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Rurak, D. W., B. S. Richardson, J. E. Patrick, L. Carmichael y J. Homan. "Blood flow and oxygen delivery to fetal organs and tissues during sustained hypoxemia". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 258, n.º 5 (1 de mayo de 1990): R1116—R1122. http://dx.doi.org/10.1152/ajpregu.1990.258.5.r1116.
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To examine the fetal cardiovascular responses to a sustained reduction in O2 delivery (DO2), studies were conducted on 13 chronically instrumented fetal lambs (128-138 days gestation) made hypoxemic for 7.9 +/- 0.5 h by lowering maternal inspired O2 concentration to 9-10%. Fetal descending aortic PO2 fell initially from 18.0 +/- 1.0 to 10.7 +/- 0.6 mmHg, whereas pH decreased progressively from 7.326 +/- 0.006 to 6.843 +/- 0.023. Blood flow to the cerebral hemispheres, myocardium, and adrenal glands rose maximally by 110.2 +/- 22.5, 253.7 +/- 41.1, and 338.7 +/- 55.0%. Cerebral hemispheric DO2 fell progressively, whereas DO2 to the myocardium and adrenal was maintained until 7.9 h, when it fell significantly. There was also a rise in blood flow to brown adipose tissue. Blood flow to the gut and skeletal muscle was maintained, whereas flow to the spleen and kidney fell. DO2 to all these tissues fell markedly because of the progressive decline in blood O2 content. It is concluded that fetal cardiovascular function was well maintained in the face of severe hypoxemia and marked acidemia.
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Grakova, E. V., K. V. Kopeva, S. N. Shilov, E. T. Bobyleva, E. N. Berezikova, V. V. Kalyuzhin y A. T. Teplyakov. "Prognostic value of humoral markers in patients with anthracycline-related cardiac dysfunction". Bulletin of Siberian Medicine 22, n.º 3 (17 de octubre de 2023): 25–35. http://dx.doi.org/10.20538/1682-0363-2023-3-25-35.
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Aim. To carry out a 12-month study on the prognostic role of humoral markers responsible for the main mechanisms of initiation of cardiotoxic myocardial damage (endothelin-1, soluble Fas-L, N-terminal pro-brain natriuretic peptide (NT-proBNP), tumor necrosis factor-α, interleukin (IL)-1β, matrix metalloproteinase (MMP)-2 and MMP9, soluble form of the ST2 protein (sST2), a tissue inhibitor of metalloproteinase-1, and tetranectin) in assessing the risk of progression of anthracycline-related left ventricular dysfunction.Materials and methods. The study included a total of 114 women aged 48.0 (46.0; 52.0) years without concomitant cardiovascular diseases and risk factors who received chemotherapy with anthracyclines in the past. The levels of serum biomarkers were determined using the enzyme immunoassay. Transthoracic echocardiography was performed at baseline and at 12 months of follow-up.Results. After 12 months of follow-up, all patients were retrospectively divided into 2 groups: group 1 (n = 54) included patients with an unfavorable course of anthracycline-related cardiac dysfunction (ARCD), group 2 (n = 60) encompassed patients with a favorable course of the disease. According to the ROC analysis, MMP-2 ≥ ≥ 338.8 pg / ml (sensitivity 57%, specificity 78%; AUC = 0.629; p = 0.025), MMP-9 ≥ 22.18 pg / ml (sensitivity 89%, specificity 87%; AUC = 0.886; p < 0.001), sST2 ≥ 32.4 ng / ml (sensitivity 64%, specificity 70.5%; AUC = 0.691; p = 0.002), and tetranectin ≤ 15.4 pg / ml (sensitivity 69%, specificity 72%; AUC = 0.764; p < 0.001) were identified as predictors of an adverse course of ARCD. When comparing ROC curves, it was found that the concentration of MMP-9 (p = 0.002) was the most significant predictor of the progression of ARCD.Conclusion. MMP-2 and -9, soluble ST2, and tetranectin can be considered as non-invasive markers for assessing the risk of ARCD progression. At the same time, an increased level of MMP-9 is the most significant predictor of ARCD progression.
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Viscuse, Paul Vincent, Miao Zhang, Jingjing Liu, Rebecca Slack Tidwell, Sumit Kumar Subudhi, Amado J. Zurita, Paul Gettys Corn et al. "Linking the Aggressive Variant Prostate Cancer (AVPC) molecular signature (-ms) to androgen indifference in a prospective clinical trial." Journal of Clinical Oncology 38, n.º 6_suppl (20 de febrero de 2020): 156. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.156.
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156 Background: AVPC are morphologically heterogeneous tumors that share clinical features with the rare, virulent, androgen-indifferent and platinum-sensitive, small cell histologic variant. The AVPC-ms is composed of ≥2 defects in TP53, RB1 and PTEN, is detectable in »30% of advanced prostate cancers and predicts for benefit from platinum combinations (Corn et al. Lancet Oncol, 2019). Preclinical studies link the AVPC-ms with androgen indifference, but a prospective clinical association with decreased sensitivity to androgen signaling inhibitors is lacking. Methods: In a phase II trial (NCT02703623), men with metastatic castration resistant prostate cancer (mCRPC) treated with abiraterone and apalutamide were classified at week 8 as having a ‘satisfactory’ decline in PSA (≥ 50% from baseline) and CTC (≤5/7.5mL) or ‘unsatisfactory’. Pretreatment biopsies were obtained for immunohistochemistry (IHC) for TP53, RB1 and PTEN and RNA sequencing. Results: 198 men were registered. 59 (31.5%) of 187 evaluable had ‘unsatisfactory’ marker declines. Age, race/ethnicity, and baseline ECOG, PSA and LDH were similar between the groups. Men in the ‘unsatisfactory’ group had higher median total alkaline phosphatase (120 vs. 86; p=0.002), bone-specific alkaline phosphatase (21 vs. 16; p=0.01), CTC (9 vs. 1; p<0.001), and urine n-telopeptides (338.5 vs 182.5; p=0.003) levels. Unsupervised clustering of RNA profiles from 45 tumor biopsies revealed two distinct clusters. The top enriched gene set (FDR q-val<0.000) included ‘epithelial mesenchymal transition’, ‘E2F targets’ and ‘G2M checkpoint’ genes in one (n=18) and ‘androgen response’ in another (n=27) cluster. Six (33.3%) and 9 (33.3%) of the samples respectively belonged to patients in the ‘unsatisfactory’ decline group. IHC and RNA sequencing of the remaining samples are ongoing. Conclusions: Signaling pathways associated with androgen indifference can be identified in the tumor biopsies of men with early mCRPC, prior to exposure to secondary androgen signaling inhibitors. Their association with the AVPC-ms and patient outcomes will be presented. If confirmed, these markers could be used to inform therapy selection. Clinical trial information: NCT02703623.
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Perez-Soriano, Eva M., Enrique Ariza, Cristina Arevalo, Isabel Montealegre-Melendez, Michael Kitzmantel y Erich Neubauer. "Processing by Additive Manufacturing Based on Plasma Transferred Arc of Hastelloy in Air and Argon Atmosphere". Metals 10, n.º 2 (30 de enero de 2020): 200. http://dx.doi.org/10.3390/met10020200.
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This research was carried out to determinate the effect of the atmosphere processing conditions (air and argon) and two specific thermal treatments, on the properties of specimens made from the nickel-based alloy Hastelloy C-22 by plasma transferred arc (PTA). Firstly, the additive manufacturing parameters were optimized. Following, two walls were manufactured in air and argon respectively. Afterwards, a determinate number of specimens were cut out and evaluated. Regarding the comparison performed with the extracted specimens from both walls, three specimens of each wall were studied as-built samples. Furthermore, a commonly used heat treatment in Hastelloy, with two different cooling methods, was selected to carry out additional comparisons. In this respect, six additional specimens of each wall were selected to be heat treated to a temperature of 1120 °C for 20 min. After the heat treatment, three of them were cooled down by rapid air cooling (RAC), while the other three were cooled down by water quenching (WQ). In order to study the influence degree of the processing conditions, and how the thermal treatments could modify the final properties of the produced specimens, a detailed characterization was performed. X-ray diffraction and microstructural analyses revealed the phases-presence and the apparition of precipitates, varying the thermal treatment. Moreover, the results obtained after measuring mechanical and tribological properties showed slight changes caused by the variation of the processing atmosphere. The yield strength of the extracted specimens from the two walls achieved values closer to the standards ones in air 332.32 MPa (±21.36 MPa) and in argon 338.14 MPa (±9 MPa), both without thermal treatment. However, the effect of the cooling rate resulted as less beneficial, as expected, reducing the deformation properties of the specimens below 11%, independently of the air or argon manufacturing atmosphere and the cooling rate procedure.
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Kidwell, Kyle, Camila Albo, Michael Pope, Latanya Bowman, Hongyan Xu, Leigh Wells, Nadine Barrett, Niren Patel, Amy Allison y Abdullah Kutlar. "Characteristics of sickle cell patients with frequent emergency department visits and hospitalizations". PLOS ONE 16, n.º 2 (22 de febrero de 2021): e0247324. http://dx.doi.org/10.1371/journal.pone.0247324.
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Vaso-occlusive episodes (VOEs) are a hallmark of sickle cell disease (SCD), and account for >90% of health care encounters for this patient population. The Cooperative Study of Sickle Cell Disease, a large study enrolling >3000 patients, showed that the majority of SCD patients (80%) experienced 0–3 major pain crises/year. Only a small minority (~5%) experienced ≥6 VOEs/year. Our study sought to further understand this difference in VOE frequency between SCD patients. We analyzed 25 patients (13M/12F, mean age of 28.8) with ≥6 ED visits or hospitalizations/year (high utilizers), and compared these with 9 patients (6M/3F, mean age of 37.6) who had ≤2 ED visits or hospitalizations/year (low utilizers). All subjects were given a demographic survey along with questionnaires for depression, anxiety, and Health Locus of Control. Each subject then underwent quantitative sensory testing (QST) with three different modalities: pressure pain sensitivity, heat and cold sensitivity, and Von Frey monofilament testing. Laboratory and clinical data were collected through subjects’ medical records. CBC and chemistry analysis showed high utilizers had higher WBC (p<0.01), ANC (p<0.01), total bilirubin (p = 0.02), and lower MCV (p = 0.03). Opioid use (morphine equivalents) over the past 6 months was significantly higher in the high utilizer group (12125.7 mg vs 2423.1 mg, p = 0.005). QST results showed lower pressure pain threshold at the ulna (224.4 KPa vs 338.9 KPa, p = 0.04) in the high utilizer group. High utilizers also had higher anxiety (9.0 vs 4.6, p = 0.04) and depression scores (10.0 vs 6.0, p = 0.051). While the low utilizer group had higher education levels with more associate and bachelor degrees (p = 0.009), there was no difference in income or employment. These data show that many biological and psychosocial factors contribute to high health care utilization in SCD. A multi-disciplinary and multi-faceted approach will be required to address this complex problem.
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Manohar, Murli, Thomas E. Goetz, Beth Saupe, Elizabeth Hutchens y Elizabeth Coney. "Thyroid, renal, and splanchnic circulation in horses at rest and during short-term exercise". American Journal of Veterinary Research 56, n.º 10 (1 de octubre de 1995): 1356–61. http://dx.doi.org/10.2460/ajvr.1995.56.10.1356.
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SUMMARY Using radionuclide-labeled 15-μm-diameter microspheres injected into the left ventricle, we examined blood flow to the thyroid gland, adrenal glands, kidneys, and various gastrointestinal tract tissues in 9 healthy horses while they were standing quietly (rest) and during exercise at 2 work intensities (8 and 13 m/s). Hemodynamic measurements were made during steady-state conditions, as judged by the stability of heart rate as well as aortic, pulmonary, and right atrial pressures. The similarity of blood flow values for the left and the right kidneys during each of the 3 conditions indicated adequate mixing of microspheres with blood. In standing horses, of all tissues examined, the thyroid gland had the highest blood flow (1,655.2 ± 338.5 ml/min/100 g)—being about threefold that in the kidneys. Adrenal blood flow, by contrast, was only 25% of that in the kidneys (589.5 ± 50.4 ml/min/100 g). Among the gastrointestinal tract tissues, glandular stomach and pancreas had the highest blood flows (214.3 ± 21.6 and 197.6 ± 23.4 ml/min/100 g, respectively). Small intestinal perfusion was not different from that in the ventral colon and cecum, but their values exceeded those for the dorsal and small colons. Exercise at 8 and 13 m/s caused significant increase in adrenal blood flow as vascular resistance decreased significantly. In the kidneys, blood flow was only insignificantly affected during exercise at 8 m/s, but at 13 m/s there was a profound reduction in renal blood flow as intense renal vasoconstriction occurred. Vasoconstriction also caused thyroid and pancreatic blood flow to decrease significantly at both levels of exertion. Significant vasoconstriction occurring in all gastrointestional tract tissues at 8 and 13 m/s caused blood flow to be diverted away from these vascular beds. Thus, our data indicated that renal, adrenal, and splanchnic organ/tissue blood flow responses of strenuously exercising horses closely resemble those described for exercising ponies.
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He, Qiang, Chenrui Wu, Long Pan, Jiachu Li, Yin Zhou, Hongxiang Cao, Ruirui Sun, Junjie Huang, Yongchen Wang y Ping Huang. "Hepatic artery infusion chemotherapy combined with donafenib and camrelizumab in patients with unresectable hepatocellular carcinoma presenting portal vein tumor thrombus: A prospective, single-arm study." Journal of Clinical Oncology 41, n.º 16_suppl (1 de junio de 2023): e16134-e16134. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e16134.
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e16134 Background: Rational and effective treatment strategies for patients with unresectable hepatocellular carcinoma (uHCC) presenting portal vein tumor thrombus (PVTT) are lacking, and hepatic artery infusion chemotherapy (HAIC) combined with tyrosine kinase inhibitors and immune checkpoint inhibitors could be an effective therapy. Herein, we evaluated the efficacy and safety of HAIC combined with donafenib and camrelizumab in patients with uHCC presenting PVTT. Methods: This prospective, single-arm, single-center study enrolled patients with uHCC presenting PVTT (distant metastases were allowed), BCLC stage C, Child-Pugh scores ≤ 7, ECOG PS ≤1, and no previous local or systemic treatment. Patients received mFOLFOX6-HAIC (every 3 weeks, no more than 6 cycles), followed by peroral donafenib (200 mg BID every day) and intravenous camrelizumab (200 mg every 3 weeks). The primary endpoint was the objective response rate (ORR; per RECIST1.1 and mRECIST). Secondary endpoints included surgical conversion rate, disease control rate, progression-free survival (PFS), overall survival (OS), duration of response, and safety. Results: Between November 2021 and September 2022, we enrolled 15 eligible patients with a median age of 53 years (range, 36-76), including 12 (80%) males. Considering enrolled patients, 14 (93.3%) were HBV+, 13(86.7%) presented with PVTT invasion into the main portal vein, Child-Pugh scores 5/6/7: 9/5/1, ECOG PS 0/1: 10/5, median tumor size was 8.4 cm (range, 5.2-13.6), and 5 (33.3%) had extrahepatic metastases. The median number of HAIC procedures was 5 (range, 1-6). The median follow-up time was 338.0 days (95% CI, 298.7-377.4). Considering the 15 evaluable patients (completed at least one cycle of treatment), the ORR was 66.7% (10/15) according to RECIST 1.1, with 0 complete response (CR) and 10 partial responses (PR). According to mRECIST, the ORR was 73.3% (11/15), with 2 CR and 9 PR. Three patients (20%) became eligible for surgical resection, with one undergoing surgical resection (two refused surgery for financial reasons). Median PFS and OS were insufficient. All 15 (100%) patients experienced treatment-related adverse events (TRAEs). Common TRAEs included hand-and-foot skin reaction (HFSR; 93.3%), abdominal pain (73.3%), hypoalbuminemia (60.0%), platelet count decreased (60.0%), nausea (60%), aspartate aminotransferase increased (53.3%), and vomiting (53.3%). Grade 3/4 TRAEs included platelet count decreased (13.3%), HFSR (13.3%), hepatic function abnormal (6.7%), and ascites (6.7%). No grade 5 TRAEs were observed. TRAEs led to drug reduction in 8 patients (53.3%). Conclusions: HAIC combined with donafenib and camrelizumab afforded promising efficacy and safety in patients with uHCC presenting PVTT. Longer follow-up is required for further evaluation. Clinical trial information: ChiCTR2100051714 .
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Asrat, Fikirte, Teshome Soromessa, Tesefaye Bekele, Rama Mohan Kurakalva, Sravya Sai Guddeti, David Russel Smart y Kristine Steger. "Effects of Environmental Factors on Carbon Stocks of Dry Evergreen Afromontane Forests of the Choke Mountain Ecosystem, Northwestern Ethiopia". International Journal of Forestry Research 2022 (27 de abril de 2022): 1–31. http://dx.doi.org/10.1155/2022/9447946.
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The purpose of this research was to quantify and compare carbon stocks in two selected dry evergreen montane forests of the Choke Mountain ecosystem that are under different management regimes. The study also attempted to assess the carbon stock along environmental gradients. The average carbon stock throughout the whole plots investigated in Anshirava forest (protected) was 180.18 t·ha−1 (53%) in AGB, 111.43 t·ha−1 (33%) in soil, 36.43 t·ha−1 (11%) in BGB, 6.09 t·ha−1 (2%) in USB, 2.69 t·ha−1 (1%) in litter, and 1.36 t·ha−1 (less than 1%) in DW. In Ziba forest (high human intervention), the average carbon stock was 106.71 t·ha−1 (44%) in AGB, 100.07 t·ha−1 (42%) in soil, 21.34 t·ha−1 (9%) in BGB, 5.41 t·ha−1 (2%) in USB, 4.82 t·ha−1 (2%) in litter, and 2.00 t·ha−1 (1%) in DW. The AGB had the greatest carbon share in both forests, followed by soil. In Anshirava and Ziba forests, the mean total carbon stocks (TCS) were 338.18 t·ha−1 and 240.36 t·ha−1, with CO2 equivalents of 1241.14 t·ha−1 and 882.12 t·ha−1, respectively. The study indicated a significant variation between the two forests. Anshirava forest has larger total carbon stocks than Ziba forest. For lower, medium, and higher altitudes, the total carbon stock variation along an altitudinal gradient was 289.67 t·ha−1, 347.93 t·ha−1, and 414.89 t·ha−1 in Anshirava forest and 270.99 t·ha−1, 204.24 t·ha−1, and 224.82 t·ha−1 in Ziba forest, respectively. As a result, a greater amount of carbon was stored at higher altitudes in Anshirava and at lower altitudes in Ziba, with no significant difference in both forests. The total carbon stock variation along slope gradient was 392.60 t·ha−1, 344.59 t·ha−1, and 295.49 t·ha−1 in Anshirava forest and 258.74 t·ha−1, 222.46 t·ha−1, and 171.46 t·ha−1 in Ziba forest for flat, intermediate, and steep slopes, respectively. This resulted in higher carbon being stored in flat slopes in both forests. Also, only at the Ziba site, a significant difference was found along the slope gradient. In each forest, eight distinct aspect facings were observed, with the western (W) aspect containing the highest value of total carbon stock in both forests. Lower values, on the other hand, were recorded in the south (S) and flat (F) aspects of Anshirava and Ziba forests, respectively. The slope aspects of both forests varied significantly. As a result, the research reveals that environmental factors have a significant impact on carbon stock value of Choke Mountain forest ecosystem, but the impact is not consistent among carbon pools.
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Touma, Z., B. Hoskin, C. Atkinson, D. Bell, O. Massey, J. H. Lofland, P. Berry, C. Karyekar y K. Costenbader. "THU0246 DIAGNOSTIC CLUSTER PROFILING OF PATIENTS IN A REAL-WORLD DATA SET WITH SYSTEMIC LUPUS ERYTHEMATOSUS". Annals of the Rheumatic Diseases 79, Suppl 1 (junio de 2020): 350.2–350. http://dx.doi.org/10.1136/annrheumdis-2020-eular.5865.
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Background:Previous systemic lupus erythematosus (SLE) studies have identified potential clusters of SLE clinical manifestations post diagnosis.Objectives:To describe the presentation of SLE at diagnosis across different cohorts of patients and describe management and outcomes after diagnosis within clusters.Methods:Cross-sectional study of 263 rheumatologists in the US and EU5. Data were collected from the Adelphi Real World 2015 Lupus Disease Specific Programme. Rheumatologists completed patient record forms (PRFs) for the next 5 prospectively consulting SLE patients; these patients completed patient self-completion (PSC) forms describing how SLE affected them. PRF data includes patient’s characteristics and management history. PSCs focused on similar data collection, including patient reported outcome measures on the humanistic burden. Age at diagnosis, symptoms at diagnosis, organ involvement at diagnosis, and severity at diagnosis were used as covariates in a latent cluster analysis.Results:Data were extracted from 1376 PRFs. Cluster analysis resulted in up to 6 clusters, and disease understanding led to the selection of a 4-cluster solution.Cluster 1 displayed the mildest disease, characterised by joint involvement, while cluster 2 displayed more skin involvement in conjunction with joint. Cluster 3 were characterised by renal involvement and cluster 4 had skin and joint involvement, but also high constitutional and haematological involvement at diagnosis (Table 1).Table 1Cluster analysisClustersOrgan involvement at diagnosis, n (%)Overall(n=1304)1(n=210)2(n=493)3(n=162)4(n=439)p-valueMusculoskeletal1145 (87.8)174 (82.9)444 (90.1)134 (82.7)393 (89.5)0.0065Mucocutaneous898 (68.9)5 (2.4)397 (80.5)95 (58.6)401 (91.3)<0.0001Neuropsychiatric87 (6.7)19 (9.0)9 (1.8)16 (9.9)43 (9.8)<0.0001Cardiorespiratory176 (13.5)36 (17.1)14 (2.8)22 (13.6)104 (23.7)<0.0001Gastrointestinal44 (3.4)8 (3.0)14 (2.8)8 (4.9)14 (3.2)0.6115Opthalmic47 (3.6)020 (4.1)10 (6.2)17 (3.9)0.0102Renal213 (16.6)15 (7.1)9 (1.8)162 (100)27 (6.2)<0.0001Constitutional425 (32.6)45 (21.4)89 (18.1)55 (34.0)236 (53.8)<0.0001Haematological452 (34.7)64 (30.5)22 (4.5)80 (49.4(286 (65.1)<0.0001Severity at diagnosis, n (%)Mild209 (16.0)55 (26.2)99 (20.1)1 (0.6)54 (12.3)<0.0001Moderate806 (61.8)122 (58.1)324 (65.7)75 (46.3)285 (64.9)Severe289 (22.2)33 (15.7)70 (14.2)86 (53.1)100 (22.8)Significant between-cluster differences were observed when comparing outcomes; cluster 4 have been diagnosed longest (mean weeks diagnosed 354.6 v. 1: 232.6, 2: 228.7, 3: 338.2, p<0.0001). Cluster 3 consulted more in the last 12 months (mean number of visits 7.9 vs. 1: 5.7, 2: 6.3, 4: 7.6).Significant differences were also observed between clusters in relation to current treatment proportions: corticosteroid (highest cluster 3: 78.4%), immunosuppressant (highest cluster 3: 75.3%), biologic DMARD (highest cluster 4: 17.8%) and antidepressant (highest cluster 4: 4.1%).Conclusion:This study demonstrates the heterogeneity of SLE at diagnosis and highlights four distinct presentations of the disease at diagnosis. Significant proportions of patients present with advanced disease, these clusters go on to present the greatest burden demonstrating the need for better diagnostic tools and novel earlier intervention.Study funded by Johnson and Johnson.Disclosure of Interests:Zahi Touma Consultant of: Consultant for Janssen, Ben Hoskin Consultant of: Consultant for Janssen, Christian Atkinson Consultant of: Consultant for Janssen, David Bell Consultant of: Janssen, Olivia Massey Consultant of: Janssen, Jennifer H. Lofland Employee of: Janssen, Pamela Berry Employee of: Janssen, Chetan Karyekar Shareholder of: Johnson & Johnson, Consultant of: Janssen, Employee of: Janssen Global Services, LLC. Previously, Novartis, Bristol-Myers Squibb, and Abbott Labs., Karen Costenbader Grant/research support from: Merck, Consultant of: Astra-Zeneca
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Yüksel, Sercan, Uğur Topal, Mehmet Z. Songür, İsmail Çalıkoğlu, Erdal Karaköse, Erdal Ercan, Zafer Teke y Hasan Bektaş. "Comparison of clinical outcomes of robotic-assisted and video-assisted esophagectomy for esophageal cancer". Journal of Cancer Research and Therapeutics 20, n.º 1 (3 de mayo de 2023): 410–16. http://dx.doi.org/10.4103/jcrt.jcrt_2518_22.
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Introduction: Robotic-assisted minimally invasive esophagectomy (RAMIE) is a recently developed technique for the treatment of resectable esophageal cancer. The present study compares the outcomes of RAMIE and video-assisted thoracoscopic esophagectomy (VATE). Method: Patients undergoing minimally invasive esophageal surgery between December 2020 and September 2022 were included in the study, while those undergoing conventional surgery were excluded. The patients were divided into two groups, as those undergoing RAMIE (Group 1) and those undergoing VATE (Group 2). The demographic and clinical characteristics, intraoperative parameters, pathological data, and postoperative parameters of the groups were compared. Results: A total of 28 patients were included in the study, with 13 patients in Group 1 and 15 patients in Group 2. The gender distribution was similar (P = 0.488), and the mean age was 64.7 and 59.0 years in Groups 1 and 2, respectively (P = 0.068). The majority of the sample was in the ASA2 category (46.2% vs. 66.7%, P = 0.341); Ca19.9 levels were higher in Group 1 than in Group 2 (25.7 vs. 13.7, P = 0.027); preoperative Hb was lower in Group 1 than in Group 2 (10.9 g/dL vs. 12.2 g/dL, P = 0.043); the most commonly performed surgery was the McKeown procedure (69.2% vs. 66.7%, P = 0.492); an intraoperative feeding jejunostomy was placed only in Group 2; the operation time was similar between the groups (338.5 min vs. 340 min, P = 0.916); and the distribution of tumor localizations was similar between the groups (P = 0.407). In terms of tumor histology, squamous cell carcinoma (SCC) was the most common tumor type in the two groups (84.6% vs. 80%, P = 0.636); the tumor diameter was similar between the groups (14.9 vs. 18.1, P = 0.652); the number of removed lymph nodes was similar between the groups (24.9 vs. 22.5, P = 0.419); and the number of metastatic lymph nodes was higher in Group 2 (0.08 vs. 1.07, P = 0.27). One patient in Group 2 underwent repeat surgery due to suspected ischemic anastomosis; the distribution of postoperative complications according to the Clavien–Dindo classification system was similar in the two groups (P = 0.650); there was no early mortality within the first 30 days in either group; one patient in Group 2 was re-admitted within 90 days of discharge with decreased oral intake; the length of hospital stay was shorter in Group 1 (9 days vs. 16.5 days, P = 0.006); and the patients in Group 2 more often received neoadjuvant therapy in proportion to the disease stage (15.4% vs. 60%, P = 0.016). Conclusion: Robotic procedures can be safely performed in esophageal cancers with complication rates and oncological radicality similar to those of other minimally invasive techniques.
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Chang, Hung, Hsiao-Wen Kao, Ming-Chung Kuo, Jin-Hou Wu, Ying-Jung Huang, Ting-Yu Huang, Tung-Huei Lin y Lee-Yung Shih. "Genetic Evolution from Chronic Myeloproliferative Neoplasms to Acute Myeloid Leukemia: An Analysis of Forty-Six Paired Samples". Blood 142, Supplement 1 (28 de noviembre de 2023): 3155. http://dx.doi.org/10.1182/blood-2023-182624.
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Background: Secondary acute myeloid leukemia (sAML) may arise from chronic myeloproliferative neoplasm (MPN). The genetic evolution pattern may be understood by paired sample analysis. Knowledge of genetic change in MPN/sAML is still limited and more extensive studies should be done. Patients and Methods: Forty-six paired samples (27 males) at diagnosis of MPN (12 polycythemia vera, 6 essential thrombocythemia, 25 primary myelofibrosis and 3 MPN-unclassified) and sAML transformation were available. Mutational analyses of 27 genes ( JAK2V617F, CALR, MPL, ASXL1, IDH1, IDH2, TET2, DNMT3A, EZH2, SRSF2, U2AF1, SF3B1, ZRSR2, SMC1, STAG2, SMC3, RUNX1, SETBP1, IKZF1, WT1, K-RAS, N-RAS, C-CBL, TP53, RAD21, BCOR and BCORL1) were performed. Mutations and their variant allele frequencies (VAF) were measured by next generation sequencing. Results: At baseline (MPN), the mutation number was 2 (maximal 5). Forty-five samples harbored driver gene mutations (31 JAK2V617F, 13 CALR and 1 MPL). Twenty-eight samples harbored at least one epigenetic regulator mutations (11 TET2, 8 DNMT3A,7 ASXL1, 5 EZH2, 2 IDH2, 1 IDH1). Twelve samples harbored spliceosome mutations which were mutually exclusive (6 SRSF2, 3 SF3B1, 2 U2AF1 1 ZRSR2). Other mutations were RUNX1, BCORL1 (n=2 each), CBL and BCOR (n=1 each). In sAML, the median mutation number was 3 (maximal 7). Loss of mutation was found for JAK2V617F (9/31), TET2 (1/11) and SRSF2 (1/6). Acquisition was most common for RUNX1 (n=9), followed by TP53, ASXL1 (n=5 each), K-RAS (n=4) , ZRSR2, STAG2 (n=3 each). The median number of acquired mutation was 1 (maximal 5). The frequencies of gene mutations are summarized in Figure 1A. The baseline VAF of JAK2V617F was high (>35%) in 80.6% (25/31). In progression to sAML, VAF was constant in 29.0% (9/31, VAF changes <10%), increased in 20.0% (9/31, increased VAF> 10%), decreased in 41.9% (13/31, decreased VAF>10%) (Figure 1B). The baseline VAF in CALR mutation was high (>35%) in 91.3% (12/13). VAF remained stable in 76.9% (10/13), and loss of CALR mutation was not observed (Figure 1B). TET2 mutations tended to be stable (7/16), but clonal expansion (5/16 of all mutation events at MPN), or acquisition (n=2) could be found during transformation to sAML. DNMT3A mutations remained stable (5/8), exhibited clonal expansion (2/8), or acquisition (n=1) in sAML progression. ASXL1 mutations remained stable (6/7), with clonal expansion (1/7), or acquisition (n=5) during MPN/sAML progression. All EZH2 mutants had clonal expansion (5/5) and one acquired in sAML (Figure 1B). We found that CALR mutationwas often the founding clone with high VAF at MPN phase, stable clone during sAML, and might acquire mutations in signaling pathways (1 CBL, 1 KRAS), epigenetic regulators (2 ASXL1, 1 IDH2), transcription factors (2 RUNX1, 1 BCOR), spliceosome (2 ZRSR2, 1 SF3B1), and cohesin complex (1 STAG2). JAK2 mutationwas often preceded by other ancestral mutations such as TET2, ASXL1, DNMT3A, EZH2, IDH2, SRSF2 or ZRSR2. During evolution, leukemia arose from non- JAK2 mutated clones with mutations in EZH2, DNMT3A, RUNX1, EZH2, SETBP1, or acquisition of TP53, SF3B1, BCOR and STAG2 mutations) in sAML. In outcome, the median time from MPN to sAML was 82 (range 3.7 to 338.5) months. Female gender, loss of JAK2V617F, presence of U2AF1 and absence of IDH1 were associated with shorter time to sAML transformation. No other genetic mutation in our gene panel or the number of mutations harbored by patients in our cohort had significant impact on time to sAML. Marked increase of VAF was observed for JAK2 (7/22) , DNMT3A (1/7) , IDH1 (2/3), IDH2 (1/3), TET2 (3/10) , EZH2 (4/5), C-CBL (1/1) and SRSF2 (1/4). Marked decrease of VAF was observed for JAK2 (4/22), MPL (1/1), DNMT3A (1/7) , ASXL1 (1/8), SF3B1 (2/3), SRSF2 (1/4) and U2AF1 (1/2). Multiple mutational clones were detected for TET2 (two clones in 4 samples and 3 clones in 1). Clonal expansion and reduction were observed in two pairs of samples upon sAML transformation. Conclusions: At the MPN stage, most patients had driver mutations with frequent co-mutations of epigenetic modifier or spliceosome genes. CALR mutant clones were stable while for JAK2, sAML often arose from clones without JAK2V617F which acquired RUNX1, TP53, ASXL1 and K-RAS. Research funding:Ministryof Science and Technology Council,Taiwan (NSTC 112-2314-B-182-055) and Ministry of Health and Welfare, Taiwan (112-TDU-B-222-124001)
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Indran, Tishya, Grigorios T. Gerotziafas, Jawed Fareed y Andrew Spencer. "Malignant Clonal Cell Proliferation in Multiple Myeloma and the Hypercoagulable State". Blood 136, Supplement 1 (5 de noviembre de 2020): 23–24. http://dx.doi.org/10.1182/blood-2020-142781.
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Introduction: The malignant clonal cell proliferation in multiple myeloma (MM) results in significant immune dysregulation through clonal specific T cell expansion, elevated levels of CD4+ CD25+FOXP3+ T regulator cells, downregulation of NK cells, high levels of IL-6 and activation of immunosuppressive tumour associated macrophages (TAM) . However, the mechanisms underlying the hypercoagulable state in MM and predisposing to venous thromboembolic (VTE) complications is unclear. Confounding disease factors is the use of immunomodulatory drugs (IMiDs) such as Lenalidomide, Thalidomide and Pomalidomide causing ubiquitination and degradation of the Ikaros Family Zinc Finger Protein (IKZF)1 and 3 by cereblon which also contributes to the prothrombotic effect despite thromboprophylaxis. Aims: The aim of this study was to analyse the changes in the coagulation profile and plasma cell disease burden with treatment, including Lenalidomide, in patients with MM to help define potential underlying mechanisms for hypercoagulability and thrombosis. Methods: Coagulation profiles and disease markers were retrospectively analysed in 16 MM patients receiving treatment with Daratumumab, Lenalidomide and Dexamethasone (DRd) at The Alfred Hospital, Melbourne from April 2019 to August 2020. Patients enrolled were transplant eligible with MM that was refractory to initial induction therapy with Velcade, Cyclophosphamide and Dexamethasone (VCD). This study was approved by The Alfred Hospital ethics committee. Statistical analysis was performed using descriptive statistics and the Wilcoxon Sign Rank Test to compare the median coagulation profiles and disease markers after 1-2 cycles of DRd and 3-4 cycles of DRd. Biomarkers included Prothrombin Time (PT), Partial Thromboplastin Time (PTT), Fibrinogen, Thrombin Clotting Time (TCT), serum paraprotein (SPEP) and serum free light chain (SFLC) with a p value of <0.05 indicating statistical significance. Results: A total 7 patients had coagulation profiles at the two time points i) post 1-2 cycles and ii) post 3-4 cycles of DRd (Table 1). 9 patients had coagulation profiles only after 3-4 cycles of DRd. A separate analysis was performed using Wilcoxon Sign Rank with imputed median differences to allow the inclusion of the 9 additional patients subsequently increasing the sample size to a total of 16 (Table 2). All patients were on anticoagulation with aspirin (n=14), rivaroxaban (n=1) or clopidogrel (n=1) at the time of the analysis. The analysis showed a statistically significant reduction in PT from median 13.6s (11.9-16.6) to 12.7s (11.7-14.1) with 3-4 cycles DRd in both analysis (p=0.006 and p= 0.027). Fibrinogen levels reduced from median of 5.4 g/L (2.8-8) to 3.98 g/L (2.3- 5.1) after 3-4 cycles (p=0.001). TCT increased after 3-4 cycles of DRd (p=0.005). Serum paraprotein demonstrated statistically significant reduction from 10.8g/L (6 -13) to 7.6 g/L (2-13) after 3-4 cycles (p=0.007). Serum free light chain assay also demonstrated reduction in median values from 82.8mg/L (8.1 - 415.7) to 54.6mg/L (0.8 - 338.6) but was not statistically significant (p=0.084). Discussion: All the patients in this study either responded to treatment or had stable disease after treatment with DRd. The data demonstrate a coagulation response to treatment. The median fibrinogen level that was above the upper limit of normal declined on treatment, the TCT increased and the PT decreased, all coinciding with the statistically significant decline in paraprotein level. A larger study is required to confirm these findings. However, this study has demonstrated that the hypercoagulable state in MM improves with disease response. Disclosures Spencer: Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Pharmamar: Other; Secura Bio: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Other: Grant/Research Support; Janssen: Consultancy, Honoraria, Other: Grant/Research Support, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Other: Grant/Research Support; BMS: Honoraria, Other: Grant/Research Support, Research Funding, Speakers Bureau; TheraMyc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Grant/Research Support; Takeda: Honoraria, Other, Speakers Bureau; Antegene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Grant/Research Support.
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Family, Leila, Su-Jau Yang, Zandra Klippel, Yanli Li, John H. Page, Roberto Rodriguez y Chun Chao. "Risk of Febrile Neutropenia (FN) in Select Myelosuppressive Chemotherapy Regimens". Blood 126, n.º 23 (3 de diciembre de 2015): 3257. http://dx.doi.org/10.1182/blood.v126.23.3257.3257.
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Abstract Introduction Febrile neutropenia (FN) is a serious adverse effect of myelosuppressive chemotherapy, which often results in hospitalization and chemotherapy dose modification. FN risk depends on patient characteristics and chemotherapy regimen risk. Understanding the FN risk associated with individual chemotherapy regimens can help guide the use of prophylactic granulocyte colony-stimulating factor (G-CSF) and patient monitoring. To this end, the NCCN has classified regimens into high (≥20%), intermediate (10%-20%), or low (<10%) FN risk based primarily on clinical trial data. However, even for the same regimen, the FN risk is often higher in clinical practice than in clinical trials. In this study, we assessed the FN risk associated with several regimens for which FN risk has not been determined or has shown substantial variability outside of a clinical trial setting, using data from Kaiser Permanente Southern California (KPSC), a large, community-based practice. Methods Included were patients diagnosed with incident non-Hodgkin's lymphoma (NHL), breast cancer (BC), or multiple myeloma (MM) between 2008 and 2013 at KPSC who initiated the following chemotherapy regimens: bendamustine ± rituximab for NHL; docetaxel, carboplatin, and trastuzumab (TCH) or docetaxel and cyclophosphamide (TC) for BC; or Q4W lenalidomide 25 mg/dexamethasone for MM. Bendamustine ± rituximab, TCH, and lenalidomide are not classified by NCCN; TC is classified as intermediate FN risk but has shown considerable variability of FN incidence when used in clinical practice. Data on cancer diagnosis, chemotherapy use, G-CSF use, neutrophil count, and infections were obtained from KPSC's electronic medical records to estimate the incidence proportions of FN and grade 3 and 4 neutropenia. FN was defined as (1) hospitalization with absolute neutrophil count (ANC) <1000/µL or (2) hospitalization with primary or secondary diagnosis codes of neutropenia (ICD-9 288.0x) and fever (ICD-9 780.6), diagnosis code for bacterial/fungal infection, or antibiotic use. Grade 3 neutropenia was defined as ANC ≥500/µL to <1000/µL; grade 4 neutropenia as ANC <500/µL. Patients who received prophylactic G-CSF within 5 days of chemotherapy initiation were excluded from analysis. Results Overall, 40 (12%) NHL patients; 149 (24%) and 340 (28%) BC patients who received TCH and TC, respectively; and 0 (0%) MM patients were excluded due to prophylactic G-CSF. Over the first 6 cycles of bendamustine (median 338.4 mg/m2) ± rituximab for NHL patients (n = 307), 7.2% experienced FN, 4.2% grade 3 neutropenia, and 17.6% grade 4 neutropenia. Over the first 6 cycles of TCH for BC patients (n = 462), 24.2% experienced FN, 10.6% grade 3 neutropenia, and 44.6% grade 4 neutropenia. Over the first 6 cycles of TC for BC patients (n = 859), 20.5% experienced FN, 9.5% grade 3 neutropenia, and 37.5% grade 4 neutropenia. Over the first 4 cycles of lenalidomide/dexamethasone for MM patients (n = 186), 3.8% experienced FN, 5.9% grade 3 neutropenia, and 18.3% grade 4 neutropenia (Table 1). Conclusions Using NCCN criteria, bendamustine ± rituximab for NHL and lenalidomide/dexamethasone for MM would be classified as low-FN-risk regimens (<10%). By contrast, BC regimens TCH and TC would be classified as high-FN-risk regimens (>20%) based on our data. These results could help inform prophylactic G-CSF use for the selected regimens in clinical practice. Table 1. Number and Incidence Proportion of Neutropenic Outcomes Overall and by Cycle Cancer: Regimen Cycle Patients n FN Events n (%) Grade 3 Neutropenia Events n (%) Grade 4 Neutropenia Events n (%) NHL: Bendamustine ± rituximab Overall 307 22 (7.2) 13 (4.2) 54 (17.6) 1 307 12 (3.9) 5 (1.6) 28 (9.1) 2 225 3 (1.3) 4 (1.8) 21 (9.3) 3 173 2 (1.2) 4 (2.3) 15 (8.7) 4 130 2 (1.5) 4 (3.1) 10 (7.7) 5 92 4 (4.4) 4 (4.4) 8 (8.7) 6 69 2 (2.9) 2 (2.9) 0 (0) BC: TCH Overall 462 112 (24.2) 49 (10.6) 206 (44.6) 1 462 70 (15.2) 39 (8.4) 138 (29.9) 2 326 13 (4.0) 15 (4.6) 42 (12.9) 3 282 17 (6.0) 9 (3.2) 39 (13.8) 4 247 6 (2.4) 8 (3.2) 31 (12.6) 5 199 4 (2.0) 6 (3.0) 25 (12.6) 6 169 8 (4.7) 3 (1.8) 12 (7.1) BC: TC Overall 859 176 (20.5) 82 (9.5) 322 (37.5) 1 859 126 (14.7) 51 (5.9) 266 (30.9) 2 649 21 (3.2) 42 (6.5) 82 (12.6) 3 571 19 (3.3) 23 (4.0) 62 (10.9) 4 511 14 (2.7) 22 (4.3) 45 (8.8) 5 94 1 (1.1) 3 (3.2) 9 (9.6) 6 84 2 (2.4) 1 (1.2) 2 (2.4) MM: Lenalidomide / dexamethasone Overall 186 7 (3.8) 11 (5.9) 34 (18.3) 1 186 2 (1.1) 8 (4.3) 17 (9.1) 2 101 3 (3.0) 5 (5.0) 14 (13.9) 3 63 2 (3.2) 2 (3.2) 8 (12.7) 4 37 0 (0) 0 (0) 4 (10.8) Disclosures Family: Amgen Inc.: Research Funding. Klippel:Amgen Inc.: Employment, Equity Ownership. Li:Amgen Inc.: Employment, Equity Ownership. Page:Amgen Inc.: Employment, Equity Ownership.
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Kidwell, Kyle Michael, Camila Albo, Michael Pope, Latanya Bowman, Hongyan Xu, Leigh Wells, Nadine Barrett et al. "Characteristics of Sickle Cell Patients with Frequent ED Visits and Hospitalizations: Demographic, Clinical, Laboratory and Psycho-Social Aspects". Blood 128, n.º 22 (2 de diciembre de 2016): 2501. http://dx.doi.org/10.1182/blood.v128.22.2501.2501.
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Abstract Vaso-occlusive episodes (VOE), are considered a hallmark of sickle cell disease (SCD), and account for >90% of health care encounters for this patient population. Although an orphan disease (total number of patients in the US ~110,000), SCD has a huge medical-economic impact, with annual hospitalization costs of nearly $ 0.5 billion by 2004 figures, mostly for VOEs. The Cooperative Study of Sickle Cell Disease (CSSCD) was a large natural history study, carried in 23 Centers in the US, enrolling >3000 patients between 1977-93. An analysis of the frequency of VOEs in CSSCD showed that the majority of patients (80%) experienced 0-3 major pain crises/year; this was similar across all genotypes of the disease (SS, SC, Sβ0 thalassemia, Sβ+ thalassemia). Only a small minority (~5%) experienced ≥6 VOEs/year. Similar findings have been reported in subsequent, smaller studies, with 5-10% of SCD patients with frequent ED visits and hospitalizations. Hydroxyurea (HU), the only disease modifying agent approved for adults with SCD, results in a ~50% reduction in the frequency of VOEs and hospitalizations. Despite this, HU is underutilized in SCD. Recent NIH evidence based guidelines includes strong recommendations for HU therapy in the majority of SCD patients. Although 230 of the 650 adult SCD patients at our Center are prescribed HU, in a recent study we found that ~40% of these patients were non-adherent, based upon their own admission, and/or the lack of anticipated change in several laboratory parameters (Hb F, MCV, Hb, WBC, reticulocyte and platelet count). A minority of SCD patients followed at our Center have frequent ED visits and hospitalizations. We conducted a study analyzing demographic, clinical, laboratory and psycho-social characteristics of 25 patients with ≥6 ED visits and hospitalizations per year (high utilizers), and compared these with 9 patients (controls) who experienced ≤2 ED visits/hospitalizations (low utilizers). Data on gender, age, genotype, number of ED visits and hospitalizations, CBC, chemistry panel, Hb F, HU usage, opioid use (morphine equivalents), education level, employment, annual income and marital status were collected. All subjects were also administered a depression, anxiety and Health Locus of Control Questionnaire, and underwent quantitative sensory testing (QST) with three different modalities: pressure pain sensitivity with a hand held, computerized algometer (AlgoMed, Medoc, Israel), heat and cold sensitivity (Q-Sense, Medoc, Israel) and Von Frey monofilament testing for neuropathic pain. Of the 25 patients (13M, 12F), 19 were SS, 4 SC, 1 SD-Los Angeles and 1 Sdβ-thalassemia. The median age was 28 (range 21-49). In the low utilizer group (6M, 3F) all were SS with a median age of 39 (range 23-46). The average number of hospitalizations in the high utilizer group was 15.6/year (range 6-33), while in the low utilizer group it was 0.44/year. Annual opioid usage as mg morphine equivalents was significantly higher in the high utilizers (12125.7 mg vs 2423.1 mg, p=0.0048). 19/25 (76%) of high utilizers, and 7/9 (78%) of low utilizers were on HU. Laboratory data on both groups are shown in Table 1. High utilizers had significantly higher WBC, ANC, total bilirubin and lower MCV. Hb F was also lower in the high utilizers (11.8% vs 17.5%) although this did not reach significance. QST results showed significantly lower pressure pain threshold at ulna (224.4 KPa vs 338.9 KPa, p=0.04), and higher baseline sensitivity with von Frey monofilament (0.92 vs 0.33, p=0.056) in the high utilizer group. High utilizers also had a higher anxiety score (9.0 vs 4.6, p=0.039) and depression score (10.0 vs 6.0, p=0.051). While the low utilizers had higher education levels with more associate and bachelor degrees (p=0.009), there was no difference in household income. These data show that multiple factors contribute to high health care utilization in SCD; these include biologic (younger age, disease severity as indicated by higher WBC and ANC, bilirubin, opioid induced hyperalgesia, and poor adherence to HU) as well as psycho-social factors (higher anxiety and depression scores, lower educational status). A multi-disciplinary and multi-faceted approach, including a sound patient education and transition program, a concerted effort to increase adherence to HU therapy, and psycho-social as well as pharmacologic approaches to anxiety and depression will be required to address this complex problem. Disclosures Kutlar: Novartis Pharmaceuticals: Research Funding.
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Chapin, John C., Katrina Piskorski, Stephen J. Eyler, Richard J. H. Smith y Jeffrey Laurence. "The Alternate Complement Pathway in Thrombotic Thrombocytopenic Purpura". Blood 120, n.º 21 (16 de noviembre de 2012): 3342. http://dx.doi.org/10.1182/blood.v120.21.3342.3342.
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Abstract Abstract 3342 The thrombotic microangiopathies (TMA) thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS) involve progressive microvascular thrombi, endothelial cell (EC) injury, vascular ischemia, and severe end-organ damage. Acquired TTP is often associated with autoantibody-mediated suppression of the ADAMTS13 vWF cleaving protease, causing vWF multimer accumulation and platelet aggregation. aHUS is associated with dysregulation of the alternate complement pathway through mutation in and/or autoantibodies against, complement regulatory proteins. It is responsive to the anti-C5 mAb eculizumab. TTP, by contrast, usually responds to plasma exchange, but in the refractory setting there are few effective treatments. We hypothesized that dysregulation of the alternate complement pathway represents a susceptibility factor for EC injury in at least a subset of TTP patients. Our objective was to identify the degree of complement dysregulation in acute TTP vs. other TMAs in vivo, and correlate these data with (1) the ability of plasma from acute TTP and aHUS patients to induce apoptotic injury in primary human microvascular EC in vitro and (2) the potential of eculizumab to block this injury. Plasmas from acute TMA patients (TTP n=12, malignancy-associated aHUS n=6, ticlopidine-associated TTP n=4, systemic Degos disease n=1), and healthy controls (n=4) were collected at time of presentation. Samples were assayed for terminal complement components sC5b-9 (MAC, membrane attack complex) and C5a by ELISA. Genomic DNA was isolated from these plasmas and amplified by standard DNA PCR, followed by semi-nested PCR using primers designed around the exon sequences of complement factor H (CFH), complement factor I (CFI) and MCP (CD46) known to be mutated in 60–80% of aHUS cases. Amplicons were sequenced and correlated with a database of previously reported mutations and SNPs with varying degrees of functional significance in the complement regulatory pathway. In our in vitro model for plasma-mediated EC injury, primary human dermal microvascular ECs were starved in medium lacking EC growth factors and then incubated for 18–24 hours with 1–2% plasma (v/v) in the presence or absence of pharmacologic levels of anti-C5 mAb (100–250μg/ml). Apoptosis was assessed by ELISA-based quantification of cytoplasmic histone-associated DNA fragments from cell lysate and propidium iodide labeling with construction of DNA histograms and assessment of A0 peaks by flow cytometry. We found significantly elevated plasma levels of C5a in all subsets of patients with TMAs compared to control plasma (42.8 ng/ml +/− 6.2 vs. 32 ng/ml +/− 6.8; p=0.014). We also found markedly elevated levels sC5b-9 in these TMAs compared to controls (1852.0 ng/ml +/− 1169.8 vs 598.8 +/− 338.7; p=0.012). Little variation was seen in TTP vs. aHUS and other TMAs, regardless of ADAMTS13 status. Complement mutations in CFH and CFI were identified in 14 (66.7%) of TMA patients: 41.6% TTP, 60% malignancy-aHUS, 100% ticlopidine TTP. In terms of interference with TMA plasma-induced MVEC apoptosis in vitro, EC injury was blocked by anti-C5 mAb eculizumab in 8 of 19 cases (5 TTP, 2 aHUS, 1 Degos). Correlation of sensitivity to plasma-mediated EC apoptosis and blockade with eculizumab with levels of terminal complement components, presence of complement regulatory factor mutations, levels of ADAMTS13 activity, and anti-ADAMTS13 antibody titers are underway. We conclude that dysregulation of the alternate complement pathway may represent a susceptibility factor in the pathophysiology of many TMAs, not only aHUS. Blockade of C5 may offer a therapeutic avenue for some patients with refractory TTP. Indeed, in a recent report our group noted the rescue of a patient with classic TTP, including ADAMTS13 activity <5% and anti-ADAMTS13 IgG, refractory to plasma exchange and a variety of immune suppressive regimens, utilizing eculizumab (Chapin J, et al. Brit J Hematol, 2012). Defining this subset, and the potential for clinical response to anti-C5 therapy, will involve exploration of other complement and complement regulatory factor mutations and autoantibodies. Disclosures: Off Label Use: Eculizumab is not FDA approved for use in the treatment of TTP. Laurence:Alexion Pharmaceuticals: Consultancy, Speakers Bureau.
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Suzuki, O., M. Koura, Y. Noguchi, K. Uchio-Yamada y J. Matsuda. "319 REDUCED SUPEROVULATION EFFICIENCY BY HIGH-DOSE TREATMENT OF DEHYDROEPIANDROSTERONE IN MICE". Reproduction, Fertility and Development 25, n.º 1 (2013): 307. http://dx.doi.org/10.1071/rdv25n1ab319.
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Strain differences in in vitro fertilizability still constitute a serious problem in mouse reproduction. To improve the in vitro fertilizability of mouse oocytes, we examined the effect of implanting time-release pellets of dehydroepiandrosterone (DHEA), a testosterone precursor, in female mice on oocyte fertilizability. The DHEA pellets (0.25, 1.5, or 5 mg pellet–1, 21-day release form, Innovative Research of America, Sarasota, FL, USA) or corresponding placebo pellets were implanted subcutaneously in 9-week-old female 129X1/SvJJmsSlc mice. On Day 18 of implantation, superovulation was induced in these females by injections of pregnant mare serum gonadotropin (PMSG) and hCG 48 h apart. On Day 21, IVF was conducted using oocytes collected from the oviducal ampullae of these females and epididymal sperm from Slc : ICR male mice using TYH medium. Then, the embryos were cultured in vitro in Whitten’s medium for 96 h. Plasma steroid levels and expression of 5 ovarian proteins (PTEN and receptors for FSH, androgen, oestrogen, and progesterone) at oocyte collection were measured by enzyme immunoassay and quantitative Western blots, respectively. Embryo development into 2-cell and blastocyst stages at each dose at 24 h and 96 h after insemination, respectively, were compared between DHEA and placebo groups using weighted ANOVA with angular transformations. Other observed values were compared using Student’s t-test. Treatment with DHEA suppressed the numbers of ovulated oocytes in the 1.5 and 5 mg groups (DHEA v. placebo: 21.0 ± 2.6 v. 32.5 ± 2.8 and 19.9 ± 1.4 v. 27.1 ± 1.6, respectively, n = 10; P < 0.05), but not in the 0.25 mg group (26.6 ± 3.2 v. 24.8 ± 2.4). Treatment with DHEA did not affect the percentages of 2-cell embryo formation at any dose, ranging 50 to 60%. In the 0.25 mg group, DHEA treatment tended to increase blastocyst formation rate (1.8 ± 0.8% v. 0.4 ± 0.4%; not significant). However, the treatment at 1.5 mg suppressed the rate (0.0 ± 0.0% v. 3.1 ± 0.7%; P < 0.05) and treatment at 5 mg did not affect the rate (1.3 ± 0.9% v. 0.8 ± 0.6%). Plasma testosterone levels were increased by DHEA at 1.5 and 5 mg (338.2 ± 39.8 v. 197.0 ± 8.9 pg mL–1 and 534.9 ± 111.4 v. 241.8 ± 34.4 pg mL–1, respectively, n = 6; P < 0.05), but not at 0.25 mg (247.4 ± 22.0 v. 252.5 ± 35.6 pg mL–1, n = 6). No significant difference was induced by DHEA in plasma DHEA, progesterone, or oestradiol at any doses. Ovarian PTEN protein was more abundant in DHEA group than in placebo group at 5 mg (P < 0.05), tended to be more abundant at 1.5 mg (P ≈ 0.14), and was not different at 0.25 mg (P ≈ 0.35). The amounts of the 4 receptor proteins were not significantly changed by DHEA at any dose. These results suggest that DHEA at a low dose (e.g. 0.25 mg pellets for 21 days) might have a potential to improve in vitro fertilizability of mouse oocytes. Higher doses of DHEA reduced superovulation efficiency, perhaps because of the high testosterone level induced by the high-dose treatment of DHEA. The high testosterone level might upregulate ovarian PTEN expression, which might suppress ovarian primordial follicle activation. A more detailed study is needed to determine the optimal dose, timing, and duration of DHEA treatment for the improvement of female fertilizability.
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Sousa Neto, Ivo Vieira de, Nuno Manuel Frade de Sousa, Frederico Ribeiro Neto, Joao Henrique Falk Neto y Ramires Alsamir Tibana. "Time Course of Recovery Following CrossFit® Karen Benchmark Workout in Trained Men". Frontiers in Physiology 13 (19 de agosto de 2022). http://dx.doi.org/10.3389/fphys.2022.899652.
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The establishment of fatigue following the acute exercise stimulus is a complex and multi-factorial process, that might arise due to a range of distinct physiological mechanisms. However, a practical method of assessing CrossFit® athletes’ recovery status has been neglected entirely in real-world sporting practice. The study describes the acute and delayed time course of recovery following the CrossFit® Benchmark Workout Karen. Eight trained men (28.4 ± 6.4 years; 1RM back squat 139.1 ± 26.0 kg) undertook the Karen protocol. The protocol consists of 150 Wall Balls (9 kg), aiming to hit a target 3 m high. Countermovement jump height (CMJ), creatine kinase (CK), and perceived recovery status scale (PRS) (general, lower and upper limbs) were assessed pre, post-0h, 24, 48 and 72 h after the session. The creatine kinase concentration 24 h after was higher than pre-exercise (338.4 U/L vs. 143.3 U/L; p = 0.040). At 48h and 72 h following exercise, CK concentration had returned to baseline levels (p > 0.05). The general, lower and upper limbs PRS scores were lower in the 24-h post-exercise compared to pre-exercise (general PRS: 4.7 ± 1.5 and 7.7 ± 1.7; p = 0.013; upper limbs PRS: 6.6 ± 1.3 and 7.5 ± 1.3; p = 0.037; lower limbs PRS: 3.9 ± 2.5 and 7.3 ± 0.1; p = 0.046). Our findings provide insights into the fatigue profile and recovery in acute CrossFit® and can be useful to coaches and practitioners when planning training programs. Moreover, recovery status can be useful to optimize training monitoring and to minimize the potential detrimental effects associated with the performance of repeated high-intensity sessions of CrossFit®.
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Janela, Dora, Fabíola Costa, Maria Molinos, Robert G. Moulder, Jorge Lains, Justin K. Scheer, Virgílio Bento, Vijay Yanamadala, Steven P. Cohen y Fernando Dias Correia. "Fear avoidance beliefs in upper-extremity musculoskeletal pain conditions: secondary analysis of a prospective clinical study on digital care programs". Pain Medicine, 6 de octubre de 2022. http://dx.doi.org/10.1093/pm/pnac149.
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Abstract Background Fear-avoidance beliefs (FAB) have been associated with poorer prognosis and decreased adherence to exercise-based treatments in musculoskeletal (MSK) pain. However, the impact of high FAB on adherence and outcomes in upper extremity musculoskeletal (UEMSK) pain is poorly explored, particularly through exercise-based digital care programs (DCP). Objective Assess the adherence levels, clinical outcomes and satisfaction in patients with UEMSK pain and elevated FAB after a fully remote multimodal DCP. Associations between FABQ-PA and clinical outcomes were conducted. Methods Secondary analysis of an ongoing clinical trial. Participants with UEMSK pain (shoulder, elbow, and wrist/hand) and elevated FAB - physical activity (FABQ-PA ≥ 15) were included. Adherence (completion rate, sessions/week, total exercise time) and mean change in clinical outcomes - disability (QuickDASH), numerical pain score, FABQ-PA, anxiety (GAD-7) and depression (PHQ-9)- between baseline and end-of-program were assessed. Associations between FABQ-PA and clinical outcomes were conducted. Results 520 participants were included, with mean baseline FAB 18.02 (SD 2.77). Patients performed on average 29.3 exercise sessions (2.8 sessions/week), totalizing 338.2 exercise minutes. Mean satisfaction was 8.5/10 (SD 1.7). Significant improvements were observed in all clinical outcomes. Higher baseline FAB were associated with higher baseline disability (p<.001) and smaller improvements in disability (p<.001) and pain (p=.001). Higher engagement was associated with greater improvements in FABQ-PA (p = 0.043) and pain (p = 0.009). Conclusions This study provides evidence of the potential benefits of a structured and multimodal home-based DCP in the management of UEMSK pain conditions in patients with elevated FAB in a real-world context. Trial Registration ClinicalTrials.gov, NCT04092946. Registered 17/09/2019; https://clinicaltrials.gov/ct2/show/NCT04092946
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Drozdzewska, Karolina, Judith Winter, Ann Kristin Barton, Roswitha Merle y Heidrun Gehlen. "Influence of feeding and other factors on adrenocorticotropin concentration and thyrotropin‐releasing hormone stimulation test in horses and ponies". Equine Veterinary Journal, 27 de noviembre de 2023. http://dx.doi.org/10.1111/evj.14030.
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AbstractBackgroundThe basal (bACTH) and post‐thyrotropin‐releasing hormone stimulation concentration of adrenocorticotropin (pACTH) are recommended for diagnosis of pituitary pars intermedia dysfunction (PPID). Many factors influence bACTH (e.g., disease, age, month) and some affect the results only in autumn (e.g., breed, colour, sex). There are discrepancies about the impact of feeding on b/pACTH.ObjectivesTo determine whether feeding, month, age, breed, colour, sex and body condition score affect b/pACTH.Study designProspective crossover.MethodsSixty‐one animals were divided into groups: healthy, PPID, treated‐PPID. The b/pACTH was measured three times (1 mg protirelin; blood collection after 10 min; mid‐November to mid‐July) after different feedings: fasting, hay, hay + grain. Friedman's test was applied to evaluate the influence of feeding on b/pACTH and linear mixed model to evaluate impact of further factors.ResultsThe b/pACTH was not significantly affected by feeding (p = 0.7/0.5). The bACTH was lowest in healthy (29.3 pg/mL, CI 9–49.5 pg/mL) and highest in PPID‐group (58.9 pg/mL, CI 39.7–78.1 pg/mL). The pACTH was significantly lower in healthy (396.7 pg/mL, CI 283.2–510.1 pg/mL) compared to PPID (588.4 pg/mL, CI 480.7–696.2 pg/mL) and treated‐PPID group (683.1 pg/mL, CI 585.9–780.4 pg/mL), highest in July (881.2 pg/mL, CI 626.3–1136.3 pg/mL) and higher in grey (723.5 pg/mL, CI 577.5–869.4 pg/mL) than other colours (338.7 pg/mL, CI 324.8–452.5 pg/mL). The size of effect for those variables was >0.5.Main limitationsSmall number of animals, subsequent bACTH measurements were significantly lower in each horse.ConclusionsThere was no evidence that feeding influences the b/pACTH. There was evidence that pergolide affects the bACTH but it had little effect on pACTH. Further investigation of the impact of month and coat colour on b/pACTH is warranted to better interpret the results.
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Wittenstein, Olaf, Fabian Krause, Mirko Fischer, Justus Domschikowski, Mirko Nitsche, Christoph Henkenberens, Daniel Habermehl y Juergen Dunst. "The tumor core boost study: A feasibility study of radical dose escalation to the central part of large tumors with an integrated boost in the palliative treatment setting". Strahlentherapie und Onkologie, 20 de julio de 2022. http://dx.doi.org/10.1007/s00066-022-01976-5.
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Abstract Purpose For patients with large tumors palliative radiotherapy often is the only local treatment option. To prevent toxicity the administered doses are low. Dose escalation to the tumor could be an option to better smyptom control and prolong local control rates. In this prospective study we used a very pragmatic approach with a simultaneously integrated boost (SIB) to an almost geometrically defined tumor core to achieve this. The primary endpoint was to demonstrate feasibility. Method Patients with solid tumors > 4 cm in diameter of different histologies were eligible in this single arm, prospective, multi-institutional clinical feasibility trial with two treatment concepts: 5 × 5 Gy with an integrated boost to the tumor core of 5 × 10 Gy or 10 × 3 Gy with a boost of 10 × 6 Gy. The objective of dose escalation in this study was to deliver a minimum dose of 150% of the prescribed dose to the gross tumor volume (GTV) tumor core and to reach a maximum of at least 200% in the tumor core. Results In all, 21 patients at three study sites were recruited between January 2019 and November 2020 and were almost evenly spread (9 to 12) between the two concepts. The treated planning target volumes (PTV) averaged 389.42 cm3 (range 49.4–1179.6 cm3). The corresponding core volumes were 72.85 cm3 on average (range 4.21–338.3 cm3). Dose escalation to the tumor core with mean doses of 167.7–207.7% related to the nonboost prescribed isodose led to PTV mean doses of 120.5–163.3%. Treatment delivery and short-term follow-up was successful in all patients. Conclusions Palliative radiotherapy with SIB to the tumor core seems to be a feasible and well-tolerated treatment concept for large tumors. The applied high doses of up to 50 Gy in 5 fractions (or 60 Gy in 10 fractions) did not cause unexpected side effects in the 42 day follow-up period. Further research is needed for more information on efficacy and long-term toxicity.
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Zhao, Qian, Yongheng Chen, Licheng Diao, Shimin Zhang, Dan Wu, Feng Xue, Qunli Xia, Hao Li, Jie Zheng y Hua Cao. "Identification of distinct cytokine/chemokine profiles in dermatomyositis with anti-transcriptional intermediary factor 1-γ antibody". Rheumatology, 11 de septiembre de 2021. http://dx.doi.org/10.1093/rheumatology/keab625.
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Abstract Objectives Dermatomyositis (DM) and clinically amyopathic dermatomyositis (CADM) patients with positive expression of anti-transcription intermediary factor 1-γ (anti-TIF1-γ) antibody (Ab) are characterized by distinct clinicopathological features. We aimed to determine the role of cytokine/chemokine profiles in the classification of anti-TIF1-γ positive DM/CADM patients. Methods Serum levels of 24 cytokines/chemokines were measured in 27 anti-TIF1-γ positive DM/CADM patients by a Luminex 200 system. Principal components analysis (PCA) and unsupervised hierarchical clustering were used to reduce variables and establish patient subgroups. Spearman’s correlation coefficient was calculated between cytokine/chemokine levels and disease activity markers. Results Among anti-TIF1-γ positive DM/CADM patients, two distinct patient clusters were identified. The diagnosis of CADM was more common in Cluster 1 than in Cluster 2 (58.3% vs 6.7%, p = 0.008). Skin disease activity was higher in Cluster 2 than in Cluster 1 as measured by CDASI-A (38.6 ± 10.4 vs 25.3 ± 10.0, p = 0.003). Patients within Cluster 2 exhibited significant muscle weakness (MRC ≤ 3, 33.3% vs 0.0%, p = 0.047), higher levels of anti-TIF1-γ Ab (92.4 ± 20.6 vs 66.9 ± 13.9, p = 0.001), and an increased malignancy rate (73.3% vs 25.0%, p = 0.021). Cluster 2 exhibited higher serum levels of CXCL10 (564.2 ± 258.8 vs 122.0 ± 97.8, p < 0.001), CCL2 (1136.6 ± 545.4 vs 441.6 ± 163.3, p < 0.001), Galectin-9 (38879.6 ± 20009.3 vs 12612.4 ± 6640.0, p < 0.001), IL-18 (436.1 ± 188.9 vs 243.0 ± 114.5, p = 0.003), TNF-α (9.3 ± 3.8 vs 5.6 ± 2.4, p = 0.007), and TNFRI (1385.1 ± 338.2 vs 2605.6 ± 928.5, p < 0.001) than Cluster 1. Conclusion In anti-TIF1-γ positive DM/CADM, we identified a “skin-predominant” cluster and a “hyperinflammation” cluster based on the cytokine/chemokine profiles. Cytokine/chemokine profiles in anti-TIF1-γ positive DM/CADM can identify discrete clusters of patients with different disease patterns, organ involvements, and clinical outcomes.
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Ufnal, Marcin, Klaudia Maksymiuk, Mateusz Szudzik y Dawid Chabowski. "Abstract P326: Trimethylamine, A Gut Bacteria Metabolite And Air Pollutant, Increases Blood Pressure, Proteinuria And Markers Of Kidney Damage In Rats." Hypertension 79, Suppl_1 (septiembre de 2022). http://dx.doi.org/10.1161/hyp.79.suppl_1.p326.
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Trimethylamine oxide (TMAO) is a biomarker in cardiovascular and renal diseases. TMAO originates from the oxidation of trimethylamine (TMA), a product of gut microbiota and industry-derived pollutant, by flavin monooxygenases (FMOs). The effect of chronic exposure to TMA on cardiovascular and renal systems is undetermined. Metabolic, hemodynamic, echocardiographic, biochemical and histopathological evaluations were performed in male, 12-week-old rats receiving water (control group) or TMA (500 μM/day) in water for 18 weeks (each group: n=9). TMA and TMAO levels, the expression of FMOs and RAS genes were evaluated in various tissues. Data are expressed as the median (Q1; Q3) or mean ± SE. In comparison to controls, rats receiving TMA had significantly increased systolic blood pressure (mmHg; 151.2 ± 7.0 vs. 126.3 ± 3.8; P<0.05), urine protein to creatinine ratio [3.4 (3.3; 4.2) vs. 1.6 (1.5; 2.8); P<0.05], urine KIM-1 levels (pg/ml; 3 519.0 ± 301.6 vs. 2 338.3 ± 244.0; P<0.05), mild degeneration of renal bodies with glomerulosclerosis, and hypertrophy of the tunica media of arteries and arterioles. There was no significant difference between the groups in body weight, water-electrolyte balance and echocardiographic parameters and RAS expression. TMA group had marginally increased 24hr TMA urine excretion [μM; 5.0 (3.8; 5.5) vs. 0.3 (0.2; 0.4); P<0.01]. However, TMA serum level [μM/l; 0.32 (0.27; 0.64) vs. 0.04 (0.03; 0.04)], TMAO serum level [49.5 (45.8; 84.8) vs. 9.0 (6.5; 11.9)] and 24hr TMAO urine excretion [255.4 (237.2; 311.1) vs. 10.6 (10.3; 11.2); all P<0.001] were increased. TMA group had lower FMOs expression in the kidneys but significantly increased TMAO levels in the liver [μM/kg; 35.9 (29.3; 41.9) vs. 5.4 (4.2; 9.6)], renal cortex [189.7 (82.2; 204.5) vs. 14.5 (13.1; 21.9)], renal medulla [192.0 (74.0; 213.7) vs. 18.5 (14.4; 27.8)] and heart [96.3 (90.3; 112.4) vs. 3.2 (2.4; 5.8); all P<0.001]. In conclusion, chronic exposure to TMA increases blood pressure and increases markers of kidney damage including proteinuria and KIM-1. TMA is rapidly oxidized to TMAO in rats, which may limit toxic effects of TMA.