-17.Pedersén, O. (2011), “Excavated and Unexcavated Libraries un Babylon”, en Babylon. Wissenskultur in Orient und Okzident, Berlin-Boston, De Gruyter, pp. 47-67.— (2021), Babylon. The Great City, Münster, Zaphon.Reade J. E. (2008), “Early Travellers on the Wonders: Suggested Sites”, en Babylon: Myth and Reality, London, British Museum, pp, 112-118.Rey, S. (2012), Poliorcétique au Proche-Orient à l’âge du Bronze. Fortifications urbaines, procédés de siège et systèmes défensifs, Beyrouth, IFPO.Sanmartín, J. (2018), Gilgamesh, rey de Uruk, Madrid, Trotta.Sasson, J.M. (1969), The Military Establishments at Mari, Roma, Pontifical Biblical Institute.Sollberger, E., Kupper, J. R. (1971), Inscriptions royales sumériennes et akkadiennes, Paris, Éditions du Cerf.Thomas, A. (dir.) (2016), L’histoire commence en Mésopotamie, París, Louvre.Van Ess, M. (2008), “Koldewey, Pionier systematicher Ausgrabungen im Orient”, en Auf dem weg nach Babylon. Robert Koldewey. Ein Archäologenleben, Mainz, Verlag Philipp von Zabern, pp. 91-103.Vidal, J. (2012), “La guerra de asedio en el período paleobabilónico según los textos de Mari”, en Fortificaciones y guerra de asedio en el mundo antiguo, Zaragoza, Libros Pórtico, pp. 21-35.Wetzel, F. (1969), Stadtmauer von Babylon, Osnabrück, Otto Zellen.Yadin, Y. (1963), The Art of Warfare in Biblical Lands, 2 vols., New York-Toronto-Londres, McGraw-Hill Book Company.

BackgroundIgA vasculitis (IgAV) has been extensively studied in children, while its natural history remains poorly studied in adults. Sparse data comparing childhood and adult-onset disease has shown significant differences in their clinical presentation, especially in the severity of renal involvement, which accounts for the major long-term morbidity. IgAV shares similar renal histologic features with IgA nephropathy (IgAN), while clinically IgAN is a chronic kidney disease which may lead to end stage renal disease and dialysis. The extent of kidney injury among adults with IgAV is still a matter of uncertainty.ObjectivesWe aimed to evaluate clinical manifestations, laboratory data, treatment patterns and long-term outcomes of pediatric and adult-onset IgAV in comparison to IgAN.MethodsThis retrospective collaborative study examined medical records of adults and children with IgAV and IgAN adult patients admitted to rheumatology clinic and in hospital pediatric departments in a 13-year period (2007-2019). Diagnosis of adults with IgAV relied on the Ankara criteria and was confirmed by a consistent skin biopsy with positive IgA staining by immunofluorescence. Children with IgAV were included in our study on a clinical basis. All IgAN patients had a kidney biopsy proven disease. We analyzed and compared frequencies of clinical manifestations, laboratory findings, treatment regimens and long-term outcomes at one year follow-up. Finally, we assessed long term outcomes, such as time to dialysis and all-cause mortality, till the end of the follow-up time.ResultsA total of 60 adult IgAV, 60 pediatric IgAV and 45 IgAN patients were included in our study. There were significantly more males in the IgAN group compared to the adult and pediatric IgAV groups (77.8%, 41.7% and 55% respectively, p=0.01). Adult IgAV patients were significantly older than IgAN patients (53.1±17.4 years vs. 45.1±15.7 years, p=0.02) and had significantly higher rates of diabetes (43.3% vs. 24.4%, p=0.05) and ischemic heart disease (18.3% vs. 4.4%, p=0.03). The pediatric IgAV group had a statistically higher rate of previous infection compared to the adult IgAV group (44.8% vs. 20%, p=0.02). At one year follow-up, IgAN patients had higher levels of serum creatinine compared to the adult IgAV group (2.002 vs. 1.100, p<0.01). Data observed until the end of the follow-up time showed no difference in time to dialysis (IgAV adults: 9.8-12.4 years, IgAN: 5.0-6.6 years, p>.41). Nevertheless, IgAV adult patients had significantly shorter survival time (5.5 years, 95% CI: 4.8-6.2 years) than IgAN patients (7.0 years, 95% CI: 6.6-7.5 years, p<.01).ConclusionThis retrospective study demonstrates that IgAV in adults presents substantial clinical manifestations, including high risk of progression to persistent renal impairment and possesses higher mortality rate in comparison with pediatric-onset disease and IgAN.References[1]Blanco R, Martínez-Taboada VM, Rodríguez-Valverde V, García-Fuentes M, González-Gay MA. Henoch-Schönlein purpura in adulthood and childhood: two different expressions of the same syndrome. Arthritis Rheum. 1997 May;40(5):859-64. doi: 10.1002/art.1780400513. PMID: 9153547.[2]Nossent J, Raymond W, Isobel Keen H, Preen D, Inderjeeth C. Morbidity and mortality in adult-onset IgA vasculitis: a long-term population-based cohort study. Rheumatology (Oxford). 2021 Dec 24;61(1):291-298. doi: 10.1093/rheumatology/keab312. PMID: 33779729.Figure 1.Disclosure of InterestsNone declared