ß-catenin inhibitors in cancer therapeutics: intricacies and way forward.

ß-catenin is an evolutionary conserved, quintessential, multifaceted protein that plays vital roles in cellular homeostasis, embryonic development, organogenesis, stem cell maintenance, cell proliferation, migration, differentiation, apoptosis, and pathogenesis of various human diseases including cancer. ß-catenin manifests both signaling and adhesive features. It acts as a pivotal player in intracellular signaling as a component of versatile WNT signaling cascade involved in embryonic development, homeostasis as well as in carcinogenesis. It is also involved in Ca2+ dependent cell adhesion via interaction with E-cadherin at the adherens junctions. Aberrant ß-catenin expression and its nuclear accumulation promote the transcription of various oncogenes including c-Myc and cyclinD1, thereby contributing to tumor initiation, development, and progression. ß-catenin's expression is closely regulated at various levels including its stability, sub-cellular localization, as well as transcriptional activity. Understanding the molecular mechanisms of regulation of ß-catenin and its atypical expression will provide researchers not only the novel insights into the pathogenesis and progression of cancer but also will help in deciphering new therapeutic avenues. In the present review, we have summarized the dual functions of ß-catenin, its role in signaling, associated mutations as well as its role in carcinogenesis and tumor progression of various cancers. Additionally, we have discussed the challenges associated with targeting ß-catenin molecule with the presently available drugs and suggested the possible way forward in designing new therapeutic alternatives against this oncogene.

Deciphering the role of aberrant DNA methylation in NAFLD and NASH.

The global incidence of nonalcoholic fatty liver disease (NAFLD) is mounting incessantly, and it is emerging as the most frequent cause of chronic and end stage liver disorders. It is the starting point for a range of conditions from simple steatosis to more progressive nonalcoholic steatohepatitis (NASH) and associated hepatocellular carcinoma (HCC). Dysregulation of insulin secretion and dyslipidemia due to obesity and other lifestyle variables are the primary contributors to establishment of NAFLD. Onset and progression of NAFLD is orchestrated by an interplay of metabolic environment with genetic and epigenetic factors. An incompletely understood mechanism of NAFLD progression has greatly hampered the progress in identification of novel prognostic and therapeutic strategies. Emerging evidence suggests altered DNA methylation pattern as a key determinant of NAFLD pathogenesis. Environmental and lifestyle factors can manipulate DNA methylation patterns in a reversible manner, which manifests as changes in gene expression. In this review we attempt to highlight the importance of DNA methylation in establishment and progression of NAFLD. Development of novel diagnostic, prognostic and therapeutic strategies centered around DNA methylation signatures and modifiers has also been explored.

Contribution of organokines in the development of NAFLD/NASH associated hepatocellular carcinoma.

Globally the incidence of hepatocellular carcinoma (HCC) is on an upsurge. Evidence is accumulating that liver disorders like nonalcoholic fatty liver disease (NAFLD) and its more progressive form nonalcoholic steatohepatitis (NASH) are associated with increased risk of developing HCC. NAFLD has a prevalence of about 25% and 50%-90% in obese population. With the growing burden of obesity epidemic worldwide, HCC presents a major healthcare burden. While cirrhosis is one of the major risk factors of HCC, available literature suggests that NAFLD/NASH associated HCC also develops in minimum or noncirrhotic livers. Therefore, there is an urgent need to understand the pathogenesis and risk factors associated with NAFLD and NASH related HCC that would help in early diagnosis and favorable prognosis of HCC secondary to NAFLD. Adipokines, hepatokines and myokines are factors secreted by adipocytes, hepatocytes and myocytes, respectively, playing essential roles in cellular homeostasis, energy balance and metabolism with autocrine, paracrine and endocrine effects. In this review, we endeavor to focus on the role of these organokines in the pathogenesis of NAFLD/NASH and its progression to HCC to augment the understanding of the factors stimulating hepatocytes to acquire a malignant phenotype. This shall aid in the development of novel therapeutic strategies and tools for early diagnosis of NAFLD/NASH and HCC.

Role of Polypeptide Inflammatory Biomarkers in the Diagnosis and Monitoring of COVID-19.

The COVID-19 (coronavirus disease 2019) pandemic that took over the world in December 2019 has had everlasting devastating impacts on the lives of people globally. It manifests a huge symptom spectrum ranging from asymptomatic to critically ill patients with an unpredictable outcome. Timely diagnosis and assessment of disease severity is imperative for effective treatment. Possibilities exist that by the time symptoms appear the viral load might increase beyond control. However, it is advisable to get adequately diagnosed as soon as the first symptom appears. There is an immediate requirement of reliable biomarkers of COVID-19 manifesting an early onset for effective clinical management, stratification of high risk patients and ensuring ideal resource allocation. In this review, we attempt to explore and describe important polypeptide inflammatory biomarkers, namely C-reactive protein, Procalcitonin, Ferritin, Lactate Dehydrogenase, Serum amyloid A, Interleukin-6, Tumor necrosis factor-alpha and LIGHT used in the detection and management of COVID-19. Viral pathogenesis and the role of these inflammatory biomarkers is highlighted, based on the evidences available till date. An integrative data monitoring along with their correlation with the natural disease progression is of utmost importance in the management of COVID-19. So further research and in-depth analysis of these biomarkers is warranted in the present scenario.

NAMPT, GRN, and SERPINE1 signature as predictor of disease progression and survival in gliomas.

Adipose tissue is an important source of adipokines involved in anti- and pro-inflammatory effects. Their involvement in certain cancers such as breast and colon cancer is known but in gliomas it remains unexplored till date. The aim of this study was to assess the status of adipokines as prognostic markers of gliomas (low grade gliomas [LGG] and glioblastoma mutiforme [GBM]). Expression status (messenger RNA [mRNA]), overall survival (OS) and disease-free survival (DFS) was identified using gene expression profiling interactive analysis server. Clinicopathological analysis and correlation between different adipokines was performed using Xena server. Protein expression status was analyzed using tissue sections from the Human Protein Atlas. Out of 11 adipokines studied visfatin (NAMPT), apelin (APLN), granulin (GRN), serpin peptidase inhibitor/plasminogen activator inhibitor type 1 (PAI-1) member 1 (SERPINE1), and chemokine (C-C motif) ligand 2 (CCL2) mRNA levels were significantly upregulated in both LGG and GBM. Interleukin 6 (IL6) mRNA was found be significantly upregulated only in GBM. NAMPT, GRN, SERPINE1, and IL6 showed reduced OS as well as worst DFS for patients having higher mRNA expression in LGG. Increased expression of CCL2 showed worst OS in LGG patients while resistin (RETN) and GRN showed the worst OS in GBM patients. Higher expression of RETN, GRN, IL6, SERPINE1, and CCL2 were found to be positively correlated with shorter DFS in GBM. In the clinicopathological analysis, NAMPT, GRN, IL6, SERPINE1, and CCL2 expressions were significantly associated between the neoplasm histological G2 and G3 grades. Furthermore, expression of NAMPT, GRN, tumor necrosis factor, IL6, SERPINE1, and CCL2 were significantly associated with histological type in LGG patients. NAMPT, GRN, SERPINE1, CCL2, and RETN expression were found to be correlated with each other in gliomas. Finally, NAMPT, GRN, and SERPINE1 were also found to be upregulated using immunohistochemistry in a lower grade and high grade gliomas as compared to normal cells. In conclusion, we have identified key adipokines, namely NAMPT, GRN, and SERPINE1 as potential diagnostic and prognostic markers that might be instrumental in the development and progression of gliomas.

Meta-analysis of mitochondrial T16189C polymorphism for cancer and Type 2 diabetes risk.

AIM: Whereas many previous studies have revealed that mitochondrial DNA (mtDNA) polymorphism T16189C is associated with the risk of cancer and Type 2 diabetes mellitus (T2DM), there are others that have disputed the same. As a result, clarity on the role of mitochondrial T16189C in these disorders is missing. The aim of this study is to evaluate the association of T16189C polymorphism with the risk of cancer and T2DM development by pooling all case-control studies available. METHODS: Published studies till November 2017 were searched from PubMed, Google scholar, Google and EMBASE and isolated a total of 36 studies having 44,203 subjects (20,439 cases and 23,764 controls) based on strict inclusion and exclusion criteria. We used the statistical software "R" to calculate the Pooled Odds Ratios and 95% confidence intervals to evaluate the association of T16189C polymorphism with a possible risk towards cancer and T2DM development. RESULT: From the meta-analysis, we obtained Pooled Odds Ratios using Random effect model for cancer (OR: 1.20, 95% CI: 0.96-1.49, P = 0.104) and for T2DM (OR: 1.22, 95% CI: 1.09-1.36, P = 0.0004). In the subgroup analysis with Random effect model, we found that both Asians and Caucasians were at a statistically significant risk (OR: 1.25, P < 0.0001 and OR: 1.20, P < 0.0001, respectively) for the development of T2DM, whereas, a statistically non-significant risk (OR: 1.28 P = 0.1965 and OR: 1.16, P = 0.1148) emerged for the development of cancer. There was no evidence of a significant publication bias (Egger's and Begg's test) in this meta-analysis. Further sensitivity analysis also demonstrated that our meta-analysis was relatively stable and credible. CONCLUSION: Individuals with 'C' allele at position 16,189 within the mitochondrial D-loop are seemingly at a higher risk of developing T2DM and cancer. However, before arriving at generalizations, it would be pertinent to conduct similar studies in different populations with larger numbers to corroborate these results, especially in cancer.