BMC Medicine[JOURNAL]
Sun
200 papers
Focal adhesion kinase FAK interplays with ROR1 in the aggressiveness of chronic lymphocytic leukemia.
Castronuovo M, Capasso G, Beltrame A … +11 more , Mouawad N, Gramegna V, Fantato P, Pagnin E, Angotzi F, Cellini A, Serafin A, Facco M, Visentin A, Trentin L, Frezzato F
BMC Med · 2026 Jun · PMID 42374527 · Full text
BACKGROUND: In chronic lymphocytic leukemia (CLL), B-cell receptor, chemokine receptor and integrin signaling contribute to disease progression by influencing cell survival, migration and microenvironment interactions. F...
BACKGROUND: In chronic lymphocytic leukemia (CLL), B-cell receptor, chemokine receptor and integrin signaling contribute to disease progression by influencing cell survival, migration and microenvironment interactions. Focal adhesion kinase (FAK) has recently been involved in these disease processes. Our recent research revealed a correlation between activated FAK and molecules involved in CLL aggressiveness, particularly in IGHV-unmutated cases, including the Lyn kinase substrates HS1 and cortactin. In this context, ROR1 is a key player, sharing connections with Lyn substrates and FAK pathways. METHODS: We assessed FAK and ROR1 bidirectional association by stimulating CLL cells with Wnt5a and measuring FAK phosphorylation by Western blot, while ROR1 expression was evaluated following FAK inhibitor treatment. Flow cytometry using CXCR4 and CD5 markers was performed to identify and sort proliferating (CXCR4/CD5) versus quiescent (CXCR4/CD5) B-cell subpopulations from CLL patients. FAK and ROR1 levels were compared between these fractions. Findings were further supported ex vivo in ibrutinib-treated patients. The FAK inhibitor defactinib was tested alone and in combination with BTK inhibitors on primary CLL cells cultured with or without stromal support, measuring apoptosis by Annexin V/PI staining. RESULTS: We demonstrated that ROR1 triggering by Wnt5a increases FAK activation, while FAK inhibition reduces ROR1 expression. Significantly higher levels of FAK and ROR1 were detected in the proliferating subpopulation corresponding to cells egressing lymph nodes compared to quiescent cells. Ex vivo experiments confirmed high FAK and ROR1 levels in circulating lymphocytes redistributing from secondary lymphoid organs. Defactinib significantly enhanced apoptosis in CLL cells when combined with BTK inhibitors, even in supportive microenvironments, showing significant efficacy also against aggressive CLLs. CONCLUSIONS: Our findings reveal a reciprocal regulatory relationship between FAK and ROR1, with both proteins enriched in CLL cells that have exited the lymph nodes. Given defactinib's favorable safety profile in solid tumor trials, combining FAK inhibition with BTK inhibitors could enhance therapeutic efficacy by limiting leukemic clone adaptability and addressing resistance and relapse. While anti-ROR1 therapies showed limited efficacy as monotherapy in CLL trials, targeting multiple nodes of this regulatory network may prove more effective.
Adjuvant systemic therapy versus active surveillance after resection following conversion therapy for hepatocellular carcinoma: a propensity score matched study.
He B, Zheng Z, Gan J … +10 more , Zuo Z, Deng M, Wen J, Mei J, Liao W, Xu L, Zhao R, Guo R, Lu L, Wei W
BMC Med · 2026 Jun · PMID 42374487 · Full text
BACKGROUND: The role of adjuvant systemic therapy after resection following conversion therapy in patients with hepatocellular carcinoma (HCC) rendered resectable by transarterial therapy combined with systemic therapy r...
BACKGROUND: The role of adjuvant systemic therapy after resection following conversion therapy in patients with hepatocellular carcinoma (HCC) rendered resectable by transarterial therapy combined with systemic therapy remains unclear. This study aimed to evaluate the impact of adjuvant systemic therapy on survival outcomes in real-world practice. METHODS: We retrospectively analyzed patients with initially unresectable HCC who underwent curative-intent resection after successful first-line transarterial therapy combined with systemic therapy between January 2018 and December 2023. Postoperative management included either adjuvant systemic therapy or active surveillance. Propensity score matching (1:2) was applied to balance baseline characteristics. Overall survival (OS) and recurrence-free survival (RFS) were evaluated using Kaplan-Meier methods and compared by log-rank tests. Subgroup and recurrence pattern analyses were also performed. RESULTS: Among 496 eligible patients, 120 received adjuvant systemic therapy and 376 underwent active surveillance. After matching, 326 patients were included (116 vs. 210). Adjuvant systemic therapy was associated with significantly improved OS (HR 0.58, 95% CI 0.38-0.89; p = 0.01) and RFS (HR 0.64, 95% CI 0.48-0.84; p = 0.002). Survival benefit of adjuvant systemic therapy was observed in patients with BCLC stage C disease (OS: HR 0.53, 95% CI 0.31-0.90, p = 0.02; RFS: HR 0.61, 95% CI 0.43-0.87, p = 0.007) and in those with BCLC stage A or B disease exceeding the up-to-seven criteria (OS: HR 0.46, 95% CI 0.22-0.95, p = 0.03; RFS: HR 0.56, 95% CI 0.34-0.91, p = 0.02). Multivariable analysis identified adjuvant systemic therapy as an independent predictor of improved OS and RFS. CONCLUSIONS: In patients undergoing resection following conversion therapy for initially unresectable HCC, adjuvant systemic therapy was associated with improved survival, particularly among those with high-risk disease features.
An ICOSL-armed oncolytic adenovirus activates CD4 T cell to potentiate antitumor immunity and synergizes with anti-PD-1 or CAR-T cell therapy in colorectal cancer.
Liu W, Ren X, Zhang Y … +11 more , Yue Q, Chen X, Zhou D, Li X, Xin Q, Kong L, Wu H, Guo C, Gu X, Wu J, Jiang C
BMC Med · 2026 Jun · PMID 42374450 · Full text
BACKGROUND: The efficacy of oncolytic adenoviruses (ADVs) in colorectal cancer (CRC) is limited by their inability to effectively expand CD4 T cells within the tumor microenvironment (TME). This study aimed to elucidate...
BACKGROUND: The efficacy of oncolytic adenoviruses (ADVs) in colorectal cancer (CRC) is limited by their inability to effectively expand CD4 T cells within the tumor microenvironment (TME). This study aimed to elucidate the underlying mechanism and overcome this bottleneck through viral engineering. METHODS: We constructed an oncolytic adenovirus expressing inducible T cell co-stimulator ligand (ICOSL), designated ADV-ICOSL, based on the backbone virus ADV-NC. Its antitumor efficacy, safety, and ability to induce immunological memory were systematically evaluated in MC38 and CT26 murine colorectal cancer (CRC) models. The mechanism of action was investigated using flow cytometry, co-culture assays, RNA sequencing, and specific pathway inhibitors. The synergistic potential with anti-PD-1 or chimeric antigen receptor T cell (CAR-T) therapy was assessed. Furthermore, a humanized ICOSL-expressing virus (ADV-hICOSL) was developed and validated in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. RESULTS: We initially discovered that ADV-NC treatment led to decreased ICOSL levels in the TME, resulting in insufficient co-stimulation for CD4 T cells. In contrast, ADV-ICOSL significantly elevated ICOSL expression and demonstrated superior antitumor efficacy and the capacity to induce long-term immune memory. Mechanistic studies revealed that ADV-ICOSL, via elevating ICOSL, activated the PI3K/Akt-NF-κB signaling axis in CD4 T cells, promoting their secretion of IL-2. IL-2, in a non-contact-dependent manner, potently enhanced the proliferation and cytotoxicity of CD8 T cells. This process was strictly dependent on CD4 T cells. Furthermore, ADV-ICOSL exhibited significant synergistic effects when combined with either anti-PD-1 or CAR-T therapy. Importantly, ADV-hICOSL effectively increased the infiltration of CD4 T and GZMB CD8 T cells in CDX/PDX models, exerting potent antitumor effects. CONCLUSIONS: Our study not only reveals that the suboptimal efficacy of conventional oncolytic adenovirus is associated with ICOSL downregulation and impaired CD4 T cell help, but also successfully develops ADV-ICOSL to reverse this limitation. This study provides a novel combinatorial strategy and a solid experimental foundation for oncolytic virotherapy in CRC.
Single-cell profiling of gastric cancer ascites reveals an epithelial-immune dual phenotype signature predictive for anti-PD-1 immunotherapy responses.
Xu T, Yang M, Huang J … +8 more , Lu L, Deng D, Shi X, Sun Y, Lovell JF, Lin Z, Zheng Y, Jin H
BMC Med · 2026 Jun · PMID 42374437 · Full text
BACKGROUND: Gastric cancer (GC) with peritoneal metastasis frequently leads to malignant ascites (MA), a highly immunosuppressive "liquid tumor microenvironment" associated with poor prognosis. Although immune checkpoint...
BACKGROUND: Gastric cancer (GC) with peritoneal metastasis frequently leads to malignant ascites (MA), a highly immunosuppressive "liquid tumor microenvironment" associated with poor prognosis. Although immune checkpoint blockade (ICB) demonstrate efficacy in some GC patients, treatment response to gastric cancer-associated peritoneal metastasis (GCPM) remains heterogeneous. The immune mechanisms driving this variability and predictive biomarkers remain unclear. METHODS: We performed single-cell transcriptomics and TCR/BCR repertoire analyses on paired MA and peripheral blood mononuclear cell (PBMC) samples from 10 advanced GC patients. Cellular clustering, trajectory inference, and intercellular communication analyses characterized immune remodeling. Clinical cohorts were used to validate prognostic and therapeutic predictive significance. RESULTS: Immune landscape of GCMA was delineated, which unveils extensive remodeling of T cells, B cells, and myeloid lineages. Notably, we identified a novel epithelial-immune dual-phenotype cell (EIDPC) population, validated by single-cell RNA sequencing and flow cytometry, exhibiting moderate malignant characteristics and potent immunoregulatory capacity. Transcriptomic and trajectory analyses suggest an epithelial origin with reprogramming toward immune evasion. Based on 10 EIDPC core genes, we developed the immune response signature of EIDPC (IRS-EIDPC), which accurately predicts anti-PD-1 therapy response and prognosis in independent gastric cancer cohort (AUC 0.929). CONCLUSIONS: This study reveals the immune landscape of malignant ascites in gastric cancer, and confirms EIDPC as a transitional malignant subpopulation with potent immunomodulatory functions. The IRS-EIDPC signature may aid in predicting immunotherapy responses and survival outcomes, provides insights into immune plasticity in malignant gastric ascites, and may help inform future precision therapeutic strategies.
Engineered iMSCs delivering wild-type IL-2 achieve dose-sparing tumor control via CD25-dependent CD8 T-cell activation.
Tang S, Han M, Wang P … +13 more , Lu F, Zhang Y, Li Z, Zhou S, Zhang Y, Wang Z, Zhao J, Luo Y, Tian Z, Feng M, Zhu G, Wu L, Liang D
BMC Med · 2026 Jun · PMID 42374407 · Full text
BACKGROUND: Interleukin-2 (IL-2), the first FDA-approved cytokine-based immunotherapy, can induce durable antitumor responses but its broader use is curtailed by life-threatening, dose-dependent toxicities. This narrow t...
BACKGROUND: Interleukin-2 (IL-2), the first FDA-approved cytokine-based immunotherapy, can induce durable antitumor responses but its broader use is curtailed by life-threatening, dose-dependent toxicities. This narrow therapeutic window has limited clinical translation for decades. Genetically engineered mesenchymal stromal cells (MSCs) have emerged as attractive IL-2 delivery vehicles due to their low immunogenicity and intrinsic tumor-homing capacity. METHODS: Human induced pluripotent stem cells (iPSCs) were edited by CRISPR/Cas9 to knock in wild-type IL-2 (wtIL-2) or a receptor-biased variant (IL-2v) into the B2M or B3 safe-harbor loci, generating cytokine-secreting iPSC-derived MSCs (iMSCs). Antitumor activity was evaluated in co-cultures of iMSCs, tumor cells, and peripheral blood mononuclear cells (PBMCs) by flow cytometry. In vivo, systemically administered iMSCs were tracked by live imaging in mice bearing subcutaneous tumors to assess biodistribution and tumor targeting. Tumor control was monitored by longitudinal tumor growth and end-point volume; toxicity was evaluated by lung wet weight and blood biochemistry. Immune cell states within the tumor microenvironment were characterized by flow cytometry and RNA sequencing. Data (mean ± s.e.m.) were analyzed in GraphPad Prism using t-tests, ANOVA, or Kruskal-Wallis tests, as appropriate (n = biological replicates; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001). RESULTS: Surprisingly, we found that under low-dose conditions, only iMSCs with IL-2 overexpression-but not unmodified iMSCs or free IL-2 alone-induced robust upregulation of CD25 on CD8 T cells. This effect likely increases T-cell sensitivity to wtIL-2 and may contribute to the improved tumor control achieved at reduced IL-2 doses. Systemic administration of wtIL-2-iMSCs preferentially activated intratumoral T cells and achieved tumor growth inhibition comparable to high-dose rhIL-2 in our model, while attenuating systemic toxicity. Transcriptomic analysis indicated that wtIL-2-iMSCs enhanced effector programs in tumor-infiltrating CD8⁺ T cells more effectively than rhIL-2 under the tested conditions. Notably, targeted integration of wtIL-2 at a novel locus within the B2M region (B3-wtIL-2-iMSCs) led to a higher transgene expression and further augmented antitumor activity in vitro and in vivo with no clear increase of systemic toxicity. Moreover, B3-wtIL-2-iMSCs exhibited synergistic antitumor effects when combined with anti-PD-1 blockade, thereby strengthening overall tumor control. CONCLUSIONS: These findings point to a mechanism by which iMSC-delivered IL-2 reshapes the tumor microenvironment through CD25-dependent CD8⁺ T-cell activation. Furthermore, the results support the concept that this platform enables a more dose-efficient cytokine delivery strategy with an improved safety profile, thereby facilitating the clinical translation of off-the-shelf allogeneic iMSC-based gene therapies.
Including randomized and non-randomized studies of interventions in evidence synthesis for harms: a meta-epidemiological study.
Mei F, Yao M, Ma Y … +5 more , Huan J, Yang L, Zou K, Li L, Sun X
BMC Med · 2026 Jun · PMID 42374394 · Full text
BACKGROUND: Non-randomized studies of interventions (NRSIs) provide important evidence on harms, especially for rare adverse events that randomized controlled trials (RCTs) are often underpowered to detect. Evidence synt...
BACKGROUND: Non-randomized studies of interventions (NRSIs) provide important evidence on harms, especially for rare adverse events that randomized controlled trials (RCTs) are often underpowered to detect. Evidence synthesis is therefore needed to integrate findings across study designs and to inform a comprehensive assessment of harms. However, synthesizing evidence from RCTs and NRSIs remains methodologically challenging. We examined how evidence from RCTs and NRSIs is synthesized in practice and how conclusions were drawn when findings conflict. METHODS: The meta-epidemiological study included systematic reviews indexed in PubMed between 1 January 2017 and 31 December 2024 that synthesized evidence from both RCTs and NRSIs for the same outcome. We evaluated methodological practices across four synthesis scenarios. For reviews that combined RCTs and NRSIs in a meta-analysis, we assessed key methodological components of the review process. For reviews that meta-analyzed RCTs and NRSIs separately, we assessed qualitative agreement between RCTs and NRSIs based on the magnitude, direction, and statistical significance of the estimates. When qualitative disagreement was observed, we further evaluated whether the review conclusions were reasonable, taking into account the certainty of evidence and the heterogeneity of the estimates. RESULTS: Of 42,341 records screened, 195 systematic reviews were included. 49 (25.1%) conducted only qualitative syntheses of both RCTs and NRSIs. 11 (5.6%) meta-analyzed only RCTs, with NRSIs synthesized qualitatively; and 7 (3.6%) meta-analyzed only NRSIs, with RCTs synthesized qualitatively. Among the 91 reviews (46.7%) that combined RCTs and NRSIs in a single meta-analysis, important methodological gaps were identified: 72.5% included NRSIs at moderate or high risk of bias, 49.5% used unadjusted estimates, and 53.8% did not conduct subgroup analyses by study design. Separate meta-analyses for RCTs and NRSIs were conducted in 37 reviews (19.0%), of which 67.6% showed qualitative disagreement between the two study designs, and 20.0% were judged to have inappropriate conclusions according to our assessment criteria. CONCLUSIONS: Systematic reviews synthesizing RCTs and NRSIs for harms frequently overlook essential methodological considerations and often draw conclusions without adequately addressing conflicting findings across study designs. These practices risk compromising the credibility of harm assessments used in clinical, regulatory, and policy decision-making.
Addressing the causes of 'missingness' in healthcare: a co-designed suite of interventions.
Lindsay C, Baruffati D, Mackenzie M … +6 more , Ellis DA, Major M, O'Donnell CA, Simpson SA, Wong G, Williamson AE
BMC Med · 2026 Jun · PMID 42363220 · Full text
BACKGROUND: Missingness refers to 'a repeated tendency not to take up offers of care that has a negative impact on the person and their life chances', visible in patterns of missed health appointments. Epidemiological wo...
BACKGROUND: Missingness refers to 'a repeated tendency not to take up offers of care that has a negative impact on the person and their life chances', visible in patterns of missed health appointments. Epidemiological work has shown that patients experiencing 'missingness' are more likely to have multiple physical and mental health conditions, to live in adverse or precarious circumstances, and experience a range of negative health outcomes. Yet existing approaches designed to address missed appointments rarely focus on these patients; when they do, it is often through a punitive lens rather than one that engages meaningfully with the causes of missingness. As a result, existing interventions are often ineffective for these patients and may instead worsen access inequalities. This study addresses this gap by outlining a co-produced 'suite' of interventions aimed at addressing the specific, complex causes of missingness. METHODS: The study synthesised findings from three co-occurring workstreams: an extensive realist review of 253 documents including peer-reviewed and grey literature; interviews with 61 'key informants' whose personal and professional experiences provided insight into causes and possible solutions; and a series of co-design workshops with a Stakeholder Advisory Group of 16 professionals and experts-by-experience aimed at designing and refining an intervention. RESULTS: The intervention consists of activities across several key domains: embedding a change of perspective around missed appointments; identification; relationships and communication; missingness coordinators; transport and logistics; flexibility; and contact around appointments. Unifying these activities, and crucial to their success, is a paradigm shift towards missed appointments that we term a 'missingness lens.' CONCLUSIONS: This intervention presented here is an evidence-informed, realistic and meaningful set of actions with the potential to address the complex causes of missingness and, by extension, access inequalities and wider health inequalities. Future interventional research into missed appointments should actively focus on or include 'missing' patients in design, implementation and the measurement of outcomes.
Social isolation and loneliness associate with early menopause and mortality in women: a UK Biobank cohort study.
Wang Y, Qi Y, Cao Z … +9 more , Xu K, Xia R, Zhao S, Cui L, Wei D, Zhao H, Tang S, Qin Y, Guo T
BMC Med · 2026 Jun · PMID 42363200 · Full text
BACKGROUND: Reproductive aging is an emerging public health priority amid demographic shifts. Early menopause (EM), indicative of accelerated reproductive aging, is associated with an elevated risk of premature mortality...
BACKGROUND: Reproductive aging is an emerging public health priority amid demographic shifts. Early menopause (EM), indicative of accelerated reproductive aging, is associated with an elevated risk of premature mortality. While social isolation (SI) and loneliness (LO) are established psychosocial determinants of health, their associations with EM and their combined effects with menopausal status on mortality risk remain unquantified. This study investigated the associations of SI and LO with EM and all-cause mortality. METHODS: This study included 79,578 Caucasian women from the UK Biobank cohort, of whom 6,778 experienced EM (menopause at age 40-45) and 72,800 experienced normal menopause (NM, age 46-55). SI (score: 0, 1, ≥2) was derived from three indicators: living arrangement, frequency of social contact, and participation in social activities; LO (score 0-2) was assessed based on self-reported loneliness and frequency of confiding in someone close. Multivariable-adjusted models were used to evaluate the odds of EM. All-cause mortality risk was assessed using Cox proportional hazards models, stratified by menopause status. RESULTS: Higher levels of SI and LO were independently associated with an increased prevalence of EM (e.g. SI ≥ 2: OR = 1.09, 95% CI 1.00-1.20; LO = 2: OR = 1.13, 95% CI 1.02-1.25). Critically, the detrimental impact of social adversity on survival was significantly greater in women with EM compared to those with NM. After full adjustment, women with EM and SI index ≥ 2 had a 55% increased mortality risk (HR = 1.55, 95% CI 1.21-1.99), whereas the risk increase for women with NM was 17% (HR = 1.17, 95% CI 1.07-1.28). A similar pattern was observed for LO (e.g. LO = 2, EM: HR = 1.42, 95% CI 1.07-1.88 vs. NM: HR = 1.14, 95% CI 1.02-1.27). Moreover, Kaplan-Meier curves showed a progressively wider survival gap between EM and NM as SI/LO levels increased. Lower SI and LO were associated with lower EM-related excess mortality. CONCLUSIONS: SI and LO were associated with EM and premature mortality. Women with EM are especially vulnerable to the negative effects of social adversity. Integrating psychological and social support into menopause care is essential, and reducing SI and LO may promote healthier aging. TRIAL REGISTRATION: NA.
A systematic review of ultra-processed food subtypes and risk of type 2 diabetes, combined with a cohort analysis, question the utility of broad food classifications for public health policy.
Fridén M, Mai M, Olsen A … +2 more , Dahm CC, Ibsen DB
BMC Med · 2026 Jun · PMID 42363199 · Full text
BACKGROUND: A key underlying principle of causal inference is that of well-defined interventions. Although ultra-processed food (UPF) has been associated with a greater risk of type 2 diabetes (T2D), subtypes of UPFs may...
BACKGROUND: A key underlying principle of causal inference is that of well-defined interventions. Although ultra-processed food (UPF) has been associated with a greater risk of type 2 diabetes (T2D), subtypes of UPFs may exert different strengths and directions of associations. The main objective of this study was to systematically evaluate the current literature on subtypes of UPFs and their associations with T2D and to contextualize these findings within the framework of sufficiently well-defined interventions for causal inference. METHODS: We searched PubMed and Embase for relevant articles. Cohort studies of adult men and women without T2D were included. Two independent researchers screened the articles and evaluated risk of bias using the ROBINS-E tool. UPFs were categorized into eight subtypes. A post-hoc analysis of 52,201participants in the Danish Diet, Cancer and Health (DCH) cohort was performed to illustrate the implications of vaguely defined interventions. We formed a fictive food group (the terrible five) combining foods that have been associated with T2D: sugar sweetened beverages, processed meat, red meat, refined grains and vegetables, and investigated the associations with T2D. RESULTS: Out of 222 articles screened for eligibility, 6 cohort studies with 635,332 participants (average follow-up of 6-26.1 years) were included. Most studies on UPF ready-to-eat-dishes; meat-based products; and artificially and sugar-sweetened beverages were positively associated with T2D whereas UPF dairy products; and sweets, snacks and confectionaries were generally inversely associated with T2D, although with some variation. Overall risk of bias was considered moderate to high in all included studies. In the DCH cohort, a positive association between the "terrible five" and T2D was observed. Intake of vegetables was inversely associated with T2D. CONCLUSIONS: The systematic review showed different strengths and directions of associations on the risk of T2D across the different subtypes of UPFs. Aggregating these sources into a coarse food category such as UPF may therefore undermine the core principle of well-defined interventions and, as illustrated in our post-hoc analysis, can mask individual associations. This study illustrates potential unintended consequences of broad food categorizations such as UPFs and hamper implementation of UPF policies without further improvement of the definition or mechanistic understanding. TRIAL REGISTRATION: The protocol was registered in PROSPERO (ID: CRD420251058458).
Next-generation of mesothelin-targeted CAR-T cells secreting anti-PD-L1 scFv for potent immunotherapy against 3D patient-derived colorectal cancer organoids.
Phanthaphol N, Kanoksing P, Riansuwan W … +9 more , Prapasrivorakul S, Ovartchaiyapong P, Mongkhonsupphawan A, Phumphuang S, Junking M, Thuwajit P, Yenchitsomanus PT, Thuwajit C, Thongchot S
BMC Med · 2026 Jun · PMID 42363170 · Full text
BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapies have revolutionized the landscape of cancer treatment, particularly in hematological malignancies. However, their successful translation to solid tumors remain...
BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapies have revolutionized the landscape of cancer treatment, particularly in hematological malignancies. However, their successful translation to solid tumors remains limited by several barriers, including immunosuppressive tumor microenvironment and on-target/off-tumor toxicity. One promising strategy to enhance efficacy of CAR-T cells is the rational selection of tumor-specific antigens coupled with engineering strategies that incorporate localized immune modulation, such as CAR-T cells secreting immune checkpoint-blocking anti-PD-L1 scFv. METHODS: To better model therapeutic responses, we established a dynamic real-time autologous co-culture platform integrating colorectal cancer (CRC) patient-derived organoids (PDOs) and CAR-T cells to assess infiltration, persistence, and cytotoxicity ex vivo. Although early clinical trials of mesothelin (MSLN)-directed CAR-T cells have demonstrated high safety, their anti-tumor efficacy remains modest, highlighting the need for improved constructs. Therefore, we engineered anti-MSLN-CAR4-T cells using fully human anti-MSLN scFv linked to a triple costimulatory backbone (CD28, 4-1BB, and CD27) fused to CD3ζ, and anti-MSLN-CAR5-T cells, incorporating an additional anti-PD-L1 scFv. RESULTS: Both CAR4- and CAR5-T cells exhibited comparable cytotoxic efficacy against MSLN/PD-L1 autologous PDOs. However, only anti-MSLN-CAR5-T cells were able to sustain potent killing activity against PD-L1 PDOs with high IFN-γ/cytolytic cytokine production at a low effector-to-target ratio (5:1), reflecting improved resilience to PD-L1-mediated suppression. CONCLUSIONS: Finally, our 14-day ex vivo CRC-PDOs/CAR-T platform provides a promising rapid and translational tool for tumor-associated antigen validation, streamlined PDO isolation, autologous CAR-T cytotoxicity testing, and personalized immunotherapy optimization in solid tumors.
40 Hz biparietal transcranial alternating current stimulation for Alzheimer's disease: a prospective study.
Ma X, Yuan M, Gao Y … +8 more , Guo Z, Liang J, Yan F, Wang S, Qiu H, He S, Li Y, Wang Y
BMC Med · 2026 Jun · PMID 42363162 · Full text
BACKGROUND: Alzheimer's disease (AD) is characterized by dysfunction in multiple cognitive domains. Patients with AD demonstrate a relative attenuation and dysregulation of theta and gamma oscillations in the temporal an...
BACKGROUND: Alzheimer's disease (AD) is characterized by dysfunction in multiple cognitive domains. Patients with AD demonstrate a relative attenuation and dysregulation of theta and gamma oscillations in the temporal and parietal lobes at an early stage. Transcranial alternating current stimulation (tACS) has been shown to modulate neural oscillations in different regions of the brain, affecting higher cognitive functions such as motor function, memory, and learning. OBJECTIVE: To observe the clinical efficacy and after-effects of biparietal 40 Hz tACS in treating AD patients, to analyze its safety and feasibility, and to deeply explore the effects of tACS on time-varying brain networks and dynamic functional connectivity. METHODS: In the study, patients with mild AD who were treated in the First Hospital of Hebei Medical University from October 2022 to August 2023 were recruited, randomly divided into tACS group or Sham group, and then respectively received either biparietal 40 Hz tACS or sham stimulation for 15 consecutive days, each lasting 30 min. Neuropsychological assessment scales were collected to assess the efficacy at three time points: pre-stimulation, post-stimulation, and 10-week follow-up. Additionally, transcranial magnetic stimulation with electroencephalography (TMS-EEG) and functional magnetic resonance imaging (fMRI) were collected to explore time-varying brain networks and functional connectivity. RESULTS: Patients with AD exhibited improvements in global cognition, memory, language, attention, and executive functions following tACS treatment compared with those before treatment. Additionally, the neuropsychiatric inventory scores were decreased significantly after tACS treatment. The clinical efficacies were not obvious in Sham group. These results indicated that tACS treatment had significant short-term efficacy and good stability. The brain time-varying EEG network patterns were analyzed using the adaptive directed transfer function. The analysis showed enhanced information flows from the temporal and prefrontal regions and from the posterior to anterior regions after tACS treatment. In contrast, decreased information flow was observed from the left to right frontal regions. The fMRI analysis revealed enhanced connectivity within default mode network and between default mode network and Frontoparietal network after active treatment. CONCLUSIONS: The 40 Hz biparietal tACS is a potentially safe and effective treatment for AD with certain long-term efficacy by modulating dynamic functional connectivity. TRIAL REGISTRATION: The trial was retrospectively registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2500115019).
Targeting CCR7-KMT2D enhances CAR-T cell efficacy by suppressing therapy-induced senescence in B-cell non-Hodgkin lymphoma.
Li J, Huang K, Wang H … +14 more , Chen W, Zhang Y, Jiang S, Cao N, Zhang W, Liu Z, Chen J, Chen D, Yang Z, Tao Q, Liu C, Zhai Z, An F, Wang J
BMC Med · 2026 Jun · PMID 42363110 · Full text
BACKGROUND: The efficacy of anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy has been demonstrated in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL). However, therapy-induced senescence...
BACKGROUND: The efficacy of anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy has been demonstrated in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL). However, therapy-induced senescence (TIS) has been identified as a novel resistance mechanism, potentially exacerbating immunosuppression and impairing CAR-T cell function. METHODS: Raji and SU-DHL-2 cells were treated with 40 nM doxorubicin (Dox) for 72 h to induce TIS, and CCR7 was inhibited with 10 µg/mL Cap-100. Cellular senescence was assessed by SA-β-Gal staining and flow cytometry; proliferation and apoptosis by CCK-8 and Annexin V/PI, respectively. CAR-T cytotoxicity was evaluated via flow cytometry. CCR7 expression on T cells from B-NHL patients and healthy controls was measured. Lentiviral transduction regulated CCR7 expression; protein expression and interactions were analyzed by Western blot and Co-IP. NF-κB and ARHGAP/RhoA pathways were inhibited using GS143 and Y27632, respectively. RESULTS: CCR7 overexpression enhanced SASP, while knockdown attenuated it. In the Dox-induced TIS model, KMT2D decreased, whereas H3K9me3, CCR7, and LGALS9 increased; CCR7 inhibition reversed these changes. Cap-100 improved CD19 CAR T killing by alleviating exhaustion in co-culture. Mechanistically, Cap-100 stabilized IκBα to inhibit NFκB, and inhibition of NFκB or ROCK reversed pro-senescence. Cap-100 reduced T cell proliferation but did not affect apoptosis or exhaustion. Clinically, CCR7 was lower on T cells from B NHL patients than healthy controls, and higher CCR7 correlated with better T cell quality. Transcriptomics showed Dox activated TIM3/Galectin 9 and PD- 1/PD-L1 pathways, while Dox + Cap-100 suppressed them. Co-IP confirmed interactions among CCR7, KMT2D, and LGALS9. Collectively, Dox induced TIS to upregulate CCR7, increasing SASP and LGALS9, which interacted with TIM-3, causing immune cell exhaustion and reducing killing efficiency; CCR7 blockade reversed this state and enhanced cytotoxicity. CONCLUSIONS: Our findings demonstrate that blockade of KMT2D-CCR7-mediated senescence enhances CD19 CAR-T cell anti-tumor activity in B-NHL.
Multimodal deep learning-based prediction of radiation-induced temporal lobe injury via anatomical imaging and spatial dose: A multicenter study.
Yang SS, Zhang LN, He Y … +3 more , Feng AL, Yang Z, OuYang PY
BMC Med · 2026 Jun · PMID 42351158 · Full text
BACKGROUND: To develop and validate a multimodal deep learning model for pre-treatment prediction of radiation-induced temporal lobe injury (RTLI), and to evaluate its generalizability across nasopharyngeal carcinoma-end...
BACKGROUND: To develop and validate a multimodal deep learning model for pre-treatment prediction of radiation-induced temporal lobe injury (RTLI), and to evaluate its generalizability across nasopharyngeal carcinoma-endemic and non-endemic regions. METHODS: In this multicenter retrospective study, 6847 patients with nasopharyngeal carcinoma from five institutions in southern and northern China were included. A 3D ResNet-based multimodal deep learning model integrating planning CT images, spatial dose distribution maps, dosimetric variables, and clinical factors was developed and validated, and subsequently evaluated in internal and multiple external test cohorts. Model performance was assessed using the concordance index and compared with reduced-modality deep learning models, a dosiomics risk model, and conventional reference models. Model interpretability was explored using gradient-weighted class activation mapping (Grad-CAM). RESULTS: The multimodal deep learning model demonstrated robust predictive performance, achieving concordance indices of 0.817, 0.825, 0.767, 0.901, and 0.815 across the internal, three southern external, and northern external test cohorts, respectively, and significantly outperforming all comparator models (all P < 0.001). Incremental performance gains were observed with multimodal integration, and CT imaging improved performance in the deep learning framework but not in the dosiomics risk model. The model enabled reliable identification of patients at high risk of RTLI. Grad-CAM visualization links model outputs to spatial dose-tissue interactions to guide radiotherapy plan optimization. CONCLUSIONS: Multimodal deep learning integrating anatomical imaging, spatial dose information, and clinical context enables accurate and generalizable pre-treatment prediction of RTLI across diverse regions. Spatially interpretable outputs further support individualized risk stratification and establish a biologically and dosimetrically informed foundation for risk-adapted radiotherapy planning.
Association of adjuvant somatostatin analogue therapy with disease-free survival in patients with gastroenteropancreatic neuroendocrine tumours: a Chinese multi-institutional propensity score matched and weighted analysis (CASSANET-GEP).
Wang H, Hao J, Su Y … +20 more , Chen Q, Li E, Wu Y, Cao D, Yu J, Lu H, Wang G, Wang C, Zhao H, Zhao D, Wang J, Wang X, Xu J, Wang M, Li X, Sun Y, Wang J, Tang Q, Song L, Chi Y
BMC Med · 2026 Jun · PMID 42351129 · Full text
BACKGROUND: Recurrence remains a major concern after curative-intent resection of gastroenteropancreatic neuroendocrine tumours (GEP-NETs), and evidence to guide postoperative adjuvant therapy is limited. METHODS: We per...
BACKGROUND: Recurrence remains a major concern after curative-intent resection of gastroenteropancreatic neuroendocrine tumours (GEP-NETs), and evidence to guide postoperative adjuvant therapy is limited. METHODS: We performed a multicentre retrospective cohort study across nine university-affiliated hospitals in China, including patients with grade 1-3 GEP-NETs who underwent curative-intent resection between January 2007 and December 2024; follow-up ended on 1 October 2025. Exposure was postoperative adjuvant SSAs. The primary endpoint was disease-free survival (DFS) and the secondary endpoint was overall survival (OS). DFS and OS were estimated using Kaplan-Meier methods, and associations were evaluated using Cox regression after propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). Time-related bias was addressed using time-dependent Cox and landmark analyses at 3 and 6 months after surgery. RESULTS: Among 1602 patients, 358 received adjuvant SSAs. After 1:1 PSM, 560 patients were retained with improved baseline balance. Adjuvant SSAs were associated with a lower recurrence risk in the overall cohort in unadjusted (HR 0.466, 95% CI 0.323-0.673; p < 0.001) and IPTW-adjusted analyses (HR 0.419, 95% CI 0.278-0.631; p < 0.001), with similar directionality in G-NETs and P-NETs, whereas estimates in E-NETs were imprecise. In time-dependent Cox analyses treating SSAs as an ever-started time-varying exposure, adjuvant SSAs remained associated with longer DFS in the whole cohort (adjusted HR 0.519, 95% CI 0.353-0.764; p < 0.001), and findings were consistent in landmark analyses at 3 months (adjusted HR 0.523, 95% CI 0.339-0.806; p = 0.003) and 6 months (adjusted HR 0.537, 95% CI 0.356-0.811; p = 0.003). In the overall cohort, 24- and 36-month DFS rates were 92.4% and 89.3% in the SSAs cohort versus 86.9% and 84.2% in controls, respectively; corresponding 24- and 36-month OS rates were 99.1% and 98.7% versus 97.2% and 96.9%, respectively. CONCLUSIONS: In this large multicentre real-world cohort, adjuvant SSAs were associated with longer DFS after curative-intent resection of GEP-NETs. The overall direction of association remained consistent in propensity-adjusted, time-dependent, and landmark analyses, supporting the robustness of the primary findings. Prospective studies are needed to confirm effectiveness and refine patient selection.
A 3D pooled PBMC-organoid co-culture platform for profiling immune susceptibility and PD-1 blockade response in gastric cancer.
Mun HB, Kwon WS, Park CH … +9 more , Koo H, Jang J, Yoon BG, Park J, Moon YJ, Lee CK, Jeung HC, Kim TS, Rha SY
BMC Med · 2026 Jun · PMID 42343402 · Full text
BACKGROUND: Peritoneal metastatic gastric cancer (PMGC) is associated with a dismal prognosis and limited benefit from immune checkpoint inhibitors (ICIs). Although PD-1/PD-L1 blockade has improved outcomes in selected p...
BACKGROUND: Peritoneal metastatic gastric cancer (PMGC) is associated with a dismal prognosis and limited benefit from immune checkpoint inhibitors (ICIs). Although PD-1/PD-L1 blockade has improved outcomes in selected patients, therapeutic responses remain highly heterogeneous, even among PD-L1-high tumors. The lack of preclinical models that functionally recapitulate tumor-immune interactions in a three-dimensional (3D) context has hindered the investigation of immune susceptibility and resistance mechanisms in PMGC. METHODS: We established a standardized allogeneic 3D co-culture platform integrating patient-derived PMGC organoids with pooled peripheral blood mononuclear cells (PBMCs) from healthy donors. An optimized Matrigel-embedded configuration was used to enable sustained immune cell infiltration and tumor-immune contact. Immune-mediated cytotoxicity, organoid susceptibility phenotypes, and responses to PD-1 blockade with pembrolizumab were functionally assessed. Comparative proteomic profiling was performed, and differential expression between groups was evaluated using appropriate statistical tests with false discovery rate correction. Group comparisons were conducted using Student's t-test. RESULTS: The optimized 3D embedded system enabled dynamic infiltration of activated T cells into organoid structures. PMGC organoids exhibited heterogeneous susceptibility to immune-mediated cytotoxicity, classifying them into cytolytic and noncytolytic phenotypes independent of HLA mismatching. Comparative proteomic profiling revealed that cytolytic lines were enriched in metabolic pathways, whereas noncytolytic lines showed enrichment of immune-related signaling. Notably, response to pembrolizumab varied even among PD-L1-high organoids. Nonresponsive PD-L1-high lines were characterized by elevated baseline expression of alternative immune checkpoint ligands, specifically CD112 (TIGIT ligand) and galectin-9 (TIM-3 ligand). CONCLUSIONS: We established a robust pooled PBMC-organoid co-culture platform that enables functional assessment of tumor-immune dynamics in PMGCs. This system serves as a functional ex vivo tool for evaluating immunotherapy responses and for examining the expression patterns of alternative immune checkpoint ligands associated with differential PD-1 blockade response. These findings support the utility of this ex vivo PMGC co-culture system for evaluating heterogeneous responses to PD-1 blockade and associated baseline differences in alternative immune checkpoint ligand expression among PD-L1-high organoids.
Clinical care patterns in the 10-years prior to primary total hip replacement: a matched population-based case-control analysis in England.
Menon D, Mathew S, Peat G … +6 more , Hellberg C, Turkiewicz A, Dell'Isola A, Englund M, Thomas G, Yu D
BMC Med · 2026 Jun · PMID 42343375 · Full text
BACKGROUND: The quality of evidence supporting recommendations for conservative hip osteoarthritis management limits the treatment options available to patients prior to surgery. The care individuals receive prior to the...
BACKGROUND: The quality of evidence supporting recommendations for conservative hip osteoarthritis management limits the treatment options available to patients prior to surgery. The care individuals receive prior to their eventual total hip replacement (THR) is likely to be variable and complex. These long-term care patterns remain undefined. METHODS: A population-based retrospective case-control study using linked primary and secondary care data (CPRD Aurum/HES APC) in England was conducted to identify the longitudinal prevalence of surgical, pharmacological and non-pharmacological care strategies in the 10 years preceding THR between 2007 and 2021. 480,598 individuals (240,299 THR recipients matched 1:1 to non-recipients) were identified. Prevalence rate ratios (PRRs) modelled chronological changes in care, referencing the 6-month period immediately prior to surgery (or index date for controls). Conditional logistic regression estimated odds ratios (ORs) for THR adjusted for confounders. RESULTS: The prevalence of all pharmacological prescriptions increased over the 10-year observation period prior to THR, with an escalation in rates for opioids, oral NSAIDs and paracetamol starting at 24 months before surgery. All medication prescriptions were consistently higher in females across all time periods. The prevalence of sick leave and referrals for physiotherapy, hip imaging and pain clinic (non-pharmacological care) also increased. Hip injection prevalence increased from 0.03% at 12 months (6 to 12 month period) to 15.1% at 6 months (0 to 6 month period) pre-THR. Prescriptions for all analgesic sub-types, antidepressants, sick leave, and referrals for physiotherapy, pain clinic and hip imaging had increased odds of THR throughout the observation period. Strong opioid use in the final 6-month period represented the strongest association with surgery (OR 5.0 [95% CI 4.7, 5.2]). Younger patients consistently demonstrated a lower prevalence of medication prescriptions, and higher prevalence of sick leave issuance, relative to older groups. CONCLUSIONS: Escalating care is observed from 24 months prior to surgery among individuals who progress to THR. Prevalence of paracetamol and opioid prescriptions are high. Important age-related differences in care provision prior to THR relating to medication prescriptions and non-pharmacological interventions are present. This is accompanied by long-term elevated rates of sick leave in the working population.
Targeting the posterior thalamic hub: hemispheric-specific encoding of pain-depression comorbidity after hemorrhagic stroke.
Jin Y, Lv Y, Wu X … +5 more , Liu C, Guo W, Cui Y, Dong Y, Tong L
BMC Med · 2026 Jun · PMID 42343355 · Full text
BACKGROUND: Post-stroke pain (PSP) and post-stroke depression (PSD) frequently co-occur after thalamic hemorrhage and may mutually exacerbate one another, with persistent pain contributing to affective dysfunction and de...
BACKGROUND: Post-stroke pain (PSP) and post-stroke depression (PSD) frequently co-occur after thalamic hemorrhage and may mutually exacerbate one another, with persistent pain contributing to affective dysfunction and depression altering sensory processing. Because current symptom-specific treatments often provide limited benefit, identifying shared neural mechanisms underlying PSP-PSD comorbidity may offer a more clinically relevant framework for developing targeted circuit-based therapies. METHODS: Twelve patients with isolated anterior or posterior thalamic hemorrhage underwent parallel multimodal assessments, including standardized pain, mood, anxiety, and cognitive evaluations together with structural MRI, diffusion tensor imaging, and resting-state functional MRI to characterize lesion topography and thalamocortical connectivity. Guided by the clinical findings, we subsequently established nucleus-specific murine models of thalamic hemorrhage using stereotactic collagenase injection. Mice underwent sequential behavioral phenotyping, fiber photometry recording, and viral tracing analyses to investigate the circuit mechanisms underlying pain-depression comorbidity. RESULTS: In patients, posterior thalamic hemorrhage was the exclusive locus for PSP-PSD comorbidity and exhibited severe disruption of thalamocortical functional connectivity, with right-sided lesions having the most profound effect. In mice, focal hemorrhage confined to the posterior thalamic nucleus (PO), but not adjacent parafascicular or ventral posterolateral nuclei, recapitulated both mechanical hyperalgesia and delayed depression-like behaviors. In the murine model, we uncovered a striking hemispheric specialization: left PO lesions induced anhedonia, while right PO lesions led to behavioral despair. PO neurons became hyperexcitable to pain after hemorrhage, a state amplified with PSD onset. Viral tracing revealed lateralized PO projections to somatosensory cortices. CONCLUSIONS: The posterior thalamic nucleus represents a lateralized thalamocortical substrate for post-stroke pain-depression comorbidity after hemorrhagic stroke. These findings support the potential value of lesion-topography-based prognostic stratification and circuit-guided neuromodulation strategies targeting both sensory and affective symptoms. A major limitation of this study is the relatively small but carefully phenotyped clinical cohort, which warrants validation in larger longitudinal studies.
Risk factors and treatment strategies for live birth in women with high BMI undergoing ART.
Nie Y, Huang Y, Kuang Z … +6 more , Yin M, Shen X, Liu Y, Gao H, Long H, Wang L
BMC Med · 2026 Jun · PMID 42337575 · Full text
BACKGROUND: Women with a high BMI represent a growing and challenging population in assisted reproductive technology, as known impairments to treatment outcomes. However, the specific risk factors contributing to recurre...
BACKGROUND: Women with a high BMI represent a growing and challenging population in assisted reproductive technology, as known impairments to treatment outcomes. However, the specific risk factors contributing to recurrent live birth failure and the potential treatment strategies to overcome initial setbacks in this group remain unclear. METHODS: In this large-scale retrospective cohort study (2010-2023), 10,581 women were stratified into overweight (BMI 24-27.99 kg/m ², n = 8,350) and obese (BMI ≥ 28 kg/m ², n = 2,231) groups. Two-tiered analysis used generalized linear mixed models (GLMMs): (1) multilevel multinomial logistic regression to identify risk factors for recurrent failure; and (2) multilevel logistic regression to evaluate treatment strategies following initial failed frozen embryo transfers (FETs). RESULTS: In the risk factor analysis, women with recurrent failure were older (33-35 years) and had poorer ovarian reserve (AFC ~ 7-9) than those with live birth (~ 31 years, AFC ~ 12-15). Multivariable analysis confirmed advanced maternal age as a key risk factor (aOR = 1.98, 95% CI: 1.85-2.12). Higher hMG dose per mature follicle increased single-failure risk versus < 350 IU: for 350-500 IU, aOR = 1.43, 95% CI: 1.16-1.76 (overweight) and 1.66, 95% CI: 1.14-2.43 (obese); for > 500 IU, aOR = 1.77, 95% CI: 1.45-2.16 (overweight) and 1.58, 95% CI: 1.1-2.25 (obese). Switching to PPOS-versus mild stimulation-was associated with a lower risk of continued failure (aOR = 0.54, 95% CI: 0.40-0.74). Propensity score matching confirmed PPOS positively related with embryological yields; live birth rates were higher but not statistically significant (45.7% vs. 43.7%). Blastocyst transfer (aOR = 0.54, 95% CI: 0.42-0.69) was associated with a lower risk of continued failure. CONCLUSIONS: This study is, to our knowledge, one of the largest studies to systematically distinguish non-modifiable baseline risks (age and AFC) from modifiable ART-related factors (stimulation protocol, hMG dosage, and embryo transfer policy) for recurrent failure in a large population with high-BMI. This distinction provides preliminary insights to implement risk-stratified clinical approaches, especially for lower-risk patients. These approaches include adopting PPOS, optimizing gonadotropin dosage, and cautiously individualizing embryo transfer strategy, which may serve as potential therapeutic alternatives after initial setbacks.
Circulating imidazole propionate and coronary heart disease risk: interplay between histidine intake, fiber, and gut microbiome.
Liang X, Zhu L, Li J … +12 more , Li Y, Ivey KL, Lee KH, Eliassen AH, Chan AT, Huttenhower C, Zhang C, Hu FB, Qi Q, Hu Y, Rimm EB, Sun Q
BMC Med · 2026 Jun · PMID 42332773 · Full text
BACKGROUND: Imidazole propionate (ImP), a microbial metabolite of histidine, may impair glucose metabolism, but its relevance to coronary heart disease (CHD) risk and potential diet-microbiota regulations remain unclear....
BACKGROUND: Imidazole propionate (ImP), a microbial metabolite of histidine, may impair glucose metabolism, but its relevance to coronary heart disease (CHD) risk and potential diet-microbiota regulations remain unclear. We aimed to examine prospective associations of plasma ImP levels and histidine intake with CHD risk, to identify ImP-predicting gut microbes, and to investigate diet-microbiome interactions influencing ImP levels. METHODS: Associations of ImP and histidine with CHD risk were evaluated using Cox models in 7,432 participants from Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-up Study. Microbiome-diet interactions influencing ImP levels were assessed using fecal metagenome and 7-day diet record data in 296 men from the Men's Lifestyle Validation Study, with replication in the Mind-Body Study. RESULTS: Higher plasma ImP was associated with increased CHD risk (HR comparing extreme quintiles = 1.82; 95%CI = 1.17-2.81; p-trend = 0.002), while histidine intake showed a non-significant inverse association. Although histidine intake was not associated with ImP levels, the intake of fiber, especially pectin, emerged as a key negative predictor. We identified 17 distinct ImP-predicting species, including Clostridium and Blautia species. A parametric ImP-microbial score was constructed based on these species to represent the microbial capacity of producing ImP. Further functional characterization uncovered that the microbial urocanate reductase gene urdA was also associated with cardiovascular risk markers. No significant interaction was observed between histidine intake and the microbial score on ImP levels, but ImP levels increased with higher histidine intake and higher microbial score only under low pectin intake (p for 3-way interaction = 0.01). Similar interactions were seen for total fiber (p = 0.09), soluble fiber (p = 0.09), and insoluble fiber (p = 0.11), without statistical significance. CONCLUSIONS: ImP, but not its dietary precursor histidine, was associated with a higher CHD risk. The gut microbial metabolism of ImP appeared context-dependent, with ImP production from histidine associated with a higher ImP-producing microbial capacity and lower fiber intake. These findings highlight the potential role of dietary fiber and gut microbiome in modulating diet-health associations related to ImP metabolism.
Matrigel/serum-free, high-fidelity patient-derived tumor-like cell clusters as an in vitro platform for large-scale compound screening and chemoresistance prediction in oral cancer.
Luo Y, Li J, Xie S … +17 more , Yin S, Li J, Zhao J, Sun Y, Qian R, He X, Ge F, Xiao Z, Sui Y, Wang L, Yu H, Lu H, Zhang H, Ye B, Shan X, Cai Z, Xi JJ
BMC Med · 2026 Jun · PMID 42332684 · Full text
BACKGROUND: Current drug regimens for oral cancer are primarily based on generalized clinical guidelines, lacking a precision medicine strategy to tailor therapies to individual patients. This gap highlights the need for...
BACKGROUND: Current drug regimens for oral cancer are primarily based on generalized clinical guidelines, lacking a precision medicine strategy to tailor therapies to individual patients. This gap highlights the need for robust humanized models that can accurately reflect tumor characteristics and guide personalized treatment selection. METHODS: We developed patient-derived tumor-like cell clusters (PTCs) for oral cancer, an ex vivo model designed to preserve key tumor features including the immune microenvironment, phenotype, and genotype. Then, a prospective observational clinical validation study (ChiCTR2300075543) was conducted in 42 patients with advanced oral squamous cell carcinoma (OSCC) to evaluate the utility of PTC-guided sensitivity testing for the TPF neoadjuvant chemotherapy regimen (docetaxel, cisplatin, fluorouracil). Additionally, the PTC platform was utilized for high-throughput drug screening, and transcriptomic analysis was performed to identify potential predictive biomarkers. RESULTS: PTCs were generated with a success rate exceeding 97% (161/165) using minimal tissue samples (≥ 10 mg). PTC-guided sensitivity testing for the TPF regimen showed ~90% (34/38) concordance with clinical outcomes in advanced OSCC patients. Moreover, the PTC platform successfully enabled high-throughput drug screening (> 100 compounds within two weeks), facilitating the identification of novel anti-cancer targets. Specifically, transcriptomic analysis revealed that upregulation of MMP13 is highly associated with treatment resistance (Pearson's r = 0.90, P < 0.01). CONCLUSIONS: Our PTC-based platform robustly preserves critical tumor characteristics and demonstrates high concordance with clinical treatment outcomes, making it a valuable tool for selecting personalized therapies in oral cancer. Its capacity for large-scale compound screening also supports novel anti-cancer target discovery. Furthermore, MMP13 emerges as a potential predictive biomarker for treatment resistance. Collectively, this PTC platform represents a transformative precision medicine approach to advance personalized therapy and drug discovery in oral cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: ChiCTR2300075543; registered prospectively on September 7, 2023.
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