High Drug Resistance Research Articles

Distribution, Drug Resistance, and Risk Factors of Infection in Liver Transplant Recipients With Liver Failure.

The aim of this study was to explore strategies for postoperative infection prevention and treatment, and how they might help to improve the prognosis in liver transplant recipients with liver failure. We retrospectively investigated 98 recipients with liver failure in the Surgical Intensive Care Unit of The First Affiliated Hospital of Xi'an Jiaotong University from January 2019 to December 2023, and the pathogens distribution, drug resistance, and risk factors of infection after liver transplantation were analyzed. The incidence of infection was 48.0%, with common infection sites including the respiratory tract, abdominal cavity, biliary tract, and bloodstream. A total of 145 pathogens were isolated, 110 (75.9%) of which were Gram-negative bacteria, 30 (20.7%) were Gram-positive bacteria, and 5 (3.4%) were fungi. The most common pathogenic bacteria were Klebsiella pneumoniae, Acinetobacter baumannii, Enterococcus faecalis, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. Drug sensitivity data showed that Klebsiella pneumoniae showed a high resistance rate (over 70%) to all tested antibiotics except for tigecycline, colistin, and ceftazidime avibactam. Acinetobacter baumannii was highly sensitive to colistin and tigecycline, with a sensitivity of over 50% to minocycline and aminoglycosides, and a resistance rate of over 70% to other tested antibiotics. No Gram-positive strain was resistant to tigecycline, linezolid, vancomycin, and teicoplanin. Risk factor analysis suggested that preoperative infection within 2 months was an independent risk factor for infection after liver transplantation in recipients with liver failure. The incidence of postoperative infection in liver failure recipients was high, and the respiratory tract and abdomen were the most common sites. The pathogenic bacteria were mainly Gram-negative bacteria, which showed an extensive and high drug resistance. Patients with liver failure who underwent liver transplantation with a preoperative infection within 2 months of the transplantation were more likely to develop an infection after surgery.

Clinical and Mycobacterium tuberculosis strain characteristics of tuberculosis patients with diabetes mellitus in Changping District, Beijing, China

BackgroundDiabetes mellitus (DM) is a major risk factor for tuberculosis (TB), However, limited research exists on their clinical and strain characteristics. This study aims to investigate the correlation between these factors in TB-DM patients in Changping District. MethodsWhole genome sequencing (WGS) and drug susceptibility tests (DST) were performed on culture-positive strains. Spearman correlation analysis was used to examine risk factors and the correlation between lineage, cavities, and hemoptysis in the TB-DM population. The specificity, sensitivity, and confidence intervals for predicting phenotypic drug resistance based on genotypic resistance were calculated.ResultsAmong the 3924 TB patients, 292 had DM, showing a doubling in the proportion of TB patients with DM over seven years. Among the 144 etiologically positive TB-DM cases treated at the Changping Institute for Tuberculosis Prevention and Treatment, 75% (108/144) of the patients exhibited tuberculosis lesions that formed cavities and 12.5% (18/144) with hemoptysis. A statistically significant difference in cavity formation across different age groups was observed (r = -0.198, P < 0.05). Out of the 144 etiologically positive patients, WGS successfully revived 73 MTB strains, with Lineage 2 being predominant. No statistical difference was found between lineages and the presence of cavities or hemoptysis. The DST results showed the highest resistance rates to isoniazid and streptomycin, both at 8.2% (6/73), with approximately one-quarter of the strains resistant to at least one anti-TB drug, and about half (47.1%, 8/17) resistant to first-line drugs. The study demonstrated good specificity but suboptimal sensitivity in predicting phenotypic drug resistance based on genotypic resistance.ConclusionsThe rising incidence of diabetes in tuberculosis patients within Changping District has intensified the spread of TB, with these patients demonstrating severe illness and high drug resistance. This study aims to develop targeted prevention and management strategies, offering crucial guidance for treating co-infections of TB and DM and controlling disease spread.

Advances in Immunotherapy and Targeted Therapy of Malignant Melanoma.

Malignant melanoma (MM) is a malignant tumor, resulting from mutations in melanocytes of the skin and mucous membranes. Its mortality rate accounts for 90% of all dermatologic tumor mortality. Traditional treatments such as surgery, chemotherapy, and radiotherapy are unable to achieve the expected results due to MM's low sensitivity, high drug resistance, and toxic side effects. As treatment advances, immunotherapy and targeted therapy have made significant breakthroughs in the treatment of MM and have demonstrated promising application prospects. However, the heterogeneity of tumor immune response causes more than half of patients to not benefit from clinical immunotherapy and targeted therapy, which delays the patient's condition and causes them to suffer adverse immune events' side effects. The combination of immunotherapy and targeted therapy can help improve therapeutic effects, delay drug resistance, and mitigate adverse effects. This review provides a comprehensive overview of the current development status and research progress of immune checkpoints, targeted genes, and their inhibitors, with a view to providing a reference for the clinical treatment of MM.

Targeting T-Cell Activation for Malaria Immunotherapy: Scoping Review.

Malaria remains a critical global health issue due to high mortality rates, drug resistance, and low treatment efficacy. The genetic variability of Plasmodium proteins complicates the development of long-lasting immunity, as it impedes the human immune system's ability to sustain effective responses. T cells play a crucial role in combating malaria, but the parasite's complex life cycle-spanning liver and blood stages-presents significant challenges in effectively activating and targeting these cells. Immunotherapy, which enhances the immune response and promotes durable T cell activity, offers a promising avenue for more effective and lasting malaria treatments. This review systematically analyzed 63 studies published in the last decade, focusing on the role of T cells in malaria. Among the studies, 87.2% targeted T cells as immunotherapy candidates, with CD4+ and CD8+ T cells each accounting for 47.6% of the studies. γδ T cells were the focus in 7.9% of cases, while 12.7% explored non-T cell contributions to enhancing T cell-mediated responses. The findings underscore the potential of T cells, particularly CD8+ T cells, in liver-stage defense and advocate for the exploration of advanced vaccine platforms and novel therapies, such as mRNA-based vectors and monoclonal antibodies.

Safety and efficacy of long-acting cabotegravir/rilpivirine versus standard oral antiretroviral therapy: a systematic review and meta-analysis.

In 2023, there were 39.9 million people living with HIV (PLWH) worldwide and 630 000 deaths related to HIV. New strategies are needed, and long-acting antiretrovirals (LAAs) are now widely considered to have great potential to help end the HIV epidemic. This systematic review and meta-analysis compare the safety and efficacy of LAA versus standard oral treatment (SOT) for HIV. PubMed and Embase databases, supplemented by ClinicalTrials.gov and grey literature, were searched. Randomized controlled trials (RCTs) reporting efficacy and/or safety of LAA versus SOT for PLWH until June 2024 were included. Efficacy (HIV RNA < 50 copies/mL) and HIV RNA ≥ 50 copies/mL, adverse events (AEs), treatment discontinuation, CD4 count, metabolic parameters and drug resistance were assessed. Prespecified subgroup analyses were conducted. The risk of bias was assessed with Cochrane RoB 2.0. Certainty of evidence was assessed using GRADE. Six RCTs were eligible for inclusion, involving 2829 participants. LAA was non-inferior to SOT in suppressing HIV RNA < 50 copies/mL [Risk Difference (RD), -0.00; 95% CI, -0.03-0.02; P = 0.83; I2 = 51%; high quality of evidence (QoE)]. LAA was associated with higher drug resistance (percentage pooled estimate, 57%; 95% CI, 33%-78% versus 9%; 95% CI, 2%-30%; moderate QoE) and risk of grade 1-4 AEs than SOT [Risk Ratio (RR), 1.22; 95% CI, 1.12-1.33; P < 0.001; I2 = 62%; moderate QoE]. LAA has non-inferior efficacy compared to SOT. However, participants receiving LAA were at a higher risk of developing drug resistance, cross-resistance and AEs.

A facile combined therapy of chemotherapeutic agent and microRNA for hepatocellular carcinoma using non-cationic nanogel.

High drug resistance remains a challenge for chemotherapy against hepatocellular carcinoma (HCC). Combining chemotherapeutic agents with microRNA (miRNA), which simultaneously regulates multiple pathways, offers a promising approach to improve therapeutic efficacy against HCC. Although cationic amphiphilic copolymers have been used to co-deliver these agents, their effectiveness is often limited by low co-encapsulation efficiency and inherent cationic toxicity. In this study, we developed a facile approach to co-deliver doxorubicin (DOX) and miRNA-26a (miR-26a) using a non-cationic nanogel. The incorporation of an amphiphilic monomer and a lysosomal enzyme-sensitive crosslinker endows the nanomedicine with several advantages, including high co-encapsulation efficiency, lysosomal escape, and minimal toxicity. miR-26a significantly increased the sensitivity of HCC to DOX by 3.35-fold through targeting multiple pathways, and promoted DOX penetration within tumor tissue through reducing type I collagen content, thereby showing significant synergistic anticancer effects. This study provides a facile and biosafe nanoplatform for the efficient co-delivery of DOX and miRNA with synergistic drug effect.

Stemness regulation in prostate cancer: prostate cancer stem cells and targeted therapy.

Increasing evidence indicates that cancer stem cells (CSCs) and cancer stem-like cells form a special subpopulation of cells that are ubiquitous in tumors. These cells exhibit similar characteristics to those of normal stem cells in tissues; moreover, they are capable of self-renewal and differentiation, as well as high tumorigenicity and drug resistance. In prostate cancer (PCa), it is difficult to kill these cells using androgen signaling inhibitors and chemotherapy drugs. Consequently, the residual prostate cancer stem cells (PCSCs) mediate tumor recurrence and progression. This review aims to provide a comprehensive and up-to-date overview of PCSCs, with a particular emphasis on potential therapeutic strategies targeting these cells. After searching in PubMed and Embase databases using 'prostate cancer' and 'cancer stem cells' as keywords, studies related were compiled and examined. In this review, we detail the origin and characteristics of PCSCs, introduce the regulatory pathways closely related to CSC survival and stemness maintenance, and discuss the link between epithelial-mesenchymal transition, tumor microenvironment and tumor stemness. Furthermore, we introduce the currently available therapeutic strategies targeting CSCs, including signaling pathway inhibitors, anti-apoptotic protein inhibitors, microRNAs, nanomedicine, and immunotherapy. Lastly, we summarize the limitations of current CSC research and mention future research directions. A deeper understanding of the regulatory network and molecular markers of PCSCs could facilitate the development of novel therapeutic strategies targeting these cells. Previous preclinical studies have demonstrated the potential of this treatment approach. In the future, this may offer alternative treatment options for PCa patients.

Copper and Antimicrobial Residues in the Liver and Kidney-Antimicrobial Resistance and Cu Tolerance Unrelated in Escherichia coli from Piglets' Faeces.

Antimicrobials, widely used in livestock, have induced the emergence of antimicrobial-resistant bacteria, prompting farmers to explore alternatives like copper. This study aims to determine antimicrobial residues and Cu concentrations in the liver and kidney of piglets and to investigate the correlation between Cu and antimicrobial use and the resistance to Cu and antimicrobials of Escherichia coli isolated from piglets' faeces. Antimicrobial residues were quantified by UHPLC-ToF-MS; Cu was quantified using FAAS; microbiological methods were used for E. coli isolation, CuSO4 minimal inhibitory concentration (MIC), and antimicrobial susceptibility; and to detect genes, Real-Time PCR was used. Cu concentrations and antimicrobial residues in piglet livers and kidneys revealed no significant differences. Antimicrobial residues were detected in a significant number of livers and kidneys. While Cu concentrations in the liver were within adequate ranges, those in the kidney exceeded the recommended levels. E. coli isolates from piglet faeces exhibited high antimicrobial drug resistance (AMR), with no clear link to Cu exposure. The genes copA, pcoA, and pcoD, associated with Cu tolerance, were predominantly found in isolates with a CuSO4 MIC of 8 mM. Cu was not used excessively, suggesting that Cu did not replace antimicrobials. E. coli was mostly resistant to antimicrobials and it was not possible to demonstrate that Cu was the trigger for this resistance. There was no relationship between Cu tolerance and AMR in E. coli isolates. This study highlights the need for further research on the complex interplay between metals, antimicrobials, and bacterial resistance in livestock, impacting 'One Health'.

Resensitizing β-Lactams by Reprogramming Purine Metabolism in Small Colony Variant for Osteomyelitis Treatment.

Small colony variant (SCV) is strongly linked to antibiotic resistance and the persistence of osteomyelitis. However, the intrinsic phenotypic instability of SCV has hindered a thorough investigation of its pathogenic mechanisms. In this study, phenotypically stable SCV strains are successfully recovered from clinical specimens, characterized by elevated drug resistance and reduced immunogenicity. Multi-omics analysis revealed that the acquired high drug resistance is associated with altered flux in the purine metabolism pathway, attributable to mutations in the hypoxanthine phosphoribosyltransferase (hpt) gene. Furthermore, this study innovatively discovered that lonidamine, an inhibitor of cellular energy metabolism, can effectively mitigate SCV resistance to β-lactam antibiotics, thereby facilitating its eradication. The underlying mechanism involves the reprogramming of purine metabolism. Therefore, a co-delivery system for lonidamine and oxacillin is constructed with amino-modified dendritic mesoporous silica as a carrier, which showed high efficacy and safety in combating SCV both in vitro and in vivo experiments. Overall, this study elucidated the pathogenic mechanisms of a class of clinically isolated SCV isolates with hpt mutations and provided a paradigm for treating SCV-associated osteomyelitis by reprogramming purine metabolism.

Multi-Locus Sequence Typing-Based Genetic Analysis, Antifungal Resistance, and Clinical Prognosis of Cryptococcus neoformans Infections in HIV-Infected Patients in Northern China.

This study aimed to investigate the molecular epidemiological characteristics and drug sensitivity of Cryptococcus from HIV-infected patients and their relationship with patients' prognosis. Seventy-six strains were collected and identified to the species level by matrix-assisted laser desorption ionization-time of flight mass spectrometry, confirmed by internal transcribed spacer sequencing. Multi-locus sequence typing was used for the typing of Cryptococcus, and its antifungal susceptibility was tested using FUNGUS 3. The clinical outcomes of the patients were reviewed at 3-, 6-, 9-, and 12-month follow-ups. All strains were Cryptococcus neoformans var. grubii classified into seven sequence types (STs) dominated by ST5, ST31, and a new ST702 strain. The 6- and 9-month survival rates were highest for patients infected with ST31, ST32, and ST174. The antifungal resistant rates were 13.2%, 2.6%, and 1.4% for fluconazole, amphotericin B, and 5-fluorocytosine. Except itraconazole, the minimum inhibitory concentration (MIC) values and wild type (WT)/non-wild type (NWT) of Cryptococcus for antifungal drugs were not related to the clinical prognosis of HIV-infected patients with cryptococcal infection. ST5 was the main ST type, and the new ST702 type was found in a patient who died in a short period of time. Cryptococcus neoformans var. grubii had a relatively high antifungal drug resistance rate to fluconazole. The WT strain accounted for the highest proportions for 5-fluorocytosine, amphotericin B, fluconazole, voriconazole, and itraconazole. The MIC values of Cryptococcus for first-line antifungal drugs showed no relationship with clinical prognosis, implying that MIC values cannot be used to predict the clinical outcome of these patients.

Genomic epidemiology and genetic characteristics of clinical Campylobacter species cocirculating in West Bengal, India, 2019, using whole genome analysis.

Campylobacter species are the most common pathogens responsible for foodborne gastroenteritis worldwide. India is a region with frequent diarrheal infections and a high level of Campylobacter infection incidence, but the detailed genomic information is limited. This study aimed to characterize 112 isolates of Campylobacter from diarrhea patients at two hospitals in Kolkata, West Bengal, by whole genome analysis. The Campylobacter isolates consisted of 90 C. jejuni, 20 C. coli, and 2 C. lari isolates. Multilocus sequence typing analysis revealed that the largest sequence type (ST) populations were ST-2131 in C. jejuni and ST-830 in C. coli and seven novel STs were found in C. jejuni and one in C. coli. Notably, ST-2131, which is rarely seen elsewhere, was positive for a sialylated LOS-related gene (wlaN +neuA + cstIII) associated with Guillain-Barré syndrome. Antibiotic resistance factors predicted from the genome sequence included blaOXA variants (58.9%), tet(O) (54.5%), tet(W) (0.9%), ant(6)-Ia (0.9%), mutation in GyrA (T86I, T86I+D90N, T86I+P104S, T86I+D90N+P104S) (79.5%), and mutation in 23S rRNA (A2075G) (12.5%). In addition to the high drug resistance of Campylobacter in Kolkata, Campylobacter pathogens were circulating that may be associated with Guillain-Barré syndrome. This study indicates the importance of genomic analysis in the surveillance of pathogens, which provides genomic information on genetic diversity, virulence mechanisms, and determinants of antimicrobial resistance.

Anticancer potential of osthole: targeting gynecological tumors and breast cancer.

Gynecological tumors, such as ovarian, endometrial, and cervical cancers, alongside breast cancer, represent significant malignancies that pose serious threats to women's health worldwide. Standard treatments, including surgery, chemotherapy, radiotherapy, and targeted therapies, are commonly utilized in clinical practice. However, challenges such as high recurrence rates, drug resistance, and adverse side effects underscore the urgent need for more effective therapeutic options. Osthole, a natural coumarin compound derived from Chinese herbal medicine, has demonstrated remarkable antitumor activity against various cancers. Emerging evidence indicates that osthole can inhibit the proliferation, invasion, and metastasis of gynecological and breast cancer cells through various mechanisms, including inducing apoptosis and autophagy, regulating the tumor microenvironment, inhibiting tumor angiogenesis, and enhancing the sensitivity of cancer cells to chemotherapy and radiotherapy. This review highlights the recent advancements in osthole research within the context of gynecological and breast cancers, focusing on its molecular mechanisms, and offers a theoretical foundation for its potential development as an anticancer agent.

Cytokines Levels and Anti-tuberculosis Drug Resistance among HIV Seropositive Patients in Ibadan, Southwest, Nigeria

Susceptibility to TB disease rises on mutations in cytokine receptors which ultimately lead to defective signaling and alter the immune surveillance and bacterial killing. Therefore, this study was undertaken to investigate the association between cytokines and anti-TB drug resistances. A total of 217 people living with human immunodeficiency virus at University College Hospital, Ibadan were recruited. Venous blood and sputum samples were collected. Sputum samples were cultured for Mycobacterium tuberculosis complex and characterized using standard methods. Anti-TB drug resistance was detected using phenotypic and genotypic methods. Cytokines levels (IL-10 and IFN-Y) were estimated using ELISA method. Association between cytokines and anti-TB drug resistance was determined using linear regression analysis. There were 105(48.4%) males and 112(51.6%) females with a mean age of 42.95 ± 8.286 years and a range of 28-65 years. The prevalence of TB among PLHIV was found to be 19.1% with male having higher rate than female (P&lt;0.05), and highest rate among aged ≥40. There was no significant association between cytokines (IL-10 and IFN-y) and sex of the subjects (P&gt;0.05). However, females had higher IFN-y level of 231.06±61.81 IU/ml when compared to 227.53±57.92 IU/ml obtained from males. The prevalence of multi-drug resistance TB was 11.9% with Rifampicin resistance having the highest rate of 5.5%. There was no significant association between cytokines (IL-10 and IFN-y) and sex, but age group &gt;40 years had higher IL-10 and IFN-y level of 226.53±52.39 IU/ml and 232.41±66.63 IU/ml respectively. There was an association between high cytokines levels and anti-TB drug resistance (P&lt;0.05). Highest cytokines levels; IL-10 (401.00±7.07 IU/ml) and IFN-Y (401.00±7.07 IU/ml) were recorded in Levofloxacin resistance. There was an association between high cytokines levels and genotypic anti- TB drug resistance (P&lt;0.05) with highest cytokines levels; IL-10 (400.12±12.37 IU/ml) and IFN-Y (472.87±31.93 IU/ml) recorded in Rifampicin resistance. This entire study revealed that there is high prevalence of MDR-TB among PLHIV, with Rifampicin monoresistance having the highest resistance rate among the drugs tested, and pro and inflammatory cytokines (IL-10 and IFN-y) play significant role in the development of Multi Drug Resistant-Tuberculosis among people living with HIV.

ONC206, an imipridone derivative, demonstrates anti-colorectal cancer activity against stem/progenitor cells in 3D cell cultures and in patient-derived organoids.

Colorectal cancer (CRC) remains one of the most frequently diagnosed and life-threatening malignancies worldwide. CRC's high recurrence rates and drug resistance have been correlated with a subpopulation of dormant slowly dividing cells termed CRC stem cells (CCSCs). Consequently, there is a pressing need to identify novel therapeutics that can effectively and specifically target CCSCs. Imipridones are promising structurally related anticancer molecules that showed efficacy in several solid and hematological preclinical models and phase I/II/III clinical trials. This study mainly aimed to assess the potential anticancer effects of ONC206, an imipridone derivative, on CRC three-dimensional in vitro culture systems using HCT116 and HT29 cells. Importantly, the study aimed at using CRC patient-derived organoids (PDOs) to test the potential therapeutic effect of ONC206. Two-dimensional cell proliferation, viability, migration, and invasion assays were used to assess the effects of ONC206 on two colorectal cancer cell lines, HCT116 and HT29, in vitro. Immunofluorescence imaging, flow cytometry, and western blot analysis were also performed to investigate the mechanism of action of this drug. Sphere formation assay and CRC PDOs were employed to evaluate the effect of ONC206 on CRC cells in a 3D setting and specifically its potency in targeting the CRC stem/progenitor subpopulation of cells. Our results showed that ONC206 was more potent than its parental moleculeONC201 in inhibiting the proliferation and viability of HCT116 and HT29 cells. Moreover, ONC206 significantly reduced the migration and invasion indices of CRC cells. These effects were accompanied by an increase in reactive oxygen species (ROS) production, sub-G1 phase accumulation, and apoptosis in HCT116 and HT29 cells. Furthermore, ONC206 significantly inhibited the 3D colonospheres growth and self-renewal ability of CCSCs more potently than ONC201, which was associated with a decrease in the expression of CSC-related markers. Lastly, ONC206 significantly reduced the growth of organoids derived from CRC patients. Collectively, our findings demonstrate that ONC206 is an effective anticancer molecule capable of targeting CCSCs, which may represent a novel therapeutic strategy that can overcome CRC resistance and recurrence.

Production, Characterization, and Application of Hydrophobin-Based IR780 Nanoparticles for Targeted Photothermal Cancer Therapy and Advanced Near-Infrared Imaging.

As a promising approach for breast cancer treatment, photothermal therapy (PTT) features high spatial selectivity, noninvasiveness, and minimal drug resistance. IR780 (a near-infrared fluorescent dye) serves as an effective photosensitizer in PTT cancer therapy. However, the clinical application of IR780 in PTT has been hindered by its poor water solubility and unstable photostability. In this study, a genetically engineered dual-functional fusion protein tLyP-1-MGF6 is successfully constructed and expressed, which presents a novel use of hydrophobin MGF6 for its amphiphilicity combined with the tumor-penetrating peptide tLyP-1 to create an innovative carrier for IR780. These results show this fusion protein serving as a biodegradable and biocompatible carrier, significantly improves the water solubility of IR780 when formulated into nanoparticles. These studies demonstrate that the IR780@tLyP-1-MGF6 nanoparticles significantly enhance tumor targeting and photothermal therapeutic efficacy in comparison with control in vitro and in vivo. These advancements highlight the potential of the unique combination hydrophobin-based IR780 delivery system as a multifunctional nanoplatform for integrated imaging and targeted photothermal treatment of breast cancer.

Analysis of genotype resistance and HIV-1 transmission risk in HIV-1-infected men who have sex with men in Guiyang, China.

As the social economy has developed and population mobility has increased, differences in the Human immunodeficiency virus type 1 (HIV-1) genotype distribution among men who have sex with men (MSM) have become apparent in the provinces and cities across China. The high variability and drug resistance characteristics of HIV-1 can lead to the widespread spread of resistant strains, which may also result in antiretroviral therapy failure and an increase in the mortality rate. The genotypic drug resistance characteristics and HIV-1 transmission risks among HIV-1-infected MSM in Guiyang, Guizhou Province were analyzed in the current study. The aim of the study was to provide a scientific basis for preventing the spread of HIV-1 strains among MSM and develop intervention measures. A cross-sectional study was conducted at the Guiyang Public Health Clinical Center. A total of 181 HIV-1-infected MSM who not received treatment at the center between 1 January 2020 and 31 December 2022 were selected. The HIV-1 pol region gene fragment, including the protease and reverse transcriptase regions, was amplified by nested PCR and RT-PCR. The maximum likelihood method was used to construct a phylogenetic tree for analyzing the HIV-1 genotypes in MSM. HIV-1 genotypic resistance was evaluated using the Stanford University HIV drug resistance database. A molecular transmission network of HIV was constructed and the risk of HIV-1 transmission was determined. We successfully amplified 173 pol gene sequences from blood samples obtained from 181 patients. The main subtype was CRF07_BC (60.69% [105/173]), followed by CRF01_AE (26.59% [46/173]), CRF08_BC (4.05% [7/173]), CRF55_01B (4.62% [8/173]), B (3.47% [6/173]), and C (0.58% [1/173]). The distribution of HIV-1 genotypes in MSM showed that there was a significant difference in the genotype composition of HIV-1-infected MSM according to registered residences and ages (p < .05). The CRF55_01B subtype accounted for the lowest proportion in Guiyang City and individuals >30 years of age. Multivariate logistic regression analysis of risk factors for drug resistance in HIV-1-infected MSM showed that the overall prevalence of pretreatment drug-resistant species was 12.72% (22/173), and age >30 years, CRF55_01B subtype, and CD4+ T lymphocyte count >350 cells/mm3 were risk factors for drug resistance in MSM HIV-1 strains. Among the pretreatment drug-resistant species, non-nucleoside reverse transcriptase inhibitors with ≥1 drug resistant-species accounted for 9.25% (16/173), followed by protease inhibitors at 4.05% (7/173) and nucleoside reverse transcriptase inhibitors at 1.73% (3/173). Non-nucleoside reverse transcriptase inhibitors resistant to the CRF07_BC and CRF01_AE genotypes were predominant. The CRF55_01B genotype was shown to be most likely to carry the V179E mutation. The molecular network included CRF07_BC and B genotypes. The results of multi-factor logistic regression analysis on the factors affecting the rate of joining the network showed that individuals >30 years of age were less likely to join the network compared to those individuals <30 years of age. The distribution of HIV-1 genotypes among MSM in Guiyang is diverse and complex. The main genotypes were shown to be CRF07_BC and CRF01_AE. The drug resistance mutation rate is high and pretreatment drug-resistant species is at a moderate level of prevalence, with NNRTIs being the most common site for drug resistance mutations. The CRF07_BC subtype and patients <30 years of age were identified as the key intervention targets in Guiyang based on the molecular transmission network. Patients should routinely undergo drug resistance testing before starting antiretroviral therapy to avoid virologic treatment failure and prevent the spread of HIV-1-resistant strains in MSM.

Self-assembled aldehyde dehydrogenase-activatable nano-prodrug for cancer stem cell-enriched tumor detection and treatment

Cancer stem cells, characterized by high tumorigenicity and drug-resistance, are often responsible for tumor progression and metastasis. Aldehyde dehydrogenases, often overexpressed in cancer stem cells enriched tumors, present a potential target for specific anti-cancer stem cells treatment. In this study, we report a self-assembled nano-prodrug composed of aldehyde dehydrogenases activatable photosensitizer and disulfide-linked all-trans retinoic acid for diagnosis and targeted treatment of cancer stem cells enriched tumors. The disulfide-linked all-trans retinoic acid can load with photosensitizer and self-assemble into a stable nano-prodrug, which can be disassembled into all-trans retinoic acid and photosensitizer in cancer stem cells by high level of glutathione. As for the released photosensitizer, overexpressed aldehyde dehydrogenase catalyzes the oxidation of aldehydes to carboxyl under cancer stem cells enriched microenvironment, activating the generation of reactive oxygen species and fluorescence emission. This generation of reactive oxygen species leads to direct killing of cancer stem cells and is accompanied by a noticeable fluorescence enhancement for real-time monitoring of the cancer stem cells enriched microenvironment. Moreover, the released all-trans retinoic acid, as a differentiation agent, reduce the cancer stem cells stemness and improve the cancer stem cells enriched microenvironment, offering a synergistic effect for enhanced anti-cancer stem cells treatment of photosensitizer in inhibition of in vivo tumor growth and metastasis.

Emphysematous pyelonephritis caused by Raoultella ornithinolytica: a case report

BackgroundEmphysematous pyelonephritis is a rare and severe urinary tract infection that is potentially life-threatening and easily progresses to septic shock. In this report, we present a unique case of emphysematous pyelonephritis caused by Raoultella ornithinolytica.Case presentationAn 86-year-old man presented with severe back pain of 3 days’ duration. He had a history of hypertension and diabetes for more than 20 years, and his infection indicators and serum creatinine were elevated. Abdominal computed tomography revealed an abnormal gas shadow around his right kidney and the anterior edge of his right psoas muscle. Consequently, he was initially diagnosed with emphysematous pyelonephritis. There was no evidence of nephrolithiasis or other anatomical or structural abnormalities that could have precipitated this focal renal infection. Both blood and drainage fluid cultures revealed R. ornithinolytica. After early anti-infection treatment, percutaneous drainage and moderate control of blood glucose, the patient gradually recovered.ConclusionsEmphysematous pyelonephritis caused by R. ornithinolytica is rare but has a high drug resistance rate potentially and may cause severe infections. Early diagnosis, prompt use of antibiotics that are sensitive to the organism, and decompression drainage could be the key to treatment.

Assay Development for High-Throughput Drug Screening Against Mycobacteria.

Mycobacterium abscessus (Mab) infections are challenging to treat due to high intrinsic drug resistance, comparable to multidrug-resistant tuberculosis. Treatments are extremely ineffective and based on a multi-drug regimen, resulting in low patient compliance. Consequently, the scientific community is urged to identify new and effective drugs to treat these infections. One of the strategies employed to this end is drug repurposing - the process of identifying new therapeutic opportunities for existing drugs in the market, circumventing the time required to establish pharmacokinetic and safety profiles of new drugs. With most studies on drug development against Mab relying on traditional and time-consuming methods, an assay for high-throughput drug screening was developed against mycobacteria using an in house developed double-reporter strain of Mab. Using liquid-handling robotics, automated microscopy, and analysis, alongside in house developed double reporter strains, bacterial viability can be rapidly measured using two different readouts, luminescence and fluorescence, without adding reagents or performing any extra steps. This reduces time and variability between assays, a major advantage for high-throughput screenings. The described protocol was validated by screening a library of 1280 compounds. The obtained results were corroborated by the literature, with efficient detection of active compounds. Thus, this work fulfilled the aim of supplying the field with a new tool to help fight this extremely drug-resistant bacteria.

Genetic insights into the connection between pulmonary TB and non-communicable diseases: An integrated analysis of shared genes and potential treatment targets.

Pulmonary Tuberculosis (PTB) is a significant global health issue due to its high incidence, drug resistance, contagious nature, and impact on people with compromised immune systems. As mentioned by the World Health Organization (WHO), TB is responsible for more global fatalities than any other infectious illness. On the other side, WHO also claims that noncommunicable diseases (NCDs) kill 41 million people yearly worldwide. In this regard, several studies suggest that PTB and NCDs are linked in various ways and that people with PTB are more likely to acquire NCDs. At the same time, NCDs can increase susceptibility to active TB infection. Furthermore, because of potential drug interactions and therapeutic challenges, treating individuals with both PTB and NCDs can be difficult. This study focuses on seven NCDs (lung cancer (LC), diabetes mellitus (DM), Parkinson's disease (PD), silicosis (SI), chronic kidney disease (CKD), cardiovascular disease (CVD), and rheumatoid arthritis (RA)) and rigorously presents the genetic relationship with PTB regarding shared genes and outlines possible treatment plans. BlueThis study aims to identify the drug components that can regulate abnormal gene expression in NCDs. The study will reveal hub genes, potential biomarkers, and drug components associated with hub genes through statistical measures. This will contribute to targeted therapeutic interventions. Numerous investigations, including protein-protein interaction (PPI), gene regulatory network (GRN), enrichment analysis, physical interaction, and protein-chemical interaction, have been carried out to demonstrate the genetic correlation between PTB and NCDs. During the study, nine shared genes such as TNF, IL10, NLRP3, IL18, IFNG, HMGB1, CXCL8, IL17A, and NFKB1 were discovered between TB and the above-mentioned NCDs, and five hub genes (NFKB1, TNF, CXCL8, NLRP3, and IL10) were selected based on degree values. In this study, we found that all of the hub genes are linked with the 10 drug components, and it was observed that aspirin CTD 00005447 was mostly associated with all the other hub genes. This bio-informatics study may help researchers better understand the cause of PTB and its relationship with NCDs, and eventually, this can lead to exploring effective treatment plans.