Diagnostic Relevance of Primary Investigations in Early Referral and Management of Colorectal Cancer Patients

Aim: Colorectal cancers are largely considered as curable yet the high mortality rates associated with it points out at deficiency in early management of the disease. The aim of this study was to analyze the diagnostic potential of routine primary investigations with an attempt to categorize symptoms for early referral of colorectal cancers patients.Methods: This study involved retrospective analysis of a cohort of 85 patients diagnosed with colorectal cancer that underwent surgery in a period of one year. The patients were arranged into different age-groups to analyze the relative incidence and prognosis of the disease with respect to generalized symptoms and clinicopathological details. Multinomial Logistic Regression analysis was employed to predict the most effective set of parameter combinations for primary prognosis of the diseased state.Results: Abdominal pain, rectal bleeding and change in bowel habits were predominantly reported symptoms; however, these were imprecise with age, sex or stage of cancer. Interestingly, almost 85% of the patients were reported anemic, with a majority of them (41.7%) having Hb 10. Anaemic patients showed significantly higher frequency of symptoms viz. change in bowel habits (p 0.023), rectal bleeding (p 0.035) and/or abdominal pain (p 0.039) compared to non-anaemic ones. The co-occurrence of any two of the symptoms further increased the likelihood of the disease in anaemic patients.Conclusion: A substantial decrease in hemoglobin count with concomitant change in bowel habits, rectal bleeding, and/or abdominal pain could be considered as potential referral markers for early management of suspected colorectal cancers patients

A novel kinase mutation in VEGFR-1 predisposes its alpha C-helix/activation loop towards allosteric activation: Atomic insights from protein simulation

Vascular endothelial growth factor receptor 1 (VEGFR-1) has been implicated in diverse pathologies, including cancers. Although VEGFR-1 is considered as functionally impaired kinase, its decoy characteristics make it an important regulator of VEGFR-mediated signaling, particularly in tumor angiogenesis. VEGFR-1 conveys signaling via its tyrosine kinase (TK) domain whose activation is regulated by phosphorylation of specific tyrosine residues. Thus dysregulation of VEGFR-1 signaling, as reported in most of the cancers, might be a consequence of altered phosphorylation that could be attributed to genotypic variations in its TK domain. Considering the importance of TK domain of VEGFR-1, we carried out its mutational screening in 84 clinically validated and histopathologically confirmed colorectal cancer patients. By means of direct DNA sequencing and SNP analyses, eight novel variations, including one synonymous, two deletion, one missense and four intronic variations, were reported in the TK domain of VEGFR-1. rs730882263:C>G variation specifically reported in colon cancer, representing a single-atomic change (Sulfur to Oxygen) in the predicted (p.Cys1110Ser) protein, was observed as potentially deleterious variation as assessed by multiple single-nucleotide polymorphism prediction servers. Molecular dynamics simulations of VEGFR-1 Wt and (p.Cys1110Ser) variant models revealed major conformational changes in variant protein presumptuously generating an open conformation thereby exposing the activation domain and consequently increasing the probability of phosphorylation events: a condition frequently reported in cancers

Root-associated fungi of Pinus wallichiana A. B. Jackson in Kashmir Himalaya

An important factor in the performance of out-planted conifers is the association of plant roots with ectomycorrhizal (EcM) fungi. However, limited information is available about the diversity of root associated EcM fungi of Pinus wallichiana A. B. Jackson, a coniferous species endemic to Himalayan forests, which has hampered the reforestation programs in the area. The study was carried at three major forest areas of the Kashmir Himalaya believed to be pure stands of Pinus wallichiana. Fine root-tips harbouring EcM were collected and processed for extraction of fungal DNA which were subsequently subjected to ITS rDNA targeted PCR/ RFLP profiling. DNA sequencing analysis of the overlapping ITS amplifications followed by global nucleotide-blast analyses of the assembled nuclear ribosomal DNA (rDNA) revealed a total of 33 fungal taxa associated with P. wallichiana, out of which 23 species were EcM fungi. Out of the 10 non-EcM fungi, we found a peculiar saprophytic wood decaying fungus, Chalara microchona associated with P. wallichiana for the first time. The study not only reveals the species richness of fungi associated with this conifer but also documents new fungal associations with it, which have not been reported so far. The results in the study set a baseline for the broad association of ectomycorrhizal fungi with P. wallichiana which may serve as guiding cue to design reforestation programs in the Kashmir Himalaya.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Irigenin, a novel lead from Western Himalayan chemiome inhibits Fibronectin-Extra Domain A induced metastasis in Lung cancer cells

Several lines of evidence indicate that Fibronectin Extra Domain A (EDA) promotes metastatic capacity of tumor cells by engaging cell surface alpha 9 beta 1 integrins. This interaction mediated by the C-C' loop of EDA activates pro-oncogenic signaling pathways leading to epithelial to mesenchymal transition (EMT) of tumor cells, thus signifying its importance in control of metastatic progression. In this context the present study was designed to explore the active compounds from selected ethno-medicinal plants of western Himalayan region for targeting EDA of Fibronectin in lung carcinoma cells. Structure based informatics for drug designing and screening was employed to generate a lead compound(s) feed that were conformationally and energetically viable. Out of 120 compounds selected, Irigenin showed best binding-affinity with C-C' loop of EDA. Irigenin specifically targeted alpha 9 beta 1 and alpha 4 beta 1 integrin binding sites on EDA comprising LEU46, PHE47, PRO48, GLU58, LEU59 and GLN60 in its C-C' loop as evaluated by energy decomposition per residue of Irigenin-EDA complex. In-vitro cell motility assays complemented with EDA knock-in and knockdown assays distinctively demonstrated that Irigenin prevents metastatic capacity of lung cancer cells by selectively blocking EDA. The results presented thus project Irigenin as a lead compound to overcome Fibronectin EDA induced metastatic progression in lung carcinoma cells