MedComm最新文献

Clear cell renal cell carcinoma (ccRCC) accounts for 70%‒80% of renal cell carcinoma cases and often shows no symptoms in early stages. Thus, approximately 30% of patients are diagnosed with advanced ccRCC. This single-center prospective single-arm study evaluated the efficacy and safety of tislelizumab combined with axitinib in patients with locally advanced ccRCC. A total of 20 eligible patients were enrolled at Nanjing Drum Tower Hospital from September 2021 to June 2024. The primary endpoint was objective response rate (ORR) before surgery, and secondary endpoints included disease-free survival (DFS), overall survival, safety, and tissue biomarker analysis. All patients completed neoadjuvant treatment, and 19 underwent planned surgery; 70% (14/20) had cT3 stage disease with a median tumor diameter of 8.3 cm. The ORR was 55% (11 partial responses), 73.6% (14/19) achieved pathological downstaging, one patient attained pathological complete response, and no grade ≥3 perioperative complications occurred. The 2-year DFS rate was approximately 90%, and biomarker analysis showed significantly higher tumor shrinkage rates in patients with RTK/RAS pathway alterations. In conclusion, tislelizumab combined with axitinib exhibits substantial efficacy and acceptable safety in neoadjuvant treatment of locally advanced ccRCC, providing preliminary clinical evidence for its application.

In the HOMAGE (Heart Omics in AGEing) trial, spironolactone reduced serum concentrations of procollagen Type I C-terminal propeptide (PICP), a fibrosis biomarker, in patients at risk of heart failure. To elucidate the underlying mechanisms, multidimensional analyses including proteomics were conducted. Olink cardiovascular and inflammation panels (n = 276 proteins) were measured in plasma from 488 HOMAGE participants at baseline, 1 month, and 9 months after randomization. Proteins associated with PICP changes were identified using machine learning algorithms (MLAs). Selected candidates were further analyzed in patients with heart failure and preserved ejection fraction (Aldo-DHF trial). Linear regression and mediation analyses assessed which MLA-selected proteins mediated spironolactone's effects on PICP. MLAs consistently linked PICP reduction to changes in biomarkers of collagen (e.g., decreased COL1A1), fatty acid metabolism (e.g., increased FABP4), immune function (e.g., increased CCL24 and IL6RA, and decreased FLT3L), neurological function (e.g., increased DNER), cell–matrix interactions (e.g., increased galectin-9 [GAL9] and decreased thrombospondin-2 [THBS2]), and reduced NT-proBNP. Mediation analysis suggested that changes in GAL9 and THBS2 were associated with spironolactone-induced PICP reduction, which was confirmed in Aldo-DHF patients. This study raises the hypothesis that spironolactone inhibits collagen synthesis via inflammatory, metabolic, and extracellular matrix pathways, and particularly through modulation of GAL9 and THBS2.

Hemidesmosomes are structures that anchor junctions between basal epithelial cells and the basement membrane, essential for skin integrity. Genetic mutation of hemidesmosomes was well documented for the inherited bullous disorder, but is rarely investigated for acquired bullous disorders. We designed a 16-gene targeted capture panel and sequenced 202 patients with hemidesmosomes-related acquired disorders and 123 healthy controls, identifying 114 pathogenic variants in 15 genes, including 20.2% novel variants. Clinical relevance (disease severity and outcome) and immunohistochemistry results demonstrated that ITGA6, LAMC2, and EPPK1 mutations significantly affected the expression of hemidesmosome-related proteins, compared with controls with non-carriers. Functional studies in Caenorhabditis elegans models with transmission electron microscopy and confocal microscopy demonstrated that ITGA6 (ina-1) mutation can disrupt the hemidesmosomes assembly network, such as cytolinker (vab-10a) and apical (mup-4) and basal (let-805), thereby disrupting the hemidesmosome structure. This represents a quantitative to qualitative change in pemphigoid disease. Transcriptomic and serum proteomic analyses further revealed that ITGA6 mutations perturb epithelial development and hemidesmosome integrity, with both missense/loss-of-function variants leading to activation of NOD-like receptor–NF-κB–TNF–pyroptosis signaling pathways. These findings highlight the critical role of hemidesmosome genetic variants in the development of not only inherited but also acquired autoimmune bullous disorders.

Human telomerase reverse transcriptase (hTERT) is overexpressed in most human cancers and is an important target for cancer therapy. In this study, HS1002 was synthesized based on the amino acid sequences of gonadotropin-releasing hormone (GnRH) and hTERT. This study aimed to evaluate HS1002's anticancer activity and its effects on the gonadotropin-releasing hormone receptor (GnRHR) and hTERT in prostate cancer cells. HS1002 increased cytosolic calcium influx in GnRHR-overexpressing HEK293 cells and showed specific molecular docking interactions with GnRHR. Compared with prostate cancer cell lines, HS1002 exhibited the highest cytotoxicity against LNCaP cells. The hTERT expression correlated with telomerase activity was suppressed by HS1002, resulting in reduced metastasis and increased apoptosis and autophagy. Additionally, HS1002 suppressed c-Myc and ERK protein expressions in LNCaP cells. Furthermore, HS1002 inhibited tumor growth and downregulated hTERT expression in the xenograft model tumor tissues. HS1002/IL-2-pretreated PBMCs also exhibited potent cytotoxicity toward LNCaP cells. In addition, HS1002 increased the production of granzyme B and IFN-γ in CD8⁺ T cells in MC38 syngeneic mice. These findings demonstrate that HS1002 suppresses prostate cancer cell growth and induces anticancer immunity, suggesting its potential as a novel therapeutic agent against prostate cancer.

Sulfonylureas, commonly used to treat type 2 diabetes (T2D), often lose effectiveness over time when used as monotherapy; however, the underlying mechanisms remain unclear. To investigate the mechanisms of sulfonylurea failure, glibenclamide-releasing pellets were implanted in KK mice, a polygenic model that spontaneously develops T2D. KK mice receiving placebo pellets (KK-Placebo) developed hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance. Notably, KK mice implanted with glibenclamide (KK-Glib) showed improved blood glucose levels during the first 7 days, returning to KK-Placebo levels thereafter. KK-Glib mice exhibited reduced plasma insulin levels and insulin secretion in response to a glucose challenge compared with the markedly elevated levels in KK-Placebo mice. KK-Glib mice showed islet hypertrophy, reduced β-cell mass and number, and increased α-cell number, resulting in elevated α:β cell ratio compared with KK-Placebo. Although mRNA expression of β-cell identity markers remained unchanged, their protein levels were reduced in KK-Glib, suggesting β-cell identity loss, which may underlie the observed impaired insulin secretion. Remarkably, KK-Glib mice showed elevated mRNA levels of Ngn3 (dedifferentiation) and α-cell identity markers along with glucagon content, suggesting α-cell neogenesis. These findings suggest that secondary failure of sulfonylurea therapy may, in part, result from loss of β-cell identity-function and increased α-cell number-identity.

This study aimed to assess the benefits of immune checkpoint inhibitors (ICIs) for patients with low or negative PD-L1 expression in advanced solid tumors. The study included cancers approved by the FDA for first-line ICI therapy without PD-L1 restrictions, incorporating phase III randomized clinical trials (RCTs) comparing immunotherapy with conventional care. Individual patient data of PD-L1 low subgroup were retrieved from Kaplan–Meier (KM) curves using IPDfromKM and KMSubtraction. Pooled analysis employed KM and restricted mean survival time (RMST) analysis to assess ICI benefit. Totally, 40 RCTs with 27,060 patients were enrolled. No survival benefit for low PD-L1 expression was observed in some cancers. In esophageal squamous cell carcinoma (ESCC), combined positive score (CPS) < 10 had significant OS benefit (HR = 0.82, p = 0.02; RMST-D = 2.34 months); tumor proportion score (TPS) < 1% showed no OS improvement (HR = 0.87, p = 0.16, RMST-D = 1.71 months). Human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal adenocarcinoma (GEA) had no OS benefit with CPS < 5, 1–4, and < 1, but significant benefits with CPS < 10 (HR = 0.87, p = 0.048; RMST-D = 1.78 months, p = 0.038) and CPS 1–9 (HR = 0.83, p = 0.0085; RMST-D = 2.21 months, p = 0.007). Patient-level data indicate that ESCCs with TPS < 1% and HER2-negative GEAs with CPS < 5 do not benefit from the addition of ICIs to conventional chemotherapy. More nuanced clinical trials and predictive biomarkers are warranted.

Neutrophils significantly accumulate within the inflamed intestinal mucosa of patients with inflammatory bowel disease (IBD), where the farnesoid X receptor (FXR) is typically downregulated. However, the mechanisms by which FXR modulates neutrophil-mediated mucosal inflammation in IBD remain elusive. Here, we demonstrated that FXR expression is markedly decreased in neutrophils from patients with active IBD. Fxr^−/− mice exhibited exacerbated colitis following DSS insults or Citrobacter rodentium infection, evidenced by heightened neutrophil-driven immune responses including increased neutrophil infiltration and neutrophil extracellular trap (NET) formation. Adoptive transfer of Fxr^−/− neutrophils into WT recipients exacerbated DSS-induced intestinal inflammation, indicating that FXR suppresses the pathogenic activity of neutrophils in a neutrophil-intrinsic manner. An ex vivo functional assay revealed that Fxr^−/− neutrophils display elevated ROS production, NET formation, and migratory capacity upon inflammatory challenge. Mechanistically, RNA-sequencing and functional assays revealed enhanced mTORC1 signaling and glycolysis in Fxr^−/− neutrophils. Consistently, pharmacological activation of FXR with INT-747 significantly restrained the mTORC1-glycolysis-mediated proinflammatory responses in neutrophils from IBD patients. Our findings identify FXR as a critical regulator of neutrophil-mediated mucosal inflammation via the mTORC1-glycolysis pathway, highlighting its therapeutic potential in IBD.

In the past few years, the incidence rate of central nervous system (CNS) diseases is still growing. Meanwhile, the molecular mechanism on the pathogenesis of neurological diseases remains elusive. Oligodendrocyte progenitor cells (OPCs) are distributed in the whole CNS and represent a population of migrating and proliferating adult progenitor oligodendrocytes that can be differentiated into oligodendrocytes (OLs). The main function of OLs is to produce myelin, the membrane wrapping tightly around the axon, which are associated with the myelination and remyelination. During regeneration, the new OLs from OPCs can regenerate lost myelin, which prevents axonal degeneration and restores its plasticity and function. Considering these energy-consuming processes, the high metabolic turnover OLs are susceptible to neurotoxic factors and its excitatory toxicity. Thus, the pathogenesis of OPC and OL are proven in neurological diseases, such as multiple sclerosis, Alzheimer's disease, major psychiatric diseases, and epilepsy. The current study reviewed the development, plasticity as well as application of OPCs and OLs researches on CNS diseases. Additionally, the effective methods and bioengineering technologies as well as biomaterials relevant to regenerative medicine are also discussed, which could provide the novel insight into the therapeutic treatment of those diseases, exploring new pathological clues, identifying the key molecules and targets as well as the potential biomarkers.