Prospects of liquid biopsy in the prognosis and clinical management of gastrointestinal cancers

Gastrointestinal (GI) cancers account for one-fourth of the global cancer incidence and are incriminated to cause one-third of cancer-related deaths. GI cancer includes esophageal, gastric, liver, pancreatic, and colorectal cancers, mostly diagnosed at advanced stages due to a lack of accurate markers for early stages. The invasiveness of diagnostic methods like colonoscopy for solid biopsy reduces patient compliance as it cannot be frequently used to screen patients. Therefore, minimally invasive approaches like liquid biopsy may be explored for screening and early identification of gastrointestinal cancers. Liquid biopsy involves the qualitative and quantitative determination of certain cancer-specific biomarkers in body fluids such as blood, serum, saliva, and urine to predict disease progression, therapeutic tolerance, toxicities, and recurrence by evaluating minimal residual disease and its correlation with other clinical features. In this review, we deliberate upon various tumor-specific cellular and molecular entities such as circulating tumor cells (CTCs), tumor-educated platelets (TEPs), circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), exosomes, and exosome-derived biomolecules and cite recent advances pertaining to their use in predicting disease progression, therapy response, or risk of relapse. We also discuss the technical challenges associated with translating liquid biopsy into clinical settings for various clinical applications in gastrointestinal cancers

Catabolic Ornithine Carbamoyltransferase Activity Facilitates Growth of Staphylococcus aureus in Defined Medium Lacking Glucose and Arginine

Previous studies have found that arginine biosynthesis in Staphylococcus aureus is repressed via carbon catabolite repression (CcpA), and proline is used as a precursor. Unexpectedly, however, robust growth of S. aureus is not observed in complete defined medium lacking both glucose and arginine (CDM-R). Mutants able to grow on agar-containing defined medium lacking arginine (CDM-R) were selected and found to contain mutations within ahrC, encoding the canonical arginine biosynthesis pathway repressor (AhrC), or single nucleotide polymorphisms (SNPs) upstream of the native arginine deiminase (ADI) operon arcA1B1D1C1. Reverse transcription-PCR (RT-PCR) studies found that mutations within ccpA or ahrC or SNPs identified upstream of arcA1B1D1C1 increased the transcription of both arcB1 and argGH, encoding ornithine carbamoyltransferase and argininosuccinate synthase/lyase, respectively, facilitating arginine biosynthesis. Furthermore, mutations within the AhrC homologue argR2 facilitated robust growth within CDM-R. Complementation with arcB1 or arcA1B1D1C1, but not argGH, rescued growth in CDM-R. Finally, supplementation of CDM-R with ornithine stimulated growth, as did mutations in genes (proC and rocA) that presumably increased the pyrroline-5-carboxylate and ornithine pools. Collectively, these data suggest that the transcriptional regulation of ornithine carbamoyltransferase and, in addition, the availability of intracellular ornithine pools regulate arginine biosynthesis in S. aureus in the absence of glucose. Surprisingly, ~50% of clinical S. aureus isolates were able to grow in CDM-R. These data suggest that S. aureus is selected to repress arginine biosynthesis in environments with or without glucose; however, mutants may be readily selected that facilitate arginine biosynthesis and growth in specific environments lacking arginine. IMPORTANCE Staphylococcus aureus can cause infection in virtually any niche of the human host, suggesting that it has significant metabolic versatility. Indeed, bioinformatic analysis suggests that it has the biosynthetic capability to synthesize all 20 amino acids. Paradoxically, however, it is conditionally auxotrophic for several amino acids, including arginine. Studies in our laboratory are designed to assess the biological function of amino acid auxotrophy in this significant pathogen. This study reveals that the metabolic block repressing arginine biosynthesis in media lacking glucose is the transcriptional repression of ornithine carbamoyltransferase encoded by arcB1 within the native arginine deiminase operon in addition to limited intracellular pools of ornithine. Surprisingly, approximately 50% of S. aureus clinical isolates can grow in media lacking arginine, suggesting that mutations are selected in S. aureus that allow growth in particular niches of the human host

Accumulation of Succinyl Coenzyme A Perturbs the Methicillin-Resistant Staphylococcus aureus (MRSA) Succinylome and Is Associated with Increased Susceptibility to Beta-Lactam Antibiotics

Penicillin binding protein 2a (PBP2a)-dependent resistance to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) is regulated by the activity of the tricarboxylic acid (TCA) cycle via a poorly understood mechanism. We report that mutations in sucC and sucD, but not other TCA cycle enzymes, negatively impact β-lactam resistance without changing PBP2a expression. Increased intracellular levels of succinyl coenzyme A (succinyl-CoA) in the sucC mutant significantly perturbed lysine succinylation in the MRSA proteome. Suppressor mutations in sucA or sucB, responsible for succinyl-CoA biosynthesis, reversed sucC mutant phenotypes. The major autolysin (Atl) was the most succinylated protein in the proteome, and increased Atl succinylation in the sucC mutant was associated with loss of autolytic activity. Although PBP2a and PBP2 were also among the most succinylated proteins in the MRSA proteome, peptidoglycan architecture and cross-linking were unchanged in the sucC mutant. These data reveal that perturbation of the MRSA succinylome impacts two interconnected cell wall phenotypes, leading to repression of autolytic activity and increased susceptibility to β-lactam antibiotics. IMPORTANCE mecA-dependent methicillin resistance in MRSA is subject to regulation by numerous accessory factors involved in cell wall biosynthesis, nucleotide signaling, and central metabolism. Here, we report that mutations in the TCA cycle gene, sucC, increased susceptibility to β-lactam antibiotics and was accompanied by significant accumulation of succinyl-CoA, which in turn perturbed lysine succinylation in the proteome. Although cell wall structure and cross-linking were unchanged, significantly increased succinylation of the major autolysin Atl, which was the most succinylated protein in the proteome, was accompanied by near complete repression of autolytic activity. These findings link central metabolism and levels of succinyl-CoA to the regulation of β-lactam antibiotic resistance in MRSA through succinylome-mediated control of two interlinked cell wall phenotypes. Drug-mediated interference of the SucCD-controlled succinylome may help overcome β-lactam resistance

Ismat Chughtai's Depiction of Homophobia Through the Story ‘Lihaaf’

This study aims to bring attention to the homophobia of the famous female writer Ismat Chughtai with the help of her infamous short story ‘Lihaaf’ published in the pre-independent India. The short story ‘Lihaaf’ is a story of a homosexual woman named Begum Jan and her homosexual husband Nawab Saheb. Through this study, we are trying to bring the homophobic depiction of characters by the writer Ismat Chughtai in the short story ‘Lihaaf’, which has been ignored for a long time

STATISTICAL ANALYSIS OF ELECTROCHEMICAL DISCHARGE MACHINING FOR SODA LIME GLASS

Electro chemical discharge machining (ECDM) is a hybrid process which combines the features of electro chemical machining (ECM) and electro discharge machining (EDM).The need for micromachining of advanced engineering materials started increase in demand in various sectors like nuclear, aerospace and medical industries. Electrochemical discharge machining (ECDM) technique is that involves high-temperature melting and accelerated chemical etching under the high electrical energy discharged and has potential to machine electrically non-conductive materials such as glass, quartz, composite, ceramics. In ECDM, gas film and sparks are generated on a tool when voltage is applied between the tool and a counter electrode. Work-piece materials are removed mainly by the heat of the sparks. The spark generation is affected by both the voltage and electrolyte conditions. In this present work, The effect of process variables such as electrolyte concentration (EC), duty factor (DF), voltage (V), on response parameters such as Material Removal Rate (MRR), Tool Wear Rate (TWR), Diametric overcut (DOC) have been investigated sodalime glass in electrochemical discharge machining (ECDM) using tungsten carbide electrode. Analysis of variance (ANOVA) and F-test were performed to determine the significant parameters at a 95% confidence interval

SUSTAINABLE MACHINING USING MINIMUM QUANTITY LUBRICATIONA COMPREHENSIVE REVIEW

In the machining process,conventional cutting fluid injected at the tool-workpiece interface as a coolant. Conventional coolant createsharmful health effects. Minimum quantity lubrication plays acrucial role in the machining process, it works as a substitute to conventional lubrication system by reducing the quantity of lubricant used. It reduces environmentalimpact also protected possible health hazard an operator. Also,machining,costscan reduce significantly.It is a method between dry and flood lubrication to ensure lubrication effects. This review article provides recent advancementsin MQL with a special emphasison turning, milling machining operations. In the end,it is concluded that there is an improvement in surface roughness,chip removal, tool life and tool wear with use of MQL when comparedwith dry machiningand conventional coolin

Statistical Analysis Of Electrochemical Discharge Machining For Soda Lime Glass

Electro chemical discharge machining (ECDM) is a hybrid process which combines the features of electro chemical machining (ECM) and electro discharge machining (EDM).The need for micromachining of advanced engineering materials started increase in demand in various sectors like nuclear, aerospace and medical industries. Electrochemical discharge machining (ECDM) technique is that involves high-temperature melting and accelerated chemical etching under the high electrical energy discharged and has potential to machine electrically non-conductive materials such as glass, quartz, composite, ceramics. In ECDM, gas film and sparks are generated on a tool when voltage is applied between the tool and a counter electrode. Work-piece materials are removed mainly by the heat of the sparks. The spark generation is affected by both the voltage and electrolyte conditions. In this present work, The effect of process variables such as electrolyte concentration (EC), duty factor (DF), voltage (V), on response parameters such as Material Removal Rate (MRR), Tool Wear Rate (TWR), Diametric overcut (DOC) have been investigated sodalime glass in electrochemical discharge machining (ECDM) using tungsten carbide electrode. Analysis of variance (ANOVA) and F-test were performed to determine the significant parameters at a 95% confidence interval

Sustainable Machining Using Minimum Quantity Lubricationa Comprehensive Review

In the machining process,conventional cutting fluid injected at the tool-workpiece interface as a coolant. Conventional coolant createsharmful health effects. Minimum quantity lubrication plays acrucial role in the machining process, it works as a substitute to conventional lubrication system by reducing the quantity of lubricant used. It reduces environmentalimpact also protected possible health hazard an operator. Also,machining,costscan reduce significantly.It is a method between dry and flood lubrication to ensure lubrication effects. This review article provides recent advancementsin MQL with a special emphasison turning, milling machining operations. In the end,it is concluded that there is an improvement in surface roughness,chip removal, tool life and tool wear with use of MQL when comparedwith dry machiningand conventional coolin