The misuse of broad-spectrum antibiotics has facilitated the emergence of carbapenem-resistant Salmonella enterica subsp. enterica (CRSE). This study aims to investigate the genomic characteristics and epidemiological patterns of two strains isolated from pediatric patients, along with 21 CRSE strains collected from humans worldwide. The antimicrobial susceptibility tests were detected by the agar microdilution method. Whole-genome sequence of the two CRSE strains was sequenced using the Illumina platform. Acquisition and analysis of WGS data were performed by the NCBI Pathogen Detection Portal, BacWGSTdb 2.0, Salmonella In Silico Typing Resource, and the Center for Genomic Epidemiology. Two S. Typhimurium isolates from children carried the carbapenemase gene blaNDM-5 and belonged to ST34. The CRSE isolates predominantly contained the carbapenem resistance gene blaOXA-48 in the United Kingdom and blaNDM in China. The virulence gene profiles of these isolates were consistent across different regions. Carbapenem-resistant S. Typhimurium and S. Kentucky were predominantly found in China and the United Kingdom, respectively. ST198 strains were prevalent in the United Kingdom, whereas all ST34 strains were identified in China. This investigation underscores the global dissemination of carbapenem-resistant Salmonella in humans, revealing variations in drug resistance, serotypes, and sequence types across different regions. Therefore, the global detection of carbapenem resistance has important guiding significance for controlling its transmission, preventing infection, and clinical treatment.

The rise of drug resistance and limitations of current antifungal treatments highlight the urgent need for innovative antifungal strategies. Here we present the development of cis-fumaramidmycin-derived analogs inhibiting the interactions of ribosome assembly factor Mrt4 with rRNA to combat fungal infections. Through antifungal screening, we identified a promising lead 20 with strong efficacy against various drug-resistant fungi, including notorious super-fungus Candida auris. A comprehensive approach combining active-and-inactive-based protein profiling (AIBPP), chemical-genetic profiling, and fluorescence polarization revealed that the antifungal activity of 20 is primarily due to selectively inhibiting essential CaMrt4-rRNA interaction by conjointly covalent engaging C96&C189 on CaMrt4 but inactive for HuMrt4-rRNA interaction, thereby disrupting fungal ribosomal assembly. Therapeutic efficacy of 20 in both Galleria mellonella larvae and murine candidiasis models validate this antifungal strategy. Collectively, our studies provide a potential and much needed therapeutic strategy to address the rapidly rising burden of drug-resistant fungal infections.

KRAS-mutant colorectal cancer (CRC) undergoes metabolic reprogramming that promotes tumor progression and drug resistance. Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment (TME), play a pivotal role in modulating these metabolic adaptations in CRC. This study applies flux sampling combined with representation learning and hierarchical clustering to a computational model of central carbon metabolism to understand how CAFs influence KRAS-mutant CRC metabolic reprogramming following targeted enzyme knockdowns. Focusing on 12 key enzymes involved in glycolysis and the pentose phosphate pathway, knockdowns were simulated under normal CRC media and CAF-conditioned media (CCM) conditions. Analysis revealed CCM induces greater metabolic heterogeneity, with knockdown models exhibiting more variable and distinct metabolic states compared to those cultured in normal CRC media, indicating CAF-derived factors diversify the metabolic responses of CRC cells to enzyme perturbations. Pathway-level flux analysis demonstrated media-specific shifts in central carbon metabolism. Predicted biomass flux showed enzyme knockdowns reduced growth across both conditions, but CCM models indicated a protective effect against perturbation. Overall, simulations illustrated CCM enhances the metabolic adaptability of KRAS-mutant CRC cells to perturbations, emphasizing the importance of including TME components in metabolic modeling and therapeutic development and suggesting that targeting tumor-CAF metabolic interactions may improve treatment strategies.

Background The purpose of this study is to explore the molecular mechanism of SIRT1 regulating chemotherapy resistance. Methods Expression level of SIRT1 in ovarian cancer cell lines SKOV3, SKOV3/DDP (cisplatin-resistant cell line) and normal ovarian epithelial cell line IOSE80 was detected. Through the intervention of β-catenin agonist BML-284, the mechanism of SIRT1 regulating glycolysis and angiogenesis through β-catenin/c-myc/PKM2 pathway was discussed. Finally, the nude mice transplanted tumor model was constructed to verify the role of SIRT1 in vivo . Results The expression of SIRT1 increased in ovarian cancer cell line, especially in cisplatin-resistant cell line SKOV3/DDP. Knocking down SIRT1 can inhibit the proliferation, invasion and migration of ovarian cancer cells, promote cell apoptosis, and reduce the drug resistance of cells to cisplatin. SIRT1 enhances the malignant biological behavior of ovarian cancer cells by promoting glycolysis and angiogenesis. SIRT1 up-regulates the expression of key glycolytic enzymes and angiogenic factors by activating β-catenin/c-myc/PKM2 pathway. In vivo experiments, knocking down SIRT1 can reduce the glycolysis level and angiogenesis ability of tumor tissue. Conclusion SIRT1 promotes glycolysis and angiogenesis of ovarian cancer cells by activating β-catenin/c-myc/PKM2 pathway, thus enhancing chemotherapy resistance. SIRT1 is expected to be a new target for ovarian cancer treatment.

Gestational trophoblastic neoplasia (GTN) represents a rare group of malignant tumors arising from trophoblastic tissue. These tumors are highly curable owing to their remarkable sensitivity to chemotherapy, yet treatment remains challenging in patients with high-risk disease, multi-drug resistance, or rare subtypes. Recent advances in immune checkpoint inhibitor (ICI) have expanded therapeutic possibilities for GTN. Some patients with recurrence or drug resistance have achieved long-term remission after treatment with programmed death receptor 1 (PD-1) and its programmed cell death ligand-1 (PD-L1) inhibitors.. Basic studies have revealed unique immunological features of GTN--including strong antigenicity, abundant immune cell infiltration, and high checkpoint expression--providing a biological rationale for immunotherapy. However, several key questions remain, including optimal treatment timing, long-term safety, fertility outcomes, and predictive biomarkers. Based on existing research findings, this review article discusses the current application status and controversies of GTN, proposes key directions for future development, and aims to provide references for clinical practice and follow-up research.

Introduction: Bortezomib (BTZ), a proteasome inhibitor, significantly improved multiple myeloma (MM) treatment; however, drug resistance remains a major challenge, limiting its effectiveness. Understanding the molecular basis of this resistance is crucial for developing new therapies and overcome the resistance issue. Long-read RNA sequencing offers a powerful method to thoroughly characterize the transcriptome, including full-length transcripts and splice variants, potentially revealing previously unknown mechanisms of bortezomib resistance.Methods: Total RNA was extracted from BTZ-resistant and BTZ-sensitive clones from two MM cell lines (AMO and H929), in three replicates. After appropriate library preparation, long-reads RNAseq was performed using Oxford Nanopore technology, on the PromethION platform. All the quality control analyses were carried out and transcript were annotated, producing an expression matrix. The R package IsoformSwitchAnalyzeR was used to analyze isoform expression and differential isoform usage of the different transcripts among the conditions.Results: The Bioinformatic analyses carried out on AMO cell line made possible to observe 53 significant switches (FDR<0.05; absolute dIF>0.1) affecting 45 different genes, involving a total of 93 isoforms. Moreover, two of these genes coded for proteasome subunits (PSMA6, PSMB10).The H929 cell line was affected by 41 significant switches on 37 genes, with 76 isoforms involved. In both cases, the BTZ-resistant clones showed a significant upregulation of the transcript ENST00000570985, coding for a Nonsense Mediated Decay (NMD)-insensitive variant of the PSMB10 gene, suggesting the potential role of non-coding transcripts in the molecular mechanisms of drug resistance. 18 switching genes were shared between both the BTZ-resistant clones of MM cell lines.The switching genes were further analysed investigating their ontology and their involvement in pathways through pathway enrichment analysis conducted on Reactome. These analyses highlighted several genes coding for histones (H2AC6, H4C15, H2BC4, H2AZ2, H1-2,H2BC4). Two transcriptomic variants referred to the H2AC6 gene were observed, with a significant increase in the NMD-sensitive transcript ENST00000314088 for the resistant cells, in which almost all the expression is dependent on this non-coding variant, suggesting the relative absence of the related protein. Of note, H2AC6 represents an elite gene related hematologic cancer according to Cancer Gene Census (Disease Ontology: DOID:2531)Conclusions: Based on what observed, long-reads RNAseq represents an important strategy to better understand isoform usage of specific genes, attributing their overall expression to specific transcript variants, paving the way for a better comprehension of molecular mechanisms underlying resistance to therapy. The high proportion of shared switching genes between BTZ-resistant cell lines, suggests a potential mechanism based on this process.

Introduction: Multiple myeloma (MM) is a plasma cell (PCs) cancer marked by strong genetic, phenotypic, and microenvironmental heterogeneity. The emergence of extramedullary disease (EMD) signals an aggressive phase linked to treatment resistance and poor outcomes. The mechanisms driving plasma cells to escape the bone marrow and infiltrate extramedullary sites remain unclear. This study uses MACSima™ imaging cyclic staining (MICS), a high-dimensional spatial imaging technology, to map protein expression patterns and cellular interactions, revealing structural and network differences between bone marrow and EMD lesions.Methods: Using MICS, researchers stained 56 biomarkers across carefully prepared BM and EMD tissue samples from 5 newly diagnosed MM patients. Data from 231,186 cells were analysed, with 105,047 annotated as PCs. Computational tools processed and statistically validated the imaging data to generate spatial maps and cellular profiles. Distinct clustering patterns of PCs and immune infiltration profiles were identified via cell-type heatmaps and spatial distance analyses. This approach allowed for comprehensive 3D mapping of malignant PCs and key tumor microenvironment components, providing an integrated spatial framework for investigating cellular organization and intercellular interactions.Results: MICS technology enabled the identification of 14 distinct cell types in BM and 9 in EMD, showcasing method's capacity to discern cellular diversity at a single-cell level. EMD lesions displayed disrupted architecture, characterized by a loss of stromal network integrity and diminished cross-talk with regulatory immune cells. Malignant PCs in EMD sites were organized into dense clusters, lacking canonical interactions with CD8⁺ T cells and dendritic cells, indicative of an immunologically permissive microenvironment. PCs at EMD sites exhibited higher expression of drug resistance markers like BCL-2 and EZH2, and reduced CD38 expression, confirmed by immunohistochemistry. The spatial arrangement of immune cells such as T-cells and macrophages, was markedly different in EMD compared to BM. PCs were overall far distant from T-cells in EMD (Figure1_Desantis).Conclusions: This study provides the first evidence that spatial imaging is essential for understanding the structural complexity of MM and its progression to EMD. Three-dimensional reconstruction of cellular networks reveals the loss of immunostromal interactions and the formation of protective niches that sustain highly aggressive plasma cell subclones. This may explain the reduced effectiveness of CD38-targeted and immune-mediated therapies (such as CAR-T and bispecific antibodies) in EMD. Although larger studies are needed to confirm these findings, they offer valuable insights for precision medicine and microenvironment-focused strategies that could transform the treatment of MM with an extramedullary phenotype.Acknowledgements: This work was supported by “Fondo per il Programma Nazionale di Ricerca e Progetti di Rilevante Interesse Nazionale-PRIN” (project n.2022ZKKWLW); by the Italian network of excellence for advanced diagnosis (INNOVA) (code PNC-E3-2022-23683266 PNC-HLS-DA), by PNRR-MCNT1-2023-12377893 DEMMMO (code H93C23001080006), by Complementary National Plan PNC-I.1 DARE-DigitAl lifelong pRevEntion initiative (code PNC0000002, CUP B53C22006420001) and by AIRC within My First AIRC Grant 2020 (n. 24534, 2021/2025).

Background Tuberculosis (TB) remains a major global health threat, causing approximately 1.5 million deaths each year. Despite progress in treatment, 15%–20% of patients still experience treatment failure or relapse, highlighting the urgent need for precise predictive tools for early identification of high-risk patients. Current methods based on clinical parameters have limitations in prediction accuracy and revealing potential biological mechanisms. Methods This study developed and validated an innovative multi-omics integration prediction model. We retrospectively collected clinical data from 467 tuberculosis patients and integrated transcriptomic data from three independent public cohorts (GSE19491, GSE31312, GSE83456), involving 3,240 differentially expressed genes. Through advanced feature engineering and bioinformatics analysis, key features were selected. We systematically evaluated 12 machine learning algorithms and adopted an ensemble learning strategy to construct the final model. Model performance was evaluated through strict cross-validation and prospective validation cohorts. Results Clinical data analysis identified age, body mass index (BMI), and C-reactive protein (CRP) levels as significant predictors of treatment response. Transcriptomic analysis revealed 1,247 differentially expressed genes between responders and non-responders, enriched in immune response and metabolic pathways. Among the tested algorithms, the ensemble model based on Extra Trees performed the best, with an area under the curve (AUC) of 0.986, significantly superior to models using only clinical data (AUC = 0.850) or only genomic data (AUC = 0.820). Feature importance analysis confirmed CRP, specific gene features (such as DNA repair and interferon response pathways), age, and BMI as the most important predictors. External validation confirmed the model’s robustness (AUC = 0.972). Conclusion This study successfully developed a high-precision prediction model integrating clinical and genomics data, capable of early identification of high-risk patients with poor treatment response. The model demonstrates excellent prediction performance and generalization ability, providing a powerful tool for moving towards tuberculosis precision medicine, guiding individualized treatment strategies to improve patient prognosis and control the spread of drug resistance. Clinical Trial Registration https://www.chictr.org.cn/ , ChiCTR2300074328, 03/08/2023.

Angiogenesis remains a fundamental hallmark of solid tumor growth and metastatic progression, and blocking the vascular endothelial growth factor (VEGF) pathway has changed how systemic therapy works for hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). However, the clinical benefits of anti-angiogenic therapy are frequently transient. Resistance arises from synchronized adaptive mechanisms that include redundant pro-angiogenic signaling, hypoxia-induced transcriptional reprogramming, metabolic reconfiguration, immune microenvironment alteration, and structural vascular evasion. Although the combination of VEGF blockade with immune checkpoint inhibitors (ICIs) has enhanced survival outcomes in pivotal trials such as IMbrave150 and CheckMate 9ER, sustained responses remain infrequent [1,2]. This review combines mechanistic and clinical evidence to create a comprehensive framework for anti-angiogenic resistance. We analyze ligand redundancy (FGF, PDGF, Ang-2), hypoxia-inducible factor (HIF)-mediated metabolic adaptation focused on glycolysis and lactate export, endothelial glycolytic regulation through PFKFB3, myeloid-driven immunosuppression, and structural resistance mechanisms such as vessel co-option and vasculogenic mimicry. We integrate these biological domains with phase III clinical trial data from HCC and RCC and suggest a translational roadmap that prioritizes orthogonal metabolic targeting, microenvironmental reprogramming, structural interception, and biomarker-guided adaptive scheduling at the top of the list during the vascular normalization window. Reconceptualizing resistance as a systems-level adaptive network establishes a basis for more resilient and region-specific therapeutic approaches.

Abstract Background India has made substantial progress in reducing Plasmodium falciparum malaria cases and has set a target to eliminate malaria by 2030. Although ACT treatment remains effective, tracking regional differences in genetic variants associated with antimalarial resistance is required for effective drug policy implementation. Methods We analysed 238 P. falciparum clinical samples from six Indian states by sequencing 15 parasite genes associated with reduced drug effectiveness. The method involved nanopore sequencing of target gene amplicons derived from dried blood spots using a highly sensitive PfMDR15 surveillance panel. Results India’s historical policy of artesunate-sulfadoxine-pyrimethamine in central India and artemether-lumefantrine in the Northeast has shaped contrasting resistance profiles. In the Northeast, chloroquine resistance persisted at high frequency (Pfcrt K76T and CVIET haplotype; Pfaat1 S258L), alongside quintuple and sextuple Pfdhfr–Pfdhps haplotypes conferring complete sulfadoxine-pyrimethamine resistance. Central India showed variable chloroquine resistance (parasites largely retained wild-type Pfcrt) and emerging lumefantrine tolerance (Pfmdr1 Y184F, Pfaat1 S258L). Interestingly, Delhi (Central India) parasites resembled profiles from the distant Northeast, which borders South East Asia. The detection of Pfaat1 S258L, previously reported only from Africa and associated with reduced lumefantrine susceptibility, suggests convergent evolution under ACT partner-drug pressure. No WHO-validated Pfk13 artemisinin resistance mutations were detected, supporting continued efficacy of artemisinin-based combination therapy (ACT). Conclusion India’s resistance landscape is fragmented, with signals of expanding lumefantrine tolerance and importation or evolution of globally relevant mutations. These findings highlight the importance of integrating molecular genomic surveillance into malaria control policy to monitor and protect ACT effectiveness and advance malaria elimination.

Gastrointestinal stromal tumors (GISTs) are primarily driven by activating mutations in the receptor tyrosine kinases KIT or PDGFRA. Targeted therapies have significantly improved patient outcomes; however, acquired drug resistance continues to limit long-term efficacy. Secondary and tertiary mutations across distinct regions of the kinase domain affect the conformational equilibrium or directly disrupt drug binding by alteration of critical residues. This perspective highlights key structural insights that elucidate the molecular basis of resistance and its interplay with kinase activation and TKI binding. A comprehensive understanding of these molecular alterations is crucial for guiding future therapeutic strategies to overcome resistance.

The aim : to perform surveillance over HIV-1 drug resistance mutations among people living with HIV without history of antiretroviral therapy as well as among those receiving antiretroviral treatment and residing in different territories of the Far Eastern Federal district. Materials and methods . A total number of 420 patients diagnosed with HIV-infection and residing in 8 constituent entities of the Far Eastern Federal district were examined. «AmpliSense® HIV-Resist-Seq» kit was used to perform sequencing of the amplified fragments of HIV-1 pol-gene coding protease and a part of reverse transcriptase to detect drug resistance mutations. Stanford University HIVdb Program was employed to retrieve information on drug-resistance mutations. Results and discussion : sub-subtype A6, which is prevalent in Russia, was also dominant in the surveyed group of patients and was isolated in 282 cases (67.1%). A total number of 49 samples were typed as subtype B (11.7%), 12 samples as subtype C (2.9%), 4 samples as subtype G (1.0%). Subtype A7 (0.2%) was detected in one patient from the Republic of Sakha (Yakutia). Different recombinant forms of the virus were identified in 72 patients (17.1%). Percentage of recombinant forms derived from subtypes A and G totaled 80.6% (n=58). Surveillance drug resistance mutations were revealed in 108 out of 248 patients undergoing antiretroviral treatment (43.5%) and in 6 out of 172 treatment-naïve patients (3.5%). Drug resistance to non-nucleoside inhibitors of reverse transcriptase drugs was most common in both treatment naïve patients and those with a prior experience of antiretroviral therapy. Conclusion : regular surveillance of acquired drug resistance provides insight into the effectiveness of HIV prevention and treatment programs in the constituent entities of the Russian Federation and will allow the development of recommendations for treatment strategies.

Multicolor SERS-encoded immuno-cocktail for longitudinal precise tracking of CTCs phenotypes in lung cancer therapeutics.

Current and emerging pharmacological treatments for visceral leishmaniasis.

Cisplatin treatment induces a shift toward a quiescent Ki-67⁻/CD44⁺/CD133⁺ cancer stem cell subpopulation in a tumorsphere model derived from a murine non-small cell lung cancer cell line.

Progress of anti-tumor research on natural products combined with doxorubicin.

Tuberculosis (TB) persists as a leading infectious disease, with progress in global control complicated by emerging drug resistance, limited access to new therapies, and persistent health disparities. This review presents a comprehensive synthesis of traditional and innovative strategies to combat TB, spanning ethnobotanical and folk medicine practices from Africa, Asia, India, Latin America, and Indigenous communities, integrated within World Health Organization frameworks for traditional medicine. The work is systematically bridging time-honored folk therapies with state-of-the-art advances in drug discovery and machine learning algorithms, nanotechnology-based delivery, and artificial intelligence, evaluating both synergy and unique roles in TB management. Additionally, TB stewardship is critically analyzed through nanocarrier platforms (liposomes, mesoporous silica, graphene oxide), artificial intelligence-driven virtual screening, and host-directed therapies, emphasizing their potential for personalization, improved bioavailability, and overcoming drug resistance. This review underscores the urgent need for the sustainable and ethical production of natural anti-TB agents, considering climate change-induced resource loss. Thus, it is providing a roadmap for integrating traditional knowledge with biomedical research, supporting equitable, culturally sensitive, and ecologically responsible TB care.

An insight into the role of nanotechnology in photothermal and photodynamic therapy of leishmaniasis.

Design and evaluation of glycyrrhetinic acid-Pt(IV) hybrids for targeted therapy of liver cancer with reduced systemic toxicity.

Current landscape and therapeutic prospects of indole hybrids for prostate cancer treatment: A mini-review.