Investigating the risk of deep vein thrombosis with JAK inhibitors: a disproportionality analysis using FDA Adverse Event Reporting System Database (FAERS).

BACKGROUND: Janus kinase (JAK) inhibitors are immune-modulating medications used to treat conditions including rheumatoid arthritis, COVID-19, ulcerative colitis, atopic dermatitis, myelofibrosis, and polycythemia Vera. However, these medications have been associated with higher incidence of deep vein thrombosis. The objective of this study was to investigate potential safety signals for DVT associated with JAK inhibitors using disproportionality analysis from the FDA Adverse Event Reporting System (FAERS) database. RESEARCH DESIGN AND METHODS: The authors retrospectively investigated case/non-case analysis using Openvigil 2.1-MedDRA-v24 (2004Q1 to 2022Q4). The preferred term used was 'deep vein thrombosis,' and the drugs included were baricitinib, tofacitinib, and upadacitinib. Reporting odds ratio, proportional reporting ratio, and information component were used to detect signals. RESULTS: Overall 114,005 AE reports related to JAK inhibitors were identified, of which 647 reports (baricitinib - 169, tofacitinib - 425, and upadacitinib - 53) associated with DVT were obtained from FAERS. On analysis, baricitinib and tofacitinib had greater signal strength for age group of 65-100 years and all three had the highest signal strength for male gender. CONCLUSIONS: Our study identified signals for DVT with baricitinib, tofacitinib, and upadacitinib. Further research using well-designed epidemiological data is needed to validate these results.

Individualization of the Dosage Regimen of Erythropoietin is Crucial in End-stage Renal Disease Patients.

The objective of this study was to understand the utilization pattern of erythropoietin in end-stage renal disease patients, along with the effect of body weight and sex on the patients' responses. In this retrospective single-center study, 120 patients were included who were on a once weekly (n = 79), twice weekly (n = 37), or thrice weekly (n = 4) regimen. The doses of erythropoiesis-stimulating agents (ESA) were collected, and the erythropoietin resistance index (ERI) was determined. The Kruskal-Wallis test was used to evaluate the dose schedules, and the once-weekly regimen produced a greater response (P = 0.001). The asymptotic significance of Pearson's Chi-square-test equating the mean ERI and body mass index (BMI) was 0.034. No statistically significant correlation was estimated between sex and mean ERI (P = 0.201). Our study demonstrated that the once-weekly regimen dominated over the others in terms of efficacy, and individuals with a higher BMI were found to respond better to the ESA therapy.

Role of histone demethylases and histone methyltransferases in triple-negative breast cancer: Epigenetic mnemonics.

Triple-negative breast cancer (TNBC) is a particularly lethal subtype of breast cancer owing to its heterogeneity, high drug resistance, poor prognosis and lack of therapeutic targets. Recent insights into the complexity of TNBC have been explained by epigenetic regulation and its ability to modulate certain oncogenes and tumour suppressor genes. This has opened an emerging area in anti-cancer therapy using epigenetic modulating drugs, highlighting the epigenetic reprogramming during tumorigenesis and tumour development. Histone methylation and demethylation are such dynamic epigenetic mechanisms mediated by histone methyltransferases (HMTs) and histone demethylases (HDMs), respectively. The interplay between HMTs and HDMs in histone methylation extrapolates their viability as druggable epigenetic targets in TNBC. In this review, we aim to summarize recent progress in the field of epigenetics focusing on HMTs and HDMs in TNBC development and their potential use in targeted therapy for TNBC management.

Antibiotic resistance in Escherichia coli isolates from poultry environment and UTI patients in Kerala, India: A comparison study.

BACKGROUND: There are only narrow insights regarding the antimicrobial resistance of pathogens in poultry environment in India and its transmission to humans. The use of antimicrobials in food animal production is not properly regulated in India. So, many clinically important antimicrobials are used indiscriminately. OBJECTIVE: Our aim was to do a comparative analysis of antibiotic resistance in Escherichia coli isolates from poultry environment and UTI patients. METHODOLOGY: Two poultry farms each from six areas in Muvattupuzha region of the state of Kerala in India were selected for the study. From each farm, samples of fresh fecal matter, litter from inside the shed, litter from outside the shed, nearby agricultural soil and control soilwere collected. E. coli was isolated from each sample, and antimicrobial susceptibility testing of E. coli was done with fifteen antibiotics. Antibiograms of UTI patients were collected from the tertiary care hospital included in the study and those were compared with the antibiograms of poultrysamples. RESULT: All samples were resistant to ampicillin, amoxicillin, meropenem and tetracycline. Similar resistance pattern in poultry environment and UTI patients was seen for antibiotics such as ampicillin, amoxicillin, amikacin, and ofloxacin. A statistically significant difference (p < .00601) was established in the total number of isolates resistant to various antibiotics from areas near to farms compared to those away from farms. CONCLUSION: E. coli were resistant not only to extended spectrum beta lactams but also to carbapenems which might have disseminated to environment where litter was used as manure. This might be due to irrational use of antibiotics in chicken and poultry feed as growth promoter.

JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy.

As the incidence of COVID-19 increases with time, more and more efforts are made to pave a way out for the therapeutic strategies to deal with the disease progression. Inflammation being a significant influencer in COVID-19 patients, it drives our focus onto the signaling cascades of the JAK/STAT pathway. JAK phosphorylation mediated by cytokine receptor activation leads to phosphorylation of STATs that translocate into the nucleus to translate for inflammatory mediators. The SARS-CoV-2 structural proteins like spike, nucleocapsid, membrane and envelope proteins along with the non- structural proteins 1-16 including proteases like 3CL pro and PLpro promote its entry and survival in hosts. The SARS-CoV-2 infection triggers inflammation via the JAK/STAT pathway leading to recruitment of pneumocytes, endothelial cells, macrophages, monocytes, lymphocytes, natural killer cells and dendritic cells progressing towards cytokine storm. This produces various inflammatory markers in the host that determine the disease severity. The JAK/STAT signaling also mediates immune responses via B cell and T cell differentiation.With an attempt to reduce excessive inflammation, JAK/STAT inhibitors like Ruxolitinib, Baricitinib, Tofacitinib have been employed that mediate its actions via suppressors of cytokine signaling, cytokine inducible SH2 containing protein, Protein inhibitor of activated STAT and protein tyrosine phosphatases. Even though they are implicated with multiple adverse effects, the regulatory authorities have supported its use, and numerous clinical trials are in progress to prove their safety and efficacy. On the contrary, the exact mechanism of JAK/STAT inhibition at molecular levels remains speculative for which further investigations are required.