Predisposing deleterious variants in the cancer-associated human kinases in the global populations.

Human kinases play essential and diverse roles in the cellular activities of maintaining homeostasis and growth. Genetic mutations in the genes encoding the kinases (or phosphotransferases) have been linked with various types of cancers. In this study, we cataloged mutations in 500 kinases genes in >65,000 individuals of global populations from the Human Genetic Diversity Project (HGDP) and ExAC databases, and assessed their potentially deleterious impact by using the in silico tools SIFT, Polyphen2, and CADD. The analysis highlighted 35 deleterious non-synonymous SNVs in the ExAC and 5 SNVs in the HGDP project. Notably, a higher number of deleterious mutations was observed in the Non-Finnish Europeans (26 SNVs), followed by the Africans (14 SNVs), East Asians (13 SNVs), and South Asians (12 SNVs). The gene set enrichment analysis highlighted NTRK1 and FGFR3 being most significantly enriched among the kinases. The gene expression analysis revealed over-expression of NTRK1 in liver cancer, whereas, FGFR3 was found over-expressed in lung, breast, and liver cancers compared to their expression in the respective normal tissues. Also, 13 potential drugs were identified that target the NTRK1 protein, whereas 6 potential drugs for the FGFR3 target were identified. Taken together, the study provides a framework for exploring the predisposing germline mutations in kinases to suggest the underlying pathogenic mechanisms in cancers. The potential drugs are also suggested for personalized cancer management.

ALKBH5 inhibitors as a potential treatment strategy in heart failure-inferences from gene expression profiling.

Heart Failure (HF) is a complex clinical syndrome in which the heart is unable to provide enough blood flow to meet metabolic needs and lacks efficient venous return. HF is a major risk factor for morbidity and mortality with cardiovascular diseases globally. Despite enormous research, the molecular markers relevant to disease prognosis and management remain not well understood. Here, we analyzed the whole transcriptomes of 18 failing hearts and 15 non-failing hearts (predominantly of Caucasian origin), by applying the standard in silico tools. The analyses revealed novel gene-markers including ALKBH5 of mRNA demethylation and KMT2E of histone modification processes, significantly over-expressed in the HF compared with the non-failing hearts (FDR < 0.05). To validate the over-expression of ALKBH5, we determined the global m6A level in hypoxic H9c2 cells using a dot blot assay. The global m6A level was found markedly lower in the hypoxic H9c2 cells than in the control cells. Additionally, the expression of ALKBH5 in the H9c2 cells was quantified by the qPCR and found to be 1.18 times higher at 12 h (p < 0.05), and 1.67 times higher at 24 h of hypoxia (p < 0.01) compared with the control cells, indicating a likely role of ALKBH5 in the failing cardiac cells. Furthermore, we identified several compounds through the virtual screening of 11,272 drug-like molecules of the ZINC15 database to inhibit the ALKBH5 in a molecular docking process. Collectively, the study revealed novel markers potentially involved in the pathophysiology of HF and suggested plausible therapeutic molecules for the management of the disease.

Current And Emerging Trends In The Management Of Pyoderma Gangrenosum: A Literature Review.

The first description of Pyoderma gangrenosum (PG) was made about a century ago. It is difficult to understand the aetiology, pathophysiology, and therapy of PG. This disease is believed to be caused by a systemic inflammatory response to neutrophil chemotaxis and faulty innate immune system control. Nearly fifty percent of the cases have underlying systemic symptoms. Significant improvements in PG management have been made over the years. The main goals of treatment are to reduce inflammation and speed up the healing of the PG wound. Even though the most recent medicines show promise, they are found on isolated case reports. The majority of patients are typically managed with topical treatment and local wound care, while resistant cases necessitate immunosuppressive medications. More progress can be made with improvements in technology in deciphering this complex disease and getting a greater understanding of the condition. The present standard therapies for refractory PG are not well supported by studies. In refractory PG, corticosteroids and cyclosporine have historically been administered. Tumour necrosis factor inhibitors are becoming a viable option; nonetheless, this requires careful research and upkeep. This review intended to describe the current trends in managing the PG. Several next-generation treatment options including the conventional therapies introduced to treat PG. We encompass the advantages and disadvantages of new treatments for PG.

Assessment of environmental impact on essential and toxic elements composition in natural honeys by using inductively coupled plasma mass spectrometry.

The quality of natural honey depends upon many factors with significant contribution of environmental factors. In this study, environmental impact on the quality of honey was assessed by determining concentrations of 11 essential and 17 toxic elements in 24 different honey samples of northern and southern regions of Pakistan and Turkey using inductively coupled plasma mass spectrometry. Statistical analysis showed higher variance in the concentrations of Cu, P, and Mo (essential), and Ga, Rb, Cs, Ba, and Pb (toxic) among all the honey samples (coefficient of variance > 100). Multivariate comparison based on botanical flora, honey bee species, and geographic regions revealed that the honeys of different botanical flora exhibited statistically nonsignificant difference in elemental composition, whereas, species wise, honeys of Apis dorsata contained significantly higher concentration of P than honeys of Apis mellifera and Apis flora (p < 0.01). Geographical regions wise, the honeys showed statistically significant difference in concentrations of six essential elements (K (p < 0.01), Mn (p < 0.001), Fe (p < 0.001), Cu (p < 0.05), P (p < 0.001), and Mo (p < 0.01)), and two toxic elements (V (p < 0.01) and As (p < 0.05)). Principal component analysis (PCA) using the essential elements contents clustered uni-floral honeys together separating out 3 multi-floral honeys including the artificial one, whereas PCA using concentrations of toxic elements showed mixed clustering of all honey samples, representing their independence of floral type. Taken together, our analyses show that the environmental factors of the geographical regions, apart from the honeybee species and the botanical flora, have profound impact on the elemental composition in the natural honeys affecting their quality. Although the concentrations of the toxic elements in the honey samples were not exceeding the permissible limit of FAO/WHO, yet we suggest regular surveillance on toxic elements in the honeys to avoid their harmful effects on human health.