Frontiers of Medicine最新文献

We hypothesized that gene networks converged between plasma cell development and multiple myeloma (MM) pathogenesis may better explain the clinical heterogeneity in individual MM patients. Here, we transformed the reciprocal expression pattern between a gene module centered on the expression of MCL1 and another gene module represented by the expression of TLR10 from individual MM transcriptomes into a myeloma classification score (MCS). MCS enabled prognostication in 1738 patients with newly diagnosed MM (NDMM) and 319 patients with relapsed/refractory MM (RRMM) from our own observational cohort, from MMRF, and from five prospective trials. MCS also enabled the discrimination between progressive and stable disease states in the longitudinal samples from 85 patients in MMRF and the PETHEMA/GEM2012MENOS65 trial. MCS further enabled prediction of the responses to bortezomib-based treatment in 425 patients enrolled in the HOVON-65/GMMG-HD4 and APEX (039) trials, and the response to carfilzomib-based treatment in 86 transplantation-eligible patients from MMRF. MCS-defined risk groups harbored distinct targetable pathways, including unfolded protein response, replication stress, genomic instability and interferon responses. However, MCS-based individualized prediction of prognosis and treatment response was independent of the hitherto available prognostic models. Thus, MCS represents an alternative biomarker for risk stratification and prediction of treatment response in individual MM patients.

Fulminant myocarditis (FM) is an acute inflammatory condition that results in a rapidly progressive, life-threatening circulatory failure and cardiogenic shock. This condition is characterized by severe endotheliitis and concurrent cytokine storm, which give rise to a wide spectrum of clinical manifestations and complications, including thromboembolism, myositis, and arrhythmia. Herein, we report an extremely rare case involving a 48-year-old woman diagnosed with FM associated with influenza virus type A, presenting with abdominal aortic occlusion due to acute thrombosis. Echocardiography revealed a significant reduction in global cardiac function (left ventricular ejection fraction, 26%), accompanied by left ventricular mural thrombosis. Enhanced computed tomography (CT) and angiography revealed an in situ aortic thrombosis affecting the infrarenal abdominal aorta and branches of the superior mesenteric artery, bilateral common iliac arteries, and internal and external iliac arteries. The patient was provided with a comprehensive treatment involving anticoagulants (enoxaparin, tirofiban), immunomodulatory agents (methylprednisolone, immunoglobulin), antiviral agent (oseltamivir), and intra-aortic thrombus aspiration via the right femoral artery. After undergoing these treatments for 19 days, her cardiac function returned to normal and subsequent CT images showed a dramatic reduction in aortic thrombosis. Moreover, full recovery of blood flow and movement function of the bilateral lower extremities was observed.

Zusanli (ST36), one of the most essential acupoints in clinical acupuncture practice, is considered as an intervention strategy for disease prevention and longevity promotion in traditional Chinese medicine (TCM). However, the prophylactic effects of ST36 have yet to be investigated in clinical studies. In the present study, we conducted a single-arm, open-label, pilot clinical trial to evaluate the prophylactic effects of stimulating the ST36 acupoint through acupuncture and moxibustion in middle-aged and elderly participants. Of the 85 participants who completed the first 2 months of acupuncture and moxibustion, 48 continued through the remaining 4 months to complete the full 6-month intervention. For 6 months acupuncture and moxibustion at ST36 significantly reduced levels of low-density lipoprotein (LDL) and uric acid (UA) in individuals with initially abnormal LDL and UA values. The median LDL levels decreased from 4.46 mmol/L (IQR 4.32-4.71) to 3.97 mmol/L (IQR 3.32-4.47) (P = 0.004) and the median UA levels decreased from 399.00 µmol/L (IQR 356.00-483.00) to 361.00 µmol/L (IQR 323.00-421.00) (P = 0.003). Additionally, ST36 intervention led to marked reductions in the levels of lactic dehydrogenase (LDH) (266.50 U/L (IQR 257.50-282.25) to 235.50 U/L (IQR 215.50-244.75), P < 0.001) at 6 months, and α-hydroxybutyrate dehydrogenase (α-HBDH) (195.50 U/L (IQR 190.25-212.00) to 181.00 U/L (IQR 165.75-187.25), P = 0.017) at 2 months. Notably, ST36 acupuncture and moxibustion also showed positive effects on sleep quality, knee joint function, and bowel movement patterns, and there were no syncope, severe pain or other adverse reactions. These findings provide clinical evidence that ST36 acupoint stimulation confers holistic health benefits for middle-aged and elderly populations, while maintaining an excellent safety profile.

Congenital heart defect (CHD) is a leading cause of neonatal mortality, with early maternal risk factors playing a significant role in its development. This systematic review and meta-analysis investigated the relationship between maternal factors during the first trimester and CHD. The study protocol was registered on PROSPERO (CRD42023476855). MEDLINE, Embase, and Cochrane TRIALS were systematically searched for eligible cohort and case-control studies. The primary outcome was the risk of the fetus developing CHD under the effects of maternal factors. The outcome was estimated by odds ratios (ORs) and 95% confidence interval (CI) using the random-effects model. Seventy-eight studies with 393 534 cases and 29 493 495 controls were included. Maternal pre-pregnancy diabetes (OR 2.91, 95% CI 2.10-4.03), obesity (OR 1.23, 95% CI 1.13-1.33), active (OR 1.28, 95% CI 1.03-1.57) and passive smoking (OR 2.67, 95% CI 1.30-5.46), and chronic hypertension (OR1.39, 95% CI 1.02-1.90) significantly increased the risk of overall CHD in offspring. While underweight was not associated with overall CHD, it showed a slight association with ventricular septal defect (OR 1.10, 95% CI 1.02-1.18). These findings emphasize the importance of optimizing maternal health and lifestyle before and during pregnancy and provide evidence for public health strategies to reduce the risk of CHD.

Endoplasmic reticulum stress (ERS) is commonly observed in liver cancer and is associated with drug sensitivity. Consequently, ERS-related genes may serve as targets for enhancing treatment sensitivity. This study analyzed RNA and proteomic sequencing data from induced and non-induced ERS and identified hypoxia-upregulated protein 1 (HYOU1) as an ERS-related gene. We confirmed that ERS regulated HYOU1 expression. Database and microarray analyses revealed that HYOU1 expression level was significantly higher in cancer tissues than in normal tissues (P < 0.05). Additionally, HYOU1 upregulation correlated with poor clinical outcomes (P < 0.05). Findings from animal experiments, CCK-8 assays, colony formation assays, wound healing assays, transwell assays, and flow cytometry results showed that HYOU1 decreased the inhibition of cell proliferation, migration, invasion, and tumor growth while inducing apoptosis. Conversely, HYOU1 overexpression caused the opposite effects. Combining RNA-sequencing data from HYOU1 knockdown and Western blot (WB) results, we have, for the first time, identified that HYOU1 activates the ERK/MAPK pathway. We show that ERS promotes resistance to lenvatinib, whereas HYOU1 knockdown increases sensitivity to lenvatinib. We believe that HYOU1 plays a crucial role in treating lenvatinib-resistant liver cancer.

The cytochrome P450 enzyme CYP4F11, a pivotal regulator of fatty acid metabolism and drug metabolism, exhibits significantly overexpression in non-small cell lung cancer (NSCLC) and is associated with poor clinical outcomes. Through integrated analysis of TCGA/GEO datasets and immunohistochemistry validation of 235 NSCLC specimens, we established CYP4F11 as a novel prognostic biomarker. Functional studies demonstrated that CYP4F11 knockdown markedly impaired NSCLC cell proliferation, clonogenicity, and migration in vitro, moreover xenograft models confirmed its tumor-promoting role in vivo. Mechanistically, we identified CYP4F11 as a direct target of tumor suppressor miR-195 via 3'-UTR binding, with miR-195-mediated suppression of CYP4F11 leading to ubiquitin-proteasomal degradation of mitochondrial malic enzyme 2 (ME2) - a critical metabolic regulator in cancer cells. Metabolomic analyses revealed that CYP4F11 depletion disrupts mitochondrial malate metabolism, while rescue experiments confirmed ME2's pivotal role in mediating CYP4F11's oncogenic effects. Our findings elucidate the CYP4F11/miR-195/ME2 regulatory axis as a crucial determinant of NSCLC progression, highlighting CYP4F11 as both a prognostic indicator and a potential therapeutic target through modulation of cancer cell metabolism.

Polycystic ovary syndrome (PCOS) is a prevalent chronic disorder characterized by reproductive, endocrine, and metabolic abnormalities in women worldwide. Increasing evidence has implicated the gut microbiota in the pathogenesis of PCOS, raising the possibility that probiotic interventions could offer therapeutic benefits. Akkermansia muciniphila (AKK), known for its metabolic and immunomodulatory properties, remains underexplored in the context of PCOS. In this study, we utilized a dehydroepiandrosterone (DHEA)-induced PCOS model in Sprague-Dawley (SD) rats to investigate the therapeutic potential of a novel AKK strain, PROBIO (referred to as AP). Treatment with AP significantly alleviated multiple PCOS-related phenotypes, including hyperandrogenism, elevated luteinizing hormone to follicle-stimulating hormone (LH/FSH) ratio, disrupted estrous cycle, abnormal ovarian morphology, and impaired glucose metabolism. Mechanistically, 16S rRNA gene sequencing and untargeted metabolomics revealed that AP partially exerted its beneficial effects by modulating DHEA-induced gut microbiota dysbiosis. Notably, metabolomic profiling indicated enhanced arginine biosynthesis and increased serum L-arginine levels in AP-treated rats. Consistently, in vivo supplementation with L-arginine reproduced the therapeutic effects of AP, ameliorating hyperandrogenism, LH/FSH imbalance, ovarian abnormalities, and estrous cycle irregularities in DHEA-induced PCOS rats. Taken together, these findings suggest that AP ameliorates PCOS phenotypes by restoring gut microbial composition, modulating host metabolism, and promoting L-arginine biosynthesis. This study highlights the potential of AP as a novel probiotic-based intervention for PCOS and underscores the therapeutic relevance of L-arginine in managing this disorder.

Direct evidence regarding ion channel-mediated initiation of baroreflex/visceral neurotransmission remains limited. Here, aortic-arch, vagus-nodose slice, and isolated neurons were employed with single-fiber/whole-cell patch-clamp recordings to record instantaneous discharge of the aortic depressor nerve, spontaneous/evoked membrane depolarizations under different pharmacological interventions. Strikingly, profiles of A-fiber's instantaneous firing frequency (IFF), including pressure threshold, rate, and sensitivity, were significantly reduced by 10 µmol/L flufenamic acid (FAA) and further suppressed by 3 µmol/L GsMTx4. Conversely, 3 µmol/L Yoda1-enhanced IFF was reversed by GsMTx4 and partially inhibited by FAA, consistent with step depolarization-evoked action potentials (APs). In < 10% of A-type neurons, spontaneous APs accompanied by major (Ma-STPs) and minor sub-threshold depolarizations (Mi-STPs) were abolished by nanomolar tetrodotoxin. FAA only blocked spontaneous APs, while GsMTx4 suppressed both APs and Ma-STPs. The equal number of APs and Ma-STPs before and after FAA suggests that spontaneous APs initiate from Ma-STPs. Further, single-cell transcriptomic analysis revealed significant Piezo1 and TRPM4 co-expression in neurons. Gene co-expression and clustering analysis support their cooperative role in the baroreflex and visceral afferent pathways, validated by gene expression data. These findings demonstrate that TTX-sensitive Na⁺ (TTX-S), Piezo1, and TRPM4 channels each possess important intrinsic functions and play unique roles in the initiation of baroreflex/visceral neurotransmission.

The immunosuppressive tumor microenvironment (TME) undermines the efficacy of many cancer therapies. This study investigated the immunomodulatory and anti-tumor activity of Azvudine (FNC), alone or in combination with anti-PD-1 blockade. We established syngeneic tumor models in immunocompetent mice. Single-cell RNA sequencing, flow cytometry, and immunological assays were employed to analyze immune cell reconstitution and functional changes following FNC administration. FNC demonstrated dose- and time-dependent tumor inhibition. It significantly expanded memory T cells, natural killer (NK) cells, and CD8⁺ cytotoxic T lymphocytes, while reducing the abundance of myeloid-derived suppressor cells (MDSCs). Flow cytometry confirmed these immunological shifts, showing enhanced infiltration of effector immune cells within the TME. Moreover, FNC induced hallmark features of immunogenic cell death (ICD), including the release of damage-associated molecular patterns such as high-mobility group box 1 (HMGB1) and calreticulin. When combined with anti-PD-1 therapy, FNC produced a synergistic anti-tumor effect, leading to durable tumor remission in all treated mice. FNC remodels the TME by mitigating immunosuppression and amplifying anti-tumor immunity, offering a promising strategy to augment existing immunotherapies. Further clinical evaluation is warranted to ascertain the translational potential of FNC in diverse oncologic settings.

Early diagnosis is vitally important for effective treatment of nasopharyngeal carcinoma (NPC). Nevertheless, the exact pathogenic mechanisms of NPC remain unclear, and early diagnosis of NPC is still limited. Herein, we showed that a specific tsRNA for NPC, 5'tiRNA-32-ValAAC-2, is a novel pathogenic factor and has potential diagnostic value for NPC screening. In this study, small RNA microarray profiling and array hybridization were used to detect expression spectrums of tsRNAs in the sera of newly diagnosed NPC patients. The upregulated tsRNAs were validated using RT-qPCR, and their clinical significance in NPC diagnosis was analyzed. Furthermore, the most highly expressed tsRNA, was further investigated. 5'tiRNA-32-ValAAC-2 could serve as a potential diagnostic biomarker for NPC. Subsequently, the effect of 5'tiRNA-32-ValAAC-2 on the growth and invasion of NPC cells was investigated. The results indicated that overexpression of 5'tiRNA-32-ValAAC-2 promoted NPC cells proliferation, migration, and invasion. In contrast, the inhibition of 5'tiRNA-32-ValAAC-2 suppressed NPC cells proliferation, migration and invasion. TargetScan and miRanda analyses revealed that UGT2B7, SYNPO2, ZNF44, PDHB, and UFM1 might serve as downstream target-genes of 5'tiRNA-32-ValAAC-2. In conclusion, 5'tiRNA-32-ValAAC-2 could potentially be a novel pathogenic factor for NPC, and it functions as a diagnostic biomarker in the primary diagnosis of NPC.