👤 Shafaath Husain

NSCLC-Squamous cell carcinoma (SCC) is characterized by poor survival largely due no definitive markers for targeted therapy. KRAS (Kirsten rat sarcoma viral oncogene homolog) is a proto-oncogene associated with resistance standard chemotherapy regimens. Discoidin domain receptor 2 (DDR2), fibroblast growth factor receptor-1(FGFR-1) and mesenchymal epithelial transition (MET) are receptor tyrosine kinases that regulate proliferation, apoptosis and invasion. The objectives were to assess frequency of FGFR1, DDR2,c-MET protein over-expression and KRAS mutations in NSCLC-SCC and to co-relate expression of molecular markers with clinico-pathological parameters. The study was a retrospective and prospective case series of 150 cases of NSCLC-SCC. Testing for KRAS, DDR-2, cMET and FGFR1 was done using immunohistochemistry (IHC). KRAS IHC was validated using real time polymerase chain reaction testing. Molecular marker expression was identified in 37.33% (n=56/150) cases, among which 80.35% (n=45/56) cases had a single mutation and 19.64% cases(n=11/56) had multiple mutations. FGFR-1 protein over-expression was identified in 8% cases and cMET protein over-expression in 4.67% cases. DDR-2 over-expression was present in 19.33% cases and KRAS protein over-expression in 14.67% cases. Co-expression of DDR-2 and KRAS was identified in 72.72% cases. DDR2 protein over-expression is identified in smokers and cases with distant metastasis. KRAS protein over-expression was more frequent in cases >40 years of age with advanced disease stage. The targets evaluated have potential drugs currently under trial phase. This may help to define the subgroup for use of targeted therapy in NSCLC-SCC and in designing new treatment protocols. Show less

Overactive urinary bladder (OAB) negatively impacts quality of life, and stress is known to play a key role in its development. However, the mechanisms linking stress to OAB are not yet fully understood. This study examined how chronic activation of neuroendocrine stress pathways, independently of environmental or psychological stressors, affects bladder function and the control of micturition. Utilizing the central role of brain-derived-neurotrophic factor (BDNF) in orchestrating the neuroendocrine stress response within the paraventricular nucleus of the hypothalamus (PVN), our novel experimental model subjected 10-week-old male Sprague Dawley rats to bilateral PVN injections of AAV2 viral vectors expressing either BDNF or GFP (for control). Urine voiding behavior was assessed in UroVoid metabolic cages over 14 weeks post-injections. Bladder strip myography, assessment of bladder wall mechanics, and histology were also conducted to determine any BDNF-induced differences in bladder contractility, capacity and morphology. Prolonged activation of neuroendocrine stress mechanisms with BDNF overexpression in the PVN significantly reduced intermicturition intervals and voided volumes, lowered bladder capacity, and induced relative bladder wall hypertrophy but had no effect on bladder wall mechanics or detrusor contractility. These results indicate that chronic activation of neuroendocrine stress pathways, even without additional environmental or psychological influences of stress, lead to a significant OAB phenotype and reduced bladder capacity. Show less

Coronary artery calcium (CAC) scoring is widely used to screen for coronary artery disease (CAD) in asymptomatic individuals. However, it detects calcified plaques and may miss non-calcified or soft plaques. This study compared the diagnostic accuracy of CAC scoring with coronary computed tomography angiography (CCTA) for detecting CAD in asymptomatic individuals with risk factors. Eighteen asymptomatic adults with a CAC score of 0 underwent CCTA to evaluate for subclinical CAD. Clinical, biochemical, and lifestyle risk factors were assessed. Diagnostic agreement between CAC and CCTA was analyzed using the Wilcoxon signed rank test. The cohort had a mean age of 51.4 ± 10.6 years, 88.8% were male, and mean body mass index (BMI) was 27.7 ± 3.6 kg/m CCTA detected non-calcified atherosclerosis missed by CAC and demonstrated superior sensitivity for early CAD detection in asymptomatic individuals. Show less

Alzheimer's disease (AD) and vascular dementia (VaD) account for most dementia cases. AD biomarkers remain costly and invasive, and no specific biomarkers exist for VaD. We analyzed plasma and brain proteomics in the UK Biobank (N=53,000) and ROSMAP (N=512) to identify shared and distinct proteomic signatures of AD and VaD and assess the influence of the APOE ε4 variant. We identified 55 AD-associated and 49 VaD-associated proteins, with 13 shared. AD proteins were enriched in glycosaminoglycan binding and cholesterol metabolism; VaD proteins in virus receptor activity, cytokine activity and metalloproteinases. Both showed IGF pathway dysregulation. APOE ε4 stratification revealed distinct AD proteomic signatures beyond GFAP and NeFL. Mendelian randomization suggested causal links for SNAP25 in AD, EDA2R and TIMP4 in VaD, and PVR in both. Findings underscore the importance of APOE genotype and highlight SNAP25, EDA2R, TIMP4, and PVR as potential biomarkers and therapeutic targets. Show less

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality. The objective of this study was to find out the differential expression of apolipoproteins (ApoAI and ApoAIV) in HCC and cases of liver cirrhosis and chronic hepatitis (controls) without HCC and to compare ApoAI and ApoAIV expression with alpha-foetoprotein (AFP), the conventional marker in HCC. Fifty patients with HCC and 50 controls comprising patients with liver cirrhosis (n=25) and chronic hepatitis (n=25) without HCC were included in this study. Total proteins were precipitated using acetone precipitation method followed by albumin and IgG depletion of precipitated protein using depletion kit. Proteins were separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The expression changes of ApoAI and ApoAIV were confirmed by western blotting using specific primary and secondary polyclonal antibodies followed by densitometric protein semi-quantitative estimation. ApoAI, ApoAIV and AFP were measured in the plasma samples by ELISA method. Semi-quantitative densitometric image analysis of the western blot images and the comparison between HCC patients with those without HCC (control) revealed differential expression of ApoAI and ApoAIV. Levels of ApoAI were significantly higher in patients with HCC compared to controls without HCC (0.279±0.216 vs 0.171±0.091 and 0.199±0.014; P <0.001). Levels of ApoAIV were significantly lower in patients of HCC compared to controls without HCC (0.119±0.061 vs 0.208±0.07 and 0.171±0.16; P <0.01). ELISA assays of apolipoproteins (ApoAI and ApoAIV) revealed similar results of expression of ApoAI and ApoAIV as detected in western blotting densitometric image analysis. Increased expression of ApoAI and decreased expression of ApoAIV in HCC patients compared to controls without HCC revealed the abnormalities in HCC. These molecules need to be studied further for their use as potential biomarkers in the future diagnostic tools along with other conventional biomarkers for screening of HCC cases. It needs further analysis in higher number of patient population. Show less