Pathogenesis and drug resistance mechanism of Burkholderia pseudomallei

Burkholderia pseudomallei is the pathogen that causes melioidosis.Melioidosis has a long duration of chronic infection,atypical clinical manifestations at acute onset,and is prone to life-threatening complications and poor prognosis.Understanding the pathogenesis and drug resistance mechanism of Burkholderia pseudomallei will effectively help the diagnosis and treatment of the disease and improve the prognosis.This review focuses on the extracellular movement of Burkholderia pseudomallei in host cells,the way of infecting host cells,virulence factors,and drug resistance mechanisms(efflux pumps,changes in target sites,etc.).This study provides a possible direction for the early diagnosis,treatment and control of melioidosis caused by this bacterium.

The role of emerging organic contaminants in the development of antimicrobial resistance

Antimicrobial resistance(AMR)threatens human and ecological health worldwide.Unless major changes occur across the human,animal and environmental sectors,the problem will continue to expand.An important component of AMR that deserves greater attention is the influence of emerging organic contaminants(EOCs)e ubiquitous compounds found,amongst others,in pharmaceuticals,personal care products,food,industrial and agricultural products,plastics and building materials.EOCs are widely used and can accumulate in the environment from varied sources,predominantly via waste streams.EOCs can interact with microbial communities potentially leading to the emergence and spread of AMR.Biocides and pharmaceuticals have been demonstrated to promote AMR development.Antimicrobial resistance is a multi-faceted problem that requires input from all sectors,with robust strategies and policies needed to make headway with solving the issues of this important threat.

The change of paradigm in the treatment of HER2-positive breast cancer with the development of newgeneration antibody-drug conjugates

HER2-positive breast cancer is an aggressive disease.As a result of the development of specific HER2-targeted therapies,such as trastuzumab,more than 20 years ago,the prognosis of these patients has improved.Metastatic HER2-positive breast cancer patients are achieving better survival rates upon treatment with anti-HER2 therapies than patients with HER2-negative disease.Double HER2 blockade with trastuzumab and pertuzumab combined with a taxane achieved an unprecedented survival of over 57 months in first-line patients.Trastuzumab emtansine,the first antibody-drug conjugate approved for patients in second-line treatment was a potent cytotoxic agent bound to trastuzumab and is currently a standard therapeutic strategy.Despite the progress in treatment development,most patients develop resistance and eventually relapse.Advances in the design of antibody-drug conjugates have led to the development of new generation drugs with enhanced properties,such as trastuzumab deruxtecan and trastuzumab duocarmazine,which are significantly changing the paradigm in the treatment of HER2-positive metastatic breast cancer.

Prevalence and characterization of plasmid-mediated blaESBL with their genetic environment in Escherichia coli and Klebsiella pneumoniae in patients with pneumonia

Background The extended spectrum 13-1actamase （ESBL）-producing Escherichia coil （E. coh） and Klebsiella pneumoniae （K. pneumoniae） are the major pathogens causing pneumonia and have a significant impact on the clinical course. Limited data exist on molecular characterization of ESBL-producing E. coli and K. pneumoniae that cause pneumonia. The aim of this study was to investigate the comprehensive multilevel characteristics of E. coil and K. pneumoniae causing pneumonia in China for the first time.

Resistance to anti-tubulin agents:From vinca alkaloids to epothilones

This review describes the mechanism of action-inhibition of microtubules-and the most important mechanisms of resistance for vinca alkaloids,taxanes and epothilones.Resistance is a major problem in vinca and taxane chemotherapy and arises in most cases from overexpression of efflux pumps that transport the drugs out of the cancer cells and from modifications of the target,the microtubules,by overexpression of tubulin isotypes or by attachment of proteins to the ends of the microtubules so that the target is no longer recognized by the drugs.In some cases,however,this process can have the opposite effect,leading to sensitization,e.g.,for vinca alkaloids in cases where taxanes are not or no longer effective.The link between resistance due to efflux pumps and the pharmacokinetics and metabolism of the drugs is also covered.Other types of resistance that are addressed include detoxification of drugs within the cancer cell and blockade of apoptosis,post-translational modifications of microtubules and other protein pathways,micro-RNAs,induction of oncogenes,and cancer stem cells,which,taken together,offer particularly multifold possibilities for preventing drug activity.The use of biomarkers for the prediction of clinical outcome and for the direction of future therapy is also addressed.

Decoding cancer's camouflage: epithelial-mesenchymal plasticity in resistance to immune checkpoint blockade

Epithelial-mesenchymal plasticity(EMP)of cancer cells contributes to cancer cell heterogeneity,and it is well established that EMP is a critical determinant of acquired resistance to cancer treatment modalities including radiation therapy,chemotherapy,and targeted therapies.Here,we aimed to explore how EMP contributes to cancer cell camouflage,allowing an ever-changing population of cancer cells to pass under the radar of our immune system and consequently compromise the effect of immune checkpoint blockade therapies.The ultimate clinical benefit of any combination regimen is evidenced by the sum of the drug-induced alterations observed in the variety of cellular populations composing the tumor immune microenvironment.The finely-tuned molecular crosstalk between cancer and immune cells remains to be fully elucidated,particularly for the spectrum of malignant cells along the epithelial to mesenchymal axis.High-dimensional single cell analyses of specimens collected in ongoing clinical studies is becoming a key contributor to our understanding of these interactions.This review will explore to what extent targeting EMP in combination with immune checkpoint inhibition represents a promising therapeutic avenue within the overarching strategy to reactivate a halting cancer-immunity cycle and establish a robust host immune response against cancer cells.Therapeutic strategies currently in clinical development will be discussed.