Drug resistance mechanisms in cancers:Execution of prosurvival strategies

One of the quintessential challenges in cancer treatment is drug resistance.Several mechanisms of drug resistance have been described to date,and new modes of drug resistance continue to be discovered.The phenomenon of cancer drug resistance is now widespread,with approximately 90% of cancer-related deaths associated with drug resistance.Despite significant advances in the drug discovery process,the emergence of innate and acquired mechanisms of drug resistance has impeded the progress in cancer therapy.Therefore,understanding the mechanisms of drug resistance and the various pathways involved is integral to treatment modalities.In the present review,I discuss the different mechanisms of drug resistance in cancer cells,including DNA damage repair,epithelial to mesenchymal transition,inhibition of cell death,alteration of drug targets,inactivation of drugs,deregulation of cellular energetics,immune evasion,tumor-promoting inflammation,genome instability,and other contributing epigenetic factors.Furthermore,I highlight available treatment options and conclude with future directions.

Characteristics of viral specimens collected from asymptomatic and fatal cases of COVID-19

We sought to determine the characteristics of viral specimens associated with fatal cases,asymptomatic cases and non-fatal symptomatic cases of COVID-19.This included the analysis of 1264 specimens found reactive for at least two SARS-CoV-2 specific loci from people screened for infection in Northern Nevada in March-May of 2020.Of these,30 were specimens from fatal cases,while 23 were from positive,asymptomatic cases.We assessed the relative amounts of SARS-CoV-2 RNA from sample swabs by real-time PCR and use of the threshold crossing value(Ct).Moreover,we compared the amount of human RNase P found on the same swabs.A considerably higher viral load was found to be associated with swabs from cases involving fatality and the difference was found to be strongly statistically significant.Noting this difference,we sought to assess whether any genetic correlation could be found in association with virus from fatal cases using whole genome sequencing.While no common genetic elements were discerned,one branch of epidemiologically linked fatal cases did have two point mutations,which no other of 156 sequenced cases from northern Nevada had.The mutations caused amino acid changes in the 3′-5′exonuclease protein,and the product of the gene,orf8.

Endoscopic retrograde cholangiopancreatography in cirrhosis-a systematic review and meta-analysis focused on adverse events

AIM To investigate indications and outcomes of endoscopic retrograde cholangiopancreatography(ERCP) in cirrhotics, especially adverse events. Patients with cirrhosis undergoing ERCP are believed to have increased risk. However, there is a paucity of literature describing the indications and outcomes of ERCP procedures in patients with cirrhosis, especially focusing on adverse events.METHODS We performed a systematic appraisal of major literature databases, including PubMed and EMBASE, with a manual search of literature from their inception until April 2017.RESULTS A total of 6,505 patients from 15 studies were analyzed(male ratio 59%, mean age 59 years), 11% with alcoholic and 89% with non-alcoholic cirrhosis, with 56.2% Child-Pugh class A, and 43.8% class B or C. Indications for ERCP included choledocholithiasis 60.9%, biliary strictures 26.2%, gallstone pancreatitis 21.1% and cholangitis 15.5%. Types of interventions included endoscopic sphincterotomy 52.7%, biliary stenting 16.7% and biliary dilation 4.6%. Individual adverse events included hemorrhage in 4.58%(95%CI: 2.77-6.75%, I^2 = 85.9%), post-ERCP pancreatitis(PEP) in 3.68%(95%CI: 1.83-6.00%, I^2 = 89.5%), cholangitis in 1.93%(95%CI: 0.63-3.71%, I^2 = 87.1%) and perforation in 0.00%(95%CI: 0.00-0.23%, I^2 = 37.8%). Six studies were used for comparison of ERCPrelated complications in cirrhosis vs non-cirrhosis, which showed higher overall rates of complications in cirrhosis patients with pooled OR of 1.63(95%CI: 1.27-2.09, I2 = 65%): higher rates of hemorrhage with OR of 2.05(95%CI: 1.62-2.58, I^2 = 2.1%) and PEP with OR of 1.33(95%CI: 1.04-1.70, I2=65%), but similar cholangitis rates with OR of 1.23(95%CI: 0.67-2.26, I^2 = 44.3%).CONCLUSION There is an overall higher rate of adverse events related to ERCP in patients with cirrhosis, especially hemorrhage and PEP. A thorough risk/benefit assessment should be performed prior to undertaking ERCP in patients with cirrhosis.

Genomic surveillance of Nevada patients revealed prevalence of unique SARS-CoV-2 variants bearing mutations in the RdRp gene

Patients with signs of COVID-19 were tested through diagnostic RT-PCR for SARS-CoV-2 using RNA extracted from the nasopharyngeal/nasal swabs.To determine the variants of SARS-CoV-2 circulating in the state of Nevada,specimens from 200 COVID-19 patients were sequenced through our robust sequencing platform,which enabled sequencing of SARS-CoV-2 from specimens with even very low viral loads,without the need of culture-based amplification.High genome coverage allowed the identification of single and multi-nucleotide variants in SARS-CoV-2 in the community and their phylogenetic relationships with other variants present during the same period of the outbreak.We report the occurrence of a novel mutation at 323aa (314aa of orf1b) of nsp12 (RNA-dependent RNA polymerase) changed to phenylalanine(F) from proline (P),in the first reported isolate of SARS-CoV-2,Wuhan-Hu-1.This 323F variant was present at a very high frequency in Northern Nevada.Structural modeling determined this mutation in the interface domain,which is important for the association of accessory proteins required for the polymerase.In conclusion,we report the introduction of specific SARS-CoV-2 variants at very high frequency in distinct geographic locations,which is important for understanding the evolution and circulation of SARS-CoV-2variants of public health importance,while it circulates in humans.

Comparative genomic analysis of Thermus provides insights into the evolutionary history of an incomplete denitrification pathway

Biological denitrification is a crucial process in the nitrogen biogeochemical cycle,and Thermus has been reported to be a significant heterotrophic denitrifier in terrestrial geothermal environments.However,neither the denitrification potential nor the evolutionary history of denitrification genes in the genus Thermus or phylum Deinococcota is well understood.Here,we performed a comparative analysis of 23 Thermus genomes and identified denitrification genes in 15 Thermus strains.We confirmed that Thermus harbors an incomplete denitrification pathway as none of the strains contain the nosZ gene.Ancestral character state reconstructions and phylogenetic analyses showed that narG,nirS,and norB genes were acquired by the last common ancestor of Thermales and were inherited vertically.In contrast,nirK of Thermales was acquired via two distinct horizontal gene transfers from Proteobacteria to the genus Caldithermus and from an unknown donor to the common ancestor of all known Thermus species except Thermus filiformis.This study expands our understanding of the genomic potential for incomplete denitrification in Thermus,revealing a largely vertical evolutionary history of the denitrification pathway in the Thermaceae,and supporting the important role for Thermus as an important heterotrophic denitrifier in geothermal environments.

A Hashing-Based Framework for Enhancing Cluster Delineation of High-Dimensional Single-Cell Profiles

Although many methods have been developed to explore the function of cells by clustering high-dimensional(HD)single-cell omics data,the inconspicuously differential expressions of biomarkers of proteins or genes across all cells disturb the cell cluster delineation and downstream analysis.Here,we introduce a hashing-based framework to improve the delineation of cell clusters,which is based on the hypothesis that one variable with no significant differences can be decomposed into more diversely latent variables to distinguish cells.By projecting the original data into a sparse HD space,fly and densefly hashing preprocessing retain the local structure of data,and improve the cluster delineation of existing clustering methods,such as PhenoGraph.Moreover,the analyses on mass cytometry dataset show that our hashing-based framework manages to unveil new hidden heterogeneities in cell clusters.The proposed framework promotes the utilization of cell biomarkers and enriches the biological findings by introducing more latent variables.

Recent Progresses in Electrochemical DNA Biosensors for MicroRNA Detection

MicroRNAs(miRNAs),as the small,non-coding,evolutionary conserved,and post-transcriptional gene regulators of the genome,have been highly associated with various diseases such as cancers,viral infections,and cardiovascular diseases.Several techniques have been established to detect miRNAs,including northern blotting,real-time polymerase chain reaction(RT-PCR),and fluorescent microarray platform.However,it remains a significant challenge to develop sensitive,accurate,rapid,and cost-effective methods to detect miRNAs due to their short size,high similarity,and low abundance.The electro-chemical biosensors exhibit tremendous potential in miRNA detection because they satisfy feature integration,portability,mass production,short response time,and minimal sample consumption.This article reviewed the working principles and signal amplification strategies of electrochemical DNA biosensors summarized the recent improvements.With the develop-ment of DNA nanotechnology,nanomaterials and biotechnology,electrochemical DNA biosensors of high sensitivity and specificity for microRNA detection will shortly be commercially accessible.