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Background Human immunodeficiency virus type 1 (HIV-1) acquired drug resistance (ADR) compromises antiretroviral therapy (ART). Methods We aggregated all HIV-1 protease–reverse transcriptase–integrase sequences over 2004–2021 at the largest HIV center in Rhode Island and evaluated ADR extent, trends, and impact using Stanford Database tools. Trends were measured with Mann-Kendall statistic, and multivariable regressions evaluated resistance predictors. Results Sequences were available for 914 ART-experienced persons. Overall ADR to any drug decreased from 77% to 49% (−0.66 Mann-Kendall statistic); nucleoside reverse transcriptase inhibitors 65% to 32%, nonnucleoside reverse transcriptase inhibitors 53% to 43%, and protease inhibitors 28% to 7% (2004–2021), and integrase strand transfer inhibitors 16% to 13% (2017–2021). Multiclass resistance decreased from 44% to 12% (2-class) and 12% to 6% (3-class). In 2021, 94% had at least one 3-drug or 2-drug one-pill-once-daily (OPOD) option. Males and those exposed to more ART regimens were more likely to have ≥2-class resistance, and higher regimen exposure was also associated with fewer OPOD options. Conclusions Comprehensive analyses within a densely-sampled HIV epidemic over 2004–2021 demonstrated decreasing ADR. Continued ADR monitoring is important to maintain ART success, particularly with rising INSTI use in all lines of therapy and 2-drug and long-acting formulations. [ABSTRACT FROM AUTHOR]

Background The prevalence and epidemiology of pre-treatment drug resistance (PDR) and acquired drug resistance (ADR) among HIV-infected individuals vary considerably in different regions of China. Both types of drug resistance have adverse effects on the antiviral treatment outcomes for patients, potentially exacerbating their poor prognosis. Currently, there is a paucity of research on the prevalence and epidemiology of PDR and ADR among HIV-infected individuals in Southwest China. Objective This study investigated the prevalence and epidemiology of pre-treatment drug resistance and acquired drug resistance among people living with HIV (PLWH) in Southwest China. Methods This was a large cross-sectional study that enrolled PLWH who visited Guiyang Public Health Clinical Center between January 1, 2021, and June 30, 2023, and underwent drug resistance gene testing. HIV-1 genotype and drug resistance were analyzed using HIV-1 pol sequence. The Stanford University HIV Drug Resistance Database was used to analyze major drug resistance mutations in the reverse transcriptase and protease Sanger sequences. Risk factors associated with pre-treatment drug resistance were evaluated using a Logistic regression model. Results A total of 1 613 individuals were included in the study, with 824 ART-naive and 789 ART-experienced. The most common genotype among ART-naive patients was B+C (47.0%), and the drug resistance rate was 18.7% (154/824) with non-nucleoside reverse transcriptase inhibitors (NNRTIs) accounting for 14.9% (123/824), nucleoside reverse transcriptase inhibitors (NRTIs) accounting for 1.7% (14/824), protease inhibitors (PIs) accounting for 2.7% (22/824), and integrase strand transfer inhibitors (INSTIs) accounting for 1.9% (16/824). Among the ART-experienced patients, the most common genotype was CRF01-AE (37.4%), with a drug resistance rate of 27.8% (219/789). The mutation rates for NNRTIs, NRTIs, PIs, and INSTIs were 7.7% (61/789), 19.3% (152/789), 2.7% (21/789), and 1.1% (9/789), respectively. Furthermore, multivariate Logistic regression modeling revealed that transmission route, CD4+ T-cell count, viral load, and the time interval between diagnosis and ART initiation were associated with an increased risk of pre-treatment drug resistance (P

Abstract Background Limited diagnostic testing for drug-resistant TB (DR-TB) may lead to high rates of misdiagnosis and undertreatment. Current diagnostic tests focus only on detection of rifampicin-resistant TB (RR-TB). This study aims to determine the impact of improved diagnostic testing for a wider range of drug resistance on DR-TB outcomes in high-burden TB settings, using the Philippines and Thailand as case studies. Methods A dynamic compartmental model was designed to simulate population level TB transmission, accounting for acquired drug resistance from treatment failure of drug susceptible TB. Three scenarios were analyzed: (1) Use of GeneXpert MTB/RIF on all presumptive TB cases (Status Quo); (2) GeneXpert MTB/RIF + GeneXpert XDR, (3) GeneXpert MTB/RIF + targeted Next Generation Sequencing (tNGS). Scenarios were modelled over a 10-year period, from 2025 to 2034. Results Compared to the status quo, Scenario 2 results in a fourfold increase in annual DR-TB cases diagnosed in the Philippines and a fivefold increase in Thailand. DR-TB treatment failure decreases by 20% in the Philippines and 23% in Thailand. Scenario 3 further increases DR-TB case detection, reducing DR-TB treatment failure by 26% in the Philippines and 29% in Thailand. Reductions in DR-TB incidence and mortality ranged from 3 to 6%. Conclusion The use of GeneXpert XDR or tNGS as an additional diagnostic test for DR-TB significantly improves DR-TB case detection and reduces treatment failure, supporting their consideration for use in high burden settings. These findings highlight the importance of detecting a wider range of TB resistance in addition to RR-TB, the potential impact these improved diagnostic tests can have on DR-TB outcomes, and the need for additional research on cost-effectiveness of these interventions.

AIMS: Drivers of the drug tolerant proliferative persister (DTPP) state have not been well investigated. Histone H3 lysine-4 trimethylation (H3K4me3), an active histone mark, might enable slow cycling drug tolerant persisters (DTP) to regain proliferative capacity. This study aimed to determine H3K4me3 transcriptionally active sites identifying a key regulator of DTPPs. METHODS: Deploying a model of adaptive cancer drug tolerance, H3K4me3 ChIP-Seq data of DTPPs guided identification of top transcription factor binding motifs. These suggested involvement of O-linked N-acetylglucosamine transferase (OGT), which was confirmed by metabolomics analysis and biochemical assays. OGT impact on DTPPs and adaptive resistance was explored in vitro and in vivo. RESULTS: H3K4me3 remodeling was widespread in CPG island regions and DNA binding motifs associated with O-GlcNAc marked chromatin. Accordingly, we observed an upregulation of OGT, O-GlcNAc and its binding partner TET1 in chronically treated cancer cells. Inhibition of OGT led to loss of H3K4me3 and downregulation of genes contributing to drug resistance. Genetic ablation of OGT prevented acquired drug resistance in in vivo models. Upstream of OGT, we identified AMPK as an actionable target. AMPK activation by acetyl salicylic acid downregulated OGT with similar effects on delaying acquired resistance. CONCLUSION: Our findings uncover a fundamental mechanism of adaptive drug resistance that governs cancer cell reprogramming towards acquired drug resistance, a process that can be exploited to improve response duration and patient outcomes.

Lung cancer patients treated with targeted therapies frequently respond well but invariably relapse due to the development of drug resistance. Drug resistance is in part mediated by a subset of cancer cells termed "drug-tolerant persisters" (DTPs), which enter a dormant, slow-cycling state that enables them to survive drug exposure. DTPs also exhibit stem cell-like characteristics, broad epigenetic reprogramming, altered metabolism, and a mutagenic phenotype mediated by adaptive mutability. While several studies have characterised the transcriptional changes that lead to the altered phenotypes exhibited in DTPs, these studies have focused predominantly on protein coding changes. As long non-coding RNAs (lncRNAs) are also implicated in the phenotypes altered in DTPs, it is likely that they play a role in the biology of drug tolerance. In this review, we outline how lncRNAs may contribute to the key characteristics of DTPs, their potential roles in tolerance to targeted therapies, and the emergence of genetic resistance in lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Genomic rearrangements of the neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, and NTRK3) are the most common mechanism of oncogenic activation for this family of receptors, resulting in sustained cancer cell proliferation. Several targeted therapies have been approved for tumours harbouring NTRK fusions and a new generation of TRK inhibitors has already been developed due to acquired resistance. We established a patient‐derived LMNA::NTRK1‐rearranged soft‐tissue sarcoma cell model ex vivo with an acquired resistance to targeted TRK inhibition. Molecular profiling of the resistant clones revealed an acquired NF2 loss of function mutation that was absent in the parental cell model. Parental cells showed continuous sensitivity to TRK‐targeted treatment, whereas the resistant clones were insensitive. Furthermore, resistant clones showed upregulation of the MAPK and mTOR/AKT pathways in the gene expression based on RNA sequencing data and increased sensitivity to MEK and mTOR inhibitor therapy. Drug synergy was seen using trametinib and rapamycin in combination with entrectinib. Medium‐throughput drug screening further identified small compounds as potential drug candidates to overcome resistance as monotherapy or in combination with entrectinib. In summary, we developed a comprehensive model of drug resistance in an LMNA::NTRK1‐rearranged soft‐tissue sarcoma and have broadened the understanding of acquired drug resistance to targeted TRK therapy. Furthermore, we identified drug combinations and small compounds to overcome acquired drug resistance and potentially guide patient care in a functional precision oncology setting. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Objectives: The safety and feasibility of repeat biopsy after systemic treatment for non-small cell lung cancer have received extensive attention in recent years. The purpose of this research was to compare complication rates between initial biopsy and rebiopsy in non-small cell lung cancer patients with progressive disease and to assess complication risk factors and clinical results after rebiopsy. Methods: The study included 113 patients initially diagnosed with non-small cell lung cancer who underwent lung biopsy at initial biopsy and rebiopsy after progression while on epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and/or chemotherapy from January 2018 to December 2021. We compared the incidence of complications between the initial biopsy and rebiopsy and analyzed the predictors factors that influenced complications in patients who underwent rebiopsy. Results: The successful rate of rebiopsy was 88.5% (100/113). With the exception of two cases where lung adenocarcinoma changed into small cell lung cancer with gefitinib treatment, 98 individuals retained their initial pathological type. The secondary EGFR T790M mutation accounts for 55.6% of acquired resistance. The total number of patients with complications in initial biopsy was 25 (22.1%) and 37 (32.7%) in the rebiopsy. The incidence of pulmonary hemorrhage increased from 7.1% at the initial biopsy to 10.6% at rebiopsy, while the incidence of pneumothorax increased from 14.2% to 20.4%. Compared with the initial biopsy, the incidence of overall complications, parenchymal hemorrhage, and pneumothorax increased by 10.6%, 3.5%, and 6.2%, respectively. In all four evaluations (pneumorrhagia, pneumothorax, pleural reaction, and overall complication), there were no significant differences between the rebiopsy and initial biopsy (all p > 0.05). The multivariate logistic regression analysis suggested that male sex (odds ratio [OR] = 5.064, p = 0.001), tumor size ≤ 2 cm(OR = 3.367, p = 0.013), EGFR-TKIs with chemotherapy (OR = 3.633, p =0.023), and transfissural approach (OR = 7.583, p = 0.026) were independent risk factors for overall complication after rebiopsy. Conclusion: Compared with the initial biopsy, the complication rates displayed a slight, but not significant, elevation in rebiopsy. Male sex, tumor size ≤ 2 cm, transfissural approach, and EGFR-TKIs combined with chemotherapy were independent risk factors for rebiopsy complications. [ABSTRACT FROM AUTHOR]

We elucidated the factors, evolution, and compensation of antimicrobial resistance (AMR) in Mycobacterium tuberculosis (MTB) isolates under dual pressure from the intra-host environment and anti-tuberculosis (anti-TB) drugs. This retrospective case-control study included 337 patients with pulmonary tuberculosis from 15 clinics in Tianjin, China, with phenotypic drug susceptibility testing results available for at least two time points between January 1, 2009 and December 31, 2016. Patients in the case group exhibited acquired AMR to isoniazid (INH) or rifampicin (RIF), while those in the control group lacked acquired AMR. The whole-genome sequencing (WGS) was conducted on 149 serial longitudinal MTB isolates from 46 patients who acquired or reversed phenotypic INH/RIF-resistance during treatment. The genetic basis, associated factors, and intra-host evolution of acquired phenotypic INH/RIF-resistance were elucidated using a combined analysis. Anti-TB interruption duration of ≥30 days showed association with acquired phenotypic INH/RIF resistance (aOR = 2·2, 95% CI, 1·0–5·1) and new rpoB mutations (p = 0·024). The MTB evolution was 1·2 (95% CI, 1·02–1·38) single nucleotide polymorphisms per genome per year under dual pressure from the intra-host environment and anti-TB drugs. AMR-associated mutations occurred before phenotypic AMR appearance in cases with acquired phenotypic INH (10 of 16) and RIF (9 of 22) resistances. Compensatory evolution may promote the fixation of INH/RIF-resistance mutations and affect phenotypic AMR. The TB treatment should be adjusted based on gene sequencing results, especially in persistent culture positivity during treatment, which highlights the clinical importance of WGS in identifying reinfection and AMR acquisition before phenotypic drug susceptibility testing. [ABSTRACT FROM AUTHOR]

Taxol (paclitaxel) is the first approved microtubule‐stabilizing agent (MSA) by binding stoichiometrically to tubulin, which is considered to be one of the most significant advances in first‐line chemotherapy against diverse tumors. However, a large number of residue missence mutations harboring in the tubulin have been observed to cause acquired drug resistance, largely limiting the clinical application of Taxol and its analogs in chemotherapy. A systematic investigation of the intermolecular interactions between the Taxol and various tubulin mutants would help to establish a comprehensive picture of drug response to tubulin mutations in clinical treatment of cancer, and to design new MSA agents with high potency and selectivity to overcome drug resistance. In this study, we described an integration of in silico analysis and in vitro assay (iSiV) to profile Taxol against a panel of 149 clinically observed, cancer‐associated missence mutations in β‐tubulin at molecular and cellular levels, aiming to a systematic understanding of molecular mechanism and biological implication underlying drug resistance and sensitivity conferring from tubulin mutations. It is revealed that the Taxol‐resistant mutations can be classified into three types: (I) nonbonded interaction broken due to mutation, (II) steric hindrance caused by mutation, and (III) conformational change upon mutation. In addition, we identified three new Taxol‐resistant mutations (C239Y, T274I, and R320P) that can largely reduce the binding affinity of Taxol to tubulin at molecular level, in which the T274I and R320P were observed to considerably impair the antitumor activity of Taxol at cellular level. Moreover, a novel drug‐susceptible mutation (M363T) was also identified, which improves Taxol affinity by 2.6‐fold and decreases Taxol antitumor EC50 values from 29.4 to 18.7 μM. [ABSTRACT FROM AUTHOR]

(1) Background: The objective of this study was to investigate the prevalence of genetic diversity and drug resistance mutations among people living with HIV (PLWH) attending clinics in Beijing. (2) Methods: A retrospective analysis was conducted on PLWH admitted to the Fifth Medical Center of People's Liberation Army (PLA) General Hospital between 1 March 2013 and 31 July 2020. The participants were analyzed for pretreatment drug resistance (PDR) and acquired drug resistance (ADR). Nested polymerase chain reaction (PCR) was utilized to amplify the pol gene from plasma RNA samples obtained from the participants. Genotypic and HIV drug resistance were determined using the Stanford University HIV Drug Resistance Database. Univariate and multifactorial logistic analyses were used to assess the risk factors for PDR. (3) Results: The overall prevalence rates of PDR and ADR were 12.9% and 27.8%, respectively. Individuals treated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) exhibited the highest prevalence of mutations. Specific mutation sites, such as V179D for NNRTIs and M184V and K65R for nucleoside reverse transcriptase inhibitors (NRTIs), were identified as prevalent mutations. Individuals treated with efavirenz (EFV) and nevirapine (NVP) were found to be susceptible to developing resistance. The multifactorial regression analyses indicated that the factors of circulating recombination form (CRF) genotype CRF07-BC and a high viral load were associated with an increased risk of PDR. CRF01-AE and CRF07-BC were the most prevalent HIV genotypes in our study. (4) Conclusions: The distribution of HIV genotypes in Beijing is complex. There is a need for baseline screening for HIV drug resistance among ART-naive individuals, as well as timely testing for drug resistance among ART-experienced individuals. [ABSTRACT FROM AUTHOR]

Sorafenib (SOR) is a molecular targeting agent commonly utilized as a primary treatment for advanced and inoperable hepatocellular carcinoma (HCC). Regrettably, the effectiveness of SOR is frequently hindered by the resistance of multiple HCC cases. The current investigation endeavors to examine the potential of the natural product quercetin (QUE) in reversing the acquired resistance of SOR-resistant cells, known as Huh7R, to SOR. Moreover, this study aims to elucidate the underlying molecular mechanism that contributes to this phenomenon. The results demonstrated that QUE significantly impeded proliferation and stimulated apoptosis in Huh7R cells, while also suppressing the growth of transplanted tumors. The impact of QUE enhanced the efficacy of SOR treatment for Huh7R. Additionally, bioinformatic and western blot analyses indicated that the underlying mechanisms may be associated with EGFR tyrosine kinase inhibitor resistance, the PI3K-AKT signaling pathway, and HCC. Furthermore, molecular docking and dynamics simulation assays revealed that QUE exhibited strong affinity and stability towards its hub targets, EGFR and AKT1. It is noteworthy that the activation of EGFR by its ligand, EGF, mitigated the effects of co-treatment with QUE and SOR. These findings suggest that QUE might potentially serve as a therapeutic agent in treating as well as facilitating SOR against Huh7R cells, which has substantial clinical and research implications for the treatment of acquired resistance to SOR in HCC. [ABSTRACT FROM AUTHOR]

Upon prolonged use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non‐small‐cell lung cancer (NSCLC), acquired drug resistance inevitably occurs. This study investigates the combined use of EGFR‐TKIs (gefitinib or osimertinib) with epigallocatechin gallate (EGCG) to overcome acquired drug resistance in NSCLC models. The in vitro antiproliferative effects of EGFR‐TKIs and EGCG combination in EGFR‐mutant parental and resistant cell lines were evaluated. The in vivo efficacy of the combination was assessed in xenograft mouse models derived from EGFR‐TKI‐resistant NSCLC cells. We found that the combined use of EGFR‐TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug‐resistant NSCLC cells. The in vivo results obtained from mouse tumor xenograft model confirmed that EGCG effectively overcame osimertinib resistance. This study revealed that EGCG suppressed cancer bypass survival signaling and altered cancer metabolic profiles, which is a promising anticancer adjuvant of EGFR‐TKIs to overcome acquired drug resistance in NSCLC. [ABSTRACT FROM AUTHOR]

Lung cancer cells often show elevated levels of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH). However, the connections between deregulated redox homeostasis in different subtypes of lung cancer and acquired drug resistance in lung cancer have not yet been fully established. Herein, we analyzed different subtypes of lung cancer data reported in the Cancer Cell Line Encyclopedia (CCLE) database, the Cancer Genome Atlas program (TCGA), and the sequencing data obtained from a gefitinib‐resistant non‐small‐cell lung cancer (NSCLC) cell line (H1975GR). Using flux balance analysis (FBA) model integrated with multiomics data and gene expression profiles, we identified cytosolic malic enzyme 1 (ME1) and glucose‐6‐phosphate dehydrogenase as the major contributors to the significantly upregulated NADPH flux in NSCLC tissues as compared with normal lung tissues, and gefitinib‐resistant NSCLC cell line as compared with the parental cell line. Silencing the gene expression of either of these two enzymes in two osimertinib‐resistant NSCLC cell lines (H1975OR and HCC827OR) exhibited strong antiproliferative effects. Our findings not only underscored the pivotal roles of cytosolic ME1 and glucose‐6‐phosphate dehydrogenase in regulating redox states in NSCLC cells but also provided novel insights into their potential roles in drug‐resistant NSCLC cells with disturbed redox states. [ABSTRACT FROM AUTHOR]

Drug resistance remains the greatest challenge in improving outcomes for cancer patients who receive chemotherapy and targeted therapy. Surmounting evidence suggests that a subpopulation of cancer cells could escape intense selective drug treatment by entering a drug‐tolerant state without genetic variations. These drug‐tolerant cells (DTCs) are characterized with a slow proliferation rate and a reversible phenotype. They reside in the tumor region and may serve as a reservoir for resistant phenotypes. The survival of DTCs is regulated by epigenetic modifications, transcriptional regulation, mRNA translation remodeling, metabolic changes, antiapoptosis, interactions with the tumor microenvironment, and activation of signaling pathways. Thus, targeting the regulators of DTCs opens a new avenue for the treatment of therapy‐resistant tumors. In this review, we first provide an overview of common characteristics of DTCs and the regulating networks in DTCs development. We also discuss the potential therapeutic opportunities to target DTCs. Last, we discuss the current challenges and prospects of the DTC‐targeting approach to overcome acquired drug resistance. Reviewing the latest developments in DTC research could be essential in discovering of methods to eliminate DTCs, which may represent a novel therapeutic strategy for preventing drug resistance in the future. [ABSTRACT FROM AUTHOR]

Increased HIV drug resistance (HIVDR) with antiretroviral therapy (ART) rollout may jeopardize therapeutic options, especially in this era of transition to fixed-dose tenofovir-lamivudine-dolutegravir (TLD). We studied acquired HIVDR (ADR) patterns and describe potentially active drugs after first- and second-line failure in resource-limited settings (RLS) like Cameroon. A laboratory-based study with 759 patients (≥15 years) experiencing virological failure was carried out at the Chantal Biya International Reference Centre (CIRCB), Yaoundé, Cameroon. Socio-demographic, therapeutic and immunovirological data from patient records were analysed according to HIV-1 genotypic profiles. Median (IQR) ART-duration was 63 (50–308) months. Median CD4 and viremia were 153 (IQR:50–308) cells/mm3 and 138,666 (IQR:28,979–533,066) copies/mL, respectively. Overall ADR was high (93.4% first-line; 92.9%-second-line). TDF, potentially active in 35.7% of participants after first-line and 45.1% after second-line, suggested sub-optimal TLD-efficacy in second-line (64.3%) and third-line (54.9%). All PI/r preserved high efficacy after first-line failure while only DRV/r preserved high-level efficacy (87.9%) after second-line failure. In this resource-limited setting (RLS), ADR is high in ART-failing patients. PI/r strategies remain potent backbones for second-line ART, while only DRV/r remains very potent despite second-line failure. Though TLD use would be preferable, blind use for second- and third-line regimens may be sub-optimal (functional monotherapy with dolutegravir) with high risk of further failure, thus suggesting strategies for selective ART switch to TLD in failing patients in RLS. [ABSTRACT FROM AUTHOR]

Abstract Drug resistance remains the greatest challenge in improving outcomes for cancer patients who receive chemotherapy and targeted therapy. Surmounting evidence suggests that a subpopulation of cancer cells could escape intense selective drug treatment by entering a drug‐tolerant state without genetic variations. These drug‐tolerant cells (DTCs) are characterized with a slow proliferation rate and a reversible phenotype. They reside in the tumor region and may serve as a reservoir for resistant phenotypes. The survival of DTCs is regulated by epigenetic modifications, transcriptional regulation, mRNA translation remodeling, metabolic changes, antiapoptosis, interactions with the tumor microenvironment, and activation of signaling pathways. Thus, targeting the regulators of DTCs opens a new avenue for the treatment of therapy‐resistant tumors. In this review, we first provide an overview of common characteristics of DTCs and the regulating networks in DTCs development. We also discuss the potential therapeutic opportunities to target DTCs. Last, we discuss the current challenges and prospects of the DTC‐targeting approach to overcome acquired drug resistance. Reviewing the latest developments in DTC research could be essential in discovering of methods to eliminate DTCs, which may represent a novel therapeutic strategy for preventing drug resistance in the future.

Monitoring of HIV drug resistance (HIVDR) remains critical for ensuring countries attain and sustain the global goals for ending HIV as a public health threat by 2030. On an individual patient level, drug resistance results assist in ensuring unnecessary treatment switches are avoided and subsequent regimens are tailored on a case-by-case basis, should resistance be detected. Although there is a disparity in access to HIVDR testing in high-income countries compared to low- and middle-income countries (LMICS), more LMICs have now included HIVDR testing for individual patient management in some groups of patients. In this review, we describe different strategies for surveillance as well as where HIVDR testing can be implemented for individual patient management. In addition, we briefly review available technologies for HIVDR testing in LMICs, including Sanger sequencing, next-generation sequencing, and some point-of-care options. Finally, we describe how South Africa has implemented HIVDR testing in the public sector. [ABSTRACT FROM AUTHOR]

Resistance to platinum‐based chemotherapy is the major cause of death from high‐grade serous ovarian cancer (HGSOC). We hypothesise that detection of specific DNA methylation changes may predict platinum resistance in HGSOC. Using a publicly available "discovery" dataset we examined epigenomic and transcriptomic alterations between primary platinum‐sensitive (n = 32) and recurrent acquired drug resistant HGSOC (n = 28) and identified several genes involved in immune and chemoresistance‐related pathways. Validation via high‐resolution melt analysis of these findings, in cell lines and HGSOC tumours, demonstrated the most consistent changes were observed in three of the genes: APOBEC3A, NKAPL and PDCD1. Plasma samples from an independent HGSOC cohort (n = 17) were analysed using droplet digital PCR. Hypermethylation of NKAPL was detected in 46% and hypomethylation of APOBEC3A in 69% of plasma samples taken from women with relapsed HGSOC (n = 13), with no alterations identified in disease‐free patients (n = 4). Following these results, and using a CRISPR‐Cas9 approach, we were also able to demonstrate that in vitro NKAPL promoter demethylation increased platinum sensitivity by 15%. Overall, this study demonstrates the importance of aberrant methylation, especially of the NKAPL gene, in acquired platinum resistance in HGSOC. [ABSTRACT FROM AUTHOR]

Treatment options for advanced gallbladder cancer (GBC) are scarce and usually rely on cytotoxic chemotherapy, but the effectiveness of any regimen is limited and recurrence rates are high. Here, we investigated the molecular mechanisms of acquired resistance in GBC through the development and characterization of two gemcitabine-resistant GBC cell sublines (NOZ GemR and TGBC1 GemR). Morphological changes, cross-resistance, and migratory/invasive capabilities were evaluated. Then, microarray-based transcriptome profiling and quantitative SILAC-based phosphotyrosine proteomic analyses were performed to identify biological processes and signaling pathways dysregulated in gemcitabine-resistant GBC cells. The transcriptome profiling of parental and gemcitabine-resistant cells revealed the dysregulation of protein-coding genes that promote the enrichment of biological processes such as epithelial-to-mesenchymal transition and drug metabolism. On the other hand, the phosphoproteomics analysis of NOZ GemR identified aberrantly dysregulated signaling pathways in resistant cells as well as active kinases, such as ABL1, PDGFRA, and LYN, which could be novel therapeutic targets in GBC. Accordingly, NOZ GemR showed increased sensitivity toward the multikinase inhibitor dasatinib compared to parental cells. Our study describes transcriptome changes and altered signaling pathways occurring in gemcitabine-resistant GBC cells, which greatly expands our understanding of the underlying mechanisms of acquired drug resistance in GBC. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is a pediatric solid cancer with high fatality, relapses, and acquired resistance to chemotherapy, that requires new therapeutic approaches to improve survival. LGR5 is a receptor that potentiates WNT/signaling pathway and has been reported to promote development and survival in several adult cancers. In this study we investigated LGR5 expression in a panel of NB cell lines with acquired resistance to vincristine or doxorubicin. We show LGR5-LRP6 cooperation with enhanced expression in drug resistant NB cell lines compared to parental cells, suggesting a role for LGR5 in the emergence of drug resistance, warranting further investigation [ABSTRACT FROM AUTHOR]

Oxidative stress reflected by elevated reactive oxygen species (ROS) in the tumor ecosystem, is a hallmark of human cancers. The mechanisms by which oxidative stress regulate the metastatic ecosystem and resistance remain elusive. This study aimed to dissect the oxidative stress-sensing machinery during the evolvement of early dissemination and acquired drug resistance in breast cancer. Here, we constructed single-cell landscape of primary breast tumors and metastatic lymph nodes, and focused on RGS5+ endothelial cell subpopulation in breast cancer metastasis and resistance. We reported on RGS5 as a master in endothelial cells sensing oxidative stress. RGS5+ endothelial cells facilitated tumor-endothelial adhesion and transendothelial migration of breast cancer cells. Antioxidant suppressed oxidative stress-induced RGS5 expression in endothelial cells, and prevented adhesion and transendothelial migration of cancer cells. RGS5-overexpressed HLECs displayed attenuated glycolysis and oxidative phosphorylation. Drug-resistant HLECs with RGS5 overexpression conferred acquired drug resistance of breast cancer cells. Importantly, genetic knockdown of RGS5 prevented tumor growth and lymph node metastasis. Our work demonstrates that RGS5 in lymphatic endothelial cells senses oxidative stress to promote breast cancer lymph node metastasis and resistance, providing a novel insight into a potentially targetable oxidative stress-sensing machinery in breast cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for new therapeutics that otherwise have shown significant successes in disease control. Hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and is widely targeted in drug development. We found that resistance to the HGF-neutralizing antibody drug candidate rilotumumab in glioblastoma cells was acquired through HGF overproduction and misfolding, which led to stress-response signaling and redirected transport inside cells that sequestered rilotumumab and misfolded HGF from native HGF and activated Met receptor. Resistant cells were more malignant but retained their sensitivity to Met kinase inhibition and gained sensitivity to inhibition of stress signaling and cholesterol biosynthesis. Defining this rapidly acquired, multisystem scheme improves our understanding of drug resistance and suggests strategies for early detection and intervention. Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for molecularly-targeted therapeutics that otherwise have shown unprecedented successes in disease control. The hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and has been a subject of targeted drug development for nearly 30 years. To anticipate and study specific resistance mechanisms associated with targeting this pathway, we engineered resistance to the HGF-neutralizing antibody rilotumumab in glioblastoma cells harboring autocrine HGF/Met signaling, a frequent abnormality of this brain cancer in humans. We found that rilotumumab resistance was acquired through an unusual mechanism comprising dramatic HGF overproduction and misfolding, endoplasmic reticulum (ER) stress-response signaling and redirected vesicular trafficking that effectively sequestered rilotumumab and misfolded HGF from native HGF and activated Met. Amplification of MET and HGF genes, with evidence of rapidly acquired intron-less, reverse-transcribed copies in DNA, was also observed. These changes enabled persistent Met pathway activation and improved cell survival under stress conditions. Point mutations in the HGF pathway or other complementary or downstream growth regulatory cascades that are frequently associated with targeted drug resistance in other prevalent cancer types were not observed. Although resistant cells were significantly more malignant, they retained sensitivity to Met kinase inhibition and acquired sensitivity to inhibition of ER stress signaling and cholesterol biosynthesis. Defining this mechanism reveals details of a rapidly acquired yet highly-orchestrated multisystem route of resistance to a selective molecularly-targeted agent and suggests strategies for early detection and effective intervention. [ABSTRACT FROM AUTHOR]

Aims: Oxidative stress reflected by elevated reactive oxygen species (ROS) in the tumor ecosystem, is a hallmark of human cancers. The mechanisms by which oxidative stress regulate the metastatic ecosystem and resistance remain elusive. This study aimed to dissect the oxidative stress-sensing machinery during the evolvement of early dissemination and acquired drug resistance in breast cancer., Methods: Here, we constructed single-cell landscape of primary breast tumors and metastatic lymph nodes, and focused on RGS5 + endothelial cell subpopulation in breast cancer metastasis and resistance., Results: We reported on RGS5 as a master in endothelial cells sensing oxidative stress. RGS5 + endothelial cells facilitated tumor-endothelial adhesion and transendothelial migration of breast cancer cells. Antioxidant suppressed oxidative stress-induced RGS5 expression in endothelial cells, and prevented adhesion and transendothelial migration of cancer cells. RGS5-overexpressed HLECs displayed attenuated glycolysis and oxidative phosphorylation. Drug-resistant HLECs with RGS5 overexpression conferred acquired drug resistance of breast cancer cells. Importantly, genetic knockdown of RGS5 prevented tumor growth and lymph node metastasis., Conclusions: Our work demonstrates that RGS5 in lymphatic endothelial cells senses oxidative stress to promote breast cancer lymph node metastasis and resistance, providing a novel insight into a potentially targetable oxidative stress-sensing machinery in breast cancer treatment., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Erdaw Tachbele,1,2 Samuel Kyobe,3 Fred Ashaba Katabazi,3 Edgar Kigozi,3 Savannah Mwesigwa,3 Moses Joloba,3 Alebachew Messele,1 Wondwossen Amogne,2 Mengistu Legesse,1 Rembert Pieper,4 Gobena Ameni1 1Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia; 2College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 3College of Health Sciences, Makerere University, Kampala, Uganda; 4Janssen Biopharma, South San Francisco, CA, USACorrespondence: Erdaw Tachbele Tel +251 911642880Email erdawt@yahoo.comPurpose: This study was conducted to investigate the drug resistance mutations and genetic diversity of HIV-1 in ART experienced patients in South Omo, Ethiopia.Patients and Methods: A cross-sectional study conducted on 253 adult patients attending ART clinics for ≥ 6 months in South Omo. Samples with VL ≥ 1000 copies/mL were considered as virological failures (VF) and their reverse transcriptase gene codons 90– 234 were sequenced using Illumina MiSeq. MinVar was used for the identification of the subtypes and drug resistance mutations. Phylogenetic tree was constructed by neighbor-joining method using the maximum likelihood model.Results: The median duration of ART was 51 months and 18.6% (47/253) of the patients exhibited VF. Of 47 viraemic patients, the genome of 41 were sequenced and subtype C was dominant (87.8%) followed by recombinant subtype BC (4.9%), M-09-CPX (4.9) and BF1 (2.4%). Of 41 genotyped subjects, 85.4% (35/41) had at least one ADR mutation. Eighty-one percent (33/41) of viraemic patients harbored NRTI resistance mutations, and 48.8% (20/41) were positive for NNRTI resistance mutations, with 43.9% dual resistance mutations. Among NRTI resistance mutations, M184V (73.2%), K219Q (63.4%) and T215 (56.1%) complex were the most mutated positions, while the most common NNRTI resistance mutations were K103N (24.4%), K101E, P225H and V108I 7.5% each. Active tuberculosis (aOR=13, 95% CI= 3.46– 29.69), immunological failure (aOR=3.61, 95% CI=1.26– 10.39), opportunistic infections (aOR=8.39, 95% CI= 1.75– 40.19), and poor adherence were significantly associated with virological failure, while rural residence (aOR 2.37; 95% CI: 1.62– 9.10, P= 0.05), immunological failures (aOR 2.37; 95% CI: 1.62– 9.10, P= 0.05) and high viral load (aOR 16; 95% CI: 5.35 51.59, P < 0.001) were predictors of ADR mutation among the ART experienced and viraemic study subjects.Conclusion: The study revealed considerable prevalence of VF and ADR mutation with the associated risk indicators. Regular virological monitoring and drug resistance genotyping methods should be implemented for better ART treatment outcomes of the nation.Keywords: HIV-1, genetic diversity, acquired drug resistance, ART experienced, South Omo, Ethiopia

Drug resistant tuberculosis contributes significantly to the global burden of antimicrobial resistance, often consuming a large proportion of the healthcare budget and associated resources in many endemic countries. The rapid emergence of resistance to newer tuberculosis therapies signals the need to ensure appropriate antibiotic stewardship, together with a concerted drive to develop new regimens that are active against currently circulating drug resistant strains. Herein, we highlight that the current burden of drug resistant tuberculosis is driven by a combination of ongoing transmission and the intra-patient evolution of resistance through severalmechanisms. Global control of tuberculosis will require interventions that effectively address these and related aspects. Interrupting tuberculosis transmission is dependent on the availability of novel rapid diagnostics which provide accurate results, as near-patient as is possible, together with appropriate linkage to care. Contact tracing, longitudinal follow-up for symptoms and active mapping of social contacts are essential elements to curb further community-wide spread of drug resistant strains. Appropriate prophylaxis for contacts of drug resistant index cases is imperative to limit disease progression and subsequent transmission. Preventing the evolution of drug resistant strains will require the development of shorter regimens that rapidly eliminate all populations of mycobacteria, whilst concurrently limiting bacterialmetabolic processes that drive drug tolerance, mutagenesis and the ultimate emergence of resistance. Drug discovery programs that specifically target bacterial genetic determinants associated with these processes will be paramount to tuberculosis eradication. In addition, the development of appropriate clinical endpoints that quantify drug tolerant organisms in sputum, such as differentially culturable/detectable tubercle bacteria is necessary to accurately assess the potential of new therapies to effectively shorten treatment duration. When combined, this holistic approach to addressing the critical problems associated with drug resistance will support delivery of quality care to patients suffering from tuberculosis and bolster efforts to eradicate this disease. [ABSTRACT FROM AUTHOR]

Abstract Background Introduction of tenofovir (TDF) plus lamivudine (3TC) and dolutegravir (DTG) in first- and second-line HIV treatment regimens in South Africa warrants characterization of acquired HIV-1 drug resistance (ADR) mutations that could impact DTG-based antiretroviral therapy (ART). In this study, we sought to determine prevalence of ADR mutations and their potential impact on susceptibility to drugs used in combination with DTG among HIV-positive adults (≥ 18 years) accessing routine care at a selected ART facility in KwaZulu-Natal, South Africa. Methods We enrolled adult participants in a cross-sectional study between May and September 2019. Eligible participants had a most recent documented viral load (VL) ≥ 1000 copies/mL after at least 6 months on ART. We genotyped HIV-1 reverse transcriptase and protease genes by Sanger sequencing and assessed ADR. We characterized the effect of ADR mutations on the predicted susceptibility to drugs used in combination with DTG. Results From 143 participants enrolled, we obtained sequence data for 115 (80%), and 92.2% (95% CI 85.7–96.4) had ADR. The proportion with ADR was similar for participants on first-line ART (65/70, 92.9%, 95% CI 84.1–97.6) and those on second-line ART (40/44, 90.9%, 95% CI 78.3–97.5), and was present for the single participant on third-line ART. Approximately 89% (62/70) of those on first-line ART had dual class NRTI and NNRTI resistance and only six (13.6%) of those on second-line ART had major PI mutations. Most participants (82%) with first-line viraemia maintained susceptibility to Zidovudine (AZT), and the majority of them had lost susceptibility to TDF (71%) and 3TC (84%). Approximately two in every five TDF-treated individuals had thymidine analogue mutations (TAMs). Conclusions Susceptibility to AZT among most participants with first-line viraemia suggests that a new second-line regimen of AZT + 3TC + DTG could be effective. However, atypical occurrence of TAMs in TDF-treated individuals suggests a less effective AZT + 3TC + DTG regimen in a subpopulation of patients. As most patients with first-line viraemia had at least low-level resistance to TDF and 3TC, identifying viraemia before switch to TDF + 3TC + DTG is important to avoid DTG functional monotherapy. These findings highlight a need for close monitoring of outcomes on new standardized treatment regimens.

Drug resistant tuberculosis contributes significantly to the global burden of antimicrobial resistance, often consuming a large proportion of the healthcare budget and associated resources in many endemic countries. The rapid emergence of resistance to newer tuberculosis therapies signals the need to ensure appropriate antibiotic stewardship, together with a concerted drive to develop new regimens that are active against currently circulating drug resistant strains. Herein, we highlight that the current burden of drug resistant tuberculosis is driven by a combination of ongoing transmission and the intra-patient evolution of resistance through several mechanisms. Global control of tuberculosis will require interventions that effectively address these and related aspects. Interrupting tuberculosis transmission is dependent on the availability of novel rapid diagnostics which provide accurate results, as near-patient as is possible, together with appropriate linkage to care. Contact tracing, longitudinal follow-up for symptoms and active mapping of social contacts are essential elements to curb further community-wide spread of drug resistant strains. Appropriate prophylaxis for contacts of drug resistant index cases is imperative to limit disease progression and subsequent transmission. Preventing the evolution of drug resistant strains will require the development of shorter regimens that rapidly eliminate all populations of mycobacteria, whilst concurrently limiting bacterial metabolic processes that drive drug tolerance, mutagenesis and the ultimate emergence of resistance. Drug discovery programs that specifically target bacterial genetic determinants associated with these processes will be paramount to tuberculosis eradication. In addition, the development of appropriate clinical endpoints that quantify drug tolerant organisms in sputum, such as differentially culturable/detectable tubercle bacteria is necessary to accurately assess the potential of new therapies to effectively shorten treatment duration. When combined, this holistic approach to addressing the critical problems associated with drug resistance will support delivery of quality care to patients suffering from tuberculosis and bolster efforts to eradicate this disease.

Tsung-Lun Li,1 Tai-Hua Chan,2 Cheng-Hui Wang,3– 5 Ruwen Jou,2,6 Ming-Chih Yu,1,3,7 Denise Utami Putri,3,* Chih-Hsin Lee,1,3,8,* Yi-Hsien Lin3 1Department of Internal Medicine, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan; 2Taiwan Centers for Disease Control, Taipei, Taiwan; 3Pulmonary Research Center, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan; 4Department of Laboratory Medicine, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan; 5School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; 6Institute of Microbiology and Immunology, National Yang-Ming Chiao Tung University, Taipei, Taiwan; 7Schools of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; 8Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Chih-Hsin Lee; Denise Utami PutriPulmonary Research Center, Wanfang Hospital, Taipei Medical University, 111 Sec. 3, Xinglong Road Wenshan District, Taipei, 116, TaiwanTel +886-2930-7930Email chleetw@tmu.edu.tw; 108336@w.tmu.edu.twAbstract: Appropriate treatment is the key element in eliminating tuberculosis (TB), and requires prompt diagnosis. We presented a case of a household contact of rifampicin-resistant TB revealing reactive IFN-gamma release assay with unsuspicious clinical and radiologic examinations. She was diagnosed with latent tuberculosis infection (LTBI) and treated with isoniazid monotherapy. On the ninth month, she developed a progressive cough and was found to harbor active TB disease with added resistance to isoniazid. An individualized anti-TB regimen consisting of moxifloxacin, kanamycin, prothionamide, ethambutol, and pyrazinamide was prescribed for 20 months, leading to sputum culture conversion and improvement of the reported symptom. No recurrence was observed on one-year follow-up. Assuming high compliance to therapy, we propose that the patient may have been underdiagnosed and received sub-optimal treatment leading to acquired-drug resistance. Conventional diagnosis methods based on immunological assay and radiographical findings may be insufficient to distinguish the incipient and subclinical states of TB from LTBI.Keywords: latent tuberculosis infection, LTBI, treatment, acquired drug resistance, drug-resistant TB, subclinical TB, case report

Objective: To determine viral load (VL) nonsuppression (VLN) rates, HIV drug resistance (HIVDR) prevalence, and associated factors among female sex workers (FSWs) in Ethiopia. Methods: A cross-sectional biobehavioral survey was conducted among FSWs in 11 cities in Ethiopia in 2014. Whole blood was collected, and HIVDR genotyping was performed. Logistic regression analysis was performed to identify factors associated with VLN and HIVDR. Results: Among 4900 participants, 1172 (23.9%) were HIV-positive and 1154 (98.5%) had a VL result. Participants were categorized into antiretroviral therapy (ART) (n = 239) and ART-naive (n = 915) groups based on self-report. From the 521 specimens (ART, 59; ART-naive, 462) with VL >=1000 copies/mL, genotyping was successful for 420 (80.6%) and 92 (21.9%) had drug resistance mutations (DRMs). Pretreatment drug resistance (PDR) was detected in 16.5% (63/381) of the ART-naive participants. Nucleoside reverse transcriptase inhibitor (NRTI), non-NRTIs (NNRTIs), and dual-class DRMs were detected in 40 (10.5%), 55 (14.4%), and 35 (9.2%) of the participants, respectively. Among 239 participants on ART, 59 (24.7%) had VLN. Genotyping was successfully performed for 39 (66.1%). DRMs were detected in 29 (74.4%). All 29 had NNRTI, 23 (79.3%) had NRTI or dual-class DRMs. VLN was associated with age 35 years or older, CD4+ T-cell count <350 cells/mm3, and being forced into selling sex. PDR and acquired drug resistance were associated with CD4+ T-cell count <350 cells/mm3 (P < 0.001). Conclusions: The high VLN and HIVDR rates among FSWs underscore the need for targeted interventions to improve ART access and virologic monitoring to maximize the benefit of ART and limit the spread of HIV and HIVDR. [ABSTRACT FROM AUTHOR]

Background: The increased use of antiretroviral therapy (ART) has decreased mortality and morbidity of HIV-1 infected people but increasing levels of HIV drug resistance threatens the success of ART regimens. Conversely, late presentation can impact treatment outcomes, health costs, and potential transmission of HIV. Objective: To describe the patterns of transmitted drug resistance (TDR) and acquired drug resistance (ADR) in HIV-1 infected patients followed in Europe, to compare its patterns in late presenters (LP) vs non-late presenters (NLP), and to analyze the most prevalent drug resistance mutations among HIV-1 subtypes. Methods: Our study included clinical, socio-demographic, and genotypic information from 26,973 HIV-1 infected patients from the EuResist Integrated Database (EIDB) between 1981 and 2019. Results: Among the 26,973 HIV-1 infected patients in the analysis, 11,581 (42.9%) were ART-naïve patients and 15,392 (57.1%) were ART-experienced. The median age was 37 (IQR: 27.0–45.0) years old and 72.6% were males. The main transmission route was through heterosexual contact (34.9%) and 81.7% of patients originated from Western Europe. 71.9% of patients were infected by subtype B and 54.8% of patients were classified as LP. The overall prevalence of TDR was 12.8% and presented an overall decreasing trend (p for trend < 0.001), the ADR prevalence was 68.5% also with a decreasing trend (p for trend < 0.001). For LP and NLP, the TDR prevalence was 12.3 and 12.6%, respectively, while for ADR, 69.9 and 68.2%, respectively. The most prevalent TDR drug resistance mutations, in both LP and NLP, were K103N/S, T215rev, T215FY, M184I/V, M41I/L, M46I/L, and L90M. Conclusion: Our study showed that the overall TDR (12.8%) and ADR (68.5%) presented decreasing trends during the study time period. For LP, the overall TDR was slightly lower than for NLP (12.3 vs 12.6%, respectively); while this pattern was opposite for ADR (LP slightly higher than NLP). We suggest that these differences, in the case of TDR, can be related to the dynamics of fixation of drug resistance mutations; and in the case of ADR with the more frequent therapeutic failure in LPs. [ABSTRACT FROM AUTHOR]

Objective To explore the effect of primary and acquired resistance to anti-human epidermal growth factor receptor 2 ( HER-2) on the overall survival of patients with HER-2 positive advanced breast cancer. Methods The clinical characteristics of HER-2 positive patients with advanced breast cancer admitted to Cancer Hospital of Chinese Academy of Medical Sciences from January 1998 to December 2018 were collected, and their neoadjuvant/ adjuvant and advanced three-line chemotherapy were summarized. Among them, targeted drugs for HER-2 included trastuzumab, pertuzumab, T-DM1, RC48-ADC, lapatinib, pyrotinib, allitinib, sipatinib, seratinib. Based on the duration of benefit from anti HER-2 treatment, the patients were divided into two groups: primary anti HER-2 resistance group and acquired anti HER-2 resistance group. In this study, the overall survival (OS) was used as the main end point. Kaplan-Meier analysis and Cox proportional risk regression model were used to analyze the effects of different drug resistance mechanisms on the overall survival. Results The whole group of 284 patients were included. The median age of recurrence and metastasis was 48 years old, 155 (54. 6%) were hormone receptor (HR) positive and 129 (45.4%·) were HR negative, 128 cases ( 45.1 %) were premenopausal and 156 cases (54.9%) were postmenopausal, 277 cases (97 .5%) had a score of 0-1 in ECoG PS and 7 cases (2.5%) had a score of more than 2 in the first diagnosis of relapse and metastasis. There were 103 cases (36.3%) in the primary drug resistance group mid 181 cases (63. 7%) in the secondary drug resistance group. The median overall survival time of the two groups was 24. 9 months and 40. 4 months, respectively, with statistical significance (P<0.001). Conclusion Primary resistance to HER-2 is one of the factors of poor prognosis in HER-2 positive breast cancer, and its mechanism needs to be further explored. [ABSTRACT FROM AUTHOR]

Acquired drug resistance represents a major obstacle to tyrosine kinase inhibitor (TKI)-induced differentiation therapy of radioiodine-refractory papillary thyroid cancer (RR-PTC); thus, there is an urgent need to elucidate the underlying mechanisms. Here, selumetinib-resistant PTC (PTCSR) cell lines, which were characterized by loss of sodium/iodide symporter expression, enhanced insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), and activated V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) signaling, were initially established using a dose escalation method. Upon knockdown of IGF2BP2 in PTCSR cells, ERBB2 signaling was inhibited, and the acquired drug resistance was partially reversed. Mechanistically, the luciferase activity assay showed that IGF2BP2 bound to the N6-methyladenosine-binding site in the coding sequence of ERBB2 mRNA, yielding an increased ERBB2 translation efficacy revealed by polysome profiling. Inhibition of ERBB2 and IGF2BP2 by lapatinib robustly rescued the PTCSR cells from acquired dedifferentiation. Our study demonstrated that IGF2BP2-dependent ERBB2 signaling activation contributes to acquired resistance to TKI, which may be a promising differentiation strategy for RR-PTC by targeting IGF2BP2. [ABSTRACT FROM AUTHOR]

Objective To investigate the expression of ARL4C in NSCLC and its correlation with clinicopathological features, as well as its role in EGFR-TKI resistance. Methods We collected the tumor and adjacent tissues of 63 NSCLC patients. The mRNA expression of ARL4C was detected by qRT-PCR and the relation between ARL4C and clinicopathological features was analyzed. The expressions of ARL4C in TKI-resistant cell line, control cell line and ARL4C overexpressing cell line were assessed by qRT-PCR and Western blot. The changes of cell activity and IC50 were detected by MTS. Transwell invasion assay was used to detect the effect of ARL4C expression on cell invasion. Results The expression level of ARL4C in NSCLC tissues was lower than that in adjacent tissues (P < 0.05). The expression of ARL4C in NSCLC was closely related to lymph node metastasis, TNM stage and pulmonary membrane invasion (P < 0.05). Compared with control cell line HCC827, the expression levels of ARL4C mRNA and protein in TKI-resistant cell line HCC827/ER and the IC50 of ARL4C overexpressing TKI-resistant cell line HCC827/ER/ARL4C-OE were significantly lower (P < 0.05). Transwell assay results showed that the overexpression of ARL4C inhibited the invasion of lung cancer cell line (P < 0.05). Conclusion The abnormal expression of ARL4C is closely related to lymph node metastasis, TNM stage and pulmonary membrane invasion of NSCLC. Overexpression of ARL4C may improve the sensitivity of NSCLC cells to EGFR-TKI and inhibit the invasion of NSCLC cells.

Abstract Background There is a general dearth of information on extrapulmonary tuberculosis (EPTB). Here, we investigated Mycobacterium tuberculosis (Mtb) drug resistance and transmission patterns in EPTB patients treated in the Tshwane metropolitan area, in South Africa. Methods Consecutive Mtb culture-positive non-pulmonary samples from unique EPTB patients underwent mycobacterial genotyping and were assigned to phylogenetic lineages and transmission clusters based on spoligotypes. MTBDRplus assay was used to search mutations for isoniazid and rifampin resistance. Machine learning algorithms were used to identify clinically meaningful patterns in data. We computed odds ratio (OR), attributable risk (AR) and corresponding 95% confidence intervals (CI). Results Of the 70 isolates examined, the largest cluster comprised 25 (36%) Mtb strains that belonged to the East Asian lineage. East Asian lineage was significantly more likely to occur within chains of transmission when compared to the Euro-American and East-African Indian lineages: OR = 10.11 (95% CI: 1.56–116). Lymphadenitis, meningitis and cutaneous TB, were significantly more likely to be associated with drug resistance: OR = 12.69 (95% CI: 1.82–141.60) and AR = 0.25 (95% CI: 0.06–0.43) when compared with other EPTB sites, which suggests that poor rifampin penetration might be a contributing factor. Conclusions The majority of Mtb strains circulating in the Tshwane metropolis belongs to East Asian, Euro-American and East-African Indian lineages. Each of these are likely to be clustered, suggesting on-going EPTB transmission. Since 25% of the drug resistance was attributable to sanctuary EPTB sites notorious for poor rifampin penetration, we hypothesize that poor anti-tuberculosis drug dosing might have a role in the development of resistance.

Abstract Background There are few data on the prevalence of acquired drug resistance mutations (ADRs) in Hunan Province, China, that could affect the effectiveness of antiretroviral therapy (ART). Objectives The main objectives of this study were to determine the prevalence of acquired drug resistance (ADR) the epidemic characteristics of HIV-1-resistant strains among ART-failed HIV patients in Hunan Province, China. Methods ART-experienced and virus suppression failure subjects in Hunan between 2012 and 2017 were evaluated by genotyping analysis and mutations were scored using the HIVdb.stanford.edu algorithm to infer drug susceptibility. Results The prevalence of HIV-1 ADR were 2.76, 2.30, 2.98, 2.62, 2.23and 2.17%, respectively, from 2012 to 2017. Overall 2295 sequences were completed from 2932 ART-failure patients, and 914 of these sequences were found to have drug resistance mutation. The most common subtype was AE (64.14%), followed by BC (17.91%) and B (11.50%). Among those 914 patients with drug resistance mutations,93.11% had NNRTI-associated drug resistance mutations, 74.40% had NRTI drug resistance mutations (DRMs) and 6.89% had PI DRMs. Dual-class mutations were observed in 591 (64.66%) cases, and triple-class mutations were observed in 43 (4.70%) cases. M184V (62.04%), K103N (41.90%) and I54L (3.83%) were the most common observed mutations, respectively, in NRTI-, NNRTI- and PI-associated drug resistance. 93.76% subjects who had DRMs received the ART first-line regimens. CD4 count, symptoms in the past 3 months, and ART adherence were found to be associated with HIV-1 DR. Conclusions This study showed that although the prevalence of HIV-acquired resistance in Hunan Province is at a low-level, the long-term and continuous surveillance of HIV ADR in antiretroviral drugs (ARVs) patients is necessary.

Abstract Background Expanded access to combination antiretroviral therapy (cART) throughout sub-Saharan Africa over the last decade has remarkably improved the prognosis of persons living with HIV (PLWH). However, some PLWH experience virologic rebound after a period of viral suppression, usually followed by selection of drug resistant virus. Determining factors associated with drug resistance can inform patient management and healthcare policies, particularly in resource-limited settings where drug resistance testing is not routine. Methods A case–control study was conducted using data captured from an electronic medical record in a large treatment program in Nigeria. Cases PLWH receiving cART who developed acquired drug resistance (ADR) and controls were those without ADR between 2004 and 2011. Each case was matched to up to 2 controls by sex, age, and education. Logistic regression was used estimate odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with ADR. Results We evaluated 159 cases with ADR and 299 controls without ADR. In a multivariate model, factors associated with ADR included older age (OR = 2.35 [age 30–40 years 95% CI 1.29, 4.27], age 41 + years OR = 2.31 [95% CI 1.11, 4.84], compared to age 17–30), higher education level (secondary OR 2.14 [95% CI 1.1.11–4.13]), compared to primary and tertiary), non-adherence to care (OR = 2.48 [95% CI 1.50–4.00]), longer treatment duration (OR = 1.80 [95% CI 1.37–2.35]), lower CD4 count((OR = 0.95 [95% CI 0.95–0.97]) and higher viral load (OR = 1.97 [95% CI 1.44–2.54]). Conclusions Understanding these predictors may guide programs in developing interventions to identify patients at risk of developing ADR and implementing prevention strategies.

BackgroundThe increased use of antiretroviral therapy (ART) has decreased mortality and morbidity of HIV-1 infected people but increasing levels of HIV drug resistance threatens the success of ART regimens. Conversely, late presentation can impact treatment outcomes, health costs, and potential transmission of HIV.ObjectiveTo describe the patterns of transmitted drug resistance (TDR) and acquired drug resistance (ADR) in HIV-1 infected patients followed in Europe, to compare its patterns in late presenters (LP) vs non-late presenters (NLP), and to analyze the most prevalent drug resistance mutations among HIV-1 subtypes.MethodsOur study included clinical, socio-demographic, and genotypic information from 26,973 HIV-1 infected patients from the EuResist Integrated Database (EIDB) between 1981 and 2019.ResultsAmong the 26,973 HIV-1 infected patients in the analysis, 11,581 (42.9%) were ART-naïve patients and 15,392 (57.1%) were ART-experienced. The median age was 37 (IQR: 27.0–45.0) years old and 72.6% were males. The main transmission route was through heterosexual contact (34.9%) and 81.7% of patients originated from Western Europe. 71.9% of patients were infected by subtype B and 54.8% of patients were classified as LP. The overall prevalence of TDR was 12.8% and presented an overall decreasing trend (p for trend < 0.001), the ADR prevalence was 68.5% also with a decreasing trend (p for trend < 0.001). For LP and NLP, the TDR prevalence was 12.3 and 12.6%, respectively, while for ADR, 69.9 and 68.2%, respectively. The most prevalent TDR drug resistance mutations, in both LP and NLP, were K103N/S, T215rev, T215FY, M184I/V, M41I/L, M46I/L, and L90M.ConclusionOur study showed that the overall TDR (12.8%) and ADR (68.5%) presented decreasing trends during the study time period. For LP, the overall TDR was slightly lower than for NLP (12.3 vs 12.6%, respectively); while this pattern was opposite for ADR (LP slightly higher than NLP). We suggest that these differences, in the case of TDR, can be related to the dynamics of fixation of drug resistance mutations; and in the case of ADR with the more frequent therapeutic failure in LPs.

Paclitaxel is widely used in the first-line treatment of ovarian cancer. Nevertheless, the development of acquired resistance to paclitaxel is a major obstacle for the therapy in clinic. Cardamonin is a novel anticancer chalcone which exhibits a wide range of pharmacological activities. However, the effect of cardamonin on paclitaxel-resistant ovarian cancer cells and its underlying molecular mechanisms are unknown. Here, we revealed whether cardamonin had a resensitivity for paclitaxel and furtherly explored the underlying mechanisms on SKOV3-Taxol cells. Our results showed that cardamonin combined with paclitaxel had a synergistic effect of anti-proliferation in SKOV3-Taxol cells, and CI was less than one. Cells apoptosis and G2/M phase arrest were enhanced by cardamonin with paclitaxel in a concentration-dependent way on SKOV3-Taxol cells (P < 0.05). Cardamonin significantly increased drug accumulation in SKOV3-Taxol cells (P < 0.05). Similar to verapamil, cardamonin decreased MDR1 mRNA and P-gp expression (P < 0.05). Cardamonin restrained NF-κB activation in SKOV3-Taxol cells (P < 0.05). Inhibitory effect of P-gp and NF-κB p65 (nuclear protein) expression was enhanced by cardamonin combined with PDTC, a NF-κB inhibitor. Cardamonin significantly inhibited the upregulation of NF-κB p65 (nuclear protein) and P-gp expression induced by TNF-α (P < 0.05). Taken together, cardamonin enhanced the effect of paclitaxel on inhibiting cell proliferation, inducing apoptosis and G2/M phase arrest, and then strengthened the cytotoxic effect of paclitaxel in SKOV3-Taxol cells. The mechanism might be involved in inhibition of P-gp efflux pump, reducing MDR1 mRNA and P-gp expression by cardamonin via suppression of NF-κB activation in SKOV3-Taxol cells. [ABSTRACT FROM AUTHOR]

Little is known about how additional second-line drug resistance emerges during multidrug-resistant tuberculosis (MDR-TB) treatment. The present study aimed to investigate the influence of microevolution, exogenous reinfection and mixed infection on second-line drug resistance during the recommended 2-year MDR-TB treatment. Individuals with MDR-TB were enrolled between 2013 and 2016 in a multicentre prospective observational cohort study and were followed up for 2 years until treatment completion. Whole-genome sequencing (WGS) was applied for serial Mycobacterium tuberculosis isolates from study participants throughout the treatment, to study the role of microevolution, exogenous reinfection and mixed infection in the development of second-line drug resistance. Of the 286 enrolled patients with MDR-TB, 63 (22.0%) M. tuberculosis isolates developed additional drug resistance during the MDR-TB treatment, including 5 that fulfilled the criteria of extensively drug-resistant TB. By comparing WGS data of serial isolates retrieved from the patients throughout treatment, 41 (65.1%) of the cases of additional second-line drug resistance were the result of exogenous reinfection, 18 (28.6%) were caused by acquired drug resistance, i.e. microevolution, while the remaining 4 (6.3%) were caused by mixed infections with drug-resistant and drug-susceptible strains. In multivariate analysis, previous TB treatment (adjusted hazard ratio (aHR) 2.51, 95% CI 1.51–4.18), extensive disease on chest X-ray (aHR 3.39, 95% CI 2.03–5.66) and type 2 diabetes mellitus (aHR 4.00, 95% CI 2.22–7.21) were independent risk factors associated with the development of additional second-line drug resistance. A large proportion of additional second-line drug resistance emerging during MDR-TB treatment was attributed to exogenous reinfection, indicating the urgency of infection control in health facilities as well as the need for repeated drug susceptibility testing throughout MDR-TB treatment. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma patients with epidermal growth factor receptor (EGFR)-activating mutations respond well to tyrosine kinase inhibitors but typically develop resistance. Current therapies mainly target differentiated cells, not cancer stem cells (CSCs), but CSCs affect the occurrence, invasion, metastasis and treatment sensitivity of malignant tumours. Recently, aerobic exercise has emerged as adjuvant therapy for cancer. Aerobic exercise can accelerate blood circulation, improve tissue oxygen supply, reduce the stress level of patients, improve the antioxidant capacity of the body, and facilitate the degradation of hypoxia-inducible factor-1 (HIF-1) in tumour tissues, thus weakening its maintenance effect on CSCs. In this study, we successfully established lung adenocarcinoma cell lines with gefitinib resistance. Long-term gefitinib induction could increase the level of oxidative stress in lung adenocarcinoma cells and reduce the antioxidant capacity, resulting in the high expression of HIF-1 and ALDH1 and leading to the enrichment of CSCs, and a decreased response to gefitinib. This may be one of the important reasons for gefitinib-acquired resistance in lung adenocarcinoma. In the case of drug resistance, effective aerobic exercise could reduce ROS, activate SOD, inhibit HIF-1 and ALDH1, and cause a reduction in CSCs to sensitise cells to gefitinib again and ultimately inhibit the malignant proliferation of tumours. Therefore, in the treatment of lung adenocarcinoma, the inhibitory effect of aerobic exercise on oxidative stress can enhance the response of drug-resistant cells to gefitinib and can be used as an effective adjunct measure in the treatment of lung adenocarcinoma.

Background: Introduction of tenofovir (TDF) plus lamivudine (3TC) and dolutegravir (DTG) in first- and second-line HIV treatment regimens in South Africa warrants characterization of acquired HIV-1 drug resistance (ADR) mutations that could impact DTG-based antiretroviral therapy (ART). In this study, we sought to determine prevalence of ADR mutations and their potential impact on susceptibility to drugs used in combination with DTG among HIV-positive adults (≥ 18 years) accessing routine care at a selected ART facility in KwaZulu-Natal, South Africa. Methods: We enrolled adult participants in a cross-sectional study between May and September 2019. Eligible participants had a most recent documented viral load (VL) ≥ 1000 copies/mL after at least 6 months on ART. We genotyped HIV-1 reverse transcriptase and protease genes by Sanger sequencing and assessed ADR. We characterized the effect of ADR mutations on the predicted susceptibility to drugs used in combination with DTG. Results: From 143 participants enrolled, we obtained sequence data for 115 (80%), and 92.2% (95% CI 85.7–96.4) had ADR. The proportion with ADR was similar for participants on first-line ART (65/70, 92.9%, 95% CI 84.1–97.6) and those on second-line ART (40/44, 90.9%, 95% CI 78.3–97.5), and was present for the single participant on third-line ART. Approximately 89% (62/70) of those on first-line ART had dual class NRTI and NNRTI resistance and only six (13.6%) of those on second-line ART had major PI mutations. Most participants (82%) with first-line viraemia maintained susceptibility to Zidovudine (AZT), and the majority of them had lost susceptibility to TDF (71%) and 3TC (84%). Approximately two in every five TDF-treated individuals had thymidine analogue mutations (TAMs). Conclusions: Susceptibility to AZT among most participants with first-line viraemia suggests that a new second-line regimen of AZT + 3TC + DTG could be effective. However, atypical occurrence of TAMs in TDF-treated individuals suggests a less effective AZT + 3TC + DTG regimen in a subpopulation of patients. As most patients with first-line viraemia had at least low-level resistance to TDF and 3TC, identifying viraemia before switch to TDF + 3TC + DTG is important to avoid DTG functional monotherapy. These findings highlight a need for close monitoring of outcomes on new standardized treatment regimens. [ABSTRACT FROM AUTHOR]

Introduction: Dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1)-dependent pathways in pancreatic neuroendocrine neoplasms (PanNENs) underlies the introduction of the mTORC1 inhibitor everolimus as treatment of advanced progressive PanNENs. Although everolimus significantly increases progression-free survival, most patients acquire secondary resistance to the drug. This study aimed at identifying mechanisms involved in acquisition of resistance to everolimus. Methods: BON-1 and everolimus-resistant (ER) BON-1 cells were used as in vitro system of sensitivity and acquired resistance. Transcriptome changes occurring in BON-1 and ER-BON-1 were investigated by RNA sequencing and validated by quantitative PCR analysis. RNA extracted from patients' biopsies was used to validate MYC upregulation. Drug screening and functional assays were performed using ER-BON-1 cells. Cell cycle progression was evaluated by FACS analysis. Results: Our results show that MYC overexpression is a key event in the development of secondary resistance to everolimus in PanNEN cell lines and in metastatic lesions from neuroendocrine neoplasm patients. MYC knockdown restored ER-BON-1 sensitivity to everolimus. Pharmacological inhibition of MYC mediated by the cyclin-dependent kinase inhibitor dinaciclib strongly reduced viability of ER-BON-1. Dinaciclib synergized with everolimus and inhibited ER-BON-1 cell cycle progression. Discussion: Our findings suggest that MYC upregulation drives the development of secondary resistance to everolimus in PanNENs and that its inhibition is an exploitable vulnerability. Indeed, our results indicate that combined treatments with cyclin-dependent kinase and mTOR inhibitors may counteract secondary resistance to everolimus in PanNENs and may pave the ground for new therapeutic regimens for these tumors. [ABSTRACT FROM AUTHOR]

Background To investigate the regulatory mechanism behind miR‐34a‐altered Axl levels in non‐small‐cell lung cancer (NSCLC) with gefitinib‐acquired resistance. Methods The expression of miR‐34a, Axl, Gas6 and related downstream signaling proteins in the EGFR mutant NSCLC cell lines were determined by qRT‐PCR and Western blot; PC9‐Gef‐miR‐34a and HCC827‐Gef‐miR‐34a cells were established by transfecting the parent cells with a miR‐34a overexpressing virus, then the expression of Axl, Gas6 and the downstream channel‐related proteins were also compared in PC9‐Gef‐miR‐34a and HCC827‐Gef‐miR‐34a and drug‐resistant strains. The survival rate of the cells were measured by CCK8 assay. A luciferase reporter detected whether Axl was the target of miR‐34a. Finally, a tumor‐bearing nude mouse model was established to verify the relationship between the expression of miR‐34a, Axl and Gas6 mRNA in vivo. Results The expression levels of Axl mRNA and protein, Gas6 mRNA and protein, and related downstream proteins in PC9‐Gef and HCC827‐Gef cell lines were higher than those in PC9 and HCC827 parental cell lines, while the expression of miR‐34a was lower than it was in the parental cell lines (P

Abstract The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors. Other alternative resistance mechanisms include activating complementary bypass pathways and phenotypic transformation. Sequential monotherapies promise to temporarily address the problem of acquired drug resistance, but evidently are limited by the tumor cells’ ability to adapt and evolve new resistance mechanisms to persist in the drug environment. Recent studies have nominated a model of drug resistance and tumor progression under targeted therapy as a result of a small subpopulation of cells being able to endure the drug (minimal residual disease cells) and eventually develop further mutations that allow them to regrow and become the dominant population in the therapy-resistant tumor. This subpopulation of cells appears to have developed through a subclonal event, resulting in driver mutations different from the driver mutation that is tumor-initiating in the most common ancestor. As such, an understanding of intratumoral heterogeneity—the driving force behind minimal residual disease—is vital for the identification of resistance drivers that results from branching evolution. Currently available methods allow for a more comprehensive and holistic analysis of tumor heterogeneity in that issues associated with spatial and temporal heterogeneity can now be properly addressed. This review provides some background regarding intratumoral heterogeneity and how it leads to incomplete molecular response to targeted therapies, and proposes the use of single-cell methods, sequential liquid biopsy, and multiregion sequencing to discover the link between intratumoral heterogeneity and early adaptive drug resistance. In summary, minimal residual disease as a result of intratumoral heterogeneity is the earliest form of acquired drug resistance. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers of minimal residual disease and contribute to preemptive combinatorial targeting of both drivers of the tumor and its minimal residual disease cells.

The inflammatory state of tumor microenvironment play an important role in non-small cell lung cancer (NSCLC) drug resistance. As the key signal pathway connecting inflammation and tumor, activated signal transduction and transcriptional activation factor 3 (STAT3) leads togenetic abnormal expression, gene silencing, genomic instability, etc. in tumor cells, and induces therapeutic resistance. STAT3 has thepotential to be a new target for reversal of resistance. In this review, we summarize the progress of STAT3 in acquired drug resistance of NSCLC, explore the possibility of STAT3 as a new target to reverse drug resistance, and provide basic theories for the new clinical treatment strategy of acquired drug resistance in NSCLC.

BackgroundTo inform efforts to prevent antituberculosis drug resistance acquired during treatment, particularly multidrug-resistant (MDR) tuberculosis, we analyzed surveillance records from the US state with the highest morbidity.MethodsSurveillance data from the California tuberculosis registry of cases reported between 1994 and 2006 were examined retrospectively. Crude risks of acquired resistance were estimated. Multivariate logistic regression was used to estimate odds ratios of demographic, clinical, and case management characteristics associated with acquired drug resistance (ADR), and secular trends in the incidence of ADR were assessed.ResultsOne in 688 patients acquired MDR tuberculosis, with crude risks varying greatly by initial drug susceptibility test results: 1 in 1909 if initially susceptible to isoniazid and rifampin, 1 in 113 if initially isoniazid resistant, and 1 in 23 if initially rifampicin resistant. Acquired isoniazid and rifampicin monoresistance occurred in 1 in 1018 and 1 in 1455 patients, respectively. Independent predictors of acquired MDR tuberculosis were initial isoniazid resistance (odds ratio [OR], 19.2; 95% confidence interval [CI], 8.25-44.7; P < .001), initial rifampicin resistance (OR, 35.9; 95% CI, 8.61-150; P < .001), human immunodeficiency virus (HIV) infection (OR, 5.07; 95% CI, 1.73-14.9; P = .003), and cavitary disease in the absence of directly observed therapy throughout therapy (OR, 2.65; 95% CI, 1.05-6.69; P = .04). The annual incidence of ADR declined over the study period.ConclusionsAlthough ADR is rare and declining in California, its costly consequences warrant improvements in treatment practices. Our findings suggest that we ensure DOT throughout the course of therapy for patients with baseline drug resistance, cavitary disease, or HIV infection.

Kinase‐targeted therapy has been established as a widely used strategy to treat liver cancer. However, a number of kinase gatekeeper mutations are clinically observed to cause acquired drug resistance during the therapy, which can be overcome by pan‐kinase inhibitors. Here, we create a systematic profile of pan‐kinase inhibitors against clinical kinase gatekeeper mutations in liver cancer pathogenesis by integrating computational modeling and experimental assay. With the profile we are able to identify those gatekeeper mutations that can potentially cause resistance or confer sensitivity to certain pan‐kinase inhibitors. The nine inhibitors are clustered into three groups in terms of their response profile across the investigated mutations. The group‐I and group‐II inhibitors are generally sensitized and caused with resistance by most mutations, respectively, while the group‐III inhibitors exhibit divergent response to different mutations. Structural and energetic analyses reveal that the sensitizing mutations can form additional favorable chemical forces with inhibitor ligands, while the resistant mutations would address unfavorable steric effect and conformational change on inhibitor binding. The marine natural product Hymenialdisine is found to have a general sensitivity for kinase gatekeeper mutations, which could be explored as a novel molecular lead scaffold to develop the wild type‐sparing inhibitors of kinase gatekeeper mutants. [ABSTRACT FROM AUTHOR]

Numerous studies have suggested benefit for heated intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal metastases from colon cancer. However, the PRODIGE 7 trial that randomized 265 colon cancer patients to surgery plus HIPEC vs. surgery alone after neoadjuvant chemotherapy (NACT) did not confirm benefit. These data were published as an abstract and not as a peer-reviewed manuscript. One concern is that prior drug exposure may select for drug resistance and blunt HIPEC efficacy. A database query identified colon cancer specimens evaluated for chemotherapy sensitivity by ex-vivo analysis of programmed cell death (EVA/PCD), a primary culture platform that examines drug-induced cell death (apoptotic & non-apoptotic) by morphologic, metabolic and histologic endpoints. Of 87 fresh colon cancer specimens, 54 (62%) were untreated and 33 (38%) had received prior folinic acid, 5-fluorouracil, oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX). In an apoptosis assay, the lethal concentration of 50% (LC50) in untreated patients was significantly lower than in patients treated by FOLFOX (p = 0.002). Then to approximate PRODIGE 7, treated patients were separated by having received oxaliplatin treatment less than or greater than 2 months before EVA/PCD analysis. The degree of resistance increasing significantly for patients who received treatment less than 2 months prior to EVA/PCD (p < 0.002). Activity for mitomycin and irinotecan was not significantly different for untreated vs. treated patients, but 5-FU was more resistant (P = 0.048). The failure of PRODIGE 7 to improve survival with surgery plus HIPEC following NACT may reflect diminished oxaliplatin cytotoxicity in patients whose residual disease has been selected for oxaliplatin and 5-FU resistance. [ABSTRACT FROM AUTHOR]

Genomic rearrangements of the neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, and NTRK3) are the most common mechanism of oncogenic activation for this family of receptors, resulting in sustained cancer cell proliferation. Several targeted therapies have been approved for tumours harbouring NTRK fusions and a new generation of TRK inhibitors has already been developed due to acquired resistance. We established a patient-derived LMNA::NTRK1-rearranged soft-tissue sarcoma cell model ex vivo with an acquired resistance to targeted TRK inhibition. Molecular profiling of the resistant clones revealed an acquired NF2 loss of function mutation that was absent in the parental cell model. Parental cells showed continuous sensitivity to TRK-targeted treatment, whereas the resistant clones were insensitive. Furthermore, resistant clones showed upregulation of the MAPK and mTOR/AKT pathways in the gene expression based on RNA sequencing data and increased sensitivity to MEK and mTOR inhibitor therapy. Drug synergy was seen using trametinib and rapamycin in combination with entrectinib. Medium-throughput drug screening further identified small compounds as potential drug candidates to overcome resistance as monotherapy or in combination with entrectinib. In summary, we developed a comprehensive model of drug resistance in an LMNA::NTRK1-rearranged soft-tissue sarcoma and have broadened the understanding of acquired drug resistance to targeted TRK therapy. Furthermore, we identified drug combinations and small compounds to overcome acquired drug resistance and potentially guide patient care in a functional precision oncology setting. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Abstract Precision medicine has shed new light on the treatment of heterogeneous cancer patients. However, intratumor heterogeneity strongly constrains the clinical benefit of precision medicine. Thus, rethinking therapeutic strategies from a different facet within the precision medicine framework will not only diversify clinical interventions, but also provide an avenue for precision medicine. Here, we explore the current approaches for targeting intratumor heterogeneity and their limitations. Furthermore, we propose a theoretical strategy with a “homogenization” feature based on iatrogenic evolutionary selection to target intratumor heterogeneity.