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1

Pembrolizumab Plus Ipilimumab Following Anti-PD-1/L1 Failure in Melanoma

المصدر: J Clin Oncol

الوصف: PURPOSE Combination of antiprogrammed cell death protein-1 (PD-1) plus anti–cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) immunotherapy shows greater response rates (RRs) than anti-PD-1 antibody alone in melanoma, but RR after initial anti-PD-1 and programmed death ligand-1 (PD-L1) antibody progression awaits robust investigation. Anti-CTLA-4 antibody alone after anti-PD-1/L1 antibody progression has a historical RR of 13%. We report the results of the first prospective clinical trial evaluating ipilimumab 1 mg/kg plus pembrolizumab following progression on anti-PD-1 immunotherapy. METHODS Patients with advanced melanoma who had progressed on anti-PD-1/L1 antibody as immediate prior therapy (including non–anti-CTLA-4 antibody combinations) were eligible. Patients received pembrolizumab 200 mg plus ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary end point was RR by irRECIST. After 35 patients, the trial met the primary end point and was expanded to enroll a total of 70 patients to better estimate the RR. RESULTS Prior treatments included 60 on anti-PD-1 antibody alone and 10 on anti-PD-1/L1 antibody–based combinations. Thirteen patients had progressed in the adjuvant setting. The median length of prior treatment with anti-PD-1/L1 antibody was 4.8 months. Response assessments included five complete and 15 partial responses, making the irRECIST RR 29% among the entire trial population. The median progression-free survival was 5.0 months, and the median overall survival was 24.7 months. The median duration of response was 16.6 months. There was no difference in median time on prior anti-PD1/L1 or time to PD1 + CTLA4 initiation between responders and nonresponders. Grade 3-4 drug-related adverse events occurred in 27% of patients. Responses occurred in PD-L1–negative, non-T-cell–inflamed, and intermediate tumor phenotypes. CONCLUSION To our knowledge, this is the first prospective study in melanoma of pembrolizumab plus low-dose ipilimumab after anti-PD-1/L1 immunotherapy failure, demonstrating significant antitumor activity and tolerability.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f53f50387d5994f75ceeba750e8bc2f9Test
https://doi.org/10.1200/jco.21.00079Test

2

H3K27me3 immunostaining is diagnostic and prognostic in diffuse gliomas with oligodendroglial or mixed oligoastrocytic morphology

المؤلفون: Claudio Ghimenton, Giampietro Pinna, Michele Simbolo, Francesco Sala, Matteo Brunelli, Serena Ammendola, Maria L. Piredda, Valeria Barresi, Nicolò Caldonazzi, Aldo Scarpa, Pietro Luigi Poliani

المصدر: Virchows Archiv

مصطلحات موضوعية: Male, Pathology, Time Factors, H3K27me3, 1p/19q Codeletion, Histones, 0302 clinical medicine, Recurrence, Medicine, Mutational status, Tumor, Brain Neoplasms, Astrocytoma, General Medicine, Middle Aged, Immunohistochemistry, Phenotype, Isocitrate Dehydrogenase, Progression-Free Survival, Local, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Pair 1, Original Article, Female, Chromosome Deletion, Human, Adult, X-linked Nuclear Protein, medicine.medical_specialty, Oligodendroglioma, macromolecular substances, Chromosomes, Pathology and Forensic Medicine, 03 medical and health sciences, Predictive Value of Tests, Biomarkers, Tumor, Humans, Molecular Biology, 1p/19q codeletion, Chromosomes, Human, Pair 19, Mutation, Neoplasm Recurrence, Local, ATRX, Pair 19, business.industry, Cell Biology, medicine.disease, Neoplasm Recurrence, business, Biomarkers, 030217 neurology & neurosurgery, Immunostaining

الوصف: Oligodendroglioma is defined by IDH mutation and 1p/19q codeletion. The latter is mutually exclusive to ATRX immunohistochemical loss and has been recently associated with the loss of H3K27me3 immunostaining. We aimed to assess the diagnostic and prognostic value of H3K27me3 immuno-expression in diffuse gliomas with oligodendroglial or mixed oligoastrocytic morphology. H3K27me3 immunostaining was performed in 69 diffuse gliomas with oligodendroglial (n = 62) or oligoastrocytic (n = 7) morphology. The integration with routinely assessed IDH mutations, ATRX immunostaining, and 1p/19q codeletion classified these cases as 60 oligodendroglial and 9 astrocytic. H3K27me3 was lost in 58/60 oligodendrogliomas with retained (n = 47) or non-conclusive (n = 11) ATRX staining, 3/6 IDH-mutant astrocytomas with ATRX loss, and 3/3 IDH-wt astrocytomas. H3K27me3 was retained in 2/60 oligodendrogliomas with retained ATRX, and in 3/6 IDH-mutant astrocytomas, two of which had lost and one retained ATRX. The combination of H3K27me3 and ATRX immunostainings with IDH mutational status correctly classified 55/69 (80%) cases. In IDH-mutant gliomas, ATRX loss indicates astrocytic phenotype, while ATRX retention and H3K27me3 loss identify oligodendroglial phenotype. Only 14 (20%) IDH-mutant cases with retained ATRX and H3K27me3 or inconclusive ATRX immunostaining would have requested 1p/19q codeletion testing to be classified. Furthermore, H3K27me3 retention was associated with significantly shorter relapse-free survival (P < 0.0001), independently from IDH mutation or 1p/19q codeletion (P < 0.005). Our data suggest that adding H3K27me3 immunostaining to the diagnostic workflow of diffuse gliomas with oligodendroglial or mixed morphology is useful for drastically reducing the number of cases requiring 1p/19q codeletion testing and providing relevant prognostic information.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::004a3d6c08fbad92e19ccd73c786a709Test
https://doi.org/10.1007/s00428-021-03134Test-1

3

Using adjuvant pharmacotherapy in the treatment of type 1 diabetes

المؤلفون: Åke SjöholmÅke Sjöholm

المصدر: Expert Opinion on Pharmacotherapy. 22:2143-2148

الوصف: Introduction: Insulin and its analogues have so far been the only approved treatment for type 1 diabetes in Europe, while in the US, the amylin analog pramlintide is approved for adjuvant use with ...

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5d461e3254acfa3b9483a59acaf274bfTest
https://doi.org/10.1080/14656566.2021.1939679Test

4

MMP‐7 affects peritoneal ultrafiltration associated with elevated aquaporin‐1 expression via MAPK/ERK pathway in peritoneal mesothelial cells

المؤلفون: Jun Ai, Gong Nirong, Daming Zuo, Fen Zhang, Zhuojun Zheng, Zhiwen Xiao, Qiaomu Yang, Yue Yin, Jia Zhou

المصدر: Journal of Cellular and Molecular Medicine

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, MAPK/ERK pathway, MAP Kinase Signaling System, Cell osmotic pressure, Cellular homeostasis, Matrix metalloproteinase, Epithelium, Cell Line, 03 medical and health sciences, Peritoneal cavity, 0302 clinical medicine, Osmotic Pressure, medicine, Extracellular, Humans, matrix metalloproteinases‐7, peritoneal membrane dysfunction, Peritoneal Cavity, Cells, Cultured, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Aquaporin 1, Chemistry, Epithelial Cells, Original Articles, Cell Biology, Middle Aged, Cell biology, 030104 developmental biology, medicine.anatomical_structure, aquaporin‐1, Matrix Metalloproteinase 7, 030220 oncology & carcinogenesis, Peritoneal Absorption, ultrafiltration failure, Molecular Medicine, Original Article, Female, extracellular signal‐regulated kinase, Peritoneal Dialysis, Mesothelial Cell, Homeostasis

الوصف: Peritoneal membrane dysfunction and the resulting ultrafiltration failure are the major disadvantages of long‐term peritoneal dialysis (PD). It becomes increasingly clear that mesothelial cells play a vital role in the pathophysiological changes of the peritoneal membrane. Matrix metalloproteinases (MMPs) function in the extracellular environment of cells and mediate extracellular matrix turnover during peritoneal membrane homeostasis. We showed here that dialysate MMP‐7 levels markedly increased in the patients with PD, and the elevated MMP‐7 level was negatively associated with peritoneal ultrafiltration volume. Interestingly, MMP‐7 could regulate the cell osmotic pressure and volume of human peritoneal mesothelial cells. Moreover, we provided the evidence that MMP‐7 activated mitogen‐activated protein kinases (MAPKs)‐extracellular signal‐regulated kinase 1/2 (ERK) pathway and subsequently promoted the expression of aquaporin‐1 (AQP‐1) resulting in the change of cell osmotic pressure. Using a specific inhibitor of ERK pathway abrogated the MMP‐7‐mediating AQP‐1 up‐regulation and cellular homeostasis. In summary, all the findings indicate that MMP‐7 could modulate the activity of peritoneal cavity during PD, and dialysate MMP‐7 might be a non‐invasive biomarker and an alternative therapeutic target for PD patients with ultrafiltration failure.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f61f848708457c8b4035d75baa6936e2Test
https://doi.org/10.1111/jcmm.16697Test

5

Napabucasin Drug‐Drug Interaction Potential, Safety, Tolerability, and Pharmacokinetics Following Oral Dosing in Healthy Adult Volunteers

المؤلفون: Matthew Hitron, Michael D. Karol, Marjie L. Hard, Xiaoshu Dai, Colleen F. Mclaughlin, Scott J. Brantley, Matthew T. Goulet

المصدر: Clinical Pharmacology in Drug Development

مصطلحات موضوعية: Male, Organic anion transporter 1, Flurbiprofen, Pharmaceutical Science, Administration, Oral, Pharmacology, 030226 pharmacology & pharmacy, Dextromethorphan, 0302 clinical medicine, phase 1 trial, Cytochrome P-450 Enzyme System, ATP Binding Cassette Transporter, Subfamily G, Member 2, Pharmacology (medical), Drug Interactions, Rosuvastatin Calcium, Omeprazole, biology, Hydroxybupropion, Articles, Repaglinide, Healthy Volunteers, Neoplasm Proteins, 030220 oncology & carcinogenesis, Female, breast cancer resistance protein transporter, medicine.drug, Half-Life, Adult, drug‐drug interactions, cytochrome P450, Midazolam, napabucasin, Original Manuscript, 03 medical and health sciences, Young Adult, Pharmacokinetics, Caffeine, medicine, Humans, Bupropion, Benzofurans, business.industry, Gene Expression Regulation, biology.protein, business, Naphthoquinones

الوصف: Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug‐drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1‐11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug‐drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration–time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%‐141.4%]), intravenous midazolam (118% [94.4%‐147.3%]), repaglinide (127% [104.7%‐153.3%]), and rosuvastatin (213% [42.5%‐1068.3%]) and decreased the area under the plasma concentration–time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%‐108.3%]), bupropion (79% [64.6%‐97.0%]), and hydroxybupropion (45% [15.7%‐129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dd249a6a220f2dc5c28a0e4212bd82e9Test
http://europepmc.org/articles/PMC8453567Test

6

Lipase elevation and type 1 diabetes mellitus related to immune checkpoint inhibitor therapy – A multicentre study of 90 patients from the German Dermatooncology Group

المؤلفون: Michael Momma, Carmen Loquai, Cristel Ruini, Corinna Kochanek, Kai-Martin Thoms, Selma Ugurel, Carola Berking, Lisa Zimmer, Friedegund Meier, Katharina C. Kähler, Lucie Heinzerling, Dirk Debus, Jessica C. Hassel, Imke Grimmelmann, Claudia Pföhler, Jochen Utikal, Rudolf A. Herbst, Thomas Eigentler, Ralf Gutzmer

المصدر: European Journal of Cancer. 149:1-10

مصطلحات موضوعية: Adult, Blood Glucose, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Skin Neoplasms, Time Factors, Medizin, Gastroenterology, Thyroiditis, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Germany, Internal medicine, Diabetes mellitus, medicine, Humans, Lipase, Adverse effect, Immune Checkpoint Inhibitors, Melanoma, Aged, Retrospective Studies, Aged, 80 and over, Type 1 diabetes, biology, business.industry, Diabetes, Immune checkpoint inhibitors, Immune-related adverse events, Ipilimumab, Nivolumab, Pancreatitis, PD-1 inhibitor, Pembrolizumab, Biomarkers, Diabetes Mellitus, Type 1, Exocrine Pancreatic Insufficiency, Female, Middle Aged, Treatment Outcome, Up-Regulation, medicine.disease, Ketoacidosis, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, biology.protein, Skin cancer, business

الوصف: Aim Immune checkpoint inhibition (ICI) triggers immune-related adverse events (irAEs). The relevance of lipase elevation remains unclear. Patients and methods Skin cancer patients with newly detected serum lipase elevation (at least twofold upper normal limit) or newly diagnosed type I diabetes mellitus upon ICI therapy were retrospectively collected at 14 German skin cancer centres. Results We identified 68 patients with lipase elevation occurring after a median time of 19 (range 1–181) weeks on ICI, 15 (22%) thereof had symptoms consistent with pancreatitis. Forty-seven patients (73%) had other irAE, mainly colitis. Discontinuation (n = 24, 35%) or interruption (n = 26, 38%) of ICI resulted in decrease of lipase after reinduction of ICI lipase levels increased again in 12 of 24 patients. In 18 patients (27%), ICI was continued unchanged, and in 12 (67%) of them, lipase levels normalised. Twenty-two patients were identified with newly diagnosed type I diabetes mellitus related to ICI, and 12 (55%) thereof had also lipase elevation mainly shortly before or after the diagnosis of diabetes. Fourteen (64%) patients had other irAE, mainly thyroiditis. Irrespective of lipase elevation, patients frequently showed a rapid onset with ketoacidosis, decreased c-peptide, and strongly increased blood glucose levels. Conclusion Increased serum lipase during ICI is often not associated with pancreatitis but with other irAE as possible cause. Therefore, it might be sufficient to regularly monitor blood glucose levels and perform further workup only in case of signs or symptoms of pancreatitis and/or exocrine pancreas insufficiency.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f46f4bea919fbf1345c4e5a2fd89e7ccTest
https://doi.org/10.1016/j.ejca.2021.02.017Test

7

Parathyroid hormone receptor stimulation induces human adipocyte lipolysis and browning

المؤلفون: Niels Jessen, Bjørn Richelsen, Steen B. Pedersen, Peter Breining, Jacob B. Hansen, Mads Kjolby

المصدر: Breining, P, Pedersen, S B, Kjolby, M, Hansen, J B, Jessen, N & Richelsen, B 2021, ' Parathyroid hormone receptor stimulation induces human adipocyte lipolysis and browning ', European Journal of Endocrinology, vol. 184, no. 5, pp. 687-697 . https://doi.org/10.1530/EJE-20-0713Test

مصطلحات موضوعية: Adult, Male, endocrine system, medicine.medical_specialty, Adipose Tissue, Brown/metabolism, Lipolysis, Endocrinology, Diabetes and Metabolism, Receptor expression, Parathyroid hormone, Adipose tissue, Parathyroid Hormone/pharmacology, 030209 endocrinology & metabolism, White adipose tissue, Lipolysis/drug effects, Adipose Tissue/drug effects, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Adipose Tissue, Brown, Receptor, Parathyroid Hormone, Type 1/metabolism, Adipocyte, Internal medicine, Brown adipose tissue, Adipocytes, medicine, Humans, Uncoupling Protein 1, Receptor, Parathyroid Hormone, Type 1, Aged, Chemistry, Thermogenesis/drug effects, Thermogenesis, Uncoupling Protein 1/metabolism, General Medicine, Middle Aged, Thermogenin, Cross-Sectional Studies, medicine.anatomical_structure, Adipose Tissue, Parathyroid Hormone, 030220 oncology & carcinogenesis, Female, hormones, hormone substitutes, and hormone antagonists, Adipocytes/drug effects

الوصف: Objective Activation of brown adipose tissue is a promising strategy to treat and prevent obesity and obesity-related disorders. Activation of uncoupling protein 1 (UCP1) leads to uncoupled respiration and dissipation of stored energy as heat. Induction of UCP1-rich adipocytes in white adipose tissue, a process known as ‘browning’, serves as an alternative strategy to increase whole body uncoupling capacity. Here, we aim to assess the association between parathyroid hormone (PTH) receptor expression and UCP1 expression in human adipose tissues and to study PTH effects on human white and brown adipocyte lipolysis and UCP1 expression. Design A descriptive study of human neck adipose tissue biopsies substantiated by an interventional study on human neck-derived adipose tissue cell models. Methods Thermogenic markers and PTH receptor gene expression are assessed in human neck adipose tissue biopsies and are related to individual health records. PTH-initiated lipolysis and thermogenic gene induction are assessed in cultured human white and brown adipocyte cell models. PTH receptor involvement is investigated by PTH receptor silencing. Results PTH receptor gene expression correlates with UCP1 gene expression in the deep-neck adipose tissue in humans. In cell models, PTH receptor stimulation increases lipolysis and stimulates gene transcription of multiple thermogenic markers. Silencing of the PTH receptor attenuates the effects of PTH indicating a direct PTH effect via this receptor. Conclusion PTH 1 receptor stimulation by PTH may play a role in human adipose tissue metabolism by affecting lipolysis and thermogenic capacity.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b9393d6212f2abdcb21a7db48ea58f29Test
https://doi.org/10.1530/eje-20-0713Test

8

Transarterial chemoembolisation enhances programmed death‐1 and programmed death‐ligand 1 expression in hepatocellular carcinoma

المؤلفون: Olivier Soubrane, Aurélie Beaufrère, Ahmed Montasser, Miguel Albuquerque, Mohamed Bouattour, Valérie Paradis, François Cauchy

المصدر: Histopathology. 79:36-46

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Carcinoma, Hepatocellular, Histology, Combination therapy, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Gastroenterology, B7-H1 Antigen, Pathology and Forensic Medicine, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, PD-L1, Internal medicine, Biomarkers, Tumor, Humans, Medicine, Chemoembolization, Therapeutic, Aged, Aged, 80 and over, biology, business.industry, Liver Neoplasms, General Medicine, Immunotherapy, Middle Aged, HCCS, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, biology.protein, Immunohistochemistry, Female, Programmed death 1, Transcriptome, business, Programmed death

الوصف: AIMS Immunotherapies represent a new alternative therapeutic approach for hepatocellular carcinomas (HCCs), and have shown promising results when used in combination therapy. The aim of this study was to evaluate the potential of transarterial chemoembolisation (TACE) to modulate programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) expression profiles in a cohort of surgically treated HCCs. METHODS AND RESULTS A total of 82 surgically treated HCCs from patients who had undergone (n = 32) or not undergone (n = 50) preoperative TACE were included in the study. Immunohistochemical expression of PD-1 and of PD-L1 were analysed and compared according to TACE treatment. Pretreatment biopsies, which were available for 30 cases (20 with TACE and 10 without), were similarly analysed. Follow-up data were retrieved from patients' charts. PD-1 expression (≥1%) in intratumoral inflammatory cells (ICs) was observed in 46% of HCCs, and PD-L1 expression (≥1%) in ICs and PD-L1 expression in tumour cells (TCs) were observed in 46% and 16% of HCCs, respectively. A low level of PD-1 expression (

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0de3b8190900c797687dcf60d91de283Test
https://doi.org/10.1111/his.14317Test

9

Efficacy of Decitabine plus Anti-PD-1 Camrelizumab in Patients with Hodgkin Lymphoma Who Progressed or Relapsed after PD-1 Blockade Monotherapy

المؤلفون: Miao Liu, Malcolm V. Brock, Qingming Yang, Fengxia Shi, Jing Nie, Liang Dong, Jiejie Liu, Weidong Han, Qian Mei, Chunmeng Wang, Yang Liu, Xiang Li, Meixia Chen

المصدر: Clinical Cancer Research. 27:2782-2791

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Adolescent, Programmed Cell Death 1 Receptor, Decitabine, Kaplan-Meier Estimate, Antibodies, Monoclonal, Humanized, Gastroenterology, B7-H1 Antigen, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Refractory, Recurrence, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, In patient, Child, Neoplasm Staging, business.industry, Anti pd 1, Middle Aged, Prognosis, Hodgkin Disease, Blockade, Treatment Outcome, 030104 developmental biology, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Retreatment, Cohort, Disease Progression, Pd 1 blockade, Hodgkin lymphoma, Female, business, medicine.drug

الوصف: Purpose: Programmed death-1 (PD-1) blockade monotherapy is effective in relapsed/refractory classical Hodgkin lymphoma (cHL), but a subset of patients is recalcitrant to PD-1 inhibitors and only a minority of patients achieves durable remission. Effective treatment regimens for those with relapsed/progressive cHL after single-agent anti-PD-1 are urgently needed. Anti-PD-1 combination with the DNA-demethylating agent decitabine showed positive preliminary results in our test cohort patients who were resistant to anti-PD-1. Here, we assess the efficacy of decitabine plus anti-PD-1 therapy in an expansion cohort and after longer follow-up. Patients and Methods: We present the response and progression-free survival rates from patients with relapsed/refractory cHL who relapsed/progressed after prior anti-PD-1 monotherapy, and who received decitabine (10 mg/day, days 1–5) plus the anti-PD-1 camrelizumab (200 mg, day 8), every 3 weeks in a phase II trial (ClinicalTrials.gov: NCT02961101 and NCT03250962). Results: Overall, 51 patients (test cohort: 25, expansion cohort: 26) were treated and 50 evaluated for efficacy. The objective response rate was 52% [nine complete responses (CR); 36%] in the test cohort, and 68% (six CRs; 24%) in the expansion cohort. Median progression-free survival with decitabine plus camrelizumab was 20.0 and 21.6 months, respectively, which was significantly longer than that achieved with prior anti-PD-1 monotherapy. Durable response was observed in an estimated 78% of patients who achieved CR at 24 months. After decitabine plus camrelizumab, the ratio increase of circulating peripheral central memory T cells directly correlated with both clinical response and progression-free survival. Conclusions: Decitabine plus camrelizumab is associated with high response rates and long-term benefits in patients with relapsed/refractory cHL who failed PD-1 inhibitors.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::91e09f7bc2baaa5514edccb162437f68Test
https://doi.org/10.1158/1078-0432.ccr-21-0133Test

10

Elevated angiotensin II induces platelet apoptosis through promoting oxidative stress in an AT1R‐dependent manner during sepsis

المؤلفون: Dun-Feng Xu, Yu-Jian Liu, Chu-Fan Xu, Yan Wang, Yan-Fei Mao, Lai Jiang, Xiao-Yan Zhu

المصدر: Journal of Cellular and Molecular Medicine

مصطلحات موضوعية: Male, 0301 basic medicine, thrombocytopenia, Apoptosis, Pharmacology, medicine.disease_cause, Mice, 0302 clinical medicine, Platelet, Cells, Cultured, platelet, Aged, 80 and over, chemistry.chemical_classification, Angiotensin II, Middle Aged, Prognosis, Losartan, 030220 oncology & carcinogenesis, Molecular Medicine, Original Article, Female, Signal Transduction, medicine.drug, Adult, Blood Platelets, reactive oxygen species (ROS), Receptor, Angiotensin, Type 1, Sepsis, 03 medical and health sciences, medicine, Animals, Humans, angiotensin II (Ang II), Aged, Cell Proliferation, Reactive oxygen species, Intrinsic apoptosis, angiotensin II receptor blocker (ARB), Original Articles, Cell Biology, medicine.disease, Oxidative Stress, 030104 developmental biology, Gene Expression Regulation, chemistry, Case-Control Studies, Reactive Oxygen Species, Angiotensin II Type 1 Receptor Blockers, Oxidative stress

الوصف: Thrombocytopenia is independently related with increased mortality in severe septic patients. Renin‐angiotensin system (RAS) is elevated in septic subjects; accumulating studies show that angiotensin II (Ang II) stimulate the intrinsic apoptosis pathway by promoting reactive oxygen species (ROS) production. However, the mechanisms underlying the relationship of platelet apoptosis and RAS system in sepsis have not been fully elucidated. The present study aimed to elucidate whether the RAS was involved in the pathogenesis of sepsis‐associated thrombocytopenia and explore the underlying mechanisms. We found that elevated plasma Ang II was associated with decreased platelet count in both patients with sepsis and experimental animals exposed to lipopolysaccharide (LPS). Besides, Ang II treatment induced platelet apoptosis in a concentration‐dependent manner in primary isolated platelets, which was blocked by angiotensin II type 1 receptor (AT1R) antagonist losartan, but not by angiotensin II type 2 receptor (AT2R) antagonist PD123319. Moreover, inhibiting AT1R by losartan attenuated LPS‐induced platelet apoptosis and alleviated sepsis‐associated thrombocytopenia. Furthermore, Ang II treatment induced oxidative stress level in a concentration‐dependent manner in primary isolated platelets, which was partially reversed by the AT1R antagonist losartan. The present study demonstrated that elevated Ang II directly stimulated platelet apoptosis through promoting oxidative stress in an AT1R‐dependent manner in sepsis‐associated thrombocytopenia. The results would helpful for understanding the role of RAS system in sepsis‐associated thrombocytopenia.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6123010f834858f85232068229ee63deTest
https://doi.org/10.1111/jcmm.16382Test

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