Zeitschriftenartikel zum Thema „248/.2/092 b“

Cultured cotyledon and leaf pieces of five cultivars of Lycopersicon esculentum Mill. were tested in six culture media for their ability to produce shoots for transformation studies. The no. of tissue pieces with callus/total tissue pieces, quality of callus (size and vigor), no. of tissue pieces with shoots/total tissue pieces, and shoot quality (size and vigor) were measured. Cultivars tested were `Campbell 28', `Flora-Dade', `UC82b', and two breeding lines, Fla.7171 and Fla.7324. The six media used were Murashige and Skoog medium supplemented with six combinations of indole acetic acid (IAA) and cytokinins: A) 1 mg/l IAA + 1 mg/l kinetin, B) 0.5 mg/l IAA + 2 mg/l kinetin, C) 0.02 mg/l IAA + 1 mg/l zeatin, D) 0.2 mg/l IAA + 2 mg/l zestin, E) 1 mg/l IAA + 2.5 mg/l BAP (6-benzyl amino purine), and F) 0.2 mg/l IAA + 1 mg/l BAP. Standard procedures were followed for culturing 4 - 5 mm pieces of cotyledon and leaves. Callus and shoot regeneration were greater, less variable and faster, in cotyledon than in leaf pieces. Media C and F gave the highest rates of callus and shoot production, respectively, in cotyledon tissue. Medium E gave the highest rate for both callus and shoot production in leaf discs. The best rates of shoot production were achieved with cotyledon tissue from cultivar UC82b cultured on media C (85.3%) and F (77.2%).

248 Background: Hypofractionated prostate cancer radiation has showed similar results in several prior phase III studies (PCG GU 003, PACE-B, and Hypo PC RT). However, prospective phase II-III clinical trial data testing 5 tx after prostatectomy is scarce. Methods: Between 2018 and 2019, 41 patients were treated after postprostatectomy for high risk features. 5 patients were treated adjuvantly, 36 for salvage including 8 with oligometastatic disease. Indications for adjuvant RT included a PSA < 0.2 and +margins, SVI, or EPE. Salvage RT was offered for PSA ≥0.2. Oligometastatic RT for patients with ≤5 RT targets. Staging included C11 PET for all cases. Total dose to the prostate bed was 30-32 Gy in 5tx QOD with IMRT, conebeam IGRT, and MRI registration. All salvage patients received ADT for 6 months and oligometastatic patients for 18 months. Dose to the metastatic sites was 30 in 5tx QOD. Of the 41 patients 8 also received SBRT to the sites of oligometastatic disease. We looked at clinical outcomes defining biochemical failure as a PSA > 0.2 after treatment, baseline adjusted CTC AE V5.0, baseline adjusted patient reported toxicities (PRO CTC AE), QOL (EPIC, PROMIS), and AUA was used for all cases. Results: Median follow up was 23 months (range 10-37). Pre-RT T stage was T2-T3b, with 47% being T3a-b; Pre RT Median PSA of 0.4 (range < 0.1-1.9); Median GS 8 (6-9); and (+) margins in 48.8%. Sites of oligometastatic disease radiated included the LN and bone. Treatment related AE were grade 0-1 in all cases, except for one patient with G2 GU incontinence. Overall QOL remained high during follow including Promis 10 overall, mental, and physical scores; urinary bother, irritative/obstructive, and AUA scores; bowel overall, bowel bother, and bowel function scores; and overall sexual, sexual function, and sexual bother scores remained at baseline levels during follow up. Only hormonal overall, hormonal function, and hormonal bother had lower scores at 3 months that recovered by 12 months in patients treated with ADT for 6 months and by 24 months in patients treated with ADT for 18 months. A total of 3 clinical failure have been seen; 2 patients with regional failures alone; and one with axial skeleton bony failures for 93% clinical control at median follow up of 23 months. All 3 patients with clinical failure were salvaged successfully with SBRT and all patients remain disease free at last follow up. A total 5 patients with raising PSAs alone have been seen. All patients have been re-staged with C11 PET. No failures in the prostate bed or previously radiated sites have been seen. Conclusions: Toxicity for RT over 5tx is lower than expected with only one case of grade 2 urinary incontinence. QOL scores remained high during follow up, minor changes in hormonal scores were seen during ADT, but recovered after. 30-32 Gy over 5 tx provided 100% control in radiated targets and metastatic sites. Clinical trial information: NCT03570827.

Synthesis of P(3HB-co-3HV-co-4HV) copolymers by the wild-type strain Cupriavidus necator B-10646 on fructose or sodium butyrate as the main C-substrate with the addition of γ-valerolactone as a precursor of 3HV and 4HV monomers was studied. Bacterial cells were cultivated in the modes that enabled production of a series of copolymers with molar fractions of 3HV (from 7.3 to 23.4 mol.%) and 4HV (from 1.9 to 4.7 mol.%) with bacterial biomass concentration (8.2 ± 0.2 g/L) and PHA content (80 ± 2%). Using HPLC, DTA, DSC, X-Ray, SEM, and AFM, the physicochemical properties of copolymers and films prepared from them have been investigated as dependent on proportions of monomers. Copolymers are characterized by a reduced degree of crystallinity (Cx 38–49%) molecular weight characteristics Mn (45–87 kDa), and Mw (201–248 kDa) compared with P(3HB). The properties of the films surface of various composition including the porosity and surface roughness were studied. Most of the samples showed a decrease in the average pore area and an increase in their number with a total increase in 3HV and 4HV monomers. The results allow scaling up the productive synthesis of P(3HB-co-3HV-co-4HV) copolymers using Cupriavidus necator B-10646.

4012 Background: Overall survival (OS) in phase III studies with 1st line combination therapy in ACC may be influenced by imbalances in salvage treatments. This is the first study that prospectively investigates the sequential vs the combined use of all available effective cytotoxic drugs. Methods: Previously untreated patients (pts), WHO PS 0–2 were randomized between 1st line capecitabine (Cap), 2nd line irinotecan (Iri), and 3rd line Cap + oxaliplatin (CapOx) (Arm A, sequential) vs 1st line CapIri and 2nd line CapOx (Arm B, combination). The dose of Cap was 1250 mg/m2 (mono) or 1,000 mg/m2 (combination) b.i.d. day 1–14, Iri 350 mg/m2 (mono) or 250 mg/m2 (combination), and Ox 130 mg/m2. All cycles were q 3 weeks with Iri/Ox given i.v. on day 1. Response was assessed q 3 cycles. Primary endpoint was OS. The study was designed to detect a 20% reduction in the hazard of death (HR=0.80) for an increase in median OS from 14 to 17.5 months (a=0.05, 2-tailed test). Results: 820 pts were randomized between Jan ‘03 and Dec ‘04 in 74 Dutch hospitals. Of 804 eligible pts, 796 received = 1 cycle. Median age was 63 (27–84) yrs, median WHO PS 0 (0–2), median follow-up 32 months. Pts (n) in arm A: 398 (1st line), 248 (2nd line), 141 (3rd line); arm B: 398 (1st line), 210 (2nd line). Median OS in arm A was 16.3 months (95%CI 14.3–18.2) and in arm B 17.7 months (95%CI 15.2–19.4), logrank p=0.2. Overall gr 3–4 toxicity over all lines did not differ significantly except for gr 3 hand-foot syndrome (HFS) (13% in A and 6% in B, p=0.0009). Death was probably related to treatment in 11 pts (neutropenic sepsis and/or diarrhea, 8 arm A, 3 arm B) and involved protocol violations in some. In 1st line significant differences in gr 3–4 toxicity in arm A vs arm B were diarrhea (10% vs 25%, p<0.0001), febrile neutropenia (1% vs 6%, p=0.0001) and HFS (12% vs 5%, p=0.0004). All-cause 60-day mortality was 3.0% (n=12) in arm A and 4.5% (n=18) in arm B. Updated results will be presented at the meeting, including data on QoL (EORTC QLQ C30). Conclusions: Combination therapy does not significantly improve OS compared with sequential therapy. Both treatment strategies are valid options for pts with ACC. No significant financial relationships to disclose.

Among microorganisms, bacteria and fungi are reported to be good sources of different types of enzymes, in particular proteases, which have a broad range of applications in industrial processes and products and are representative of most worldwide enzyme sales. The genus Bacillus is probably the most important bacterial source of proteases and is capable of producing high yields of neutral and alkaline proteolytic enzymes with remarkable properties, such as high stability toward extreme temperatures, pH, organic solvents, detergents, and oxidizing compounds. Earlier we have shown the ability of a number of strains of Bacillus sp. isolated from the bottom sediments of the Black Sea: 051, 054, 052 (depth 2080 m), and 247 (depth 1888 m) to display elastase activity (20.83 U/mL, 19.96 U/mL, 15.62 U/mL and 12.15 U/mL, respectively). Since the bacterial population of the deep-sea bottom sediments of the Black Sea has been little studied, the purpose of this work was to search for effective protease producers among the microbiota of the Black Sea water and sediments obtained from its various depths. Methods. The objects of the study were 20 cultures isolated from bottom sediments from 4 points at depths of 888–2080 m in the Black Sea. The cultures were grown under conditions of deep cultivation at 28 °С, with a mixing speed of the nutrient medium of 230 rpm for 2 days. Methods for determining proteolytic (elastolytic, fibrinolytic, fibrinogenolytic, and collagenase) activity in the culture liquid supernatant were used. Results. The research on the ability of the supernatants of the studied cultures to hydrolyze various proteolytic substrates has shown that promising for further investigations can be cultures 248 and 249, isolated under the same conditions (1499 m, 15–20 cm), but being representatives of different species, namely Bacillus subtilis and B. licheniformis, respectively. Supernatants of their culture liquids showed the greatest activity toward fibrin (20.5 U/mL and 19.0 U/mL) and fibrinogen (21.66 U/mL and 20 U/mL, respectively), while cultures of B. licheniformis 249 (1499 m, 15–20 cm), Priestia megaterium 55 (1537 m, 0–5 cm), and B. subtilis 1 (1499 m, 5–10 cm), which were isolated under different conditions, showed high activity toward elastin (33.3 U/mL, 31.2 U/mL and 29 U/mL, respectively). B. subtilis 1 is able to hydrolyze all investigated proteolytic substrates: elastin, fibrin, fibrinogen, and collagen, but the level of these activities was lower than in the above-mentioned strains. Conclusions. According to their catalytic properties, a number of representatives of bacteria Bacillus licheniformis 249, Priestia megaterium 55, and Bacillus subtilis 1 isolated from the deep-water bottom sediments of the Black sea may be promising for further research as producers of enzymes with elastolytic, fibrinolytic, and fibrinogenolytic activity.

1,3-Dimethyldiaza-2-arsenanium tetrachlorogallate (crystal data: C5H12AsCl4GaN2, M = 386.61, orthorhombic, space group Pca21, a = 14.432(3) Å, b = 6.7580(14) Å, c = 13.905(3) Å, V = 1356.2(5) Å3) is synthesized by the routine chloride ion abstraction procedure from 2-chloro-1,3-dimethyldiaza-2-arsenane (crystal data: C5H12AsClN2, M = 210.54, monoclinic, space group P21/n, a = 7.206(1) Å, b = 9.650(1) Å, c = 13.021(2) Å, β = 99.61(2)°, V = 892.8(2) Å3). X-ray crystallographic studies of both compounds are described together with that for 2-chloro-1,3-dimethyldiaza-2-arsolidine (crystal data: C4H10AsClN2, M = 196.51, monoclinic, space group P21/n, a = 6.959(7) Å, b = 9.23(2) Å, c = 12.14(2) Å, β = 95.4(1)°, V = 777(4) Å3) providing useful structural comparisons. In contrast to the closely related arsolidinium salts, the diazarsenanium gallate exhibits a monomeric solid state structure. Rapid and quantitative cycloaddition reactions of the diazarsolidinium and diazarsenanium cations with 2,4-dimethylbutadiene give similar cycloadducts. The Diels–Alder type arsolidinium adduct is structurally characterized (crystal data: C10H20AsCl4GaN2, M = 454.73, orthorhombic, space group Pca21, a = 18.471(2) Å, b = 7.000(2) Å, c = 13.738(1) Å, V = 1776.2(8) Å3), and the related structure of the arsenanium cycloadduct is confirmed by 2D NMR. Key words: arsenium, cycloadditions, arsenanium, Diels–Alder, cyclochloroarsines.

Reactions of 2-substituted 11-chloro-6,11-dihydrodibenzo[b,e]thiepins with trimethylsilyl cyanide in dichloromethane in the presence of stannic chloride afforded nitriles IIb-IId in high yields. Heating of IIa-IId with 2-aminoethylammonium toluene-4-sulfonate to 200 °C gave the title compounds Ia-Id which were transformed to hydrogen maleates. Compound Ic (hydrogen maleate VÚFB-17 092) showed in several tests a clear thymoleptic (potential antidepressant) character.

Abstract Introduction: High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HCT) is the standard of care for younger patients with newly diagnosed multiple myeloma (MM). In approximately 15% of MM patients the monoclonal (M) spike consists of k or l light chains only as opposed to heavy + light chains. It remains unclear whether light chain (LC) MM has a different prognosis compared to other monoclonal protein subtypes after an auto-HCT. Methods: We retrospectively analyzed 1067 patients with MM who underwent auto-HCT between January 1, 2004 and January 1, 2011 at our institution. We evaluated the outcome of newly diagnosed patients with LCMM and compared it to patients with IgG or IgA MM, who underwent an auto-HCT after induction therapy. Primary endpoints were complete remission (CR), progression-free survival (PFS) and overall survival (OS) from the date of auto-HCT. Kaplan-Meier analysis with the log-rank test was performed for univariate comparison of survival. Cox proportional hazards regression method was used for univariate and multivariate analyses. Results: Of 1067 patients who underwent auto-SCT during the period, 223 underwent auto-SCT after relapse, and were excluded. From the remaining 844 who underwent auto-SCT in first remission, we excluded 102 patients (AL amyloidosis 60, POEMS and other plasma cell disorders 10, non-secretory MM 15, IgD 10, IgM 6 and IgE 1) from the analysis. The remaining 742 patients were divided as follows: IgA, 162 patients (22%); IgG, 444 (60%) and LC, 136 (18%). Baseline patient characteristics are described in Table 1. Patients with LCMM were younger and had a higher CR rate to induction. Median follow-up for the entire cohort after auto-HCT was 38 months (range, 0.2-87.0). Post auto-HCT, 28% with IgG/IgA MM and 38% with LCMM achieved a CR (p=0.015). Median PFS was 26.0 months and 27.7 months in IgG/IgA MM and LCMM groups, respectively (p= 0.742). Median OS was not reached and 71.1 months in IgG/IgA MM and LCMM groups, respectively (p= 0.18, Figure 1). Multivariate Cox regression analysis for PFS identified <PR after auto-SCT, non-diploid karyotype, and induction chemotherapy without thalidomide or bortezomib as adverse prognostic factors. Multivariate Cox regression analysis for OS identified presence of hypodiploidy or monosomy 13/del13, higher lactate dehydrogenase pre-transplant, lower hemoglobin pre-transplant, and <PR after auto-HCT as adverse prognostic factors. M protein subtype did not affect PFS (hazard ratio [HR], 1.040; 95% confidence interval [CI], 0.825-1.311; p=0.742) or OS (HR, 1.313; 95% CI, 0.874-1.971; p=0.190). Conclusions: Patients with LCMM have a higher CR rate after auto-HCT, but their PFS and OS were similar to patients with IgG/IgA MM. Table 1. Patient Characteristics Variables, No. (%)/median (range) IgG/IgA myelomaN= 606 Light chain myelomaN= 136 P Median age at transplant, (y) 59 (31-80) 56 (32-78) .004 Age >65 years 138 (23) 23 (17) .134 Male 357 (59) 74 (54) .337 Ethnicity .731 Caucasian 399 (66) 94 (69) African American 99 (16) 22 (16) Mixed 87 (14) 18 (13) Asian 16 (3) 2 (2) Cytogenetic abnormalities at diagnosis by conventional cytogenetics Diploid 180 (30) 36 (27) .159 Hyperdiploid 93 (15) 9 (7) .008 Hypodiploid 27 (5) 11 (8) .082 t(11;14) 4 (1) 3 (2) .092 Monosomy 13 / del 13 44 (7) 9 (7) .789 Other high-risk abnormalities 2 (0) 1 (1) .456 Induction chemotherapy Bortezomib or IMiD-based 507 (84) 123 (90) .046 Pre-transplant evaluation Bone marrow plasma cell, (%) 2 (0-71) 2 (0-50) .136 Bone marrow plasma cell >10% 90 (15) 18 (13) .735 Hemoglobin, (g/dL) 11.3 (4.4-16.0) 10.8 (6.8-15.3) .025 Lactate dehydrogenase, (IL/L) 526 (221-5062) 526 (239-2748) .522 Calcium, (mg/dL) 9.0 (7.6-10.4) 9.0 (7.5-11.0) .055 Creatinine, (mg/dL) 0.9 (0.4-12.5) 0.9 (0.5-9.8) .017 Beta-2 microglobulin (mg/dL) 2.4 (1.1-40.0) 2.8 (1.2-33.8) .001 Time from diagnosis to auto-HCT (month) 8.0 (1.9-174.4) 6.8 (2.4-44.6) .001 Pre-transplant disease status .004 ≥ CR 24 (4) 15 (11) VGPR/PR 545 (90) 109 (80) SD/PD 37 (6) 12 (9) Conditioning regimen .008 Melphalan alone 508 (84) 126 (93) Melphalan-based regimen 98 (16) 10 (7) Final response after transplant .080 ≥ CR 168 (28) 52 (38) VGPR/PR 353 (58) 70 (52) SD/PD 81 (13) 14 (10) Figure 1. a) Progression-free survival, b) Overall survival in patients with light chain myeloma compared to those with IgG/IgA myeloma Figure 1. a) Progression-free survival, b) Overall survival in patients with light chain myeloma compared to those with IgG/IgA myeloma Disclosures Shah: Celgene: Consultancy, Research Funding. Thomas:Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding.

The radiosource 4C39.25 (0923+392) is an 18 mag quasar with a redshift of 0.699. Throughout the seventies its compact structure at centimetric wavelengths consisted of 2 components separated by an angle of about 2 milliarcseconds (mas). In the eighties the structure has been found to consist of 3 components (Marcaide et al., 1985; Shaffer et al., 1987). The angular separation between the “a” and “c” components (see Fig. 1, which shows our most recent map of this source made at a wavelength of 2.8 cm) has remained constant at about 2 mas, while component “b” is separating from component “c” at a rate which we estimate from 2.8 cm observations as 0.18± 0.01 mas/yr, and which translates into an apparent linear separation velocity of 4.0 ± 0.2 c (HO=100 km/s/Mpc, qO=0.5, c is the speed of light).

Abstract Background Outcomes in patients (pts) with secondary acute myeloid leukemia (sAML) (therapy related myeloid neoplasms and AML with myelodysplasia related changes (MRC) per WHO 2016 classification (Arber et al, Blood 2016)) are poor. Pts treated with hypomethylating agents (HMAs) have suboptimal responses to induction chemotherapy (IC) upon transformation to AML. Previously, it was retrospectively demonstrated that the IC with cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) yields significantly higher response rates (64%) than 7+3 (cytarabine and anthracycline) (29%) in pts with prior HMA exposure (Jaglal et al, Leukemia Research 2014). Following the recent approval of CPX-351 for induction in sAML subgroup, we investigated outcomes after CPX-351 to cladribine based regimens and 7+3 in pts with sAML with prior HMA exposure. Methods We identified pts with sAML who had prior HMA treatment for an antecedent hematologic malignancy (AHM) and later received induction chemotherapy upon AML transformation from Moffitt Cancer Center (MCC) (n=229), Memorial Sloan Kettering Cancer Center (n=11) and Roswell Park Comprehensive Cancer Center (n=2). Patients were divided into 3 cohorts based on induction regimen: (A) cladribine based (CLA+/-G+/-M) (B) standard 7+3 and (C) CPX-351. Demographics, disease-specific variables, and outcomes were collected in accordance with the institutional review board approved protocol. Responders (R) were defined as pts achieving CR or CRi as defined by the 2003 International Working Group (IWG) criteria after 1 or 2 cycles of the either induction regimen whereas non-responders (NR) were defined as responses other than CR/CRi. Pts receiving a second induction with a different regimen were considered NR. Fisher's exact test and the ANOVA test were used to determine significance for continuous and categorical variables. Kaplan-Meier analysis with log-rank test was performed to estimate overall survival (OS). Results Among 242 pts who received IC for AML after HMA failure for prior AHM, 114 were treated with (A) cladribine based regimen (B) 94 pts with standard 3+7 and (C) 34 pts with CPX-351 (Cohort C). Baseline characteristics for all 3 cohorts are outlined in Table 1A. Median age for cohort A, B, and C were 65 (33-82), 66 (26-81), and 69 (36-82), respectively. Males comprised of 68.4%, 63% and 52.9% of the cohorts A, B and C, respectively. No pts had favorable-risk karyotype as defined by European LeukemiaNet (ELN) 2017 criteria. Adverse risk karyotype was noted in 42.1% of cohort A, 34.6% of cohort B and 22.7% of cohort C (p=.337). The majority of pts received azacitidine as their HMA for their AHM (88.7%, 84.9% and 82.4% in cohorts A, B, C, respectively) and median number of cycles administered prior to transformation to AML were 6, 4 and 5 for cohorts A, B, and C, respectively. Response rates in each cohort are summarized in Table 1B. The CR/CRi rate was 53% in cohort A, 32% in cohort B and 41.1% in cohort C (p=.005 between cohort A and B) (p=.329 between cohorts A and C) (p=.526 between cohorts B and C). The early death rates (<60 days of induction) were not significantly different among the 3 cohorts, at 12%, 8% and 2.9% in cohorts A, B and C respectively (p=.200). In pts who received ≤ 4 cycles of HMAs prior to AML transformation, response rates to CPX-351 were higher (64.3%) than in pts who received >4 cycles of HMAs (25.0%) (p=.0397). Cohort A (56.5% vs. 50.0%, p=.288) and B (39.1% vs. 25.5%, p=.175) did not demonstrate such a difference (Table 1C and 1D). There was a trend towards better OS (19.9 vs. 5.5mo) with CPX-351 treated pts with ≤ 4 cycles of HMAs compared to >4 cycles (p=.092) (Figure 1). To date, 70.0% of responding pts in cohort A have undergone an allogeneic stem cell transplant compared to 31.0% in cohort B and 28.6% in cohort C (p=.15). There was no significant difference in median OS among the 3 groups, cohort A (7.27 months), cohort B (7.63 months) and cohort C (7.07 months) (p=.887). Among responders, the mOS did not differ (12.93, 21.7, and 19.9 months for cohorts A, B, and C respectively, p=.635). Conclusions We demonstrate that cladribine-based induction regimens and CPX-351 yield higher CR/CRi rates compared to 7+3 in pts with sAML after HMA failure. Prolonged duration of HMA exposure may lower response potential with CPX-351 upon AML transformation. Median OS remains poor and did not differ among the 3 groups illustrating the unmet need for therapy for sAML pts after HMA failure. Disclosures Goldberg: AROG: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Pfizer: Research Funding. Sallman:Celgene: Research Funding, Speakers Bureau. List:Celgene: Research Funding. Wang:Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau. Tallman:AROG: Research Funding; Cellerant: Research Funding; AbbVie: Research Funding; ADC Therapeutics: Research Funding; Orsenix: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; BioSight: Other: Advisory board. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sweet:Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Agios: Consultancy; Astellas: Consultancy; Phizer: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Phizer: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Jazz: Speakers Bureau; BMS: Honoraria; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria.

The room-temperature single-crystal X-ray diffraction determined structures of the Mn(tpp)Br.C7H8, Mn(tpp)(NCO), Mn(tpp)I.C7H8, Mn(tpp)(CO2CH3).0·5C7H8, and Mn(tpp)(NCS).0·5C7H8 complexs are described. The monoclinic P21/c unit cell of Mn(tpp)(NCO) has a 14·82(1), b 17·136(5), c 14·576(5) Å, β 111·41(5)°, V 3446(3) Å3, Z 4. The refinement converged with conventional R(|F|) 0·053 for No 3199 (I > 3·0σ(I)) ‘observed’ reflections. The monoclinic P 21/m unit cell of Mn(tpp)Br.C7H8 has a 9·984(1), b 15·453(6), c 13·583(3) Å, β 103·99(2)°, V 2033(1) Å3, Z 2, R 0·039 for No 2668. The Mn(tpp)I.C7H8 structure is triclinic, P-1, with a 22·28(1), b 14·466(4), c 13·555(6) Å, α 76·32(3), β 81·74(4), γ 74·75(3)°, V 4079(3) Å3, Z 4, R 0·050 for No 9039. The triclinic P-1 crystal structures of the Mn(tpp)(CO2CH3).0·5C7H8 and Mn(tpp)(NCS).0·5C7H8 complexes are isomorphous. The Mn(tpp)(CO2CH3).0·5C7H8 structure has a 26·18(1), b 13·503(3), c 12·074(6) Å, α 66·08(4), β 81·36(4), γ 86·71(5)°, V 3858(3) Å3, Z 4, R 0·075 for No 6388. Solvate disorder, requiring a rigid body model, islargely responsible for the relatively high residuals. The Mn(tpp)(NCS).0·5C7H8 structure has a 25·442(6), b 13·746(3), c 12·182(5) Å, α 66·97(3), β 78·59(3), γ 87·90(2)°, V 3839(2) Å3, Z 4, R 0·061 for No 5506. The asymmetric units of the iodo, acetato and isothiocyanato structures each contain two crystallographically independent complex molecules that are sensitive to crystal packing forces. The metal ion displacements from the least-squares planes formed by the pyrrole nitrogen atoms are 0·299(1) and 0·274(1) Å for the Mn(tpp)(NCO) and Mn(tpp)Br.C7H8complexes, and 0·240(1) and 0·252(1), 0·281(1) and 0·278(1), and 0·243(1) and 0·244(1) Å for the independent (a) and (b) complex molecules of Mn(tpp)I.C7H8, Mn(tpp)(CO2CH3).0·5C7H8, and Mn(tpp)(NCS).0·5C7H8 respectively. The axial Mn–X bond lengths are 2·029(5) and 2·490(1) Å for the Mn(tpp)(NCO) and Mn(tpp)Br.C7H8 complexes, and 2·767(1) and 2·730(1), 2·028(5) and 2·010(5), and 2·067(6) and 2·072(5) Å for the (a) and (b) complex molecules of Mn(tpp)I.C7H8, Mn(tpp)(CO2CH3).0·5C7H8, and Mn(tpp)(NCS).0·5C7H8. One of the independent complex molecules in the Mn(tpp)(CO2CH3).0·5C7H8 structure appears to exhibit acetate coordination through a carbonyl oxygen.

Syntheses and room-temperature single-crystal X-ray studies are recorded for a variety of salts of cations derived from protonated 2,2′-bipyridine and 1,10-phenanthroline (bpyH+ and phenH+) with polyhalobismuthate(III) anions. ‘[(phenH)(phenH2)(H2O)2] [BiCl6]’ is triclinic, P-1, a 9·791(1), b 9·338(3), c 8·311(3) Å, α 73·46(3), β 69·71(2), γ 86·36(2)°, Z = 1; conventional R on |F| was 0·027 for No 4852 independent ‘observed’ (I > 3σ(I)) reflections. [BiCl6]3- is closely octahedral, accompanied by an interesting protonation/hydrogen-bonding array among the other moieties. The latter comment applies also to ‘[(phenH2)(H2O)][BiCl5](∞|∞)’, monoclinic, P2/c, a 8·388(1), b 12·004(1), c 17·146(3) Å, β 98·26(1)°, Z = 4, R 0·047 for No 2670, the anion array being a one-dimensional polymer with bridging chlorine atoms occupying cis sites in the pseudo-octahedral coordination sphere of the bismuth. [bpyH2]4 [Bi4Cl20] is monoclinic, P21/c, a 14·228(4), b 14·217(2), c 16·254(4) Å, β 110·14(2)°, Z = 2, R 0·045 for No 2777; in the novel centrosymmetric tetramer, the four bismuth atoms are bridged into a square array by four linearly coordinated halogen atoms at the centres of the edges, a pair of these lying cis in the pseudo-octahedral coordination sphere of each bismuth. [bpyH]3 [Bi2Cl9] is triclinic, P-1 a 19·288(7), b 14·251(3), c 7·644(3) Å, α 75·02(2), β 80·15(3), γ 72·76(2)°, Z = 2, R 0·072 for No 3600, the two pseudo-octahedrally coordinated bismuth atoms being bridged by three chlorine atoms on a mutual octahedral face, [Cl3Bi(µ-Cl)3BiCl3]3-. [phenH] [BiCl4](∞|∞),H2O is triclinic, space group P-1, a 12·119(7), b 10·169(6), c 7·247(4) Å, α 69·30(4), β 75·05(4), γ 77·92(5)°, Z = 2, R 0·035 for No 2348. The anion is a one-dimensional polymer, successive metal atoms being bridged by pairs of chlorine atoms lying cis in the pseudo-octahedral coordination sphere. [bpyH]4 [Bi2I10] is monoclinic, P21/n, a 13·426(4), b 14·396(6), c 14·539(5) Å, β 101·31(3)°, Z = 2, R 0·11 for No 1862; the anion is of the form [I4Bi(µ-I)2BiI4]4- with quasi-octahedral bismuth. [bpyH] [BiI4](∞|∞) is monoclinic, C2/c, a 12·442(5), b 18·41(2), c 7·714(2) Å, β 92·80(3)°, Z = 4, R 0·080 for No 850, with a polymeric one-dimensional anion comparable to that in [phenH] [BiCl4](∞|∞),H2O. The structure of the 2,6-dimethylpyridinium salt of [BiCl6]3- is also recorded, as its acetonitrile solvate; triclinic, P-1, a 15·025(2), b 10·357(3), c 9·964(1) Å, α 83·14(2), β 89·32(1), γ 86·61(2)°, Z = 2, R 0·046 for No 3601; there is also an isomorphous bromide, and also an isostoichiometric bromide modelled as monoclinic, Cm, a 18·128(6), b 10·348(2), c 10·241(2) Å, β 121·31(3)°, Z = 2, R 0·050 for No 1379. Bands in the far-infrared and Raman spectra due to the v(BiCl) modes are assigned in [(phenH)(phenH2)(H2O)2] [BiCl6] and [bpyH2]4 [Bi4Cl20], and are discussed in relation to the structures of the complexes.

Abstract Background: In patients (pts) with previously treated aHCC, pembro demonstrated comparable efficacy and safety vs placebo (pbo) in the phase 3 KEYNOTE-240 (NCT02702401) and KEYNOTE-394 (NCT03062358) studies in global and Asian populations, respectively. The hazard ratio ([HR]; 95% confidence interval [CI]) for OS was 0.781 (0.611-0.998) in KEYNOTE-240 and 0.79 (0.63-0.99) in KEYNOTE-394; HR (95% CI) for PFS was 0.78 (0.61-0.99) and 0.74 (0.60-0.92), respectively. ORR differences with pembro vs pbo were similar in KEYNOTE-240 (13.8% [95% CI, 7.7-19.5]) and KEYNOTE-394 (11.4% [95% CI, 6.7-16.0]). We performed a prespecified meta-analysis of KEYNOTE-240 and KEYNOTE-394 to obtain a more precise estimate of the pembro treatment effect. Methods: In KEYNOTE-240 and KEYNOTE-394, pts with confirmed aHCC and progression or intolerance to sorafenib or oxaliplatin-based chemotherapy (KEYNOTE-394 only) were randomized 2:1 to pembro (200 mg IV Q3W) or pbo for ≤35 cycles, both with best supportive care. Inclusion/exclusion criteria were similar. Meta-analysis of pt data pooled from the ITT population of the pembro and pbo arms of each study was completed. OS, PFS (blinded independent central review [BICR] per RECIST 1.1), and ORR (BICR per RECIST 1.1) were assessed. Results: In total, 578 pts who received pembro and 288 who received pbo were included. The HR for OS and PFS and the difference in ORR for pembro vs pbo in all pts was 0.79 (95% CI, 0.67-0.93), 0.76 (0.64-0.89), and 12.5 (8.8-16.2), respectively (Table). Results were consistent across subgroups, including viral etiology, BCLC stage, and age. Conclusions: This meta-analysis of two studies with similar design, inclusion/exclusion criteria, and endpoints, showed improvement in OS, PFS, and ORR with pembro vs pbo across studies. These data also show consistent outcomes between the studies, providing further evidence for the benefit of second-line pembro for aHCC globally. All Patients Patients With Sorafenib-Treated aHCC Pembrolizumab(n = 578) Placebo(n = 288) Pembrolizumab(n = 550) Placebo (n = 274) OS, median (95% CI), mo 14.2 (12.8-16.2) 12.5 (10.2-13.6) 14.2 (12.8-16.0) 12.5 (10.4-13.6) HR (95% CI)a,b 0.79 (0.67-0.93) 0.78 (0.66-0.92) PFS, median (95% CI), mo 2.8 (2.7-2.9) 2.7 (1.6-2.8) 2.8 (2.7-2.9) 2.7 (1.6-2.8) HR (95% CI)a,b 0.76 (0.64-0.89) 0.76 (0.64-0.90) ORR, % (95% CI) 15.4 (12.6-18.6) 2.8 (1.2-5.4) 15.6 (12.7-18.9) 2.9 (1.3-5.7) Estimated treatment difference, (95% CI)b,c 12.5 (8.8-16.2) 12.6 (8.8-16.4) aHCC, advanced hepatocellular carcinoma; CI, confidence interval; HR, hazard ratio.aStratified Cox proportional hazard model with treatment as a single covariate and Efron’s method of tie handling was used to estimate the OS and PFS HR and its 95% CI.bStratification was performed per protocol and within each protocol, by strata used in the analysis of the respective protocol.cMiettinen & Nurminen method was used to estimate the difference in ORR and its 95% CI. Citation Format: Richard S. Finn, Kangsheng Gu, Xi Chen, Philippe Merle, Kyung-Hun Lee, Mohamed Bouattour, Peiguo Cao, Wei Wang, Ann-Lii Cheng, Liangjun Zhu, Ho Yeong Lim, Masatoshi Kudo, Yueyin Pan, Ting-Tsung Chang, Julien Edeline, Wei Li, Ping Yang, Chen Li, Jianfeng Li, Abby B. Siegel, Shukui Qin. Pembrolizumab (pembro) for previously treated advanced hepatocellular carcinoma (aHCC): Meta-analysis of the phase 3 KEYNOTE-240 and KEYNOTE-394 studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT222.

The electrochemical reduction of the anti-inflammatory drug ketoprofen was studied in a Britton-Robinson (B-R.) buffer series of pH 2–11 using dc-polarography, cyclic voltammetry, and coulometry techniques. The electrode reaction pathway of the drug at the dropping mercury electrode was proposed and discussed. A new adsorptive cathodic stripping square-wave voltammetric procedure was optimized for the assay of bulk drug in a B-R. buffer of pH 2.0. The peak current was linear with the drug concentration over the ranges 2 × 10–9 to 2 × 10–7 M of the bulk drug, using a 60 s accumulation time period at –0.6 V (vs. Ag/AgCl/KCls). The percentage recovery of the bulk drug was 99.57 ± 0.54 and a detection limit of 0.10 ng mL–1 was achieved. The proposed procedure was successfully applied for the assay of ketoprofen in pharmaceutical formulation (Ketofan®) and human plasma. The percentage recoveries were 99.66 ± 0.47 and 101.76 ± 0.64 in pharmaceutical formulation and human plasma, respectively. A detection limit of 0.14 ng mL–1 plasma was achieved which was below that reported in literature using the different analytical techniques.Key words: ketoprofen (Ketofan®) determination, polarography, cyclic voltammetry, adsorptive cathodic stripping square-wave voltammetry, human plasma.

Six monoclonal antibodies were developed to pregnancy-specific β1-glycoprotein (PSβ1G). Studies of ascitic fluid antibodies by a double-antibody radioimmunoassay (RIA) included an evaluation of titers, dose–response parameters, and mass action properties. Four of the antibodies demonstrated moderate to high titers ranging from 1/40 000 to > 1/120 000, as determined by the specific binding of 125I-labeled PSβ1G. In inhibition studies utilizing a standard containing known quantities of placental PSβ1G, two of the antibodies (AR#11 and B#2) were highly sensitive and only slightly lower in this regard than a high affinity polyclonal antiserum. The binding affinities of AR#11 and B#2 monoclonals were greater than 109 mol−1 which underline their importance as potential clinical reagents for the RIA of PSβ1G. The Scatchard plots, for several of the antibodies, were linear and in full agreement with a single order of binding sites predicted for specific monoclonal reagents. Immunodiffusion results provide preliminary evidence that at least three distinct determinants on PSβ1G are recognized by a number of the monoclonal antibodies. Further studies on the fine specificities of the antibodies by solid-phase RIA, as well as a detailed evaluation of their clinical applications, are in progress.

Abstract Background: Treatment with rhu-Epo ameliorates anemia in a subset of LR-MDS patients, however, effective salvage therapy is limited. LEN promotes erythroid lineage competence and expansion of primitive erythroid precursors in vitro. In the MDS-002 and MDS-005 trials, treatment with LEN improved erythropoiesis, yielding RBC transfusion-independence in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. We previously reported that LEN restores Epo-responsiveness in MDS progenitors by inducing formation of lipid rafts enriched for signaling competent JAK2/Epo-receptor complexes and excluding large isoforms of the JAK2/lyn kinase-phosphatase CD45 (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In a pilot study of Epo-refractory MDS patients, addition of EA yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome resistance and augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo. Methods: Patients with Low or Intermediate-1 (Int-1) risk IPSS MDS with hemoglobin <9.5 g/dL who were unresponsive to rhEpo treatment or were TD (>2 units/mo) with serum Epo >500mU/mL were eligible for study. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). Primary endpoint was IWG 2006 major erythroid response (MER) rate after 4 cycles. Arm A non-responders were offered cross-over to combined therapy. Secondary endpoints included analysis of response biomarkers. Results: Between April 2009 and May 2016, 248 patients were enrolled and 195 were randomized and will be included in the primary analysis. Interim analysis of 163 patients (Arm A, 81; B, 82) accrued before July 2015 showed that the study met predefined stopping criteria. Baseline characteristics were balanced between arms. Median age was 74 years (range, 47-89) receiving a median of 2 RBC units/mo (0-8). Overall, 64 (39%) patients had Low IPSS risk and 90 (55%) Int-1 risk. Among these, 150 received prior rhuEpo (92%) and 27, azanucleosides (17%). In an ITT analysis, MER rate was significantly higher with combination therapy, Arm B 25.6% (n=21) vs. Arm A 9.9% (n=8) (P=0.015). Among 116 patients evaluable at week 16, 33.3% (20/60) and 14.3% (8/56) achieved MER, respectively (P=0.018), with a median response duration of 25.4 months vs. not reached in Arm A responders. Response to combined treatment was associated with baseline CD45-isoform distribution in erythroid precursors. Patients achieving MER had a significantly lower CD45 RA+RB:RO ratio (median, 1.51) compared to non-responders (median, 4.21; P=0.04), favoring homo-dimerization of the short CD45-RO isoform and inhibition of phosphatase activity. MER rate in Arm B patients with a low isoform ratio (< median) was 72.7% vs. 18.2% in the high ratio group (P=0.03). Thirty-four Arm A non-responders crossed over to combination-therapy with only 1 MER. There was no difference in the frequency or distribution of >Grade 3, non-hematologic AEs. Conclusions: LEN restores sensitivity to rhEpo in Epo-refractory LR-non-del(5q) MDS patients to yield durable and significantly higher rates of erythroid response to combination treatment without added toxicity. Erythroid CD45 isoform profile may serve as a response biomarker for selection of candidates for combination therapy. Disclosures Bennett: Celgne: Membership on an entity's Board of Directors or advisory committees. Altman:Syros: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Schiffer:Teva: Other: DSMB member; BMS: Research Funding; Ariad: Research Funding; Pfizer: Other: DSMB member.

Room-temperature single-crystal X-ray studies are recorded for 2- and 4-nitrophenoxide salts of silver(I) and thallium(I), M(2-np) and Tl(4-np) (anhydrous), and Ag(4-np).H2O. Ag(2-np) is monoclinic, P21/c, a 9·012(4), b 5·743(5), c 12·594(5) Å, β 104·34(4)°, Z = 4; conventional R on |F| was 0·042 for No 1378 independent ‘observed’ (I > 3σ(I)) reflections. Tl(2-np) is monoclinic, C2/c, a 27·250(3), b 3·712(1), c 15·147(3) Å, β 114·41(1)°, Z = 8, R 0·025 for No 1346. Ag(4-np).H2O is monoclinic, P21/a, a 5·613(6), b 13·191(7), c 9·844(5) Å, β 92·50(6)°, Z = 4, R 0 ·033 for No 622. Tl(4-np) is tetragonal, I 41/a, a 18·037(8), c 8·979(8) Å, Z = 16, R 0·043 for No 924. An acid salt of the latter, Tl(4-np).(4-npH)3, triclinic, P-1, a 11·861(8), b 11·45(1), c 11· 423(1) Å, α 114·00(6), β 109·78(5), γ 96·87(7)°, Z = 2, R 0·042 for No 3814, is isomorphous with its rubidium analogue. These comprise a novel array of structures: although the structures of the silver(I) complexes are two-dimensional sheets with familiar head-tail connecting ligands, a strong silver-aromatic carbon interaction is found in Ag(2-np) (Ag–C 2·496(5) Å). Tl(2-np) and Tl(4-np) both present unusual forms related to the stair-polymer and cubane adducts found in 1 : 1 coinage metal(I)/halide-unidentate nitrogen base adducts; Tl(2-np) is a double-stranded stair-polymer array, with the phenoxide oxygen atoms incorporated in the stair and the nitro oxygen atoms linking successive thallium atoms. The structure of Tl(4-np) is based on a tetranuclear cubane motif of -4 symmetry, [Tl(O-phenoxide)]4, these being linked into a three-dimensional network by further Tl · · · O-nitro interactions from adjacent units. The structure of silver(I) picrate monohydrate, isomorphous with its sodium counterpart, is also recorded: monoclinic, C 2/m, a 12·818(7), b 20·208(8), c 3· 741(1) Å, β 88·25(3)°, Z = 4, R 0·047 for No 1042, void of any significant Ag · · · C contacts.

BackgroundEosinophilic granulomatosis with polyangiitis (EGPA) is a heterogeneous disease with a variable, relapsing course. Real-world data regarding specific characteristics of relapses in this patients are scarce.ObjectivesWe aim to describe and analyse the relapses presented in a single-center cohort of EGPA patients.MethodsMedical charts of EGPA patients regularly controlled at our department were reviewed to describe demographics, clinical characteristics at diagnosis and at relapse, number of relapses, disease activity at relapse, treatment of the relapses, damage accrual, and laboratory results. The definition of relapse was the same used in the MIRRA trial: a) active vasculitis (BVAS >0), b) active asthma or active nasal or paranasal sinus disease leading either to an increase in the dose of prednisone > 4mg/day, initiation of or increase in immunosuppressive therapy, or hospitalization[1].ResultsA total of 59 EGPA patients were followed regularly at our department. All fulfilled either ACR 1990 and/or MIRRA trial inclusion criteria for EGPA. The mean age at diagnosis was 51.6 years, 59.3% were female and 91.5% were Caucasian. Among them, 76.3% were ANCA positive and 23.7% were ANCA negative. The mean time of follow-up was 10.7 ± 8.2 years. During the follow-up, a total of 324 relapses were diagnosed in 47 patients, with 12 patients experiencing no relapse. A relapse-free survival analysis showed that 35% of patients had a relapse in the first year, 51% at 2 years, 59% at 3 years and 64% at 5 years. The main clinical symptoms at relapse were asthma (in 248 flares, 76.5% of them), followed by rhinitis (100, 30.9%), sinusitis (60, 18.5%), skin involvement (19, 5.9%), fever (18, 5.6%), arthralgia (16, 4.9%), lung infiltrates (15, 4.6%), myalgia (12, 3.7%), peripheral nervous system involvement (11, 3.4%), cardiac involvement (6, 1.9%), arthritis (3, 0.9%), weight loss (2, 0.6%), alveolar hemorrhage (2, 0.6%), gastrointestinal involvement (2, 0.6%) and central nervous system involvement (2, 0.6%). No renal involvement was seen at flare. Median BVAS at relapse was 2 (IQR 2-4, range 0-28). When determined, median blood eosinophils at relapse were 500 cells/mm3(IQR 100-1000) and in 73% of the measures eosinophils did not reach 10% of the total leucocyte count. Median CRP was 0.6 mg/dl (IQR 0.2-2.4) and median ESR 14 mm/h (IQR 8-32). ANCA were measured in 37 relapses only, being positive in 14 of them. The median prednisone dose at relapse was 6.25mg/day and the median increase for treating the relapse was 30 mg/day. In 53 relapses, patients were already taking azathioprine. In 47, mepolizumab. In 36, methotrexate. In 11, mofetil mycophenolate. When comparing patients who relapsed vs. those who did not, and those who relapsed less than 1 time every 2 years vs those who relapsed more than 1 time every 2 years, no predictive factor of relapse was seen.ConclusionAfter a mean follow-up of 10.7 years, 324 relapses were diagnosed in 59 patients. First relapse occurred in 35% of patients at 1 year and in 64% at 5 years. The clinical spectrum of relapses was predominantly asthma, followed by ear, nose and throat, being vasculitic manifestations much less frequent. No predictive factors of relapse were identified.References[1]Wechsler ME et al. N Engl J Med. 2017.Figure.AcknowledgementsThis study was supported by Instituto de Salud Carlos III (ISCIII) through the project PI18/00461, part of Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016, and co-funded by the European Union. Roberto Ríos-Garcés is a recipient of a Río Hortega grant from Instituto de Salud Carlos III, Spain (CM19/00032).Disclosure of InterestsRoberto Ríos-Garcés: None declared, José Hernández-Rodríguez: None declared, Sergio Prieto-González: None declared, Maria C. Cid Paid instructor for: Vifor and GSK, Consultant of: GSK, Abbvie and Janssen, Grant/research support from: Kiniksa, Georgina Espígol-Frigolé Consultant of: Janssen.

Sustained visible emission in the region 440–850 nm from the B → X system of IF is observed when a gas phase mixture (~0.5 mbar) of an alkyl iodide with F2 in He is photolysed at 248 nm by a KrF laser. The total intensity and decay rate of the IF(B) emission is a strong function of the identity of the alkyl iodide and can be correlated with the 248 nm photon yields for the production of I*(2p1/2). The half-lives for the IF(B) decays range from 5 μs for t-C4H9I to 770 μs for n-C3F7I. Decay curves for the I*(2p1/2) concentrations are also measured by atomic fluorescence. The mechanism for IF(B) formation in these systems is discussed and it is suggested that IF(B) is produced either by a recombination process involving I* and F atoms or by multistep collisional excitation of ground state IF(X) by I*. The F atoms can be produced following the photolysis pulse by the reaction of the alkyl radical with molecular fluorine and IF(X) can result either from the reaction of F atoms with the alkyl iodide or from a dark reaction between molecular fluorine and the alkyl iodide.

Background: BCL2, a key protein regulator of the apoptotic pathway, is constitutively expressed in various malignancies, which is a hallmark of cancer cell. BCL2 inhibitors have been shown to be safe and effective and are approved for the treatment of patients with chronic lymphocytic leukemia/small cell lymphoma (CLL/SLL) or acute myeloid leukemia (AML). Venetoclax, the first and only approved BCL2 inhibitor, is associated with gastrointestinal toxicities and tumor lysis syndrome (TLS). Therefore, ICP-248 was developed as a potent and highly selective inhibitor of BCL2 and has shown antitumor activity superior to venetoclax in preclinical studies. Preclinical studies of ICP-248 have demonstrated favorable pharmacokinetics profile, broad safety window and excellent safety profile, as well as synergistic effect in anti-tumor activity in combination with Orelabrutinib, a novel and highly selective BTK inhibitor. Methods: ICP-CL-1201 is a phase I study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ICP-248 in patients with relapsed or refractory B-cell malignancies ( ClinicalTrials.gov ID: NCT05728658). The study will be conducted in 2 parts. Part 1 will evaluate ICP-248 as monotherapy at the target dose of 100mg, 200mg, 300mg, 400mg, 500mg and 600mg (once daily and 28 days per cycle) and will explore different ramp-up dosing strategies. Part 2 will evaluate ICP-248 in selected and proposed indications. The dose escalation in Part 1 will follow the 3+3 design with dose-limiting toxicity (DLT) observation window with 49 days. Eligible patients include those with CLL/SLL and B-cell non-Hodgkin lymphomas (NHLs) who failed on available therapy. Key exclusion criteria include CNS involvement, prior exposure to BCL2 inhibitors and clinically significant cardiovascular disease. Adverse events (AEs) are reported per common terminology criteria for AEs (CTCAE) v5.0. Efficacy was evaluated according to the Lugano 2014 or International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria. Minimal residual disease was evaluated with flow or next generation sequencing. Results: As of 30 th July, 2023 (data cutoff date) 3 patents (mantle cell lymphoma [MCL], SLL and CLL) had been enrolled at the dose level of 100 mg QD; age ranging from 53 to 68; follow-up ranging from 1.9 to 4.7 months); median of prior regimen numbers was 3 (range, 1-3; 2 out 3 patients failed on zanubrutinib or pirtobrutinib). ICP-248 demonstrated a favorable PK profile, approximate dose proportionality was observed across the ramp-up stage. No DLTs and SAEs were observed. All the AEs were grade 1 to 2 (mainly neutropenia) without dose interruption and modifications. No TLS including laboratory TLS was observed. Two patients with MCL and SLL were assessed as complete response (CR) at the end of cycle 2, and the CLL patient was assessed as stable disease without sign and symptom of disease and recovering hematology. Undetectable MRD was confirmed in the patient with SLL and MCL. Conclusions: Preliminary results suggest that ICP-248 is safe and well tolerated in relapsed or refractory B-cell malignancies. The favorable clinical pharmacological and safety profiles support current dose ramp up strategy. Preliminary efficacy data demonstrated good response with deep remission. Further assessment of safety and efficacy with additional dose levels and dosing strategies will be pursued in expanded patient population and in the combination with orelabrutinib.

Measurements of the gas phase proton transfer equilibrium [1]: AH + B− = A− + BH with a pulsed electron high pressure mass spectrometer (PHPMS) lead to [Formula: see text] and [Formula: see text] data. These relative acidities are converted to the absolute acidities [2]: AH = A− + H+bycalibration of the relative [Formula: see text] and [Formula: see text] scale to the known values for [Formula: see text] and [Formula: see text] of a reference compound(HCl). Earlier determinations that included 16 aliphatic AH are extended in the present work and provide data for 47 aliphatic carboxylic acids. These include halogen, OH, CH3O, C2H5O, PhO, and NH2 substituted acetic acids, and halogen substituted, unsaturated, and cyclic RCO2H of higher carbon number. The effects of the various substituents on the gas phase acidity are briefly examined. Keywords: acidities in gas phase, proton transfer equilibria, ion-molecule equilibria, mass spectrometry.

Abstract Background: ARQ 092 is an oral allosteric, potent and selective AKT inhibitor with in vitro and in vivo activity in solid and hematological tumors. ARQ 092-101, the first clinical trial of ARQ 092, has enrolled more than 100 subjects with advanced solid tumors or recurrent malignant lymphoma. As reported previously, the dose escalation portion of the study has been completed and two dosing schedules (intermittent and weekly), are recommended for phase 2 studies. The recommended phase 2 dose (RP2D) for the intermittent dosing schedule is 200 mg once daily (QD) (one week on, one week off) and for the weekly dosing schedule is 300 mg twice daily (BID) (one day on, six days off). [1, 2] Enrollment in an expansion cohort at RP2Ds is ongoing. Here we report the results from 11 subjects with lymphoma/CLL. Material and Methods: Subjects with lymphoma/CLL have been enrolled and treated in the dose escalation and expansion cohorts with intermittent or weekly dosing schedule at the RP2Ds. Tumor responses for subjects with lymphoma were evaluated based on the Revised Response Criteria for Malignant Lymphoma. Adverse events were evaluated based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Blood samples were collected for PK analysis. Archival or biopsy tumor tissue samples were collected for genetic analysis. Results: As of 15 Jun 2015, 11 subjects with lymphoma/CLL (73% male; median age 78 years; 5 follicular, 3 mantle cell, 2 diffuse large B cell, 1 CLL; 4 in dose escalation cohorts, 7 in expansion cohort) have been enrolled and treated at initial doses of 120 to 270 mg QD intermittently (n=7) or 300 mg BID weekly (n=4). All subjects have received at least one prior systemic therapy (median 2, range 1-6). Median duration on study treatment for all 11 subjects was 8 weeks (range 1 to 30 weeks). One subject with CLL and two with follicular lymphoma experienced durable partial responses, respectively with times to response of 8, 8 and 24 weeks and response durations of 16, 8+, and 2+ weeks. The two follicular PR subjects, one of whom had an AKT1 (E17K) mutation, remain on study treatment. In addition, one subject with follicular and one with mantle cell lymphoma experienced stable diseases. Four subjects experienced progressive diseases and two were not evaluable for tumor responses due to early consent withdrawal and clinical disease progression. Table 1. Common drug-related adverse events (≥10%) included macula-papular rash 45%, hyperglycemia 36%, mucosal inflammation 18% and stomatitis 18%. Response Follicular N=5 CLL N=1 Mantle cell N=3 Diffuse large B cell N=2 Total N=11 PR 2 1 3 SD 1 1 2 PD 1 2 1 4 NE 1 1 2 ORR 40% 100% 0% 0% 27% DCR 60% 100% 33% 0% 45% Conclusions: The safety profile of lymphoma subjects is consistent with subjects with solid tumors enrolled in this study. Preliminary signs of single agent activity have been documented with 3 PRs in heavily pretreated lymphoma/CLL including one with AKT1 (E17K) mutation. [1] First-in-human study with ARQ 092, a novel pan AKT-inhibitor: Results from the advanced solid tumors cohorts. M. Saleh et al., Abstract LB-197, AACR 104th Annual Meeting, 6-10 Apr 2013. Washington, D.C. U.S. [2] First-in-human study with ARQ 092, a novel pan AKT-inhibitor, in subjects with advanced solid tumors or recurrent malignant lymphoma. M. Saleh et al., Abstract 320, EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics , 18-21 Nov 2014, Barcelona, Spain Disclosures Harb: Onyx Pharmaceuticals: Consultancy. Chai:ArQule, Inc.: Employment. Larmar:ArQule, Inc.: Employment. Abbadessa:ArQule, Inc.: Employment. Schwartz:ArQule, Inc.: Employment.

Abstract Introduction Somatization, the experience of having somatic symptoms (e.g., pain, fatigue, dizziness) with resultant psychological distress, has been described among working adults and contributes to work-related absences. Whether somatization affects employees’ sleep quality and sleep duration is unclear. We examined the association of somatization with sleep quality and duration. Methods Data came from the 4th wave of the multi-site Worksite Blood Pressure Study, which assessed psychological factors and ambulatory blood pressure. A total of 472 participants without major cardiovascular disease from 10 worksites in NYC were recruited across 4 waves and ~11 years. At Wave 4, participants completed the Brief Symptom Inventory (BSI) and a sleep questionnaire derived from the Sleep Heart Health Study. Items from the BSI were averaged and T-scored (normed to mean=50, SD=10). Items assessing sleep quality were averaged (higher scores indicated worse sleep quality). Weekday sleep duration was also reported using a one-time sleep diary. Analyses were restricted to participants providing complete data (N= 238). Linear regression models were specified predicting (1) sleep quality and, separately (2) sleep duration from somatization. Covariates were age, sex, race/ethnicity, body mass index, marital status, years of education, family income, employment status, and average work hours per week. Results Of the 238 participants, 79.8% were male, 11.8% were Black, 5.9% were Hispanic/Latinx, and 76.5% were married. Median family income was $70,000-$79,999. Mean age was 52.4 years (SD=8.1), mean years of education was 17.9 (SD=3.1), mean body mass index was 27.9 kg/m2 (SD=3.8), and mean hours worked per week (among those currently employed; n=191) was 42.0 (SD=10.9). Mean somatization score was 49.5 (SD=9.3), mean sleep quality was 8.4 (SD=4.3), and mean sleep duration was 6.5 hours/night (SD=1.1). Higher somatization scores were significantly associated with worse sleep quality, B=0.15, 95% CI 0.09, 0.20, p&lt; 0.001. The association of somatization with sleep duration was not significant, B= 0.01, 95% CI -0.00, 0.02, p=0.18. Conclusion There was an association between somatization and sleep quality but not with sleep duration. Future research should examine whether treatment modalities for somatization among working adults improve sleep quality and overall occupational health. Support (if any) P01HL47540, NIH/NHLBI K23HL141682

AbstractLet $0\lt a\lt b\lt 1$ and let $T$ be the doubling map. Set $ \mathcal{J} (a, b): = \{ x\in [0, 1] : {T}^{n} x\not\in (a, b), n\geq 0\} $. In this paper we completely characterize the holes $(a, b)$ for which any of the following scenarios hold: (i) $ \mathcal{J} (a, b)$ contains a point $x\in (0, 1)$; (ii) $ \mathcal{J} (a, b)\cap [\delta , 1- \delta ] $ is infinite for any fixed $\delta \gt 0$; (iii) $ \mathcal{J} (a, b)$ is uncountable of zero Hausdorff dimension; (iv) $ \mathcal{J} (a, b)$ is of positive Hausdorff dimension. In particular, we show that (iv) is always the case if $$\begin{eqnarray*}b- a\lt \frac{1}{4} { \mathop{\prod }\nolimits}_{n= 1}^{\infty } (1- {2}^{- {2}^{n} } )\approx 0. 175\hspace{0.167em} 092\end{eqnarray*}$$ and that this bound is sharp. As a corollary, we give a full description of first- and second-order critical holes introduced by N. Sidorov [Supercritical holes for the doubling map. Preprint, see http://arxiv.org/abs/1204.1920] for the doubling map. Furthermore, we show that our model yields a continuum of ‘routes to chaos’ via arbitrary sequences of products of natural numbers, thus generalizing the standard route to chaos via period doubling.

Ephoron album was the dominant summer mayfly in shallow riffles in the agricultural zone of the Valley River, Manitoba, in 1982 and 1983. There was one generation per year; eggs deposited in August hatched in late May of the following year and nymphs developed rapidly during the summer months. The eggs required a cold period to promote hatching and hatching success of eggs treated in the laboratory at −2 °C for varying periods of time was positively correlated to the length of the exposure period. No eggs hatched following exposure to 4 or 10 °C. Production for 1982 was estimated by four methods for the production interval of only 72 days: the instantaneous growth rate method (1.32 ± 0.44 g fresh dry weight∙m−2∙year−1), the Allen curve method (1.32 g∙m−2∙year−1), the removal – summation method (1.43 ± 0.41 g∙m−2∙year−1), and the size–frequency method (1.48 ± 0.51 g∙m−2∙year−1). Confidence intervals (95%) were calculated using the method of C. C. Krueger and F. B. Martin for the size–frequency estimate of production and by bootstrapping for the removal–summation and instantaneous growth estimates.

Intravaginal progesterone (P4) releasing devices are widely used in hormonal protocols for fixed-time artificial insemination (FTAI). To reduce production cost in Brazilian farms, after first use these devices are currently reused once or twice, providing good reproductive efficiency in cattle. The aim of this study was to compare P4 plasma concentrations among time in ovariectomized cows receiving 3 different commercially available devices: Sincrogest® (SIN, 1 g of P4), Cronipres® (CRO, 1 g of P4 and 3 rings of 0,1 g of P4 for the third use) and Primer® (PRI, 1 g of P4). For each type, new (1st use, n = 2), once-used (2nd use, n = 2) and twice-used (3rd use, n = 2) devices were tested. Blood samples were collected at times 0 (before device insertion), 2, 4, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, and 192 h (Day 0 to Day 8). P4 plasma concentrations were measured by radioimmunoassay and the averages for each experimental group were submitted to analysis of variance adding repeated-measures in time factor. Comparisons were made among 3 types of device in each of 3 uses. P4 concentrations (ng mL–1) and standard deviation in the periods in which there was statistical difference (P < 0.05; a,b,cdifferent letters in the same period differ statistically) were as follows: First use: the 3 brands did not differ during the test and in Day 8 P4 levels remained near 2 ng mL–1. Second use: 2 h – SIN (3.7 ± 0.8)ab, CRO (5.4 ± 0.4)a, PRI (3 ± 0.4)b; 6 h – SIN (4 ± 0.5)a, CRO (4.9 ± 0.2)a, PRI (2.9 ± 0.3)b; and 144 h – SIN (2.2 ± 0.4)b, CRO (0.8 ± 0.3)a, PRI (1.3 ± 0.1)ab. On Day 8, Primer® and Sincrogest® P4 levels remained between 1 and 2 ng mL–1, whereas Cronipres® levels remained below 1 ng mL–1. Third use: 2 h – SIN (3.2 ± 0.04)b, CRO (7.9 ± 0.5)a, PRI (2.4 ± 0.2)b; 4 h – SIN (2.4 ± 0.4)b, CRO (5.4 ± 0.2)a, PRI (2.8 ± 0.3)b; 6 h – SIN (2.5 ± 0.8)b, CRO (7.4 ± 1.8)a, PRI (2.7 ± 0.5)b; 8 h – SIN (2.3 ± 0.2)b, CRO (5.3 ± 1.4)a, PRI (2 ± 0.1)b; 10 h – SIN (3.1 ± 0.2)b, CRO (5.5 ± 0.5)a, PRI (2.5 ± 0.2)b. 12 h – (2.7 ± 1.3)b, CRO (5.8 ± 0.6)a, PRI (2.2 ± 0,1)b; and 120 h – SIN (1.3 ± 0.2)a, CRO (0.9 ± 0.2)b, PRI (0.8 ± 0.04)b. On Day 8, all levels remained below 1 ng mL–1. In this study, P4 released concentrations differed in 3 of 15 periods in second-use device tests. In third-use device tests, Cronipres® released significantly more P4 from 2 to 12 h. It is unclear, however, if greater release of P4 in the first 24 h is advantageous, considering that Sincrogest and Primer® P4 concentrations remained above 2 ng mL–1. Additionally, it was noticed that P4 release decreased according to the number of previous uses. These findings suggest a variety of possibilities matching different device brands and different animal categories depending on animal steroid metabolism rate and consequent need for exogenous P4 supplementation. However, for such a claim, further studies on this topic are needed. Supported by FAPESP – Fundação de Amparo à Pesquisa do estado de São Paulo.

Protection of suspect rights related to human rights protection. In the Criminal Procedure Code Investigators are given the authority for forced attempts in the form of arrest, detention, confiscation and so on. If a person is named a suspect, he is confronted by the investigator whose job it is to find, collect evidence about the criminal act that occurred. The purpose of this study 1. To analyze the determination of suspects 2. To analyze the obstacles faced by law enforcers and their solutions. The research methods used are 1. Approach method 2. Type or research specifications 3. Types of data and data sources 4. Data collection methods 5. Data analysis methods. And the conclusions in this study are 1. The implementation of the determination of the suspect, that the legality of the determination of the suspect in the investigation process can be recognized if the rights of the suspect are fulfilled. a. The investigator can only determine the status of a suspect after the results of the investigation have obtained sufficient initial evidence of at least 2 (two) types of evidence. b. to determine sufficient preliminary evidence by means of a case title. 2. Constraints faced by law enforcers related to the determination of suspects and the solutions are a. suspects often provide complicated statements in front of investigators and removing evidence will take time to reveal the criminal acts committed. b. the summons of witnesses, victims and experts are often not on time c. Lack of budget support. The solution to these constraints is a. in the future, operational funds for witnesses who are summoned are needed to provide information so as to facilitate the investigation process. b. the need for regulations that limit the length of time a person has the status of a suspect to avoid potential human rights violations and to provide legal certainty for justice seekers.

A number of Democritean fragments may loosely be called ‘political’, concerned as they are with questions to do with the π⋯λις – with government, with the duties and dangers of public office, with justice, law and order. The majority of them (B 248–66) have been preserved in chapters of Stobaeus’ anthology entitled ‘On the State’ (iv 1), ‘On Laws and Customs’ (iv 2), ‘On Government’ (iv 5).

The flat-top pyramid patterned sapphire substrates (FTP-PSSs) have been prepared for the growth of GaN epilayers and the fabrication of lateral-type light-emitting diodes (LEDs) with an emission wavelength of approximately 470 nm. Three kinds of FTP-PSSs, which were denoted as FTP-PSS-A, FTP-PSS-B, and FTP-PSS-C, respectively, were formed through the sequential wet etching processes. The diameters of circle areas on the top regions of these three FTP-PSSs were 1, 2, and 3 μm, respectively. Based on the X-ray diffraction results, the full-width at half-maximum values of rocking curves at (002) plane for the GaN epilayers grown on conventional sapphire substrate (CSS), FTP-PSS-A, FTP-PSS-B, and FTP-PSS-C were 412, 238, 346, and 357 arcsec, while these values at (102) plane were 593, 327, 352, and 372 arcsec, respectively. The SpeCLED-Ratro simulation results reveal that the LED prepared on FTP-PSS-A has the highest light extraction efficiency than that of the other devices. At an injection current of 350 mA, the output powers of LEDs fabricated on CSS, FTP-PSS-A, FTP-PSS-B, and FTP-PSS-C were 157, 254, 241, and 233 mW, respectively. The results indicate that both the crystal quality of GaN epilayer and the light extraction of LED can be improved via the use of FTP-PSS, especially for the FTP-PSS-A.

Abstract: The use of dyes in food today is very apprehensive. Many foods contain dyes that are prohibited to be used in food. The addition of the dye will have an impact on health. The aim of this research was to know the effectiveness of the administration of extra virgin olive oil to the number of granulosa cell and 17β estradiol level of Rats exposed by rhodamin B. The design of this study was true experimental with post test approach of group design control. The subject of the study was 30 white mice Rattus novergicus in the age of 12 weeks weight average 220 grams and in healthy condition. Rats were divided into 5 groups. Control group without treatment, positive control treatment with rhodamine B 18 mg / 200gr. Treatment 1 administration of rhodamine B 18 mg / 200gr and EVOO (Extra Virgin Olive Oil) 1.5 ml / KgBB, treatment 2 rhodamine B 18 mg / 200gr and EVOO 3 ml / KgBB, treatment 3 rhodamine B 18 mg / 200gr and EVOO 4,5 ml / KgBB. The number of granulosa cells was determined by HE staining, the level of 17β estradiol with ELISA. The data was analyzed by Kruskal Wallis test, Spearman Rank and Simple Linear Regression with degree of significance α <0.05. The average number of granulosa cells and the lowest levels of 17β estradiol were found in the positive control group and the highest average was in the treatment group 3. There was one dose that could significantly increase granulosa cells and the beta estradiol levels compared with the treatment group the other with niali α <0.05. The administration of EVOO affected the number of granulosa cells and the levels of 17β estradiol in rats exposed by rhodamine B.Keyword: granulosa cells, estradiol, rhodamin B, oxidative stress

Efficient syntheses of the cis and trans isomers of [OsCl2(Me2SO)4] are reported. While a structural study of thetrans isomer confirms the spectroscopically assigned all-S-bound Me2SO configuration, a crystallographic determination of the cis isomer reveals a previously unheralded all-S-bound Me2SO geometry, in contrast to the spectroscopically inferred configuration predominant in solution which has one O-bound ligand. Fortrans-[OsCl2(Me2SO)4], crystals are tetragonal, space group I 4/m, with a 9·092(2), c 11·212(3) Å, Z 2, 566 unique reflections (34 parameters), converging at R 0·026 and Rw 0·032. For cis-[OsCl2(Me2SO)4], crystals are triclinic, space group P-1, with a 8·193(2), b 8·941(3), c 13·837(3) Å, α 79·77(2), β 79·91(2), γ 65·03(2)°, Z 2, 4152 unique reflections (173 parameters), converging at R 0·021 and Rw 0·018.

We have previously described increased fasting plasma glucose levels in patients with normocalcemic primary hyperparathyroidism (NPHPT) and co-existing prediabetes, compared to prediabetes per se. This study evaluated the effect of parathyroidectomy (PTx) (Group A), versus conservative follow-up (Group B), in a small cohort of patients with co-existing NPHPT and prediabetes. Sixteen patients were categorized in each group. Glycemic parameters (levels of fasting glucose (fGlu), glycosylated hemoglobin (HbA1c), and fasting insulin (fIns)), the homeostasis model assessment for estimating insulin secretion (HOMA-B) and resistance (HOMA-IR), and a 75-g oral glucose tolerance test were evaluated at baseline and after 32 weeks for both groups. Measurements at baseline were not significantly different between Groups A and B, respectively: fGlu (119.4 ± 2.8 vs. 118.2 ± 1.8 mg/dL, p = 0.451), HbA1c (5.84 ± 0.3 %vs. 5.86 ± 0.4%, p = 0.411), HOMA-IR (3.1 ± 1.2 vs. 2.9 ± 0.2, p = 0.213), HOMA-B (112.9 ± 31.8 vs. 116.9 ± 21.0%, p = 0.312), fIns (11.0 ± 2.3 vs. 12.8 ± 1.4 μIU/mL, p = 0.731), and 2-h post-load glucose concentrations (163.2 ± 3.2 vs. 167.2 ± 3.2 mg/dL, p = 0.371). fGlu levels demonstrated a positive correlation with PTH concentrations for both groups (Group A, rho = 0.374, p = 0.005, and Group B, rho = 0.359, p = 0.008). At the end of follow-up, Group A demonstrated significant improvements after PTx compared to the baseline: fGlu ((119.4 ± 2.8 vs. 111.2 ± 1.9 mg/dL, p = 0.021) (−8.2 ± 0.6 mg/dL)), and 2-h post-load glucose concentrations ((163.2 ± 3.2 vs. 144.4 ± 3.2 mg/dL, p = 0.041), (−18.8 ± 0.3 mg/dL)). For Group B, results demonstrated non-significant differences: fGlu ((118.2 ± 1.8 vs. 117.6 ± 2.3 mg/dL, p = 0.031), (−0.6 ± 0.2 mg/dL)), and 2-h post-load glucose concentrations ((167.2 ± 2.7 vs. 176.2 ± 3.2 mg/dL, p = 0.781), (+9.0 ± 0.8 mg/dL)). We conclude that PTx for individuals with NPHPT and prediabetes may improve their glucose homeostasis when compared with conservative follow-up, after 8 months of follow-up.

Background:Belimumab (BLM), a recombinant human monoclonal antibody directed against B-cell activating factor (BAFF), is the first approved biological agent for patients with active severe systemic lupus erythematosus (SLE) and lupus nephritis (LN). There is clinical evidence that combining BLM with B cell depleting therapy can ameliorate disease activity in severe, refractory SLE patients1. Although BLM is a B cell directed therapy and has been shown to significantly decrease total B cells, flow cytometry observations suggest a rapid increase of circulating memory B cells (MBC)2.Objectives:To investigate dynamics of B-cell subsets in SLE patients treated with or without BLM, with a focus on assessing MBC characteristics.Methods:Extensive B cell subset phenotyping was performed by high-sensitivity (HS) flow cytometry (acquisition of 107 leukocytes; per EuroFlow protocols3) on samples from active LN or SLE patients with major organ involvement treated with standard of care (SOC) consisting of high dose steroids and mycophenolate mofetil combined with or without the addition of BLM. MBC gene expression profiles were characterized with single-cell RNA and V(D)J sequencing (ScRNA-SEQ).Results:By employing HS flowcytometry, we established that the absolute increase in circulating MBC in SLE and LN patients was significant for patients who initiated BLM (Figure 1). The increase was observed in a broad range of MBC subsets (Unswitched, IgG1+, IgG2+, IgA1+, IgA2+) at 2 and 4 weeks following initiation of BLM treatment. This rise in MBC could hypothetically be attributed to either proliferation of blood MBC, BLM induced migration of tissue-resident MBCs or BLM related retention of tissue-destined MBC in the blood. ScRNA-SEQ analysis of cell cycle gene-expression was performed and established in both groups a non-proliferating phenotype [in approximately ~94%] of MBC post-treatment, including absence of MKI67 as active proliferation marker. Clonal diversity analysis comparing week 2 with baseline revealed an unexpected decrease of the largest MBC clones in BLM, whereas no change in clonality was observed with SOC alone. Together these data indicate that proliferation is unlikely to be responsible for the observed increase in MBC by BLM. Furthermore, a clear difference was found in gene-expression levels between both treatment groups: BLM was responsible for the upregulation of 72 vs 10 genes in SOC, likewise 162 vs 32 genes were downregulated. Most importantly, a significant downregulation of the migration genes SELL (CD62L), CCR7, ITGB1, RAC2 and ICAM2, were specifically seen in BLM treated patients. This may reflect disrupted lymphocyte trafficking, preventing MBCs from transmigrating from the blood into tissue owing to reduced migration molecules, or preventing MBCs from being retained at the tissue level owing to reduction in tissue adhesion proteins.Conclusion:The addition of BLM to SOC significantly increases MBCs in patients with SLE independently of proliferation, accompanied by a strong modulation of gene expression, including reduced expression of migration markers pointing towards disrupted lymphocyte trafficking. These data may have important implications for improving treatment strategies in patients with LN or severe SLE, as a deeper depletion of autoreactive MBCs could be established by adding B-cell-depleting therapy after the initiation of BLM.Figure 1.Change in pre-germinal center and memory B cell counts from baseline to week 4 of patients with SLE or LN treated with SOC (n=8) or SOC+BLM (n=11).References:[1]Arends EJ et al. Long-term effects of combined B cell immunomodulation with rituximab and belimumab in severe, refractory systemic lupus erythematosus: 2-year results. Nephrol Dial Transplant. 2020 Jun 27 gfaa117.[2]Stohl W et al. Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with SLE. Arthritis Rheum. 2012;64(7):2328-2337.[3]Blanco et al, Age-associated distribution of B and plasma cell subsets in peripheral blood - J Allergy Clin Immunol 2018 141 2208-2219.Disclosure of Interests:Eline J. Arends: None declared, Mihaela Zlei: None declared, Christopher M. Tipton: None declared, Zgjim Osmani: None declared, Sylvia Kamerling: None declared, Ton Rabelink: None declared, Ignacio Sanz: None declared, Jacques J.M. van Dongen Paid instructor for: BD Biosciences: Educational Services (fees for LUMC), Consultant of: BD Biosciences and Cytognos (fees for LUMC), Grant/research support from: GSK (flow cytometry studies for GSK BLISS-BELIEVE study NCT03312907), Cees van Kooten: None declared, Y.K. Onno Teng Consultant of: Aurinia provided financial compensation for consultancy, Grant/research support from: GSK provided belimumab for free for the Synbiose-2 clinical trial and provided an unrestricted grant to conduct the study.

This review essay uses three books to explore some aspects of Ismailism. The books are THE FATIMIDS 2. THE RULE FROM EGYPT, by Shainool Jiwa. London/New York: I. B. Tauris / The Institute of Ismaili Studies, 2023, pp. VIII + 240. ISBN: 9781780769486; COMMAND AND CREATION. A SHI‘I COSMOLOGICAL TREATISE. A Persian edition and English translation of Muḥammad al-Shahrastānī’s Majlis-i maktūb. Edited and Translated by Daryoush Mohammad Poor. London/New York: I. B. Tauris / The Institute of Ismaili Studies (Ismaili Texts and Translation Series, 25), 2021, pp. XVI + 138 + LXXXIV. ISBN: 9780755602971; and FAITH AND ETHICS: THE VISION OF THE ISMAILI IMAMAT, by M. Ali Lakhani. London/New York: I. B. Tauris / The Institute of Ismaili Studies, 2018, pp. 1 colour illustration + XXIV + 248. ISBN: 9781788312486.

Abstract To advance SARS-CoV-2 vaccines in infants younger than 5 years, we tested the efficacy of two SARS-CoV-2 vaccine platforms against challenge with the delta variant one year after immunization of infant rhesus macaques (RM). Infant RMs (n=8/ group; 2 month-old) were immunized intramuscularly at weeks 0 and 4 with 30 mg stabilized prefusion SARS-CoV-2 S-2P spike (S) protein (Washington strain) encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or 15 mg S protein mixed with 3M-052 in stable emulsion (Protein). At 1 year, vaccinated and age-matched unvaccinated RM (n=8) were challenged intranasally (106 pfu) and intratracheally (2×106 pfu) with B.1.617.2. Lung pathology was blindly assessed on day 7. Viral RNA copies of the N gene (vRNA) were measured by qPCR in nasal and pharyngeal swabs. Severe lung pathology was observed in 7 of 8 controls compared to 1 of 8 or 0 of 8 RM in the mRNA-LNP or protein group, respectively. On days 2 and 4, vRNA copies/ml were significantly higher in pharyngeal swabs of control RM (day 2: 4.2p&gt; Supported by grants from NIH PO1 AI117915

ABSTRACTOn a global and regional scale, Indonesia has one of the least environmentally sustainable economies in the Asia-Pacific region. Consumption is one of the key factors contributing to environmental degradation. By using materialism and environmental knowledge as mediators, this study aimed to understand how religiosity affects ethical consumption. This research used quantitative methods with structural equation modeling (SEM) analysis techniques based on partial least squares (PLS). The data came from a questionnaire distributed online. 153 valid questionnaires were selected for analysis. All respondents came from Indonesia, were adults (from 18 years old), and were Muslims. Findings show that religiosity influences ethical consumption, materialism, and environmental knowledge. This research also reveals that materialism and environmental knowledge influence ethical consumption, as well as the mediating effect of materialism and environmental knowledge on the influence between religiosity and ethical consumption. So, all hypotheses from this research can be accepted. These findings contribute theoretically to explaining the relationship between religiosity, materialism, environmental knowledge, and ethical consumption. Thus, this findings contribute to the field of Islamic economics. Practically, the findings of this research can help marketers formulate communication strategies that take into account the level of religiosity of consumers in Indonesia. Marketers must avoid unethical practices to encourage ethical consumption.Keywords: Religiosity, ethical consumption, materialism, environmental knowledge ABSTRAKPada skala global dan regional, Indonesia merupakan salah satu negara dengan perekonomian paling tidak ramah lingkungan di kawasan Asia-Pasifik. Konsumsi merupakan salah satu faktor utama yang berkontribusi terhadap degradasi lingkungan. Dengan menggunakan materialisme dan enviromental knowledge sebagai mediator, penelitian ini berupaya memahami bagaimana religiosity mempengaruhi ethical consumption. Penelitian ini menggunakan metode kuantitatif dengan teknik analisis Structural Equation Model (SEM) berbasis Partial Least Square (PLS). Data berasal dari kuesioner yang disebarkan online. 153 kuesioner yang valid dipilih untuk analisis. Seluruh responden berasal dari Indonesia, dewasa (mulai 18 tahun) dan beragama Islam. Temuan menunjukkan bahwa religiosity berpengaruh terhadap ethical consumption, materialism, dan environmental knowledge. Selain itu juga diketahui bahwa materialism dan environmental knowledge berpengaruh ethical consumption, serta adanya efek mediasi dari materialism dan environmental knowledge pada pengaruh antara religiosity dan ethical consumption. Sehingga, semua hipotesis penelitian ini dapat diterima. 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AbstractNew and previously existing photometric colors and spectroscopic H and He line strengths are used to compare CV disk systems below the period gap (P=80–130 min) with those directly above (P=190–240 min). Significant differences are found in the mean U-B,V-J colors and in the Hβ equivalent widths on the 2 sides of the gap. A detailed comparison from UV-IR of 3 high inclination novalike systems with periods near 3.3 hr (PG1012−029, PG1030+590 and V1315 Aql) shows similar continuum distributions (and implied mass accretion rates) but large differences in high excitation lines (HeII1640,4686;CIV1550).

AIM: The aim of the study was to investigate the effectiveness of using micro-osteoperforations (MOPs) or piezocision in accelerating tooth movement, during canine retraction, compared to standard canine retraction. PATIENTS AND METHODS: A split-mouth study design was carried out with two Groups A and B. Each group contained 10 patients; in each patient, one side was used as a control side and the contralateral side received either MOPs (Group A) or piezocision (Group B). The assessment data were collected by direct intraoral measurements, every 2 weeks, over a 3 months retraction period. RESULTS: Independent t-test, paired t-test, and ANOVA were used to analyze the results. In Group A, there was a statistically significant difference between the study and control sides (p < 0.001) with a total of 4.2 ± 0.5 mm canine retraction in the MOPs assisted canine retraction side versus a 2.8 ± 0.2 mm total canine retraction in the control side. For Group B, there was a statistically significant difference between the study and control sides (p < 0.001) with a total of 3.6 ± 0.4 mm canine retraction in the piezocision-assisted canine retraction side versus a 2.8 ± 0.2 mm total canine retraction in the control. CONCLUSION: MOPs and piezocision techniques accelerated the rate of canine retraction during orthodontic treatment, with the MOPs being slightly more effective.

BackgroundImmunotherapy with immune checkpoint inhibitors such as PD-(L)1 and CTLA-4 blocker has become an important part of cancer treatment. For the cancers resistant to these drugs, however, many other therapeutic targets are being tested to modulate the tumor microenvironment (TME) toward anti-cancer immunity. Due to the functional flexibility, macrophages play an essential role in orchestrating tissue immunity including TME. CD47 is one of the key targets that modulate macrophages, which is often overexpressed on cancer cells.1 When it binds to its receptor, SIRPα, it gives a ‘don’t-eat-me’ signal and inhibits phagocytosis of cancer cells by macrophages.2 IMC-002 is a fully human IgG4 monoclonal antibody targeting human CD47, which has been engineered to possess optimal efficacy and safety profile. IMC-002 does not induce hemagglutination and contains a hinge stabilizing S228P mutation to prevent Fab arm exchange.MethodsA series of in vitro functional assays including ligand binding, cell surface binding and phagocytosis assays were performed. Putative epitopes for IMC-002 were identified using synthetic peptide libraries. In vivo efficacy of IMC-002 was tested in human breast cancer models. Pharmacokinetic parameters and toxicity profiles were assessed in mice and cynomolgus monkeys.ResultsIMC-002 strongly bound to CD47 ligand and to various types of CD47-expressing cancer cells including solid and hematological cancers. IMC-002 also bound to human CD4 T cells and, to a lesser degree, to CD8 T cells, but not to NK or B cells. Interestingly, IMC-002 showed no binding to RBCs which highly express CD47 and thus, did not induce RBC agglutination in vitro. IMC-002 induced phagocytosis of cancer cells by human blood CD14+ monocyte-derived macrophages and strongly suppressed tumor growth in a dose-dependent manner in xenograft animal models. Treating IMC-002 with tumor antigen targeting IgG1 type therapeutics increased phagocytosis compared to single treatment. Epitope mapping analysis revealed that compared to RBC-binding anti-CD47 antibody and a natural ligand, SIRRα-Fc, IMC-002 bound to distinct parts of CD47 antigen, which may be responsible for the cell-selective binding of IMC-002. Consistent with the in vitro data, IMC-002 was well tolerated in cynomolgus monkeys with no adverse effects including hematologic toxicity at doses up to 100 mg/kg. IMC-002 showed a typical pharmacokinetic profile of therapeutic antibody with a half-life of 5–10 days. Given its differential binding profile toward tumor cells vs normal cells such as RBC, preclinical data was thoroughly analyzed to simulate human PK and to come up with the optimal first-in-human dose.ConclusionsPreclinical efficacy and safety profiles of IMC-002 provide a strong rationale for assessing therapeutic potential in clinical studies. Particularly, IMC-002 is expected to be beneficial for hematologic cancer patients because it has been engineered to minimize hematological toxicities such as anemia which is a class effect of the CD47-targeting antibodies. The first-in-human (FIH) study of IMC-002 is ongoing in the US sites. The purpose of the study is to assess the safety and tolerability of IMC-002 and determine the recommended Phase 2 dose (RP2D) of IMC-002 in subjects with metastatic or locally advanced solid tumors and relapsed or refractory lymphomas.Ethics ApprovalAll experimental procedures were performed according to the guidelines of the Institutional Animal Care and Use Committee (IACUC) of the contract research organizations.ReferencesWillingham, S. B. et al. The CD47-signal regulatory protein alpha (SIRPα) interaction is a therapeutictarget for human solid tumors. Proc. Natl Acad. Sci. USA 2012;109:6662–6667.Majeti, R. et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 2009;138:286–299.

Infectious coryza (IC) adalah penyakit bakterial yang menyerang saluran pernapasan ayam, yang dapat bersifat akut sampai kronis yang disebabkan Avibacterium paragallinarum. IC merusak saluran pernapasan bagian atas, terutama rongga hidung. Pengamatan perubahan makroskopik pada embrio yang mengalami kematian setelah inokulasi pada telur ayam berembrio (TAB) specific pathogenic free (SPF) sebagai salah satu karakteristik isolat A. paragallinarum belum banyak dilakukan. Penelitian ini bertujuan untuk mengetahui karakteristik isolat A. paragallinarum melalui inokulasi pada telur ayam berembrio TAB SPF umur 7 hari. TAB SPF umur 7 hari berjumlah 50 butir dibagi menjadi 5 kelompok masing-masing terdiri dari 10 butir yaitu kelompok kontrol negatif, A. paragallinarum serotipe A/221; serotipe B/Spross; serotipe B/2448; dan serotipe C/2447. Bakteri terlebih dahulu dikultur pada media cair dan diinkubasi selama 24 jam pada suhu 37oC. Suspensi bakteri dengan volume 0,2 ml (6x108 cfu/ml) diinjeksikan pada TAB SPF, diinkubasi pada suhu 37oC dan diamati adanya kematian sebanyak 2 kali sehari. Embrio yang mati dilakukan skoring perubahan makroskopik. Embrio yang berasal dari TAB SPF pada kelompok yang diinokulasi A. paragallinarum serotipe A/ 221, B/Spross, B/2448, and C/2447 mengalami hemoragi dan kekerdilan. Keseluruhan isolat A. paragallinarum bersifat patogen pada telur ayam berembrio.

Abstract Clonal evolution of DCIS to invasion Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5-10%) of DCIS patients develop subsequent invasive breast cancer (IBC). If not treated, at least 3 out of 4 women with DCIS will not develop IBC1-3. This implies many women with non-progressive, low-risk DCIS are likely to carry the burden of overtreatment. To solve this DCIS dilemma, two fundamental questions need to be answered. The first question is, how the subsequent IBC is related to the initial DCIS lesion. The second question is how to distinguish high- from low-risk DCIS at the time of diagnosis. This is essential to take well-informed DCIS management decisions, i.e., surgery, followed by radiotherapy in case of breast conserving treatment with or without subsequent endocrine treatment, or test whether active surveillance for low-risk DCIS is safe. How is the subsequent IBC related to the initial DCIS? The high genomic concordance in DNA aberrations between DCIS and IBC suggest that most driver mutations and CNA events are acquired at the earliest stages of DCIS initiation. It has therefore been assumed that most solid tumours arise from a single cell and that the probability of two independent tumours arising from the same tissue is low4-6. However, lineage tracing and genomic studies strongly suggest both direct and independent clonal lineages during the initiation of DCIS and evolution to IBC. In these processes, mammary stem cells have been implicated in DCIS initiation. Role of mammary stem cells in DCIS initiation Lineage tracing mouse model experiments have shown the fate of individual cells and lineages that acquire mutations before a tumour is established7-9. This is also relevant for DCIS initiation10,11, as different pools of MaSCs drive the growth and development of the ductal network and are considered the cell of origin for breast cancers9,10. The ductal trees remain quiescent until puberty, during which extension, branching and termination of terminal end buds (TEBs) leads to its expansion throughout the fat pad7,12,13. Any oncogenic mutation that occurs in a fetal MaSC will spread throughout the ductal network to a large part of the ductal tree, leading to sick lobes9. By contrast, oncogenic mutations acquired by a single MaSC during puberty spread to a smaller number of offspring located in small clusters in a part of the ductal network8,14. Direct lineage models for DCIS progression Direct lineage models postulate that DCIS has a single cell of origin that acquires mutations and progresses to IBC15-18. This is also supported by the high genomic concordance of CNAs and mutations in synchronous DCIS–IBC regions6,15,17,19-21 and the results of a recent large longitudinal study that profiled pure DCIS and recurrent IBC using multiple sequencing techniques, which estimated direct clonal lineages in approximately ~80% of patients18. Two distinct direct lineage models have been proposed: the evolutionary bottleneck model and the multiclonal invasion model. In the evolutionary bottleneckmodel, a single clone (or a limited number of clones) with an invasive genotype is selected and breaks through the basement membrane to migrate into surrounding tissues15,16,22, while other clones are unable to escape the ducts21-28. The multiclonal invasion model posits that most or all subclones can escape the basement membrane, establishing invasive disease6,16,17,20. The multiclonal model has not been studied widely in pure DCIS and recurrent IBC samples. Independent lineage model for DCIS progression DCIS lesions and IBCs can arise from different initiating cells in the same breast independently5,20,29-32. An analysis of sequential DCIS–IBC pairs in a unique, large-scale, in-depth study of 95 matched pure DCIS and recurrent IBC showed that ~20% of the IBC recurrences were indeed clonally unrelated to the primary DCIS18, as is also supported by some mathematical model studies33. The potential role of a field effect IBC can develop in the same breast as an initial DCIS even after treatment, which could be explained by the presence of a field effect34-37. Alternatively, the sick lobe hypothesis proposes that a single lobe harbours first-hit mutations, acquired in utero or during early mammary development37-42. This could also explain the restriction of IBC to the ipsilateral side of the breast39,43,44. Germline mutations may also explain the emergence of independent lineages in DCIS and IBC patients, lowering the threshold for cancer development32,43-46. Convergent evolution model of DCIS progression A third model for the emergence of IBC from DCIS is convergent evolution, in which the same mutations and CNA are selected and expanded during tumour growth such that environmental factors fuel competition between distinct clones and push them towards a similar genotype. Ultimately, two independent clonal lineages from different ancestral cells then happen to share multiple genomic aberrations or driver mutations across regions47-49. Although independent lineages are considered uncommon (~20%) in ipsilateral recurrences, they occur at much higher frequencies in contralateral recurrences (&gt;80%), in which single-nucleotide polymorphism and comparative genomic hybridization microarrays show few (or no) genomic alterations shared in tumours from the contralateral breast cancer18,50,51. How to distinguish high- from low-risk DCIS at the time of diagnosis? The genomic and transcriptomic profile present at the time of DCIS diagnosis may contain crucial information on the risk of progression of DCIS to IBC. Thus far, it has been unclear whether prognostic gene expression markers can be used to separate indolent DCIS from potentially progressive DCIS. To this end, microarrays and RNA-seq have been applied for the comparison of bulk RNA from microdissected DCIS and IBC tissue. In synchronous DCIS–IBC, a limited number of transcriptional differences have been found and the few events discovered often varied extensively across different tumours52-56. Although these differences were strong, the added value of these studies is uncertain as they are often confounded by small sample size, lack of matched receptor status data, and low sample purity. Despite these limitations, these studies have implicated the epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) remodelling pathways as potentially relevant for the progression of DCIS to IBC55-62. We studied two large DCIS cohorts: the Sloane cohort, a prospective breast screening cohort from the UK (median follow-up of 12.5 years), and a Dutch population-based cohort (NKI, median follow-up of 13 years). FFPE tissue specimens from patients with pure primary DCIS after breast-conserving surgery (BCS) +/- RT that did develop a subsequent ipsilateral event (DCIS or invasive) were considered as cases, whereas patients that did not develop any form of recurrence up to the last follow-up or death were considered as controls. We performed copy number analysis (CNA) and RNAseq analysis on 229 cases (149 IBC recurrences and 80 DCIS recurrences) and 344 controls. We classified DCIS into the PAM50 subtypes using RNAseq data which revealed an enrichment of luminal A phenotype in DCIS that did not recur (P = 0.01, Fisher Exact test). No single copy number aberration was more common in cases compared to controls. RNAseq data did not reveal any genes significantly over/under expressed in cases versus controls after false discovery rate (FDR) correction. However, by limiting the analysis to samples that had not had RT and excluding pure DCIS recurrences we developed a penalized Cox model from RNAseq data. The model was trained on weighted samples (to correct for the biased sampling of the case control dataset) from the NKI series with double loop cross validation. Using this predicted hazard ratio, the samples were split into high, medium and low risk quantiles, with a recurrence risk of 20%, 9% and 2.5%, respectively at 5 years (p&lt;0.001, Wald test). The NKI-trained predictor was independently validated in the Sloane No RT cohort (p = 0.02, Wald test). GSEA analysis revealed proliferation hallmarks enriched in the recurrence predictor (FDR = 0.058). The NKI-RNAseq predictor was more predictive of invasive recurrence than PAM50, clinical features (Grade, Her2 and ER) and the 12-gene Oncotype DCIS score (p &lt; 0.001, permutation test using the Wald statistic) in both the NKI and Sloane series. In the methylation analysis, 50 controls were compared with 35 cases. We could identify Variably Methylation Regions (VMRs) and Differentially Methylated Regions (DMRs) between cases and controls. Interestingly, VMRs were enriched in cell adhesion pathways Conclusion The recently acquired knowledge described above on how often the subsequent IBC is directly related to the initial DCIS and on molecular markers predicting the risk of DCIS progression is essential for accurate DCIS risk assessment. 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AbstractArsenohopeite, ideally Zn3(AsO4)2·4H2O, is the arsenate analogue of hopeite, Zn3(PO4)2·4H2O (it is isostructural with α-hopeite). It was found as a single colourless to blue crystalline grain from the Tsumeb mine, Namibia. The holotype specimen is ∼1 × 1 × 1 mm in size. Arsenohopeite is associated with tiny white fibres of an unidentified Zn- and As-bearing phase. It is orthorhombic, space group Pnma, with a = 10.804(2), b = 19.003(4), c = 5.112(1) Å, V = 1049.5(4) Å3 and Z = 4. Electron microprobe analysis yielded: ZnO 44.92, Fe2O3 0.92, MnO 0.51, MgO 0.20, CuO 0.02, As2O5 45.84 (wt.%). The empirical formula is (Zn2.80Fe0.06Mn0.04Mg0.03)Σ2.93(As1.01O4)2·4H2O, based on 12 oxygen atoms. Optically, the mineral is biaxial negative, with α = 1.598(2), β = 1.606(2), γ = 1.613(2) (white light) and 2Vcalc = 86°. It is not pleochroic or fluorescent. Arsenohopeite is translucent with a vitreous lustre. It is brittle, has an uneven fracture and (by analogy with hopeite) a cleavage that is perfect on {010}, good on {100} and poor on {001}. The calculated density is 3.420 g cm–3. The five strongest calculated powder diffraction lines are [d in Å (I)(hkl)]: 9.502 (100)(020), 2.926 (95)(241), 4.937 (50)(011), 4.110 (48)(230) and 3.567 (31)(240). The crystal structure of arsenohopeite has been solved by direct methods and refined in space group Pnma to R1 = 0.0353. Raman spectroscopy confirms the crystal-structure data and indicates the presence of weak hydrogen bonds.

We report a vertical β-Ga2O3 Schottky barrier diode (SBD) with BaTiO3 as field plate oxide on a low doped thick epitaxial layer exhibiting 2.1 kV breakdown voltage. A thick drift layer of 11 μm with a low effective doping concentration of 8 × 1015 cm–3 is used to achieve high breakdown voltage. Using the high-k dielectric with a dielectric constant of 248, the breakdown voltage increases from 816 V for the non-field-plated SBD to 2152 V (>2× improvement) for the field-plated SBD without compromising the on-state performance. The diode dimensions are varied to analyze the effect of edge high-field related leakage with reverse bias and also the effect of current spreading during forward operation. Very uniform distribution of breakdown voltages of 2152 ± 20 V are observed for the diode diameters from 50 to 300 μm for the field-plated SBDs. The on and off state power losses are also analyzed and compared with the non-field-plated devices and the switching losses are estimated analytically.

Background: Phospholipids adsorbed to negatively-charged proteoglycan matrix form phospholipid (membrane), have negatively charged surface (-PO4-) and are hydrophilic. Strong adsorption and strong cohesion are necessary for phospholipids to provide a good lubricant. The surface energy of spherical lipid bilayers have "bell-curve" shaped has amphoteric character and lowest surface energy at a pH 7.4 ± 1 of the natural joint. Objectives: The amphoteric character of the natural surface of the articular cartilage was determined by measuring the surface energy of the model spherical bilayer lipid membrane. It was found that the friction (f) vs. pH 2.0 to 9.0 of the pair (cartilage/cartilage) has the amphoteric character by exposing "bell-curve" shaped with an isoelectric point (IEP). Methods: The friction coefficient (f) was measured with the sliding pin-on-disc tribotester the friction between two surfaces (cartilage/cartilage) pair. The method of interfacial tension measurements of the spherical lipid bilayer model vs the pH over the range 0.2 to 9.0 was used. Results: The dependence of friction coefficient between two cartilage surfaces on the pH over the range 2.0 to 9.0 is demonstrated by a “bell - curve” in Fig. 2(A). The surface energy of a model spherical bilayer lipid membrane vs. the pH has the character of a “bell - curve” with an (IEP) is shown in Fig. 2(B). Conclusion: The amphoteric effect on friction between the bovine cartilage/cartilage contacts has been found to be highly sensitive to the pH of an aqueous solution. In this paper we demonstrate experimentally that the pH sensitivity of cartilage to friction provides a novel concept in joint lubrication on charged surfaces. The change in friction was consistently related to the change of charge density of an amphoteric surface.

Object. The authors present a retrospective analysis of 248 immunocompetent patients with primary intracerebral lymphoma treated at 19 French and Belgian medical centers between January 1980 and December 1995.Methods. This study involved 127 female and 121 male patients with a median age of 61 years (range 2–88 years). All tumors available for review were classic diffuse non-Hodgkin's lymphoma, for which the phenotype was determined in 220 patients: 212 (96.4%) were B-cell and eight (3.6%) were T-cell type tumors. According to the Revised European—American classification of lymphoid neoplasms, most lesions were diffuse large cell tumors (62%). A total of 196 tumors were reviewed in 127 patients for whom preoperative computerized tomography and magnetic resonance studies were available. There was a single lesion in 66% of the cases, with a supratentorial location in 87%. Tumor location in the basal ganglia, corpus callosum, or fornix, infiltration of the periventricular ependyma, or a mirror pattern, were strongly suggestive of a lesion of lymphomatous origin. The histological diagnosis was obtained after surgical resection in 116 patients, with the remainder undergoing biopsy sampling only. Of the 248 patients studied, 129 (52%) received chemotherapy plus radiation therapy, 60 (24%) received radiation therapy alone, 35 (14%) received chemotherapy alone, and 24 (10%) received no postsurgical treatment.Conclusions. Using univariate analysis, the authors determined prognostic factors that were significantly associated with a favorable impact on survival including age younger than 60 years, radiation therapy (without evidence of a dose—response relationship), radiation therapy combined with chemotherapy, and chemotherapy consisting of anthracycline. Partial surgical resection was an unfavorable prognostic factor. Multivariate analysis was used to confirm the independent prognostic value of radiation therapy, age, chemotherapy consisting of anthracyclines or methotrexate, and partial surgical resection. This European survey provides a reasonable basis for the treatment of primary intracerebral lymphoma with the following sequence: stereotactic biopsy sampling, chemotherapy with a methotrexate- and anthracycline-based regimen, followed by cranial irradiation.

Abstract Abstract 4294 Multiple myeloma (MM) is a bone marrow localized plasma cell tumor comprising 1% of all cancers and 10–15% of hematological malignancies. Despite significant advances in treatment, such as bortezomib, patients currently only have a 5-year survival rate of approximately 35%. The identification of improved therapeutic options therefore remains a priority. There is increasing evidence for a role of the immune system in tumor progression. Examples include the remission of some leukemias and lymphomas in immunocompetent patients while allogeneic stem cell transplantation also has a graft-versus-tumor effect in MM. The immunotherapeutic targeting of tumor-associated antigens (TAAs) on MM cells therefore represents an important approach for improved treatment of this disease. MM cells express a number of TAAs, of which cancer testis antigens (CTAs) are of particular interest. Their restricted normal tissue distribution combined with widespread expression in tumors makes them attractive immunotherapeutic targets whilst minimizing potential problems with autoimmunity. Reports of cytotoxic T cells (CTLs, the major effector cells in tumor immunity) and CD4-positive T-helper cells recognizing the NY-ESO-1 and MAGE CTAs in patients with MM suggests the presence of a spontaneous immune response to these molecules, which can be boosted through vaccination with CTAs such as NY-ESO-1. We previously identified PAS (Per ARNT Sim) domain containing 1 (PASD1) protein as a novel diffuse large B-cell lymphoma (DLBCL)-associated CTA. Importantly, PASD1 has a restricted normal tissue distribution but is present in a range of hematological malignancies, including MM. Subsequent in vitro studies have identified immunogenic PASD1 peptides that elicit PASD1-driven CTL or CD4-positive T-helper responses in peripheral blood mononuclear cells from DLBCL patients. Studies using a pre-clinical in vivo murine model have confirmed the immunogenicity of the PASD1 CTL peptides. These critical steps support the use of PASD1 as a potential immunotherapeutic target in DLBCL. The current study was performed to ascertain whether the PASD1 CTL peptides were immunogenic in MM patients and thus have utility for immunotherapy in this disease. Blood samples were obtained from 9 post-treatment myeloma patients attending the John Radcliffe Hospital following informed consent. Peripheral blood mononuclear cells were incubated with the PASD1 CTL peptides PASD1(1)38-47 (QLLDGFMITL) and PASD1(2)167-175 (YLVGNVCIL). A gamma-interferon ELISPOT release assay was performed after 8–10 days. The results are summarized in Table 1.Table 1:Gamma-IFN response to PASD1 in patients with MM.PatientsMHC Class I*Gamma-IFN response to peptides/50,000 cellsPASD1(1)PASD1(2)HIV-1PHADSA*0201+2+/−112+/−41+/−1100+/−14MWA*0201+52+/−244+/−220+/−266+/−8DMA*0201− A*2601+28+/−246+/−68+/−298+/−10JBA*0201+0+/−00+/−02+/−088+/−12JYA*0201+–––72+/−10DAA*0201−2+/−20+/−00+/−082+/−10GGA*0201−58+/−268+/−244+/−288+/−10MDA*0201−52+/−228+/−242+/−292+/−12RSA*0201––––*Results were considered positive if the number of spots in the test wells were at least twice that found in the irrelevant HIV-1 cultures. A significant gamma-interferon response was detected to one or both of the PASD1 peptides in 2/4 A*0201-positive evaluable patients. Analysis of the SYPETHI web-based algorithm predicted the PASD1 peptides used here to be immunogenic in the context of A*2601 and this was confirmed in the one A*2601+ patient studied here. No significant response was detected in the 3 A*0201 and A*2601-negative patients. Double immunolabeling studies using antibodies to PASD1 and CD138 showed PASD1 to be present in a subset of tumor cells in all 7 patients with evaluable ELISPOT data. Our findings demonstrate the immunogenicity of both the PASD1(1) and PASD1(2) peptides in patients with MM. These ‘generic’ peptides therefore represent vaccine candidates for inclusion in a vaccine targeting multiple PASD1-positive hematological malignancies. Disclosures: Banham: University of Oxford: Patents & Royalties. Pulford:Leukaemia and Lymphoma Research: Patents & Royalties.

TRATAMENTO PARA DESENTUPIMENTO DE GOTEJADORES CONVENCIONAIS Marconi Batista Teixeira; Ralini Ferreira de Melo; Rubens Duarte Coelho; Osvaldo Rettore Neto; Pablo Atahualpa de Aguiar RibeiroDepartamento de Engenharia Rural, Escola Superior de Agricultura Luiz de Queiroz, Universidade de São Paulo, Piracicaba, SP, marconi@esalq.usp.br 1 RESUMO Este trabalho teve como objetivo verificar a recuperação de emissores convencionais que apresentavam, em campo, problemas de entupimento causados por problemas biológico ou químico. O experimento foi realizado em uma Bancadade ensaios instalada no Laboratório de Irrigação do DER – ESALQ – USP, utilizando-se os seguintes tratamentos químicos da água para recuperação dos emissores: a) 10 mg L-1 de cloro livre; b) 50 mg L-1 de cloro livre; e c) ácido nítrico a pH 2,0. A fonte de cloro utilizada foi hipoclorito de sódio (10%), sendo que o pH foi mantido na faixa de 5,5 a 6,0 para maior ação do ácido hipocloroso. A aplicação das dosagens foi feita durante 2 horas, deixando as linhas gotejadoras descansarem expostas à ação dos tratamentos por 24 horas, quando, então, realizava-se a leitura de vazão. O delineamento experimental adotado foi o DIC em esquema fatorial 5x3, sendo utilizados os testes “F” para análise de variância e Tuckey a 5% de significância para comparação de médias. O tratamento com 50 mg L -1 de cloro livre foi o mais eficiente estatisticamente a 5% de significância pelo teste de Tukey para recuperação da vazão dos gotejadores a valores próximos da vazão nominal de catálogo. UNITERMOS: irrigação localizada, tratamento químico, uniformidade de distribuição de água. TEIXEIRA, M. B.; MELO, R. F. de; COELHO, R. D.; RETTORE NETO, O.; RIBEIRO, P. A. de A. TREATMENT FOR CLOGGED EMITTERS 2 ABSTRACT This work aimed to verify the recovery of conventional emitters that presented blockage problems in the field caused by biological or chemical problems. The experiment was performed in a trial counter installed in the Irrigation Laboratory at ESALQ-USP, using the following chemical water treatments for clogged emitters: a) 10 mg Lˉ¹ of free chlorine, b) 50 mgLˉ¹ of free chlorine, and c) nitric acid at 2.0 pH. The used chlorine source was sodium hypochlorite (10%) and pH was kept from 5.5 to 6.0. The application was done for 2 hours, then the line emitters rested and exposed to the action of the treatments for 24 hours, when then the flow reading was made. The adopted experimental outline was DIC in a 5x3 factorial scheme, using Tests “F” for variance analysis and Tukey’s at 5% to compare averages. The treatment to recover emitter discharge to its original value was statistically more efficient according to Tukey’s test at 5%, when 50 mgLˉ¹ of free chlorine was applied. KEY WORDS: trickle irrigation, chemical treatment, uniformity of dripper discharge

PURPOSE Pembrolizumab demonstrated antitumor activity and safety in the phase II KEYNOTE-224 trial in previously treated patients with advanced hepatocellular carcinoma (HCC). KEYNOTE-240 evaluated the efficacy and safety of pembrolizumab in this population. PATIENTS AND METHODS This randomized, double-blind, phase III study was conducted at 119 medical centers in 27 countries. Eligible patients with advanced HCC, previously treated with sorafenib, were randomly assigned at a two-to-one ratio to receive pembrolizumab plus best supportive care (BSC) or placebo plus BSC. Primary end points were overall survival (OS) and progression-free survival (PFS; one-sided significance thresholds, P = .0174 [final analysis] and P = .002 [first interim analysis], respectively). Safety was assessed in all patients who received ≥ 1 dose of study drug. RESULTS Between May 31, 2016, and November 23, 2017, 413 patients were randomly assigned. As of January 2, 2019, median follow-up was 13.8 months for pembrolizumab and 10.6 months for placebo. Median OS was 13.9 months (95% CI, 11.6 to 16.0 months) for pembrolizumab versus 10.6 months (95% CI, 8.3 to 13.5 months) for placebo (hazard ratio [HR], 0.781; 95% CI, 0.611 to 0.998; P = .0238). Median PFS for pembrolizumab was 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 2.5 to 4.1 months) for placebo at the first interim analysis (HR, 0.775; 95% CI, 0.609 to 0.987; P = .0186) and 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 1.6 to 3.0 months) at final analysis (HR, 0.718; 95% CI, 0.570 to 0.904; P = .0022). Grade 3 or higher adverse events occurred in 147 (52.7%) and 62 patients (46.3%) for pembrolizumab versus placebo; those that were treatment related occurred in 52 (18.6%) and 10 patients (7.5%), respectively. No hepatitis C or B flares were identified. CONCLUSION In this study, OS and PFS did not reach statistical significance per specified criteria. The results are consistent with those of KEYNOTE-224, supporting a favorable risk-to-benefit ratio for pembrolizumab in this population.