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PubMed2026

CSNK1E sustains stemlike drug persistence in diffuse large B-cell lymphoma.

Relapsed or refractory (R/R) disease occurs in up to 40% of patients with diffuse large B-cell lymphoma (DLBCL) following first-line immunochemotherapy. However, the molecular mechanisms underlying drug persistence remain incompletely defined. In this study, we performed single-cell RNA and B-cell receptor sequencing on paired diagnostic and R/R samples from 8 patients who were either treatment-refractory or relapsed after remission, and validated our findings in 3 independent patient cohorts. We found that drug-persistent cells exhibited a transcriptional profile indicative of a less-differentiated state and adopted a memory B-cell-like program with enhanced stemlike properties, which correlated with unfavorable clinical outcomes across multiple DLBCL cohorts. Functionally, drug-persistent cells showed significantly increased in vitro clonogenicity and in vivo tumor-initiating capacity. Mechanistically, the WNT signaling regulator casein kinase 1ɛ (CSNK1E) was upregulated in these stemlike drug-persistent cells, in part through the activation of the A proliferation-inducing ligand (APRIL)-TNFRSF13B axis. Notably, CSNK1E inhibition impaired the growth and tumor-initiating capacity of drug-persistent cells and potentiated the efficacy of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)-based treatment, both in vitro and in vivo. Together, our study reveals the stemlike transcriptional and functional properties of drug-persistent cells, and identifies CSNK1E as a critical mediator and therapeutic vulnerability that may improve the efficacy of standard immunochemotherapy in DLBCL.

Lymphoma, Large B-Cell, Diffuse↗

PubMed2026

CAR T-cell therapy as a definitive consolidation for older adults with B-ALL in first complete remission.

We report a phase 1 study assessing the safety and efficacy of CD19 chimeric antigen receptor (CAR) T cells as definitive consolidation in older adults (aged ≥55 years) with B-cell acute lymphoblastic leukemia (B-ALL) in first complete remission (CR1). Eighteen patients received lymphodepletion followed by infusion of memory-enriched CD19 CAR T cells. The median age was 64 years, and all patients were measurable residual disease (MRD)-negative before lymphodepletion. There were no dose-limiting toxicities, grade ≥2 cytokine release syndrome, or any grade immune effector cell-associated neurotoxicity syndrome. Estimated 18-month event-free and overall survival were 84% and 100%, respectively. CAR T cells expanded in the blood and cerebrospinal fluid despite patients' MRD-negative status. Comparing clinical samples from patients with relapsed/refractory (R/R) B-ALL from our historical trial (ClinicalTrials.gov identifier: NCT02146924) and patients in CR1, we found that the blood and CAR T-cell products from patients with R/R B-ALL were hyperinflammatory and hyperimmunometabolic, respectively. First-line CAR T-cell therapy was safe and well tolerated and potentially extended remission in patients in MRD-negative CR1. These findings support further investigation of the early use of CAR T-cell therapy for B-ALL. This trial was registered at www.clinicaltrials.gov as NCT05707273.

Humans↗

PubMed2026

Evaluation of the efficacy of optical genome mapping in prenatal diagnosis: a retrospective cohort study.

BACKGROUND: Optical genome mapping (OGM) is an emerging cytogenetic method for concurrently detecting structural variants (SVs) and copy number variants (CNVs). However, its clinical application in prenatal diagnosis remains underexplored. METHODS: This study retrospectively evaluated the clinical validity of OGM in prenatal diagnosis by comparing with two routine genetic testing methods: karyotyping and chromosomal microarray analysis (CMA). Both positive and negative cases detected by routine genetic methods were enrolled to evaluate the technical concordance of OGM and its capability to improve diagnostic rate in negative cases. The exclusion criteria were balanced centromeric translocations, mosaic cases with cellular fractions < 20%, and loss of heterozygosity (LOH) < 25 Mb. All samples subjected to OGM testing were anonymized and analyzed blindly. The results from OGM were compared with those from routine genetic testing, and statistical analyses were performed to assess technical concordance and diagnostic rate. RESULTS: Of 217 samples (166 positive samples and 51 negative samples for routine genetic testing), all were successfully tested with OGM, including 2 umbilical cord blood samples, 4 chorionic villi samples, and 211 cultured amniotic fluid samples. Of the 207 reportable chromosomal aberrations from 166 positive samples, the blinded concordance between OGM and CMA, karyotyping, and combination of karyotyping plus CMA was 97.81%, 96.36%, and 97.10%, respectively. OGM missed six aberrations initially, including one LOH, two marker chromosomes, and three microdeletions. However, after reanalysis, its concordance improved to 100% with CMA and 99.03% with karyotyping plus CMA. OGM also diagnosed one additional case of a 3-kb deletion in 51 negative samples, improving the diagnostic rate by 1.96%. Moreover, OGM reclassified the pathogenicity of two microdeletions from pathogenic to uncertain significance in 2 positive cases. Furthermore, OGM clarified the diagnosis suspected by routine genetic testing and improved diagnostic accuracy in some cases. CONCLUSION: As far as we know, this is the largest retrospective study on OGM in prenatal diagnosis, and it includes a broad range of sample types. The results showed that OGM exhibits high concordance among the tested methods and increases the diagnostic rate. Thus, OGM has the potential to become a first-line technique for prenatal diagnosis in the future.

Humans↗

PubMed2026

Radiogenomics predicts immune microenvironment heterogeneity and response to combination immunotherapy in hepatocellular carcinoma.

BACKGROUND: The combination of immune checkpoint inhibitors (ICIs) with anti-angiogenic agents is the preferred first-line therapy option for patients with advanced hepatocellular carcinoma (HCC), yet only a subset of patients responds, urging the quest for prediction biomarkers. We aimed to integrate genomics with radiology to propose an immune-derived radiogenomics biomarker of response to such combination immunotherapy and evaluate its added value in clinical context. METHODS: We integrated bulk RNA sequencing (RNA-seq) and proteomics data of 994 HCC patients with single-cell RNA-seq data of 11 samples across multiple datasets to identify an immune-related signature (IRS) that may influence sensitivity or resistance to such combined immunotherapy strategy, followed by verification of selected marker genes using immunohistochemistry and cytological experiments. We then trained/validated a cross-modality radiogenomics biomarker using machine learning based on TCIA database that was further tested in multi-scale independent cohorts covering 754 HCC patients. RESULTS: Integrative multi-omics analysis identifed a parsimonious 2-gene prognostic signature including KPNA2 and SMG5 that was significantly associated with immune heterogeneity and response to combination immunotherapy. Machine-learning pipeline exported the optimal 4-feature radiogenomics biomarker using support vector machine that significantly discriminated prognosis (hazard ratio 1.415–1.890; p < 0.05 for all) and modestly predicted response to ICI plus anti-angiogenic therapy (area under the curve 0.720–0.829) in independent retrospective series across major imaging modalities (computed tomography/magnetic resonance imaging). In a prospective neoadjuvant cohort, this biomarker also showed favorable performance for predicting pathological response and tumor recurrence, accompanied by biological validation through single-cell RNA-seq analysis of pre-treatment biopsies. CONCLUSIONS: Our study provides a cross-device-cross-modal radiogenomics biomarker that can improve patient selection for emerging ICI plus anti-angiogenic therapy with novel potential therapeutic targets in HCC.

Humans↗

PubMed2026

Multiomics analysis reveals that senescent CXCL16+ macrophages promote lung adenocarcinoma progression through TGF-β signalling.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer and remains a leading cause of cancer-related mortality worldwide. Although, immunotherapy has become a cornerstone of first-line treatment, only 20-30% of patients achieve a durable clinical benefit, largely because of the complexity and heterogeneity of the tumour immune microenvironment. Emerging evidence indicates that cellular senescence, particularly within immune cells, contributes to tumour progression by impairing antitumour immunity; however, its mechanistic role in LUAD remains incompletely understood. METHODS: We performed an integrative multiomics analysis incorporating genome-wide association studies (GWASs), bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics to characterize immune heterogeneity in LUAD. Cellular senescence was validated by performing staining for senescence-associated β-galactosidase and the canonical markers p16 and p21. SHAP analysis was applied to evaluate the contribution of CXCL16+ macrophages. Functional roles were assessed using coculture assays, in vitro and in vivo tumour models, orthotopic tumour implantation, and multiplex immunofluorescence staining of clinical specimens. RESULTS: A summary data-based on Mendelian randomization analysis integrating GWAS and TCGA data identified CXCL16 as a senescence-associated gene that is causally linked to the LUAD risk. Single-cell RNA sequencing revealed that CXCL16 is predominantly expressed in macrophages, and the pseudotime analysis together with β-galactosidase staining confirmed its association with macrophage senescence. Spatial transcriptomics and immunofluorescence staining showed the marked enrichment of CXCL16+ macrophages in LUAD tissues. The cell-cell communication analysis further revealed a strong association between the number of CXCL16+ macrophages and the activation of the TGF-β signalling pathway within the tumour microenvironment. Functionally, CXCL16+ macrophages promoted LUAD progression via TGF-β signalling, as validated in vitro and in subcutaneous and orthotopic tumour models. Molecular dynamics simulations additionally suggested that LUAD patients with high levels of CXCL16+ macrophage infiltration may exhibit increased sensitivity to bosutinib. CONCLUSIONS: CXCL16 promotes macrophage senescence, and senescent CXCL16+ macrophages drive LUAD progression through TGF-β signalling. These findings identify CXCL16+ macrophages as a biologically and therapeutically relevant immune cell population, highlighting a potential target for precision intervention in LUAD.

Humans↗

PubMed2026

A descriptive analysis of Streptococcus suis-associated disease in Irish pigs from 2010 to 2024: serotypes, pathology, and antimicrobial resistance.

BACKGROUND: Streptococcus suis is a major cause of respiratory and systemic diseases in post-weaned pigs, leading to significant production losses and animal welfare concerns. This study provides the first long-term national level analysis of Streptococcus suis-associated disease (SSAD) in the Republic of Ireland. We examined the pig diagnostic submissions, characterised serotype distribution, antimicrobial susceptibility, and co-infection patterns from 2010 to 2024. RESULTS: The findings confirm that serotypes 9 and 2 or 1/2 were most frequently associated with disease. We observed a significant shift in recent years where serotype 9 has surpassed serotype 2 or 1/2 in number of occurrences. S. suis was frequently co-detected with viral pathogens including porcine reproductive and respiratory syndrome virus (PRRSV), porcine circovirus type 2, and swine influenza virus (SIV), as well as bacterial pathogens such as Actinobacillus pleuropneumonia and Pasteurella multocida, typically from pneumonic lungs. While resistance to tetracycline and erythromycin was high (44.4% to 65.8%), isolates remained susceptible to first-line beta-lactam antibiotics such as penicillin (7.9% resistance), ampicillin (5.5% resistance) and amoxycillin/clavulanate (0% resistance). CONCLUSION: The observed heterogeneity between and within herds challenges successful implementation of vaccination and highlights the need for ongoing disease monitoring. These findings provide the first in-depth assessment of SSAD in Ireland's pig population which will offer valuable insights for future surveillance efforts, including genomic studies and supporting evidence-based strategies and vaccine selection for controlling S. suis in Irish pig sector.

Ireland↗

PubMed2025

What is on the Horizon Beyond Platinum and Immunotherapy for Patients With Advanced Non-Small Cell Lung Cancer Without Actionable Genomic Aberrations?

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. While targeted therapy and immunotherapy have transformed first-line management, most patients without actionable genomic alterations (AGAs) will experience disease progression within the first year of their initial treatment. Here, we review pivotal trials, emerging strategies, challenges, and unmet needs for patients with advanced NSCLC without AGAs. Docetaxel with or without ramucirumab is the standard second-line therapy for patients who have progressed after platinum-based chemotherapy and immunotherapy. Targeted therapy is only suitable for patients with specific AGAs. Understanding the hallmarks of cancer immune evasion is key to developing new strategies beyond chemoimmunotherapy. The combination of antiangiogenic agents with immune checkpoint inhibitors (ICIs) has shown mixed results after progression on platinum and ICI. Bispecific antibodies, particularly ivonescimab, have shown encouraging early efficacy in this space. Artificial intelligence-driven pathomics and radiomics tools may help to refine treatment selection in the future. Chimeric antigen receptor T-cell therapy remains investigational. Patients with advanced NSCLC without AGAs who progressed after chemoimmunotherapy have limited treatment options. Novel therapies such as specific antibodies have shown promising results. Future progress will depend on the development of predictive biomarkers and understanding the mechanisms of resistance to ICIs to guide drug development.

Humans↗

PubMed2025

Effects of recombination on multi-drug resistance evolution in Plasmodium falciparum malaria.

When multiple beneficial alleles at multiple loci are present in a population but not linked together in any one individual, there is no general evolutionary result that determines whether recombination will speed up or slow down the emergence and evolution of genotypes carrying multiple beneficial alleles. Translated to infectious disease control, this evolutionary uncertainty means that when multiple types of drug resistance are present we do not know whether recombination will act more strongly to (1) bring together single-resistant genotypes into multi-drug resistant (MDR) genotypes, or (2) break apart MDR genotypes into single-resistant genotypes. In this paper, we introduce a new version of an established and validated individual-based malaria transmission model where we have added 25 drug-resistance related loci, individual mosquito bites, and mosquitoes feeding on multiple hosts in a single meal (interrupted feeds) allowing for recombination events of different Plasmodium falciparum genotypes from different hosts. Recombination among P. falciparum genotypes in this model occurs from two sources of variation, multi-clonal infections in single hosts and interrupted feeds on multiple hosts, and we show that 80% to 97% of MDR recombinant falciparum genotypes are projected to occur from single uninterrupted bites on hosts with multi-clonal infections (for malaria prevalence > 5%). Increases in the model's interrupted feeding rate slowly increase the number of recombination events occurring from interrupted feeds. A comparison of drug-resistance management strategies with this new model shows that, over a 15-year timeframe, triple artemisinin-combination therapies (ACT) strategies show the largest reductions in treatment failures and the longest delays until artemisinin resistance reaches a critical 1% threshold. Multiple first-line therapies (MFT) are second best under these criteria, and ACT cycling approaches are third best. When compared to cycling strategies, MFT strategies generate a greater diversity of recombinant genotypes but fewer recombination events generating MDR and slower emergence of these recombinant MDR genotypes.

Plasmodium falciparum↗

PubMed2025

Paratyphoid fever and the genomics of Salmonella enterica serovar Paratyphi A in Taiwan.

BACKGROUND: Salmonella enterica serovar Paratyphi A (S. Paratyphi A) has emerged as a significant global health concern due to the progressive development of antimicrobial resistance and its broader geographic distribution. In Taiwan, paratyphoid fever was historically rare and predominantly associated with imported cases. Since 2022, however, a marked increase in domestically acquired infections has been observed, prompting investigations into their origin and likely route of introduction. METHODS: We analyzed surveillance data on 223 patients with paratyphoid fever reported in Taiwan between January 2001 and December 2024. Whole-genome sequencing and antimicrobial susceptibility testing were performed on 88 S. Paratyphi A isolates obtained from both imported and domestically acquired infections from 2007 to 2024. Phylogenetic analysis and genotyping were conducted to assess genetic relatedness and to trace potential sources of introduction by comparing them with global isolates. RESULTS: Although 55.2% of paratyphoid fever infections were imported, domestically acquired infections became predominant after 2022. Most isolates (76.1%) were resistant to nalidixic acid and nonsusceptible to ciprofloxacin due to gyrA mutations at codon 83 (S83F or S83Y). The majority of domestic isolates were classified as ST129 and paratype 2.4 and showed close genetic relatedness to strains from Indonesia. Of the 31 domestic isolates collected between 2022 and 2024, 30 clustered with Indonesian strains, and 28 exhibited nearly identical genomic profiles, which suggested a prolonged outbreak likely linked to a common external source, such as contaminated imported food. CONCLUSIONS: The genomic evidence suggests that the recent increase in domestically acquired S. Paratyphi A infections in Taiwan represents a prolonged outbreak rather than a sustained epidemiological shift. These infections were closely related to strains from Indonesia, suggesting a potential epidemiological link between the two countries in the transmission of paratyphoid fever. While 76.1% of isolates were nonsusceptible to ciprofloxacin due to gyrA mutations, susceptibility to traditional first-line agents remained high. The observed decline in case numbers in 2024 may indicate that the outbreak is subsiding. Genomic surveillance played a crucial role in tracing sources of infection and informing targeted public health responses.

Paratyphoid Fever↗

PubMed2025

Mutations in the transcriptional regulator MAB_2885 confer tedizolid and linezolid resistance through the MmpS-MmpL efflux pump MAB_2302-MAB_2303 in Mycobacterium abscessus.

Mycobacterium abscessus (MAB) is a clinically significant multidrug-resistant (MDR) pathogen, particularly implicated in pulmonary infections among cystic fibrosis (CF) patients. Tedizolid (TZD), an oxazolidinone-class antibacterial drug, has been recommended as an alternative treatment for MAB-infected patients who are intolerant to or whose isolate is resistant to first-line drugs including linezolid (LZD). To investigate the TZD resistance mechanisms in MAB, we isolated 23 TZD-resistant MAB mutants and performed whole-genome sequencing (WGS) to identify resistance-associated genes. Frequent mutations were identified in MAB_2885, encoding a putative TetR transcriptional regulator, and MAB_2303, encoding a putative mycobacterial membrane protein large (MmpL). Drug susceptibility testing confirmed that MAB_2885 mutations contribute to both TZD and LZD resistance in MAB. RNA-seq analysis revealed that restoring wild-type MAB_2885 in mutants downregulated the MAB_2302-MAB_2303. Electrophoretic mobility shift assay (EMSA) showed the MAB_2885 protein binds to its target sequence upstream of MAB_2302-MAB_2303, further confirming their regulatory relationship. The W91R mutation in the MAB_2885 protein was found to impair its DNA-binding activity compared to the wild-type. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis confirmed that MAB_2302-MAB_2303 functions as a TZD efflux pump. Additionally, overexpression of MAB_2885 in M. abscessus subsp. bolletii and M. abscessus subsp. massiliense also increased their TZD susceptibility and downregulated their respective MmpS-MmpL orthologs. Overall, our study demonstrates that mutations in MAB_ 2885 contribute to TZD and LZD resistance by disrupting the negative regulation of the downstream MAB_2302-MAB_2303, which functions as a direct efflux pump for TZD. These findings provide new insights into oxazolidinone resistance mechanisms in MAB and identify potential biomarkers for detecting drug resistance.

Mycobacterium abscessus↗

PubMed2025

Long-Term Effectiveness of Tenofovir Alafenamide Versus Entecavir in Treatment-Naive Chronic Hepatitis B: A Real-World Evidence from the Global Alliance for the Study of Hepatitis B Virus.

INTRODUCTION: Although both tenofovir alafenamide (TAF) and entecavir (ETV) are recommended first-line treatments for chronic hepatitis B, comparative data on their effectiveness remain limited. We aim to compare their virologic (VR), biochemical (BR), and complete (CR) response rates. METHODS: This retrospective study enrolled treatment-naive chronic hepatitis B patients who initiated either TAF or ETV in 2016 or after across 22 international centers and evaluated their treatment response after balancing their characteristics using inverse probability treatment weighting and through Fine-Gray competing-risks analysis of the balanced cohort. RESULTS: The study included 1,605 patients (784 TAF and 821 ETV patients with significant background differences) of whom 1,553 (96.8%) were from Asia. Inverse probability treatment-weighting analysis yielded a total weighted cohort of 1,660 (822 TAF and 838 ETV patients with balanced characteristics). The 5-year cumulative VRs were high in both groups with a slightly higher rate in TAF patients (98.0% vs 93.9%, P < 0.001), and similar findings were found in a subgroup analysis by median hepatitis B virus (HBV) DNA (5.5 log IU/mL). However, there was no significant difference in the 5-year BR rates overall (93.7 vs 92.8%, P = 0.484) or by alanine aminotransferase (ALT) cutoff of 2× upper limit of normal. TAF patients had a slightly higher 5-year cumulative CR overall (94.9% vs 89.4%, P = 0.001) and in high HBV DNA (96.9% vs 87.9%, P < 0.001) or ALT ≥2× upper limit of normal patients (97.3% vs 90.6%, P < 0.001), but not in those with lower HBV DNA or ALT. DISCUSSION: BR rates were similar with ETV and TAF, while VR and CR were higher with TAF, although the difference was modest (<5% overall, 7%-9% in high HBV DNA or ALT groups). Antiviral selection between TAF vs ETV should be based mainly on cost, side effect profile, and patient preference.

Adult↗

PubMed2026

A study on the mechanism of action of B7H4 in HER2-positive gastric cancer and its sensitivity to trastuzumab therapy.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) is characterized by high malignancy and a poor prognosis. Trastuzumab is the first-line targeted therapy for this disease, but the frequent development of primary and acquired resistance severely compromises treatment efficacy and impedes improvements in patient outcomes. B7H4 is a critical negative immune checkpoint molecule that has been demonstrated to contribute to tumor progression and targeted therapy resistance in multiple cancers. However, the specific mechanisms by which B7H4 regulates sensitivity to trastuzumab in HER2-positive GC remain unclear. This study aims to investigate the expression and biological functions of B7H4 in HER2-positive GC, elucidate the molecular mechanisms underlying B7H4-mediated trastuzumab resistance, and thereby provide a theoretical basis for targeted resistance intervention and therapeutic optimization for this malignancy. METHODS: The study began with an analysis of The Cancer Genome Atlas (TCGA) database and immunohistochemical staining of tissue sections to assess the expression levels of B7H4 and HER2, as well as the correlation between their expression. Furthermore, the correlation between B7H4 expression and various pathological parameters in patients with HER2-positive GC was analysed. Western blot analysis was used to screen for co-expressing cells, and short hairpin RNA (shRNA) was employed to knockdown B7H4. The effects of B7H4 knockdown on the proliferation, migration and invasion of HER2-positive GC cells were assessed using colony formation assays, Cell Counting Kit-8 (CCK-8) assays, cell scratch assays and Transwell assays, respectively. RNA sequencing (RNA-Seq) was utilised to analyse the biological processes and signalling pathways regulated by B7H4 and to detect relevant biomarkers. Colony formation assays and CCK-8 assays were employed to evaluate the therapeutic sensitivity of trastuzumab to HER2-positive GC cells following B7H4 knockdown. RESULTS: Analysis of the TCGA database and immunohistochemical staining of tissue sections revealed that B7H4 and HER2 were co-expressed in GC tissues, and their expression levels were positively correlated. Clinical correlation analysis revealed that B7H4 expression was significantly associated with tumor size, grade, depth of invasion, lymph node metastasis, distant metastasis, vascular invasion and nerve invasion in HER2-positive GC patients. Western blot analysis demonstrated co-expression of B7H4 and HER2 in NCI-N87 cells. Knockdown of B7H4 resulted in varying degrees of inhibition of proliferation, migration and invasion in NCI-N87 cells. RNA-seq results indicated that B7H4 knockdown affected biological processes such as cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT), and was significantly associated with the nuclear factor κB (NF-κB) signalling pathway. Knockdown of B7H4 significantly enhanced the sensitivity of HER2-positive GC cells to trastuzumab. CONCLUSIONS: B7H4 is highly expressed in HER2-positive GC and is associated with poor prognosis. B7H4 promotes tumor cell proliferation, migration and invasion by activating the NF-κB signalling pathway and driving the EMT process. B7H4 expression influences the sensitivity of HER2-positive GC cells to trastuzumab; inhibition of B7H4 significantly enhances the antitumor efficacy of trastuzumab.

B7H4↗

PubMed2026

Lipid metabolic reprogramming of tumor-associated macrophages drives resistance to immune checkpoint blockade in lung cancer: a narrative review of mechanisms and therapeutic strategies.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs), represented by programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), have shown remarkable efficacy in non-small cell lung cancer (NSCLC); however, many patients still develop resistance to immunotherapy. Although small cell lung cancer (SCLC) is also an important histological type of lung cancer, NSCLC accounts for the majority of lung cancer cases. Current research on ICI development, first-line treatment efficacy, and the mechanisms of lipid metabolism in tumor-associated macrophages (TAMs) is predominantly focused on NSCLC. In patients with advanced NSCLC, objective response rates (ORRs) with PD-1/PD-L1 inhibitor monotherapy remain limited. Only in patients with high PD-L1 expression [tumor proportion score (TPS) ≥50%] and without sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements does the ORR increase to approximately 40-45%. TAMs are a key component of the immunosuppressive tumor microenvironment (TME). Lipid metabolic reprogramming profoundly influences the functional and transcriptional features of TAMs. This review aims to integrate relevant evidence, elucidate how TAM lipid metabolism promotes immunosuppression and resistance to ICIs, and outline potential therapeutic strategies. METHODS: We searched PubMed/MEDLINE, Web of Science, and Scopus for publications up to June 2026 using terms combining lung cancer, TAMs, lipid metabolism, and immune checkpoint blockade/resistance. Mechanistic, translational, and clinically relevant studies were selected by author consensus. KEY CONTENT AND FINDINGS: Lipid uptake, de novo lipogenesis, fatty acid oxidation (FAO), cholesterol remodeling, and eicosanoid metabolism are not independent processes in TAMs. Lipid metabolic reprogramming in TAMs ultimately suppresses type I interferon (IFN-I) signaling, upregulates PD-L1 expression, and impairs the function of CD8+ T cells with stem-like features, thereby establishing an immunosuppressive TME and leading to resistance to ICIs. In lung cancer, hypoxia, high lactate levels, and tobacco exposure further shape the lipid phenotype of TAMs, such as lipid raft enrichment and lipid-laden macrophage subsets like SPP1+ macrophages. Different driver genomic backgrounds differentially impact tumor cell-intrinsic metabolism and the lipid metabolic programs of myeloid cells. In preclinical models, interventions targeting these metabolic axes, including TAM-directed delivery systems, have demonstrated potential therapeutic benefit when combined with anti-PD-1/PD-L1 therapy. CONCLUSIONS: Targeting TAM lipid metabolism to convert immunologically cold tumors into more inflamed, ICI-responsive tumors is a promising strategy to overcome resistance in NSCLC. Identification of predictive biomarkers of therapeutic response and development of cell-selective drug delivery systems come to be major challenges.

Non-small cell lung cancer (NSCLC)↗

PubMed2026

Incidental MSH6 Germline Pathogenic Variant Identified through Tumor-only Comprehensive Genomic Profiling in a Patient with Small Cell Lung Cancer.

A 55-year-old woman was diagnosed with limited-disease small cell lung cancer (LD-SCLC) after incidental detection of a lung nodule. First-line chemotherapy achieved partial response, but recurrence occurred after one year. During second-line therapy, comprehensive genomic profiling (CGP) revealed a germline MSH6 frameshift mutation. Although lung tumor immunohistochemistry showed the retained expression of mismatch repair (MMR) protein, a prior colon cancer specimen showed the loss of MSH6 expression and deficient MMR expression. Germline genetic testing confirmed Lynch syndrome. Cascade testing identified the same mutation in her daughter. This case outlines a tumor-to-germline workflow with testing of at-risk relatives and highlights the importance of prudent interpretation of presumed germline variants.

Humans↗

PubMed2026

Efficacy of S-1 Monotherapy for Salivary Duct Carcinoma With MYC Amplification.

BACKGROUND/AIM: Salivary duct carcinoma (SDC) is a rare, highly aggressive subtype of salivary gland carcinoma, commonly characterized by overexpression of erb-b2 receptor tyrosine kinase 2 [ERBB2, commonly known as human epidermal growth factor receptor 2 (HER2)] and androgen receptor positivity. Anti-HER2 therapy, platinum-based chemotherapy, and androgen-deprivation therapy (ADT) are commonly provided as standard systemic treatments for advanced SDC; however, effective therapeutic options after failure of these treatments remain limited. The clinical efficacy of S-1 monotherapy in SDC and its predictive biomarkers are not well established. Herein, we present a case in which S-1 monotherapy showed efficacy in a case of SDC after resistance to anti-HER2 therapy, platinum-based chemotherapy, and ADT. CASE REPORT: The patient was a 70-year-old man diagnosed with HER2-positive and androgen receptor-positive SDC of the submandibular gland, who presented with multiple lung metastases. He initially received trastuzumab plus docetaxel as first-line therapy, followed by platinum-based chemotherapy and ADT, but experienced disease progression after each treatment. Comprehensive genomic profiling revealed amplifications of ERBB2 and MYC proto-oncogene bHLH transcription factor (MYC). S-1 monotherapy was started as a late-line therapy. Computed tomography scans 2 months later showed shrinkage of lung and liver metastases, with disease control maintained for more than 5 months. CONCLUSION: S-1 monotherapy may represent a treatment option for patients with advanced SDC refractory to anti-HER2 therapy, platinum-based chemotherapy, and ADT, particularly in cases harboring MYC amplification.

Humans↗

PubMed2026

Effectiveness of Wearable Digital Therapeutics in Improving Sleep Outcomes Among Individuals With Insomnia: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Wearable devices are increasingly used for sleep monitoring and as adjunctive treatment. Existing meta-analyses mostly pool composite digital therapies and rarely isolate stand-alone wearables or distinguish between objective and subjective end points. Whether stand-alone wearable interventions improve sleep outcomes in adults with insomnia, and which factors moderate treatment heterogeneity, remains unclear. OBJECTIVE: This study aims to evaluate the effectiveness of wearable digital interventions on sleep outcomes in adults with insomnia versus control strategies and explore moderators of effectiveness, including device-wearing position, intervention duration, and control type, using meta-regression. METHODS: This systematic review and meta-analysis was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‑Analyses) 2020 statement and the PRISMA-S (Preferred Reporting Items for Systematic Reviews and Meta‑Analyses Literature Search Extension) guideline. Five electronic databases and clinical trial registries were searched from inception to May 18, 2026. Eligible studies were randomized controlled trials (RCTs) evaluating wearable digital interventions in adults with insomnia compared with sham, waitlist, usual care, or active control conditions and had an intervention duration of at least 1 week. Study screening, data extraction, and risk-of-bias assessment were carried out independently by 2 reviewers. Pooled estimates were calculated using a restricted maximum likelihood random-effects model with the Hartung-Knapp-Sidik-Jonkman correction. Heterogeneity was assessed using the I² statistic, and 95% prediction intervals (PIs) were calculated for the primary analyses. The certainty of evidence was rated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. RESULTS: Sixteen RCTs (N=910) were included. Wearable digital interventions were associated with a significant reduction in objective sleep-onset latency (SOL; mean difference [MD] -4.52, 95% CI -8.38 to -0.67, PI -9.52 to 0.47 min) and a significant improvement in subjective sleep efficiency (SE; MD 2.00%, 95% CI 1.90%-2.11%, PI 1.85%-2.15%). Subjective total sleep time (TST) also showed a significant increase (MD 19.11, 95% CI 2.98-35.24, PI -16.20 to 54.43 minutes). Meta-regression showed that control type, intervention duration, and device location did not explain the heterogeneity of the insomnia severity index (ISI) (R²=0). Sensitivity analysis confirmed the robustness of pooled ISI estimates, and an Egger test indicated no small-study effects (P=.07). Certainty of evidence ranged from moderate to high. CONCLUSIONS: Wearable digital interventions provide selective benefits for objective SOL, subjective SE, and subjective TST in adults with insomnia, with no improvement in overall ISI. Despite statistically significant effects on several sleep parameters, wide PIs, substantial heterogeneity, and limited study numbers indicate preliminary, nonconclusive findings. Wearables should be viewed as affordable adjunctive tools requiring further validation, not substitutes for first-line cognitive behavioral therapy for insomnia. Large-scale, long-term RCTs with standardized protocols and patient-level external validation are required to consolidate the evidence base.

Humans↗

PubMed2026

Spinal meningiomas: histopathological grading using a benchmark radiomics model with notes on disease control.

OBJECTIVE: Spinal meningiomas (SMs) are common primary spinal tumors for which surgery is considered the first-line treatment when safe and feasible. The ability to extrapolate the tumor grade from preoperative imaging may significantly inform early patient expectation-setting regarding recurrence. Building on radiomics studies in cranial meningiomas, the authors aimed to construct a benchmark radiomics model to preoperatively identify the histological grade of SMs. METHODS: Institutional surgical records from May 2012 to November 2025 were queried for pathology-confirmed meningiomas below the foramen magnum, with preoperative contrast-enhanced imaging available for segmentation. SMs were classified as low-grade (WHO grade 1) and high-grade (WHO grade 2 tumors and grade 1 tumors with atypia). Tumors were manually segmented, and features were extracted using the PyRadiomics software package. An ensemble model of k-nearest neighbors, random forest, and support vector machine classifiers was trained using nested cross-validation on a subset of 10 features to differentiate tumor grades. Clinical data for the cohort were also extracted, and disease control in an adjunctive clinical series was assessed. RESULTS: Seventy-four patients were included in radiomics analysis, with an area under the receiver operating characteristic curve of 0.879 and a mean F1 score of 0.748. The model's top 5 features were all texture features that differed significantly (p < 0.05) across low- and high-grade SMs. These included measures of tumor textural and contrast-enhancement heterogeneity, with overlap with features reported in radiomics models for histological grading of intracranial meningiomas. Fifty-five patients with a median radiographic follow-up of 22.2 (range 1.9-86.4) months remained for clinical analysis after exclusion of patients with less than 1 month of follow-up and syndromic meningiomas. Four recurrences occurred at a median of 20.8 (range 1.8-41.8) months. High-grade tumor pathology did not significantly impact progression-free survival (p = 0.682, log-rank test; Cox regression high vs low grade hazard ratio [HR] 0.62, 95% CI 0.06-6.11, p = 0.685). Subtotal resection was associated with poorer progression-free survival than gross-total resection (p = 0.004, log-rank test; Cox regression subtotal vs gross-total resection HR 10.62, 95% CI 1.46-77.05, p = 0.019). These findings remain contextualized within a relatively limited follow-up window and small recurrence event count, suggesting a need to characterize the interplay between tumor grade and extent of resection as drivers of local disease control in SMs. CONCLUSIONS: A preoperative radiomics model can stratify high-grade SMs using open-source tools applied to single-institution data.

Humans↗

PubMed2026

Genomic surveillance reveals escalating antimicrobial resistance and plasmid diversity in clinical Salmonella 1,4,[5],12:i:- ST34 isolates from Guizhou Province, China.

INTRODUCTION: Salmonella 1,4,[5],12:i:- ST34 has emerged as a significant public health issue due to its association with various antimicrobial resistance genes (ARGs) and transferable plasmids. However, its genomic characteristics and potential influence on public health in Guizhou have not been comprehensively assessed. METHODS: From 2019 to 2023, a 5-year surveillance was conducted in nine cities (prefectures) of Guizhou Province. We integrated phenotypic and genomic analyses of 281 clinical Salmonella 1,4,[5],12:i:- ST34 isolates to investigate the prevalence of ARGs and plasmids and to analyze the molecular epidemiology and evolution. RESULTS: The isolates exhibited resistance to first-line antibiotics, with 22.4% for ciprofloxacin, 11.4% for azithromycin, 18.5% for ceftazidime, and 39.1% for cefotaxime. ARGs showed substantial agreement with phenotypes for tetracycline, macrolides, third-generation cephalosporins (3GCs), carbapenems, and colistin (80.8-100.0% consistency; Kappa: 0.50-1.00). Plasmid analysis identified IncQ1 (84.3%) and IncHI2/IncHI2A (26.3%) as the main replicons, with the variety of plasmid replicons increasing from 7 to 21 over the 5 years. ARGs associated with resistance to critically important antibiotics (CIAs) were frequently predicted to be located on plasmid-associated contigs, with significant associations observed between IncHI2/IncHI2A plasmids and ARGs conferring resistance to fluoroquinolones, macrolides, and cephalosporins (P < 0.05). Molecular typing divided 281 isolates into 37 cgSTs, with cgST52428 being the most common. Molecular epidemiological analysis revealed that Guizhou isolates primarily clustered together, sharing close genetic ties with those from Sichuan and Guangdong, and exhibited the highest genetic similarity to pork-derived isolates. Phylogenetic analysis revealed clustering of CIA-resistant ARGs and plasmids in Clades 4 and 5, with a significant association between IncHI2/IncHI2A plasmids and CIA-resistant ARGs (χ2 = 112.12, P < 0.001). Additionally, class 1 integron was associated with higher ARG burdens, while virulence-associated genes were conserved and predominantly chromosome-associated. Gene-content analysis revealed that isolates in Clades 4 and 5 harbored the largest mean gene complements, and cgST52428 isolates also harbored the largest among dominant cgSTs. DISCUSSION: This study presents a comprehensive genomic profile of Salmonella 1,4,[5],12:i:- ST34 in Guizhou, providing essential data for exploring the resistance characteristics and investigating the molecular epidemiology of Salmonella 1,4,[5],12:i:-.

ST34↗