Development Of Drug Resistance Research Articles

STAT3-specific nanocarrier for shRNA/drug dual delivery and tumor synergistic therapy

Non-small cell lung cancer (NSCLC) is a major disease with high incidence, low survival rate and prone to develop drug resistance to chemotherapy. The mechanism of secondary drug resistance in NSCLC chemotherapy is very complex, and studies have shown that the abnormal activation of STAT3 (Signal Transducer and Activator of Transcription 3) plays an important role in it. In this study, the pGPU6/GFP/Neo STAT3-shRNA recombinant plasmid was constructed with STAT3 as the precise target. By modifying hydrophilic and hydrophobic blocks onto chitosan, a multifunctional vitamin E succinate-chitosan-polyethylene glycol monomethyl ether histidine (VES-CTS-mPEG-His) micelles were synthesized. The micelles could encapsulate hydrophobic drug doxorubicin through self-assembly, and load the recombinant pGPU6/GFP/Neo STAT3-shRNA (pDNA) through positive and negative charges to form dual-loaded nanoparticles DOX/VCPH/pDNA. The co-delivery and synergistic effect of DOX and pDNA could up-regulate the expression of PTEN (Phosphatase and Tensin Homolog), down-regulate the expression of CD31, and induce apoptosis of tumor cells. The results of precision targeted therapy showed that DOX/VCPH/pDNA could significantly down-regulate the expression level of STAT3 protein, further enhancing the efficacy of chemotherapy. Through this study, precision personalized treatment of NSCLC could be effectively achieved, reversing its resistance to chemotherapy drugs, and providing new strategies for the treatment of drug-resistant NSCLC.

Comparison of Mutant Prevention Concentrations of Fluoroquinolones Against ESBL-Positive and ESBL-Negative Klebsiella pneumoniae Isolates from Orthopedic Patients.

The majority of Klebsiella pneumonia isolates possess the extended-spectrum beta-lactamase (ESBL) enzymes. Therefore, K. pneumoniae can easily develop drug resistance. How to effectively overcome the problem of drug resistance in K. pneumoniae is still a research hotspot. This study aimed to compare the mutant prevention concentration (MPC) of ESBL-positive and ESBL-negative K. pneumoniae isolated from orthopedic patients, which may provide a basis for the effective use of drugs to control the enrichment of resistance mutants of K. pneumoniae. The MPC90 values of 55 isolates of ESBL-positive K. pneumoniae against 4 fluoroquinolones were 32 µg/mL for levofloxacin and gatifloxacin, 16 µg/mL for ciprofloxacin, and 4 µg/mL for gemifloxacin. The selection index value was 8 for levofloxacin and ciprofloxacin and 2 for gemifloxacin and gatifloxacin, respectively. For ESBL-negative K. pneumoniae isolates, the MPC90 values were 16 µg/mL for levofloxacin and ciprofloxacin, 4 µg/mL for gemifloxacin, and 32 µg/mL for gatifloxacin. The selection index value was 8 for levofloxacin and ciprofloxacin, 2 for gemifloxacin, and 4 for gatifloxacin. For the ESBL-positive K. pneumoniae, the %T>MIC90 order was gemifloxacin > levofloxacin > ciprofloxacin > gatifloxacin. For the ESBL-negative K. pneumoniae, the %T>MIC90 order was levofloxacin > gemifloxacin > ciprofloxacin > gatifloxacin. The mutant-preventing ability of gatifloxacin and gemifloxacin was the strongest among the 4 fluoroquinolones. So gemifloxacin may be the first choice of drug to treat K. pneumoniae infection.

Quantitative Prediction of Human Immunodeficiency Virus Drug Resistance

Drug resistance of pathogens, including viruses, is one of the reasons for decreased efficacy of therapy. Considering the impact of HIV type 1 (HIV-1) on the development of progressive immune dysfunction and the rapid development of drug resistance, the analysis of HIV-1 resistance is of high significance. Currently, a substantial amount of data has been accumulated on HIV-1 drug resistance that can be used to build both qualitative and quantitative models of HIV-1 drug resistance. Quantitative models of drug resistance can enrich the information about the efficacy of a particular drug in the scheme of antiretroviral therapy. In our study, we investigated the possibility of developing models for quantitative prediction of HIV-1 resistance to eight protease inhibitors based on the analysis of amino acid sequences of HIV-1 protease for 900 virus variants. We developed random forest regression (RFR), support vector regression (SVR), and self-consistent regression (SCR) models using binary vectors containing values from 0 or 1, depending on the presence of a specific peptide fragment in each amino acid sequence as independent variables, while fold ratio, reflecting the level of resistance, was the predicted variable. The SVR and SCR models showed the highest predictive performances. The models built demonstrate reasonable performances for eight out of nine (R2 varied from 0.828 to 0.909) protease inhibitors, while R2 for predicting tipranavir fold ratio was lower (R2 was 0.642). We believe that the developed approach can be applied to evaluate drug resistance of molecular targets of other viruses where appropriate experimental data are available.

Long-term stability of acquired drug resistance and resistance associated mutations in the fungal pathogen Nakaseomyces glabratus (Candida glabrata)

The limited number of available antifungal drugs and the increasing number of fungal isolates that show drug or multidrug resistance pose a serious medical threat. Several yeast pathogens, such as Nakaseomyces glabratus (Candida glabrata), show a remarkable ability to develop drug resistance during treatment through the acquisition of genetic mutations. However, how stable this resistance and the underlying mutations are in non-selective conditions remains poorly characterized. The stability of acquired drug resistance has fundamental implications for our understanding of the appearance and spread of drug-resistant outbreaks and for defining efficient strategies to combat them. Here, we used an in vitro evolution approach to assess the stability under optimal growth conditions of resistance phenotypes and resistance-associated mutations that were previously acquired under exposure to antifungals. Our results reveal a remarkable stability of the resistant phenotype and the underlying mutations in a significant number of evolved populations, which conserved their phenotype for at least two months in the absence of drug-selective pressure. We observed a higher stability of anidulafungin resistance over fluconazole resistance, and of resistance-conferring point mutations as compared with aneuploidies. In addition, we detected accumulation of novel mutations in previously altered resistance-associated genes in non-selective conditions, which suggest a possible compensatory role. We conclude that acquired resistance, particularly to anidulafungin, is a long-lasting phenotype, which has important implications for the persistence and propagation of drug-resistant clinical outbreaks.

Sono-blasting Triggered Cascading-Amplification of Oxidative Stress for Enhanced Interventional Therapy of Hepatocellular Carcinoma.

Interventional therapy is widely regarded as a highly promising treatment approach for nonsurgical liver cancer. However, the development of drug resistance and tolerance to hypoxic environments after embolization can lead to increased angiogenesis, enhanced tumor cell stemness, and greater invasiveness, resulting in metastasis and recurrence. To address these challenges, a novel approach involving the use of lecithin and DSPE-PEG comodified Ca2+ loaded (NH4)2S2O8 (LDCNSO) drug in combination with transcatheter arterial embolization (TAE) has been proposed. The sono-blasting effect of LDCNSO under ultrasound triggers a cascading amplification of oxidative stress, by releasing sulfate radical (·SO4-), hydroxyl radical (·OH), and superoxide (·O2-), inducing Ca2+ overload, and reducing glutathione (GSH) levels, which eventually leads to apoptosis. LDCNSO alongside TAE has demonstrated remarkable therapeutic efficacy in the rabbit orthotopic cancer model, resulting in significant inhibition of tumor growth. This research provides valuable insights for the effective treatment of orthotopic tumors.

Enzyme-instructed intramitochondrial polymerization for enhanced anticancer treatment without the development of drug-resistance

Intracellular polymerization in living cells motivated chemists to generate polymeric structures with a multitude of possibilities to interact with biomacromolecules. However, out-of-control of the intracellular chemical reactions would be an obstacle restricting its application, providing the toxicity of non-targeted cells. Here, we reported intracellular thioesterase-mediated polymerization for selectively occurring polymerization using disulfide bonds in cancer cells. The acetylated monomers did not form disulfide bonds even under an oxidative environment, but they could polymerize into the polymeric structure after cleavage of acetyl groups only when encountered activity of thioesterase enzyme. Furthermore, acetylated monomers could be self-assembled with doxorubicin, providing doxorubicin loaded micelles for efficient intracellular delivery of drug and monomers. Since thioesterase enzymes were overexpressed in cancer cells specifically, the micelles were disrupted under activity of the enzyme and the polymerization could occur selectively in the cancer mitochondria. The resulting polymeric structures disrupted the mitochondrial membrane, thus activating the cellular death of cancer cells with high selectivity. This strategy selectively targets diverse cancer cells involving drug-resistant cells over normal cells. Moreover, the mitochondria targeting strategy overcomes the development of drug resistance even with repeated treatment. This approach provides a way for selective intracellular polymerization with desirable anticancer treatment.

Norwogonin aids in fighting MRSA-induced pneumonia by targeting agrAC to inhibit α-hemolysin production.

The increasing prevalence of infections related to methicillin-resistant Staphylococcus aureus (MRSA) necessitates the exploration of innovative therapeutic strategies that diverge from conventional antibiotic treatments. This is imperative to effectively combat resistance and manage these infections. The adoption of antivirulence strategies has emerged as a particularly promising avenue. This approach applies a heightened selective pressure on pathogens, thereby diminishing the likelihood of bacteria evolving resistance to antibiotics. In our pursuit of novel therapeutics for treating MRSA infections, we have focused on agents that inhibit the virulence of S. aureus without impeding its growth, aiming to minimize the development of drug resistance. α-Hemolysin, a critical virulence factor encoded by the hla gene, is a cytotoxin that forms pores in host cell membranes and plays a pivotal role in the progression of disease during bacterial infections. Herein, we identified that norwogonin could effectively inhibit Hla production via targeting agrAC, a crucial protein in quorum sensing, resulting in dose-dependent inhibition of hemolytic activity without suppressing S. aureus growth. In vitro assays illustrated that norwogonin decreased the thermal stability of agrAC, providing evidence of interaction between norwogonin and agrAC. Meanwhile, norwogonin alleviated Hla-mediated A549 cell damage and reduced lactate dehydrogenase release. In vivo studies suggested that norwogonin treatment blocked the establishment of a mouse model of pneumonia caused by S. aureus USA300. Notably, norwogonin enhanced the antibacterial potency of oxacillin. In conclusion, norwogonin is a promising candidate for treating S. aureus infections, offering a novel alternative to traditional antibiotics by targeting virulence factors and enhancing the efficacy of existing treatments.

Construction of Iron-Scavenging Hydrogel via Thiol-Ene Click Chemistry for Antibiotic-Free Treatment of Bacterial Wound Infection.

Bacteria, especially drug-resistant strains, can quickly cause wound infections, leading to delayed healing and fatal risk in clinics. With the growing need for alternative antibacterial approaches that rely less on antibiotics or eliminate their use altogether, a novel antibacterial hydrogel named Ovtgel is developed. Ovtgel is formulated by chemically crosslinking thiol-modified ovotransferrin (Ovt), a member of the transferrin family found in egg white, with olefin-modified agarose through thiol-ene click chemistry. Ovt is designed to sequester ferric ions essential for bacterial survival and protect wound tissues from damages caused by the reactive oxygen species (ROS) generated in Fenton reactions. Experimental data have shown that Ovtgel significantly enhances wound healing by inhibiting bacterial growth and shielding tissues from ROS-induced harms. Unlike traditional antibiotics, Ovtgel targets essential trace elements required for bacterial survival in the host environment, preventing the development of drug resistance in pathogenic bacteria. Ovtgel exhibits excellent biocompatibility due to the homology of Ovt to mammalian transferrin. This hydrogel has the potential to serve as an effective antibiotic-free solution for combating bacterial infections.

Evolutionary accumulation of FKS1 mutations from clinical echinocandin-resistant Candida auris

Introduction: Drug resistance to echinocandins, first-line drugs used to treat Candida auris infection, is rapidly emerging. However, the accumulation of mutations in genes other than FKS1 (before an isolate develops to resistance via FKS1 mutations), remains poorly understood. Methods Four clinical cases and 29 isolates associated with the incremental process of echinocandin resistance were collected and analyzed using antifungal drug susceptibility testing and genome sequencing to assess the evolution of echinocandin resistance. Findings: Six echinocandin minimum inhibitory concentration (MIC)-elevated C. auris strains and seven resistant strains were isolated from the urinary system of patients receiving echinocandin treatment. Meanwhile, phylogenetic analyses illustrated that the echinocandin-resistant strains were closely related to other strains in the same patient. Genomic data revealed that the echinocandin-resistant strains had FKS1 mutations. Furthermore, three categories (ECN-S/E/R) of non-synonymous mutant SNP genes (such as RBR3, IFF6, MKC1, MPH1, RAD2, and MYO1) in C. auris appeared to be associated with the three-stage-evolutionary model of echinocandin resistance in C. glabrata: cell wall stress, drug adaptation, and genetic escape (FKS mutation). Interpretation: Echinocandin-resistant C. auris undergoes spatial and temporal phase changes closely related to echinocandin exposure, particularly in the urinary system. These findings suggest that FKS1 mutations mediate an evolutionary accumulation of echinocandin resistance followed by modulation of chromosome remodeling and DNA repair processes that ultimately lead to FKS1 hot spot mutations and the development of drug resistance. This study provides an in-depth exploration of the molecular pathways involved in the evolution of Candida auris echinocandin resistance.

Coumarin-based Aldo-Keto Reductase Family 1C (AKR1C) 2 and 3 Inhibitors.

A series of 7-substituted coumarin derivatives have been characterized as pan-aldo-keto reductase family 1C (AKR1C) inhibitors. The AKR1C family of enzymes are overexpressed in numerous cancers where they are involved in drug resistance development. 7-hydroxy coumarin ethyl esters and their corresponding amides have high potency for AKR1C3 and AKR1C2 inhibition. Coumarin amide 3a possessed IC50 values of 50 nM and 90 nM for AKR1C3 and AKR1C2, respectively, and exhibits 'drug-like' metabolic stability and half-life in human and mouse liver microsomes and plasma. Compound 3a was employed as a chemical tool to determine pan-AKR1C2/3 inhibition effects both as a radiation sensitizer and as a potentiator of chemotherapy cytotoxicity. In contrast to previously reported pan-AKR1C inhibitors, 3a demonstrated no radiation sensitization effect in a radiation-resistant prostate cancer cell line model. Pan-AKR1C inhibition also did not potentiate the in vitro cytotoxicity of ABT-737, daunorubicin or dexamethasone, in two patient-derived T-cell ALL and pre-B-cell ALL cell lines. In contrast, a highly selective AKR1C3 inhibitor, compound K90, enhanced the cytotoxicity of both ABT-737 and daunorubicin in the T-cell ALL cell line model. Thus, the inhibitory profile of the AKR1C family inhibitor required to effect enhancement of chemotherapeutic cytotoxicity may be chemotherapeutic agent-specific in leukemia.

Programming tumor evolution with selection gene drives to proactively combat drug resistance.

Most targeted anticancer therapies fail due to drug resistance evolution. Here we show that tumor evolution can be reproducibly redirected to engineer therapeutic opportunity, regardless of the exact ensemble of pre-existing genetic heterogeneity. We develop a selection gene drive system that is stably introduced into cancer cells and is composed of two genes, or switches, that couple an inducible fitness advantage with a shared fitness cost. Using stochastic models of evolutionary dynamics, we identify the design criteria for selection gene drives. We then build prototypes that harness the selective pressure of multiple approved tyrosine kinase inhibitors and employ therapeutic mechanisms as diverse as prodrug catalysis and immune activity induction. We show that selection gene drives can eradicate diverse forms of genetic resistance in vitro. Finally, we demonstrate that model-informed switch engagement effectively targets pre-existing resistance in mouse models of solid tumors. These results establish selection gene drives as a powerful framework for evolution-guided anticancer therapy.

Adhesin Component Member STAG2 Enhances Cisplatin Tolerance in Colorectal Cancer Cells through the Epithelial-Mesenchymal Transition Pathway.

Platinum-based compounds are commonly used as an initial treatment for colorectal cancer (CRC). However, the development of drug resistance in patients with CRC necessitates the administration of high drug concentrations during clinical treatment, thereby augmenting the toxicity of platinum-based compounds and increasing the mortality rate. STAG2 is a significantly associated drug-resistance gene in many cancers, but it has not been studied in colorectal cancer. Therefore, the present study aimed to investigate the role and drug sensitivity of the cisplatin-resistant gene STAG2. The effects of STAG2 on drug resistance and survival rates of patients with CRC were examined using the Genomics of Drug Sensitivity in Cancer (GDSC) and Kaplan-Meier (KM) plotter databases. Subsequently, a sh-STAG2-HT-29 cell line was generated using a knockdown test of STAG2, and the half-maximal inhibitory concentration (IC50) of the two cell lines was determined using a cell viability test. We then used various techniques, including the Cell Counting Kit-8 (CCK-8), plate cloning, 5-ethynyl-2'-deoxyuridine (EdU) fluorescence staining, flow cytometry for cell cycle detection, the scar assay, the Transwell invasion assay, and Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) fluorescence staining for apoptosis detection, to investigate the functionality of the four subgroups of cancer cell lines. Additionally, Western blotting (WB) was used to identify the potential pathways associated with the observed functional alterations. Finally, the phenotype, tumor weight, mouse weight, tumor volume, and tumor tissue structure of the developed tumors were assessed using the subcutaneous tumor formation method. Database analysis indicated that STAG2 plays a role in facilitating drug resistance among individuals with CRC. Furthermore, mutations in this gene lead to increased sensitivity to cisplatin, and its overexpression was associated with an unfavorable prognosis. Following the successful development of STAG2 knockdown cells, differences in IC50 concentrations were observed between HT-29 and sh-STAG2-HT-29 cells. A treatment concentration of 10 μM cisplatin was selected, and the proliferation, migration, and invasion capabilities of cancer cells decreased after STAG2 knockdown. Additionally, the sensitivity of the cells to cisplatin therapy was increased, which was potentially mediated by the epithelial-mesenchymal transition (EMT) pathway. In mice, the tumorigenic potential of HT-29 cells was reduced by STAG2 knockdown, accompanied by a decrease in resistance to cisplatin therapy. STAG2 acts as a proto-oncogene in CRC, and its resistance to cisplatin therapy is more prominent. This study confirmed the role of STAG2 in CRC and provided a theoretical basis for the further development of STAG2 as an auxiliary criterion for determining dosage when patients are treated with platinum drugs.

Anthelmintic Activity of Foeniculum vulgare Seeds and Meta-Analysis of Some Other Medicinal Plants from Pakistan

Helminthiasis diseases caused by parasitic worms in animals have been a significant challenge worldwide, resulting in substantial economic losses and decreased productivity in the agricultural sector. The use of synthetic drugs to treat these infections has several drawbacks, including the development of drug resistance, high costs, and potential toxicities to both animals and humans. Therefore, researchers looked for other ways to solve the problem and found that medicinal plants might have anthelmintic activities because they have many secondary metabolites. These metabolites have demonstrated the potential to act as natural anthelmintics, making them attractive options for developing novel drugs. Firstly, an experiment was done to test the effectiveness of Foeniculum vulgare seed extract against Gastrothylax crumenifer. Subsequently, we employed a meta-analysis approach to identify plant species and compounds with the most promising anthelmintic activities. The methodology will involve a comprehensive search of various databases to identify relevant research articles on the anthelmintic activity of medicinal plants. The study found that Foeniculum vulgare seed extract was effective against Gastrothylax crumenifer. The study also identified the most active and promising medicinal plants that warrant further investigation for their potential to eradicate parasites. Furthermore, a meta-analysis revealed anthelmintic activity in 34 plants, with the Musaceae, Solanaceae, and Asteraceae families receiving the most extensive research. The findings have implications for developing cost-effective and safe anthelmintic treatments for animals.

Comprehensive approach to in silico identification and in vitro validation of anti-filarial hit molecules targeting the dimer interface of thioredoxin peroxidase 1 in Wuchereria bancrofti: a progress in anti-filariasis drug development.

Lymphatic filariasis (LF) remains a significant health challenge for populations in developing countries. LF is a parasitic disease transmitted by mosquitoes, mainly caused by the filarial nematode, Wuchereria bancrofti, prevalent in tropical and subtropical regions. Since the present drugs develop complications, including adverse side effects, lack of specificity, and development of drug resistance, the present study focused on developing the potential anti-filariasis drugs targeting crucial proteins for the nematode life cycle. We have identified the therapeutic compounds by targeting the enzyme thioredoxin peroxidase 1 (WbTPx1), which facilitates the conversion of hydrogen peroxide into water, an essential mechanism by which the nematode survives against oxidative stress in the host. This approach might resolve treatment efficacy and activity difficulties at various stages of filarial parasitic worms. We modeled the structure of WbTPx1 and employed the structure-based virtual screening approach, focusing on the dimer interface region of the protein. ADMET prediction profiles of the non-toxic, top-ranked hits with higher docking scores demonstrate higher affinity to the nematode protein than its human homolog. The molecular dynamic simulation studies show WbTPx1-hit complexes' stability and the intactness of hits in the binding site. Further, in vitro validation of identified hits using Setaria digitata, a cattle nematode, showed better IC50 and higher inhibition than the standard drug ivermectin, indicating the potential to inhibit enzyme activity and the development of drug candidates for controlling LF.

Diabetes Driven Oncogenesis and Anticancer Potential of Repurposed Antidiabetic Drug: A Systemic Review.

Diabetes and cancer are two prevalent disorders, pose significant public health challenges and contribute substantially to global mortality rates, with solely 10 million reported cancer-related deaths in 2020. This review explores the pathological association between diabetes and diverse cancer progressions, examining molecular mechanisms and potential therapeutic intersections. From altered metabolic landscapes to dysregulated signaling pathways, the intricate links are delineated, offering a comprehensive understanding of diabetes as a modulator of tumorigenesis. Cancer cells develop drug resistance through mechanisms like enhanced drug efflux, genetic mutations, and altered drug metabolism, allowing them to survive despite chemotherapeutic agent. Glucose emerges as a pivotal player in diabetes progression, and serving as a crucial energy source for cancer cells, supporting their biosynthetic needs and adaptation to diverse microenvironments. Glycation, a non-enzymatic process that produces advanced glycation end products (AGEs), has been linked to the etiology of cancer and has been shown in a number of tumor forms, such as leiomyosarcomas, adenocarcinomas, and squamous cell carcinomas. Furthermore, in aggressive and metastatic breast cancer, the receptor for AGEs (RAGE) is increased, which may increase the malignancy of the tumor. Reprogramming glucose metabolism manifests as hallmark cancer features, including accelerated cell proliferation, angiogenesis, metastasis, and evasion of apoptosis. This manuscript encapsulates the dual narrative of diabetes as a driver of cancer progression and the potential of repurposed antidiabetic drugs as formidable countermeasures. The amalgamation of mechanistic understanding and clinical trial outcomes establishes a robust foundation for further translational research and therapeutic advancements in the dynamic intersection of diabetes and cancer.

RSL3 enhances ROS-mediated cell apoptosis of myelodysplastic syndrome cells through MYB/Bcl-2 signaling pathway

Myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies and seriously threaten people’s health. Current therapies include bone marrow transplantation and several hypomethylating agents. However, many elderly patients cannot benefit from bone marrow transplantation and many patients develop drug resistance to hypomethylating agents, making it urgent to explore novel therapy. RSL3 can effectively induce ferroptosis in various tumors and combination of RSL3 and hypomethylating agents is promising to treat many tumors. However, its effect in MDS was unknown. In this study, we found that RSL3 inhibited MDS cell proliferation through inducing ROS-dependent apoptosis. RSL3 inhibited Bcl-2 expression and increased caspase 3 and PARP cleavage. RNA-seq analysis revealed that MYB may be a potential target of RSL3. Rescue experiments showed that overexpression of MYB can rescue MDS cell proliferation inhibition caused by RSL3. Cellular thermal shift assay showed that RSL3 binds to MYB to exert its function. Furthermore, RSL3 inhibited tumor growth and decreased MYB and Bcl-2 expression in vivo. More importantly, RSL3 decreased the viability of bone marrow mononuclear cells (BMMCs) isolated from MDS patients, and RSL3 had a synergistic effect with DAC in MDS cells. Our studies have uncovered RSL3 as a promising compound and MYB/Bcl-2 signaling pathway as a potential target for MDS treatment.

HIV-1 infection kinetics, drug resistance, and long-term safety of pre-exposure prophylaxis with emtricitabine plus tenofovir alafenamide (DISCOVER): week 144 open-label extension of a randomised, controlled, phase 3 trial

Data characterising the long-term use and safety of emtricitabine plus tenofovir disoproxil fumarate as daily oral pre-exposure prophylaxis (PrEP) are scarce and there are uncertainties regarding the value of routine HIV-1 RNA testing during oral PrEP follow-up. The DISCOVER trial was a randomised, controlled, phase 3 trial in which cisgender men and transgender women aged 18 years and older with a high likelihood of acquiring HIV were recruited from 94 clinics in Europe and North America and randomly assigned to receive either emtricitabine plus tenofovir disoproxil fumarate (200/25 mg) tablets daily, with matched placebo tablets, or emtricitabine plus tenofovir alafenamide (200/300 mg) tablets daily, with matched placebo tablets, for at least 96 weeks. After completion of the trial, participants were offered enrolment in this 48-week open-label extension study of emtricitabine plus tenofovir alafenamide. In participants diagnosed with HIV during the randomised and open-label phases of the study, we characterised HIV-1 test results and measured HIV-1 RNA viral load retrospectively when available. Adherence based on tenofovir diphosphate concentrations in dried blood spots and genotypic resistance were assessed in participants diagnosed with HIV. Safety assessments included adverse events, laboratory parameters, and, in a subset of participants, bone mineral density. HIV-1 incidence in participants initially randomly assigned to receive emtricitabine plus tenofovir alafenamide was estimated using a Poisson distribution. Changes from baseline in safety endpoints were described in participants assigned to received emtricitabine plus tenofovir alafenamide and in those who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase. This trial is registered with ClinicalTrials.gov, NCT02842086, and is ongoing. Between Sept 13, 2016, and June 30, 2017, 5399 participants were enrolled and randomly assigned in DISCOVER. 2699 were assigned to receive emtricitabine plus tenofovir disoproxil fumarate and 2700 were assigned to receive emtricitabine plus tenofovir alafenamide, of whom 2693 and 2694, respectively, received at least one dose of study drug. 2115 (79%) assigned to emtricitabine plus tenofovir disoproxil fumarate switched to emtricitabine plus tenofovir alafenamide in the open-label phase, and 2070 (77%) continued with emtricitabine plus tenofovir alafenamide in the open-label phase. As of data cutoff (Dec 10, 2020), after 15 817 person-years of follow-up, 27 new HIV-1 diagnoses were observed across the total study period, with three occurring during the open-label phase. In participants who were initially assigned to emtricitabine plus tenofovir alafenamide, the incidence was 0·13 per 100 person-years (95% CI 0·061-0·23; ten of 2670). Stored plasma samples were available for 23 of 27 participants, including 22 with incident infection. In four (17%) of 23 participants, retrospective testing detected HIV-1 RNA before serological HIV-1 test positivity; one was a suspected baseline infection. Of the three incident cases, all three were non-adherent to PrEP and none developed drug resistance. Among participants taking emtricitabine plus tenofovir alafenamide for up to 144 weeks, markers of glomerular filtration and proximal renal tubule dysfunction (β2-microglobulin to creatinine ratio and retinol-binding protein to creatinine ratio) improved or remained stable at 144 weeks compared with baseline, bone mineral density in hip and lumbar spine increased or remained stable from baseline to week 144 (n=191), cholesterol and glucose concentrations remained stable, and median bodyweight increased by less than 1 kg per year. In participants who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase (2115 [79%] of 2693), markers of glomerular filtration and proximal renal tubule dysfunction improved or remained stable, bone mineral density increased, cholesterol concentrations increased, glucose concentrations were similar, and median bodyweight increased more compared with those who remained on emtricitabine and tenofovir alafenamide. Routine HIV-1 RNA testing for follow-up of individuals on daily oral PrEP provides modest additional clinical benefit. Long-term use of emtricitabine and tenofovir alafenamide as daily oral PrEP is safe and well tolerated and can be an especially appropriate choice for people with bone or renal morbidities. Gilead Sciences.

To explore the putative molecular targets of Diabetic Nephropathy and their inhibition utilizing potential phytocompounds.

This review critically addresses the putative molecular targets of Diabetic Nephropathy (DN) and screens effective phytocompounds that can be therapeutically beneficial, and highlights their mechanistic modalities of action. DN has become one of the most prevalent complications of clinical hyperglycemia, with individual-specific variations in the disease spectrum that leads to fatal consequences. Diverse etiologies involving oxidative and nitrosative stress, activation of polyol pathway, inflammasome formation, Extracellular Matrix (ECM) modifications, fibrosis, and change in dynamics of podocyte functional and mesangial cell proliferation adds up to the clinical complexity of DN. Current synthetic therapeutics lacks target-specific approach, and is associated with the development of inevitable residual toxicity and drug resistance. Phytocompounds provides a vast diversity of novel compounds that can become an alternative therapeutic approach to combat the DN. Relevant publications were searched and screened from research databases like GOOGLE SCHOLAR, PUBMED and SCISEARCH. Out of 4895 publications, the most relevant publications were selected and included in this article. This study critically reviews over 60 most promising phytochemical and provides with their molecular targets, that can be of pharmacological significance in context to current treatment and concomitant research in DN. This review highlights those most promising phytocompounds that have the potential of becoming new safer naturally-sourced therapeutic candidates and demands further attention at clinical level.

Brain-targeting biomimetic disguised manganese dioxide nanoparticles via hybridization of tumor cell membrane and bacteria vesicles for synergistic chemotherapy/chemodynamic therapy of glioma

Glioma is a prevalent brain malignancy associated with poor prognosis. Although chemotherapy serves as the primary treatment for brain tumors, its effectiveness is hindered by the limited ability of drugs to traverse the blood–brain barrier (BBB) and the development of drug resistance linked to tumor hypoxia. Herein, we report the creation of hybrid camouflaged multifunctional nanovesicles comprising C6 cell membranes (mT) and bacterial outer membrane vesicles (OMVs) and co-loaded with manganese dioxide nanoparticles (MnO2 NPs) and doxorubicin (DOX) to synergistically enhance the chemotherapy/chemodynamic therapy (CDT) of glioma. Owing to OMV-mediated BBB penetration and mT-inherited tumor-homing properties, MnO2-DOX@mT/OMVs can penetrate the BBB and enhance the tumor cell-specific uptake of DOX via “proton sponge effect”-mediated lysosomal escape. This enhances the apoptotic effect induced by DOX and minimizing DOX-associated cardiotoxicity by facilitating the accumulation of DOX at the tumor site. Furthermore, the MnO2 NPs in MnO2-DOX@mT/OMVs can generate potent CDT by accelerating the Fenton-like reaction with DOX-generated H2O2 and achieving glutathione (GSH)-depletion-induced glutathione peroxidase 4 (GPX4) inactivation. These results showed that MnO2-DOX@mT/OMVs, designed for brain tumor targeting, significantly inhibited tumor growth and exhibited favorable biological safety. This innovative approach offers the augmentation of anticancer treatment efficacy via a potential combination of chemotherapy and CDT.

Survival outcomes and prognostic factors of advanced gastrointestinal stromal tumors: in the era of multiple tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) have shown great efficacy in the treatment of advanced gastrointestinal stromal tumors (GISTs), significantly prolonging the survival of patients. In the era of imatinib, a few studies reported some prognostic factors for patients with advanced GISTs, such as age, sex, performance status, diameter of the largest lesions, KIT exon mutations, and some hematological examination results. However, with the advent of more TKIs, the prognostic factors for patients with advanced GISTs have not been fully understood in the era of multiple TKIs. In this study, we aimed to identify independent prognostic factors associated with the survival of patients diagnosed with advanced GISTs. Data on clinicopathologic characteristics, treatment approaches, and survival were retrospectively collected for patients with primary unresectable or recurrent GISTs treated from January 2010 to July 2023 at the First Affiliated Hospital of Chongqing Medical University, China. Univariable and multivariable Cox proportional hazards regression models were used to identify independent prognostic factors of survival. A total of 194 patients were included in the analysis. The median follow-up duration was 59.9 months (range, 2.7-141.7 months). The median overall survival (mOS) in this cohort was 76.5 months (95% confidence interval, 63.4 to 89.6 months). All patients received TKI therapy during the follow-up period, and 56.2% received two or more types of TKIs. In multivariable Cox analysis, younger age, a single lesion at enrollment, no previous use of TKIs, smaller tumor burden, good Eastern Cooperative Oncology Group performance status (ECOG PS ≤1), and lesions limited to the liver were independent prognostic factors for better survival. We found that a single lesion at enrollment, no previous use of TKIs, a smaller tumor burden, and lesions limited to the liver were associated with better survival. Drug resistance is a severe challenge for advanced GISTs, and several factors mentioned above may be correlated with the development of drug resistance, leading to the poor survival of patients.