Novel Fused Pyrimidines as Potent Cyclin-Dependent Kinases Inhibitor for Gastric Adenocarcinoma: Combined In Vitro, In Silico Anticancer Studies.

Our research aims to design novel pyrimidine derivatives inspired by the common pyrimidine core found in many FDA-approved drugs. However, extensive prior research on the pyrimidine scaffold has made discovering new molecules more challenging. To overcome this obstacle, we employed a molecular hybridisation strategy, opting to hybridise tetralin and pyrimidine, recognising their potential in cancer therapeutics.

Genetic alteration of mRNA editing enzyme APOBEC3B in the pathogenesis of ovarian endometriosis.

Research Question: What are the specific genetic alterations and associated network in endometriotic cells responsible for the disease pathogenesis?

Design: Case control experimental study involving 45 women with endometriosis who underwent laparoscopic surgery (case) and 45 normal samples from women undergoing total abdominal hysterectomy (control). The endometrial samples were subjected to whole exome sequencing (WES) of endometriotic tissue and copy number variation analysis. Validation of gene hits were obtained from WES using polymerase chain reaction techniques, immunological techniques, in-silico tools and transgenic cell line models.

PI3K/AKT/mTOR inhibitors as potential extracellular matrix modulators for targeting EMT subtype gastric tumors.

Targeting the extracellular matrix (ECM) is considered as a promising strategy in cancer therapeutics. This study was designed to identify the potential ECM modulators for gastric cancer therapeutics. Exploration of the expression profiles of gastric tumors revealed the elevated expression of ECM genes in gastric tumor tissues compared to the adjacent normal tissues with increased expression in diffuse subtype gastric tumors and specifically in epithelial to mesenchymal transition (EMT) molecular subtype tumors.

OCT4-mediated transcription confers oncogenic advantage for a subset of gastric tumors with poor clinical outcome.

Deregulated transcription programs and signaling pathways are the critical factors involved in the process of carcinogenesis. Signaling pathway-based classification of tumors is expected to pave the way for the development of targeted therapeutics. We investigated the OCT4-mediated transcription program in the gene expression profiles of 939 gastric tumor samples.

Identification of oncogenic signaling pathways associated with the dimorphic metabolic dysregulations in gastric cancer subtypes.

Metabolic dysregulations have been identified as intrinsic hallmarks of cancer cells. Investigations of altered metabolic processes, in the context of the associated oncogenic signaling pathways are expected to pave way for the development of targeted cancer therapeutics. We have recently identified the enrichment of glucose and glutamine metabolism in a subset of intestinal subtype gastric tumors at the level of expression of genes, gene sets and the occurrence of metabolites.

Delineation of gastric tumors with activated ERK/MAPK signaling cascades for the development of targeted therapeutics.

The ERK/MAPK signaling pathway is activated in various cancers including gastric cancer. Targeting the ERK/MAPK/MEK pathway has been considered as a promising strategy for cancer therapy. However, MEK inhibition leads to a series of resistance mechanisms due to mutations in MEK, elevated expression of RAS or RAF proteins and activation of the associated signaling pathways.

Ethics of DNA research on human remains: five globally applicable guidelines.

We are a group of archaeologists, anthropologists, curators and geneticists representing diverse global communities and 31 countries. All of us met in a virtual workshop dedicated to ethics in ancient DNA research held in November 2020. There was widespread agreement that globally applicable ethical guidelines are needed, but that recent recommendations grounded in discussion about research on human remains from North America are not always generalizable worldwide.

Small peptide inhibitor from the sequence of RUNX3 disrupts PAK1-RUNX3 interaction and abrogates its phosphorylation-dependent oncogenic function.

P21 Activated Kinase 1 (PAK1) is an oncogenic serine/threonine kinase known to play a significant role in the regulation of cytoskeleton and cell morphology. Runt-related transcription factor 3 (RUNX3) was initially known for its tumor suppressor function, but recent studies have reported the oncogenic role of RUNX3 in various cancers. Previous findings from our laboratory provided evidence that Threonine 209 phosphorylation of RUNX3 acts as a molecular switch in dictating the tissue-specific dualistic functions of RUNX3 for the first time.

Identification of kinases and kinase inhibitors for the differential targeting of Wnt/β-catenin signaling in gastric cancer subtypes.

The oncogenic signaling pathway Wnt is often activated in many cancers including gastric cancer. Wnt signaling pathway is considered as a potential target for developing new targeted therapeutics. Kinase inhibitors are the promising class of drugs for many diseases including cancers.

Calcium channel blockers lercanidipine and amlodipine inhibit YY1/ERK/TGF-β mediated transcription and sensitize the gastric cancer cells to doxorubicin.

Elevated expression of YY1 is known to confer anti-apoptotic phenotype and hence is an attractive target for cancer therapeutics. In a repurpose screening, towards the identification of the inhibitors of YY1 regulated transcription in gastric cancer cells, the calcium channel blockers lercanidipine and amlodipine have been identified to inhibit YY1 more efficiently. We further probed these calcium channel blockers for their potential feature of alleviating the drug resistance in gastric cancer cells.

YY1 regulated transcription-based stratification of gastric tumors and identification of potential therapeutic candidates.

Gastric cancer is one of the leading causes of cancer-related death worldwide. The transcription factor YY1 regulates diverse biological processes, including cell proliferation, development, DNA damage responses, and carcinogenesis. This study was designed to explore the role of YY1 regulated transcription in gastric cancer.

Development of a cell-based pathway modulator screening system to screen the targeted cancer therapeutic candidates.

To overcome the issues of poor prognosis and to tackle the non-responsiveness to various chemotherapeutics; it is necessary to develop targeted cancer therapeutic agents. Also, it is being necessary to understand the molecular targets of the drug candidates and drugs in the context of cellular signaling pathways, to make progress towards the development of targeted cancer therapeutics. Towards addressing these, we have established a cell-based and pathway-focused drug screening system for the pathways such as MYC, E2F, WNT, ERK, NRF1/2, HIF1α, p53, YY1 and NFκB.

Smart dual MRI-optical imaging agent based on a rhodamine appended Fe(III)-catecholate complex.

A rhodamine appended Fe(iii)-catecholate complex Fe(RhoCat)3 is reported as a smart dual-modal T1 MRI-optical imaging probe. The high spin Fe(iii) coordination sphere and rhodamine unit act as MRI and optical reporters, respectively. The probe showed a r1-relaxivity of 4.

Occurrence of differing metabolic dysregulations, a glucose driven and another fatty acid centric in gastric cancer subtypes.

Gastric cancer is one of the most common cancers and ranks third in cancer-related deaths across globe. Cancer cells are known to take advantage of the altered metabolic processes to sustain their survival, proliferation, and cancer progression. In this investigation, we explored the available genome-wide expression profiles of few hundreds of gastric tumors and non-cancerous gastric tissues and analyzed in the context of metabolic pathways.

Identification of the targeted therapeutic potential of doxycycline for a subset of gastric cancer patients.

The identification of new drugs for the targeted therapy of gastric cancer remains an important need. The RAS/RAF/MEK/ERK/ELK1 signaling cascade is activated in many cancers, including gastric cancer. To identify the targetable inhibitors of the ERK/MAPK pathway, we performed a repurposing screening of a panel of antimicrobial agents in gastric cancer cells using an ERK/MAPK-driven firefly luciferase reporter assay.

Abacavir induces the transcriptional activity of YY1 and other oncogenic transcription factors in gastric cancer cells.

Yin Yang 1 (YY1) is a ubiquitous transcription factor with both transcriptional activating and repressing functions. Targeting YY1 is considered as a potential therapeutic strategy for several malignancies. Telomerase Reverse Transcriptase (TERT) is also considered as a potential target for cancer therapeutics.

Coexpressed modular gene expression reveals inverse correlation between immune responsive transcription and aggressiveness in gastric tumours.

The existing large number of gene expression profiles of tumour samples offers a great advantage for the integrative functional genomic exploration of molecular dysregulation in cancers. The clusters of genes (modules) derived from a gastric cancer (GC) coexpression network were explored to understand their clinical and functional significance. Among the modules derived from the GC mRNA expression network, six modules were relatively highly expressed in diffuse type gastric tumours.

Integrative transcriptome analysis of liver cancer profiles identifies upstream regulators and clinical significance of ACSM3 gene expression.

Purpose: Hepatocellular carcinoma (HCC) is one of the most common human malignancies. It has frequently been associated with metabolic perturbations and liver damages. Various members of the family of acyl-CoA synthetases are known to be involved in the production of bioactive fatty acids, and altered expression of its encoding genes has been found to be involved in metabolic perturbations.

Amplified 7q21-22 gene MCM7 and its intronic miR-25 suppress COL1A2 associated genes to sustain intestinal gastric cancer features.

Frequent amplification of 7q21-22 genomic region is known in gastric cancer. Multiple genes including SHFM1, MCM7, and COL1A2 were reported to be the potential cancer candidate genes of this 20 Mb amplicon. This amplicon has two polycistrionic miRNA clusters and in the present study, miR-106b-25 cluster located in intron-13 of MCM7 was identified to express in gastric tumors.

Naringenin Ameliorates Doxorubicin Toxicity and Hypoxic Condition in Dalton's Lymphoma Ascites Tumor Mouse Model: Evidence from Electron Paramagnetic Resonance Imaging.

Doxorubicin (DOX) is a well-known cytotoxic agent used extensively as a chemotherapeutic drug to eradicate a wide variety of human cancers. Reactive oxygen species (ROS)-mediated oxidative stress during DOX treatment can induce cardiac, renal, and hepatic toxicities, which can constrain its use as a potential cytotoxic agent. The present work investigates the antioxidant potential of naringenin (NAR) against DOXinduced toxicities of a Dalton's lymphoma ascites (DLA) tumor-bearing mouse model.

Juxtaposed genes in 7q21-22 amplicon contribute for two major gastric cancer sub-Types by mutual exclusive expression.

Genomic Copy Number Variations (CNV) and the associated gene signatures are useful for cancer prognosis, diagnosis, and targeted therapeutics. Earlier, 7q21-22 region was reported for frequent amplification in gastric cancer and potential candidate genes were identified. An analysis of the expression pattern of the 159 genes located in this amplicon revealed the consistent elevated expression of 21 genes in gastric tumors.

NFκB activation demarcates a subset of hepatocellular carcinoma patients for targeted therapy.

Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. It is a heterogeneous disorder and >80 % of the tumors develop in patients with liver cirrhosis, resulting from chronic inflammation and/or fibrosis. Here, we set out to identify novel targets for HCC therapy and to define a subgroup of patients that might benefit most from it.

Integrative analysis of transcriptome and miRNome unveils the key regulatory connections involved in different stages of hepatocellular carcinoma.

Dysregulated molecular processes are the major factors that drive and feed the signaling processes involved in carcinogenesis. In recent years, regulation of mRNAs by microRNAs (miRNAs) has been found to play a vital role in many cancers including hepatocellular carcinoma (HCC). However, genomewide studies defining molecular regulatory circuits at both mRNA and miRNA levels are just emerging.

Molecular Portrait of Oral Tongue Squamous Cell Carcinoma Shown by Integrative Meta-Analysis of Expression Profiles with Validations.

Oral Tongue Squamous cell carcinoma (OTSCC), the most frequently affected oral cancer sub-site, is associated with a poor therapeutic outcome and survival despite aggressive multi- modality management. Till date, there are no established biomarkers to indicate prognosis and outcome in patients presenting with tongue cancer. There is an urgent need for reliable molecular prognostic factors to enable identification of patients with high risk of recurrence and treatment failure in OTSCC management.