Drug resistance mechanisms in cancers:Execution of prosurvival strategies

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

Role of targeting ferroptosis as a component of combination therapy in combating drug resistance in colorectal cancer

Colorectal cancer(CRC)is a form of cancer that is often resistant to chemotherapy,targeted therapy,radiotherapy,and immunotherapy due to its genomic instability and inflammatory tumor microenvironment.Ferroptosis,a type of non-apoptotic cell death,is characterized by the accumulation of iron and the oxidation of lipids.Studies have revealed that the levels of reactive oxygen species and glutathione in CRC cells are significantly lower than those in healthy colon cells.Erastin has emerged as a promising candidate for CRC treatment by diminishing stemness and chemoresistance.Moreover,the gut,responsible for regulating iron absorption and release,could influence CRC susceptibility through iron metabolism modulation.Investigation into ferroptosis offers new insights into CRC pathogenesis and clinical management,potentially revolutionizing treatment approaches for therapy-resistant cancers.

MATHEMATICAL MODELING AND BIFURCATION ANALYSIS FOR A BIOLOGICAL MECHANISM OF CANCER DRUG RESISTANCE

Drug resistance is one of the most intractable issues in targeted therapy for cancer diseases.It has also been demonstrated to be related to cancer heterogeneity,which promotes the emergence of treatment-refractory cancer cell populations.Focusing on how cancer cells develop resistance during the encounter with targeted drugs and the immune system,we propose a mathematical model for studying the dynamics of drug resistance in a conjoint heterogeneous tumor-immune setting.We analyze the local geometric properties of the equilibria of the model.Numerical simulations show that the selectively targeted removal of sensitive cancer cells may cause the initially heterogeneous population to become a more resistant population.Moreover,the decline of immune recruitment is a stronger determinant of cancer escape from immune surveillance or targeted therapy than the decay in immune predation strength.Sensitivity analysis of model parameters provides insight into the roles of the immune system combined with targeted therapy in determining treatment outcomes.

Prox1 Suppresses Proliferation and Drug Resistance of Retinoblastoma Cells via Targeting Notch1

Objective Retinoblastoma(RB)is a prevalent type of eye cancer in youngsters.Prospero homeobox 1(Prox1)is a homeobox transcriptional repressor and downstream target of the proneural gene that is relevant in lymphatic,hepatocyte,pancreatic,heart,lens,retinal,and cancer cells.The goal of this study was to investigate the role of Prox1 in RB cell proliferation and drug resistance,as well as to explore the underlying Notch1 mechanism.Methods Human RB cell lines(SO-RB50 and Y79)and a primary human retinal microvascular endothelial cell line(ACBRI-181)were used in this study.The expression of Prox1 and Notch1 mRNA and protein in RB cells was detected using quantitative real time-polymerase chain reaction(RT-qPCR)and Western blotting.Cell proliferation was assessed after Prox1 overexpression using the Cell Counting Kit-8 and the MTS assay.Drug-resistant cell lines(SO-RB50/vincristine)were generated and treated with Prox1 to investigate the role of Prox1 in drug resistance.We employed pcDNA-Notch1 to overexpress Notch1 to confirm the role of Notch1 in the protective function of Prox1.Finally,a xenograft model was constructed to assess the effect of Prox1 on RB in vivo.Results Prox1 was significantly downregulated in RB cells.Overexpression of Prox1 effectively decreased RB cell growth while increasing the sensitivity of drug-resistant cells to vincristine.Notch1 was involved in Prox1’s regulatory effects.Notch1 was identified as a target gene of Prox1,which was found to be upregulated in RB cells and repressed by increased Prox1 expression.When pcDNA-Notch1 was transfected,the effect of Prox1 overexpression on RB was removed.Furthermore,by downregulating Notch1,Prox1 overexpression slowed tumor development and increased vincristine sensitivity in vivo.Conclusion These data show that Prox1 decreased RB cell proliferation and drug resistance by targeting Notch1,implying that Prox1 could be a potential therapeutic target for RB.

Inferring Mycobacterium Tuberculosis Drug Resistance and Transmission using Whole-genome Sequencing in a High TB-burden Setting in China

Objective China is among the 30 countries with a high burden of tuberculosis(TB)worldwide,and TB remains a public health concern.Kashgar Prefecture in the southern Xinjiang Autonomous Region is considered as one of the highest TB burden regions in China.However,molecular epidemiological studies of Kashgar are lacking.Methods A population-based retrospective study was conducted using whole-genome sequencing(WGS)to determine the characteristics of drug resistance and the transmission patterns.Results A total of 1,668 isolates collected in 2020 were classified into lineages 2(46.0%),3(27.5%),and 4(26.5%).The drug resistance rates revealed by WGS showed that the top three drugs in terms of the resistance rate were isoniazid(7.4%,124/1,668),streptomycin(6.0%,100/1,668),and rifampicin(3.3%,55/1,668).The rate of rifampicin resistance was 1.8%(23/1,290)in the new cases and 9.4%(32/340)in the previously treated cases.Known resistance mutations were detected more frequently in lineage 2 strains than in lineage 3 or 4 strains,respectively:18.6%vs.8.7 or 9%,P<0.001.The estimated proportion of recent transmissions was 25.9%(432/1,668).Multivariate logistic analyses indicated that sex,age,occupation,lineage,and drug resistance were the risk factors for recent transmission.Despite the low rate of drug resistance,drug-resistant strains had a higher risk of recent transmission than the susceptible strains(adjusted odds ratio,1.414;95%CI,1.023–1.954;P=0.036).Among all patients with drug-resistant tuberculosis(DR-TB),78.4%(171/218)were attributed to the transmission of DR-TB strains.Conclusion Our results suggest that drug-resistant strains are more transmissible than susceptible strains and that transmission is the major driving force of the current DR-TB epidemic in Kashgar.

PHLDA2 reshapes the immune microenvironment and induces drug resistance in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a malignancy known for its unfavorable prognosis.The dysregulation of the tumor microenvironment(TME)can affect the sensitivity to immunotherapy or chemotherapy,leading to treatment failure.The elucidation of PHLDA2’s involvement in HCC is imperative,and the clinical value of PHLDA2 is also underestimated.Here,bioinformatics analysis was performed in multiple cohorts to explore the phenotype and mechanism through which PHLDA2 may affect the progression of HCC.Then,the expression and function of PHLDA2 were examined via the qRT-PCR,Western Blot,and MTT assays.Our findings indicate a substantial upregulation of PHLDA2 in HCC,correlated with a poorer prognosis.The methylation levels of PHLDA2 were found to be lower in HCC tissues compared to normal liver tissues.Besides,noteworthy associations were observed between PHLDA2 expression and immune infiltration in HCC.In addition,PHLDA2 upregulation is closely associated with stemness features and immunotherapy or chemotherapy resistance in HCC.In vitro experiments showed that sorafenib or cisplatin significantly up-regulated PHLDA2 mRNA levels,and PHLDA2 knockdown markedly decreased the sensitivity of HCC cells to chemotherapy drugs.Meanwhile,we found that TGF-βinduced the expression of PHLDA2 in vitro.The GSEA and in vitro experiment indicated that PHLDA2 may promote the HCC progression via activating the AKT signaling pathway.Our study revealed the novel role of PHLDA2 as an independent prognostic factor,which plays an essential role in TME remodeling and treatment resistance in HCC.

Research progress in tumor angiogenesis and drug resistance in breast cancer

Angiogenesis is considered a hallmark pathophysiological process in tumor development. Aberrant vasculature resulting from tumor angiogenesis plays a critical role in the development of resistance to breast cancer treatments, via exacerbation of tumor hypoxia, decreased effective drug concentrations within tumors, and immune-related mechanisms. Antiangiogenic therapy can counteract these breast cancer resistance factors by promoting tumor vascular normalization. The combination of antiangiogenic therapy with chemotherapy, targeted therapy, or immunotherapy has emerged as a promising approach for overcoming drug resistance in breast cancer. This review examines the mechanisms associated with angiogenesis and the interactions among tumor angiogenesis, the hypoxic tumor microenvironment, drug distribution, and immune mechanisms in breast cancer. Furthermore, this review provides a comprehensive summary of specific antiangiogenic drugs, and relevant studies assessing the reversal of drug resistance in breast cancer. The potential mechanisms underlying these interventions are discussed, and prospects for the clinical application of antiangiogenic therapy to overcome breast cancer treatment resistance are highlighted.

Deciphering resistancemechanisms and novel strategies to overcome drug resistance in ovarian cancer:a comprehensive review

Ovarian cancer is among the most lethal gynecological cancers,primarily due to the lack of specific symptoms leading to an advanced-stage diagnosis and resistance to chemotherapy.Drug resistance(DR)poses the most significant challenge in treating patients with existing drugs.The Food and Drug Administration(FDA)has recently approved three new therapeutic drugs,including two poly(ADP-ribose)polymerase(PARP)inhibitors(olaparib and niraparib)and one vascular endothelial growth factor(VEGF)inhibitor(bevacizumab)for maintenance therapy.However,resistance to these new drugs has emerged.Therefore,understanding the mechanisms of DR and exploring new approaches to overcome them is crucial for effective management.In this review,we summarize the major molecular mechanisms of DR and discuss novel strategies to combat DR.

Analysis of The Correlation Between inhA Gene Mutation and Resistance to Protionamide in Drug-Resistant Mycobacterium Tuberculosis

Objective: To investigate the characteristics of katG and inhA gene mutations in multidrug-resistant tuberculosis (MDR-TB), pre-extensively drug-resistant tuberculosis (preXDR-TB), and their correlation with resistance to protionamide (Pto). Methods: A total of 229 patients with MDR-TB and pre-XDR-TB diagnosed in the Eighth Affiliated Hospital of Xinjiang Medical University from January 2020 to February 2024 were selected to analyze the characteristics of katG and inhA mutations in MTB clinical isolates and their correlation with Pto resistance. Results: The mutation rate of katG (with or without inhA mutation) was 85.2%. The mutation rates in MDR-TB and pre-XDR-TB were 87.4% (125/143) and 81.4% (70/86), respectively. The mutation rate of inhA (including katG mutation) was 14.8% (34/229), which was 12.6% (18/143) and 18.6% (16/86) in MDR-TB and pre-XDR-MTB, respectively. There was no difference in mutation (P > 0.05). Conclusion: The total resistance rate to Pto in 229 strains was 8.7% (20/229), which was 8.4% (12/143) and 9.3% (8/86) in MDR-TB and pre-XDR-TB, respectively. Among the inhA mutant strains, 13 were resistant to the Pto phenotype, and the resistance rate was 65% (13/20). In MDR-TB and pre-XDR-TB strains resistant to Pto, inhA gene mutations occurred in 66.7% (6/9) and 63.6% (7/11), respectively. The resistance rates of MDR-MTB and pre-XDR-TB strains without inhA gene mutation to Pto were 2.4% (3/125) and 5.7% (4/70), respectively.

Natural Products and Antiviral Resistance

Viral diseases are minacious with the potential for causing pandemics and treatment is complicated because of their inherent ability to mutate and become resistant to drugs. Antiviral drug resistance is a persistent problem that needs continuous attention by scientists, medical professionals, and government agencies. To solve the problem, an in-depth understanding of the intricate interplay between causes of antiviral drug resistance and potential new drugs specifically natural products is imperative in the interest and safety of public health. This review delves into natural product as reservoir for antiviral agents with the peculiar potentials for addressing the complexities associated with multi-drug resistant and emerging viral strains. An evaluation of the mechanisms underlying antiviral drug activity, antiviral drug resistance is addressed, with emphasis on production of broad-spectrum antiviral agents from natural sources. There is a need for continued natural product-based research, identification of new species and novel compounds.

Mechanisms of resistance to trastuzumab in HER2-positive gastric cancer

Gastric cancer is one of the most prevalent cancers worldwide,and human epidermal growth factor receptor 2(HER2)-positive cases account for approximately 20%of the total cases.Currently,trastuzumab+chemotherapy is the recommended first-line treatment for patients with HER2-positive advanced gastric cancer,and the combination has exhibited definite efficacy in HER2-targeted therapy.However,the emergence of drug resistance during treatment considerably reduces its effectiveness;thus,it is imperative to investigate the potential mechanisms underlying resistance.In the present review article,we comprehensively introduce multiple mechanisms underlying resistance to trastuzumab in HER2-positive gastric cancer cases,aiming to provide insights for rectifying issues associated with resistance to trastuzumab and devising subsequent treatment strategies.

Effect and mechanism of Qingre Huashi decoction on drug-resistant Helicobacter pylori

BACKGROUND Helicobacter pylori(HP),the most common pathogenic microorganism in stomach,can induce inflammatory reactions in the gastric mucosa,causing chronic gastritis and even gastric cancer.HP infection affects over 4.4 billion people globally,with a worldwide infection rate of up to 50%.The multidrug resistance of HP poses a serious challenge to eradication.It has been monstrated that compared to bismuth quadruple therapy,Qingre Huashi decoction(QHD)combined with triple therapy exhibits comparable eradication rates but with a lower incidence of adverse reactions;in addition,QHD directly inhibit and kill HP in vitro.METHODS In this study,12 HP strains were isolated in vitro after biopsy during gastroscopy of HP-infected patients.In vitro,the minimum inhibitory concentration(MIC)values for clinical HP strains and biofilm quantification were determined through the E-test method and crystal violet staining,respectively.The most robust biofilm-forming strain of HP was selected,and QHD was evaluated for its inhibitory and bactericidal effects on the strain with strong biofilm formation.This assessment was performed using agar dilution,E-test,killing dynamics,and transmission electron microscopy(TEM).The study also explored the impact of QHD on antibiotic resistance in these HP strains with strong biofilm formation.Crystalline violet method,scanning electron microscopy,laser confocal scanning microscopy,and(p)ppGpp chromatographic identification were employed to evaluate the effect of QHD on biofilm in strong biofilm-forming HP strains.The effect of QHD on biofilm and efflux pump-related gene expression was evaluated by quantitative polymerase chain reaction.Non-targeted metabolomics with UHPLC-MS/MS was used to identify potential metabolic pathways and biomarkers which were different between the NC and QHD groups.RESULTS HP could form biofilms of different degrees in vitro,and the intensity of formation was associated with the drug resistance of the strain.QHD had strong bacteriostatic and bactericidal effects on HP,with MICs of 32-64 mg/mL.QHD could inhibit the biofilm formation of the strong biofilm-forming HP strains,disrupt the biofilm structure,lower the accumulation of(p)ppGpp,decrease the expression of biofilm-related genes including LuxS,Spot,glup(HP1174),NapA,and CagE,and reduce the expression of efflux pump-related genes such as HP0605,HP0971,HP1327,and HP1489.Based on metabolomic analysis,QHD induced oxidative stress in HP,enhanced metabolism,and potentially inhibited relevant signaling pathways by upregulating adenosine monophosphate(AMP),thereby affecting HP growth,metabolism,and protein synthesis.CONCLUSION QHD exerts bacteriostatic and bactericidal effects on HP,and reduces HP drug resistance by inhibiting HP biofilm formation,destroying its biofilm structure,inhibiting the expression of biofilm-related genes and efflux pump-related genes,enhancing HP metabolism,and activating AMP in HP.

Nature’s Pharmacy under Siege: Investigating Antibiotic Resistance Pattern in Endophytic Bacteria of Medicinal Plants

Antibiotic resistance poses a significant global health threat, necessitating a thorough understanding of its prevalence in various ecological contexts. Medicinal plants, renowned for their therapeutic properties, host endophytic bacteria that produce bioactive compounds. Understanding antibiotic resistance dynamics in these bacteria is vital for human health and antibiotic efficacy preservation. In this study, we investigated antibiotic resistance profiles in endophytic bacteria from five medicinal plants: Thankuni, Neem, Aparajita, Joba, and Snake plant. We isolated and characterized 113 endophytic bacteria, with varying resistance patterns observed against multiple antibiotics. Notably, 53 strains were multidrug-resistant (MDR), with 14 exhibiting extensive drug resistance (XDR). Thankuni-associated bacteria displayed 44% MDR and 11% XDR, while Neem-associated bacteria showed higher resistance (60% MDR, 13% XDR). Aparajita-associated bacteria had lower resistance (22% MDR, 6% XDR), whereas Joba-associated bacteria exhibited substantial resistance (54% MDR, 14% XDR). Snake plant-associated bacteria showed 7% MDR and 4% XDR. Genus-specific distribution revealed Bacillus (47%), Staphylococcus (21%), and Klebsiella (11%) as major contributors to MDR. Our findings highlight diverse drug resistance patterns among plant-associated bacteria and underscore the complexity of antibiotic resistance dynamics in diverse plant environments. Identification of XDR strains emphasizes the severity of the antibiotic resistance problem, warranting further investigation into contributing factors.

Identification of TNFRSF1A as a novel regulator of carfilzomib resistance in multiple myeloma

Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug resistance is a pervasive obstacle to treating MM.Therefore,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies.To elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells.Differential gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion molecules.The upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion molecules.Furthermore,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules.Furthermore,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity.Furthermore,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules.The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity.Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.

PPP1R14A is Associated with Immunotherapy Resistance in Head and Neck Squamous Cell Carcinoma Identified by Single-Cell and Bulk RNA-Sequencing

Objective To identify nivolumab resistance-related genes in patients with head and neck squamous cell carcinoma(HNSCC)using single-cell and bulk RNA-sequencing data.Methods The single-cell and bulk RNA-sequencing data downloaded from the Gene Expression Omnibus database were analyzed to screen out differentially expressed genes(DEGs)between nivolumab resistant and nivolumab sensitive patients using R software.The Least Absolute Shrinkage Selection Operator(LASSO)regression and Recursive Feature Elimination(RFE)algorithm were performed to identify key genes associated with nivolumab resistance.Functional enrichment of DEGs was analyzed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses.The relationships of key genes with immune cell infiltration,differentation trajectory,dynamic gene expression profiles,and ligand-receptor interaction were explored.Results We found 83 DEGs.They were mainly enriched in T-cell differentiation,PD-1 and PD-L1 checkpoint,and T-cell receptor pathways.Among six key genes identified using machine learning algorithms,only PPP1R14A gene was differentially expressed between the nivolumab resistant and nivolumab sensitive groups both before and after immunotherapy(P<0.05).The high PPP1R14A gene expression group had lower immune score(P<0.01),higher expression of immunosuppressive factors(such as PDCD1,CTLA4,and PDCD1LG2)(r>0,P<0.05),lower differentiation of infiltrated immune cells(P<0.05),and a higher degree of interaction between HLA and CD4(P<0.05).Conclusions PPP1R14A gene is closely associated with resistance to nivolumab in HNSCC patients.Therefore,PPP1R14A may be a target to ameliorate nivolumab resistance of HNSCC patients.

Erythropoietin-induced hepatocyte receptor A2 regulates effect of pyroptosis on gastrointestinal colorectal cancer occurrence and metastasis resistance

Erythropoietin-induced hepatocyte receptor A2(EphA2)is a receptor tyrosine kinase that plays a key role in the development and progression of a variety of tumors.This article reviews the expression of EphA2 in gastrointestinal(GI)colorectal cancer(CRC)and its regulation of pyroptosis.Pyroptosis is a form of programmed cell death that plays an important role in tumor suppression.Studies have shown that EphA2 regulates pyrodeath through various signaling pathways,affecting the occurrence,development and metastasis of GI CRC.The overexpression of EphA2 is closely related to the aggressiveness and metastasis of GI CRC,and the inhibition of EphA2 can induce pyrodeath and improve the sensitivity of cancer cells to treatment.In addition,EphA2 regulates intercellular communication and the microenvironment through interactions with other cytokines and receptors,further influencing cancer progression.The role of EphA2 in GI CRC and its underlying mechanisms provide us with new perspectives and potential therapeutic targets,which have important implications for future cancer treatment.

Roles of the tumor microenvironment in the resistance to programmed cell death protein 1 inhibitors in patients with gastric cancer

Despite the continuous developments and advancements in the treatment of gastric cancer(GC),which is one of the most prevalent types of cancer in China,the overall survival is still poor for most patients with advanced GC.In recent years,with the progress in tumor immunology research,attention has shifted toward immunotherapy as a therapeutic approach for GC.Programmed cell death protein 1(PD-1)inhibitors,as novel immunosuppressive medications,have been widely utilized in the treatment of GC.However,many patients are still resistant to PD-1 inhibitors and experience recurrence in the advanced stages of PD-1 immunotherapy.To reduce the occurrence of drug resistance and recurrence in GC patients receiving PD-1 immunotherapy,to maximize the clinical activity of immunosuppressive drugs,and to elicit a lasting immune response,it is essential to research the tumor microenvironment mechanisms leading to PD-1 inhibitor resistance in GC patients.This article reviews the progress in studying the factors influencing the resistance to PD-1 inhibitors in the GC tumor microenvironment,aiming to provide insights and a basis for reducing resistance to PD-1 inhibitors for GC patients in the future.

Distribution and Drug Resistance Analysis of 2287 Strains of Pathogenic Bacteria in Children’s Blood Culture

Background: Bloodstream infection is a serious infectious disease. In recent years, the drug resistance of pathogenic bacteria to commonly used anti-infective drugs has been widely concerned, which also makes the treatment of bloodstream infection face severe challenges. Objective: To explore the distribution characteristics of blood culture-positive pathogens and the resistance to antibacterial drugs, so as to provide clinicians with accurate laboratory evidence, so as to guide clinicians to rationally apply antibiotics, improve clinical treatment effects, and reduce the emergence of drug-resistant strains. Methods: From January 2019 to June 2022, 2287 positive blood culture specimens of patients in Guangzhou Women and Children’s Medical Center were retrospectively analyzed, and the proportion of different pathogenic bacteria, the distribution of pathogenic bacteria in different departments, and the multi-drug resistance of different pathogenic bacteria were counted. Results: Among the 2287 blood culture positive samples, 1560 strains (68.20%) of gram-positive bacteria and 727 strains (31.80%) of gram-negative bacteria were strained. The top three departments in the distribution of pathogenic bacteria were pediatric intensive care unit (600 strains), pediatric internal medicine (514 strains), and pediatric emergency comprehensive ward (400 strains). The pathogens with high detection rates were: Staphylococcus epidermidis (24.09%), Staphylococcus humans (23.74%), Escherichia coli (13.21%) and Klebsiella pneumoniae (8.71%). The pathogens with high multi-drug resistance rates were: Streptococcus pneumoniae (93%), Staphylococcus epidermidis (83.76%), Enterobacter cloacae (75.61%) and Staphylococcus humans (62.43%). Conclusion: In our hospital, gram-positive bacteria were the main pathogenic bacteria in the blood culture of children patients. The children’s intensive care unit was the department with the largest distribution of pathogenic bacteria, and the multiple drug resistance rate of Streptococcus pneumoniae was the highest.

Smart drug delivery systems to overcome drug resistance in cancer immunotherapy

Cancer immunotherapy,a therapeutic approach that inhibits tumors by activating or strengthening anti-tumor immunity,is currently an important clinical strategy for cancer treatment;however,tumors can develop drug resistance to immune surveillance,resulting in poor response rates and low therapeutic efficacy.In addition,changes in genes and signaling pathways in tumor cells prevent susceptibility to immunotherapeutic agents.Furthermore,tumors create an immunosuppressive microenvironment via immunosuppressive cells and secrete molecules that hinder immune cell and immune modulator infiltration or induce immune cell malfunction.To address these challenges,smart drug delivery systems(SDDSs)have been developed to overcome tumor cell resistance to immunomodulators,restore or boost immune cell activity,and magnify immune responses.To combat resistance to small molecules and monoclonal antibodies,SDDSs are used to co-deliver numerous therapeutic agents to tumor cells or immunosuppressive cells,thus increasing the drug concentration at the target site and improving efficacy.Herein,we discuss how SDDSs overcome drug resistance during cancer immunotherapy,with a focus on recent SDDS advances in thwarting drug resistance in immunotherapy by combining immunogenic cell death with immunotherapy and reversing the tumor immunosuppressive microenvironment.SDDSs that modulate the interferon signaling pathway and improve the efficacy of cell therapies are also presented.Finally,we discuss potential future SDDS perspectives in overcoming drug resistance in cancer immunotherapy.We believe that this review will contribute to the rational design of SDDSs and development of novel techniques to overcome immunotherapy resistance.

Assessment of the Indirect Cost of Drug Resistant Tuberculosis Treatment to Patients in a High Burden, Low Income Setting in Mozambique

Introduction: Tuberculosis is closely linked to poverty, with patients facing significant indirect treatment costs. Treating drug-resistant tuberculosis further increases these expenses. Notably, there is a lack of published data on the indirect costs incurred by patients with drug-resistant tuberculosis in Mozambique. Objective: To assess the indirect costs, income reduction, and work productivity incurred by patients undergoing diagnosis and treatment for Drug-Resistant Tuberculosis (DRTB) in Mozambique during their TB treatment. Methods: As part of a comprehensive mixed-methods study conducted from January 2021 to April 2023, this research utilized a descriptive cross-sectional approach, incorporating both quantitative and qualitative methods. The primary goal was to evaluate the costs incurred by the national health system due to drug-resistant TB. Additionally, to explore the indirect costs experienced by patients and their families during treatment, semi-structured interviews were conducted with 27 individuals who had been undergoing treatment for over six months. Results: All survey participants unanimously reported a significant decline in labour productivity, with 70.3% experiencing a reduction in their monthly income. Before falling ill, the majority of respondents (33.3%) earned up to $76.92 monthly, representing the minimum earnings range, while 29.2% had a monthly income above $230.77, the maximum earnings range. Among those who experienced income loss, the majority (22.2%) reported a decrease of up to $76.92 per month, and 18.5% cited a loss exceeding $230.77 per month. Notably, patients with Drug-Resistant Tuberculosis (DRTB) have not incurred the direct costs of the disease, as these are covered by the government. Conclusion: The financial burden of treating Drug-Resistant Tuberculosis (DRTB), along with the income reduction it causes, is substantial. Implementing a patient-centred, multidisciplinary, and multisector approach, coupled with strong psychosocial support, can significantly reduce the catastrophic costs DRTB patients incur.