Influence of sodium-glucose Co-transporter 2 inhibitors on clinical and biochemical markers of dehydration during the Holy Ramadan

Background and aimsAlteration of the hydration status with the use of sodium-glucose co-transporter- 2 inhibitors (SGLT2i) during the Holy Ramadan has not been studied in depth. Precisely, we aimed to detect the potential alteration of hydration status in adult Muslims with type 2 diabetes mellitus (T2D) who used SGLT2i during Ramadan.MethodsAn observational non-interventional study included 245 patients with type 2 diabetes mellitus of matched age and sex. The study included 3 groups: empagliflozin group; 87 patients, dapagliflozin group; 85 patients and control group; 73 patients without the use of SGLT2i. Participants in each group were well-settled on their medications for more than 3 months before the onset of Ramadan. Clinical and biochemical parameters of hydration status were evaluated during the last week of Ramadan.ResultsWe noticed a higher prevalence of orthostatic dizziness and postural hypotension among SGLT2i users than non-SGLT2i users (p < 0.001). The mean arterial blood pressure was significantly lowered among users of empagliflozin and dapagliflozin than non-SGLT2i users; 93.7 ± 5.1 and 93.1 ± 6.9 versus 106.2 ± 4.3, p < 0.001, respectively. Moreover, patients who used empagliflozin or dapagliflozin exhibited significantly higher values of urine specific gravity; 1029.6 ± 1.5 and 1029.1 ± 1.6 versus 1016.9 ± 4.4, p < 0.001, serum osmolality; 300.7 ± 10.2 and 297.8 ± 8.9 versus 290.9 ± 6.7, p < 0.001, and BUN/creatinine ratio; 24.1 ± 4.1 and 23.2 ± 4.6 versus 16.3 ± 4.2, p < 0.001 than non-SGLT2i users.ConclusionSignificant clinical and biochemical markers of dehydration were noticed among users of SGLT2i during the Holy Ramadan.     

Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057 microsatellite instability-high solid tumors

Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are predictive biomarkers for immune-checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI-H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592-gene panel; a subset of MSI-H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene-specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co-expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI.     

Anti-Oxidant,Anti-Hemolytic Effects of Crataegus aronia Leaves and Its Anti- Proliferative Effect Enhance Cisplatin Cytotoxicity in A549 Human Lung Cancer Cell Line

Objective: For Arabian traditional medicine, Crataegus aronia syn. Azarolus (L) Bosc. ex DC (Rosaceae) is widely used to treat diabetes, sexual weakness, cardiovascular diseases and cancer. The anti-cancerous and anti-hemolysis effects of the hydroalcoholic extract of this plant have never been investigated before. The present study aims to evaluate the biological activities of the hydroalcoholic extract of Crataegus aronia leaves in combination with cisplatin, one of the most widely employed chemotherapeutics, on A549 human lung cancer cell line. Methods: The anti-oxidant and anti-proliferative activities of leaves, fruits, seeds of C. aronia were investigated by DPPH method and MTT assay; respectively. Cell migration activity was investigated by wound healing and by cell aggregation assays. The effect of C. aronia in inducing cell cycle arrest along with activating cell apoptosis was evaluated by flow cytometry and Western blot assays, respectively. Results: Our results showed that C. aronia leaves (C. aronia L.) had the highest anti-oxidant and anti-proliferative activities. The leaves extract was potent against hemolysis of the human erythrocytes and showed elevated decrease in migration by reducing wound healing migration and by increasing cell aggregation. Finally, C. aronia L. treatment exhibited apoptotic activity on A549 cells by the down-regulation of PARP-1, caspase-3 and Bcl-2 proteins and by increasing the percentage of A549 cells in sub G0 cell cycle. Moreover, the co-treatment of C. aronia L. and cisplatin remarkably sensitised A549 cells to cisplatin. Conclusion: The results suggested that C. aronia L. could be used as a potential treatment against human lung cancer exhibiting minimal side effects on human health.     

Evaluating upadacitinib for the treatment of rheumatoid arthritis

ABSTRACT

Introduction

The introduction of JAKs inhibitors for the treatment of rheumatoid arthritis represents a promising new era in the management of the disease. New compounds under investigation, like upadacitinib, with greater selectivity for JAK1 inhibition have recently been approved for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to conventional synthetic disease-modifying antirheumatic drugs.     

An evaluation of empagliflozin and it’s applicability to hypertension as a therapeutic option

ABSTRACT

Introduction

Sodium-glucose cotransporter 2 (SGLT2) inhibitors such as Empagliflozin are novel antihyperglycemic drugs approved for the treatment of type 2 diabetes (T2D). In addition to its glucose-lowering effects, Empagliflozin promotes weight loss, blood pressure reduction, and other beneficial metabolic benefits.     

PD-1/PD-L1抑制剂对比常规疗法治疗癌症的有效性和安全性的Meta分析

目的:系统性评价程序性死亡因子1/程序性死亡因子1配体(PD-1/PD-L1)抑制剂对比常规疗法治疗癌症的有效性和安全性。方法:计算机全面检索PubMed、MEDLINE、EMBASE数据库，收集PD-1/PD-L1抑制剂治疗癌症的文献研究，检索时间为2000年1月1日至2019年6月30日。两位研究人员独立收集和整理资料，评价纳入文献研究的偏倚风险，应用Review Manager 5.3软件对纳入研究进行数据整理。结果:最终纳入11项随机对照试验，共6 295例研究对象，其中PD-1/PD-L1抑制剂试验组3 220例，常规疗法药物对照组3 075例。Meta分析结果显示，PD-1/PD-L1抑制剂试验组的客观反应率（ORR）［RR=1.87，95%CI（1.33，2.64），P＜0.001］、完全缓解率（CR）［RR=2.45，95%CI（1.27，4.73），P＜0.001］和部分缓解率（PR）［RR=1.81，95%CI（1.28，2.54），P＜0.001］优于常规疗法对照组，结果均有统计学差异；在疾病控制率（DCR）［RR=1.03，95%CI（0.89，1.20），P=0.65］和疾病进展率（PD）［RR=1.16，95%CI（0.95，1.40），P=0.14］方面，两组比较无统计学差异；而在疾病稳定率（SD）［RR=0.72，95%CI（0.63，0.82），P＜0.001］方面显示常规疗法对照组优于PD-1/PD-L1抑制剂试验组。药物安全性方面，不良反应发生率（AEs）［RR=0.96，95%CI（0.88，1.04），P=0.28］两组无统计学差异，但在3-5级不良反应发生率［RR=0.44，95%CI（0.28，0.68），P＜0.001］方面，PD-1/PD-L1抑制剂试验组明显低于常规疗法对照组。结论:PD-1/PD-L1抑制剂与常规疗法药物相比，可明显提高癌症患者临床治疗的ORR、CR和PR，且出现3-5级不良反应发生率更低，从而证实PD-1/PD-L1抑制剂的有效性和安全性优于常规疗法。     

Estudios farmacogenéticos en la enfermedad de Alzheimer

IntroductionAlzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response.DevelopmentWe review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial.ConclusionsPotential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as aging.     

The activity prediction of indole inhibitors against HCV NS5B polymerase

Non‐structural viral protein 5B (NS5B) is a viral protein in hepatitis C virus. Although various inhibitors against NS5B have been found, the activity prediction of similar untested inhibitors is still highly desirable. In this respect, the Tchebichef moments (TMs) calculated from the images of molecular structures were regarded as the independent variables while the inhibitory activity (pIC₅₀) was the dependent variable, and the predictive model was established by means of stepwise regression. The R‐squared of leave‐one‐out cross‐validation (Q²) for the training set and the R‐squared of prediction () for external independent test set were 0.919 and 0.927, respectively. The obtained model was also evaluated strictly. Compared with the multivariate curve resolution with alternating least squares (MCR‐ALS) and the QSAR approaches derived from the literature, the proposed method is more accurate and reliable. This study not only provides an effective approach to predict the biological activity of RNA replication's inhibitors, but also extends the QSAR modeling technique.