National Medical Products Administration

Myocardial ischemia is the common etiology of heart failure (HF). However, the precise molecular mechanisms that govern the ischemic myocardium into HF remain poorly defined. Selective accumulation of succinate is a hallmark of ischemia. Succinate is a predominant regulator of protein succinylation modification. The present study unravels the novel role of succinate in ischemia-induced HF via succinylation. A clinical cohort study that was performed on 1554 Chinese patients with coronary artery disease (CAD) indicated that serum succinate levels were positively correlated with the increase of HF biomarker, decrease of left ventricular ejection fraction (LVEF), incidence of HF, and risk of death. In cardiomyocytes deprived of oxygen and glucose (OGD) and in mice subjected to ligation of the left anterior descending coronary artery (LAD), succinate levels and global protein succinylation were elevated. Succinylation proteomic analysis identified the α-subunit of mitochondrial ATP synthase (ATP5A1) as an important succinylated protein, and K531 was identified as the functional succinylation site. Ablation of succinylation by the ATP5A1-K531R mutant ameliorated OGD-induced cardiomyocyte death, mitochondrial dysfunction and energy metabolic dysfunction. K531R delivered by cardiac-specific adeno-associated virus (AAV9) achieved short-term cardioprotective effects against ischemic injury, and exerted prolonged protective effects against HF development. Sirtuin 5 was confirmed as a desuccinylase of ATP5A1, whereas carnitine palmitoyltransferase 1A (CPT1A) was recognized as a trans-succinylase. Mechanistically, succinylation of ATP5A1-K531 impeded the assembly of ATP synthase and impaired its activity. Elevated succinate potentially serves as a risk predictor of HF. Targeting desuccinylation of ATP5A1-K531 might be a promising therapeutic strategy.

The application of Bayesian statistics in pivotal clinical trials has gained increasing attention, particularly for underpowered confirmatory trials such as those in pediatric and rare disease populations. Bayesian external information borrowing offers a promising approach to enhance statistical efficiency by leveraging historical data. However, regulatory acceptance requires clear evidence on operating characteristics and practical design guidance. This study systematically compares two widely used Bayesian borrowing frameworks—mixture prior (MP) and inflated standard error (ISE)—under two borrowing strategies: treatment response borrowing (TRB) and treatment effect borrowing (TEB). Benchmarking against conventional frequentist methods and Japanese approaches, we evaluate type I error and power across a comprehensive grid of sample sizes, borrowing weights, and decision thresholds. Beyond these quantitative findings, we provide a fully reproducible template that demonstrates how to rigorously explore, visualize, and justify design choices for Bayesian borrowing in regulatory submissions. The paper specifies what simulation outputs, performance metrics, and graphical summaries should be presented to reviewers, and illustrates how to ensure that all reported results align with statistical common sense. In doing so, it serves as both a practical case study and a reusable toolkit to bridge the gap between methodological theory and regulatory practice.

Lateral patellar compression syndrome (LPCS) is characterized by abnormal pressure elevation in the lateral patellofemoral joint. The histopathological basis of LPCS, particularly regarding microvascular and inflammatory changes in the lateral joint capsule and lateral retinaculum, remains unclear. This study aimed to systematically compare the histological characteristics of these tissues between patients with LPCS and controls to characterize tissue-level features associated with LPCS and to explore the potential implications of these findings for understanding pathophysiology and informing future research on surgical strategy selection. This retrospective case–control study included 26 patients with LPCS and 23 control patients (with meniscal injuries, patellar dislocation, patellofemoral osteoarthritis, or synovial cyst). Intraoperative tissue specimens of the lateral joint capsule and lateral retinaculum were obtained. Histological evaluation was performed using immunohistochemical staining for Factor Ⅷ (F8, microvessels), CD3 (T cells), CD20 (B cells), and CD68 (macrophages). Microvessel density and inflammatory cell density were quantified and compared between groups. Microvessel density was significantly higher in both the lateral joint capsule (48.84 ± 14.12/mm2 vs. 34.72 ± 15.40/mm2, P = 0.002) and the lateral retinaculum (27.50 ± 11.33/mm2 vs. 17.13 ± 9.26/mm2, P = 0.007) of patients with LPCS compared to controls, with large effect sizes (Cohen's d > 1.0). Within both groups, microvessel density was significantly higher in the joint capsule than in the retinaculum (both P < 0.001). In contrast, no statistically significant between-group differences were detected in the densities of CD3 + T cells, CD20 + B cells, or CD68 + macrophages in either tissue. However, in multivariate regression models adjusting for age and sex, the between-group differences in microvessel density were attenuated and no longer statistically significant; interaction terms were also not significant. Unadjusted analyses showed increased microvessel density in the lateral joint capsule and lateral retinaculum of patients with LPCS while no statistically significant between-group differences were detected in classical inflammatory cell densities (CD3 + , CD20 + , CD68 +) under the current immunohistochemical panel. Because the association with microvessel density was not statistically significant after adjustment for age and sex, these findings should be interpreted as hypothesis-generating and potentially influenced by demographic factors. Larger age- and sex-matched studies, ideally with clinical correlation, are needed to determine whether angiogenesis is an independent pathological feature of LPCS and whether it relates to outcomes.

The transformation of non-small cell lung cancer (NSCLC) into small cell lung cancer (SCLC) is a recognized treatment resistance mechanism, most often arising from EGFR-mutant lung adenocarcinoma (LUAD). However, the underlying mechanisms of transformation remain poorly understood. Single-cell RNA sequencing was employed to analyze the tumor cell heterogeneity and to map the intratumoral immune cell landscape of 73,195 cells from five LUAD, three transformed small cell lung cancer (T-SCLC) and four SCLC patients. Multiplex immunofluorescence (mIF) staining and in vitro studies were further conducted to validate the stem-like feature of a malignant cell cluster and the enrichment and the function of interferon-stimulated gene-positive (ISG+) lymphocytes in transformation. Although increased intratumoral heterogeneity was observed upon SCLC transformation, a stem-like malignant cell subpopulation was identified to recur across subtypes and groups as the pioneering force of lineage plasticity for SCLC transformation. Further mIF staining and transcription factor analysis validated the stem-like feature. Additionally, tumor immune microenvironment (TIME) analysis revealed that ISG+ T cells and B cells were enriched in T-SCLC. Further cell co-culture analyses disclosed that ISG+ lymphocytes promoted neuroendocrine differentiation in LUAD cells via type I interferons (IFN-Is). Deciphering cell-cell interactions revealed that the stem-like malignant cells might activate and attract ISG+ T cells. Finally, we developed an ISG-associated gene signature that significantly correlates with poor prognosis in LUAD. Our findings provide a comprehensive understanding of the lineage plasticity and the immune landscape in T-SCLC, highlighting the crucial role of the stem-like cell cluster and ISG+ lymphocytes in LUAD-to-SCLC transformation.

Retrospective Cohort. This study aimed to: (1) compare opioid use between primary and revision fusion patients; (2) evaluate differences in non-opioid analgesic use; and (3) identify risk factors of long-term opioid consumption. Preoperative opioid exposure and revision surgery are recognized risk factors for prolonged postoperative opioid use after lumbar fusion, yet long-term data remain limited. Patients who underwent elective 1-3 level lumbar spine fusion between were retrospectively identified and chart reviewed (2018-2023). Opioid and non-opioid prescription data was extracted from the state prescription drug monitoring program (PDMP) at 30 days, 90 days, 1 year, and 2 years. Patients were stratified into primary versus revision fusion cohorts and compared using bivariate and multivariable analyses. A total of 1,938 patients were analyzed (1,498 primary, 440 revision). Revision patients had greater preoperative opioid morphine milligram equivalent (MME) burden (953 vs. 334, P<0.001). Postoperatively, opioid use rates were similar through 30 days, but revision patients demonstrated higher MME use at 90 days (428 vs. 219, P<0.001), 1 year (1,142 vs. 382, P<0.001), and 2 years (1,550 vs. 497, P<0.001). Gabapentinoid use was also higher in revision patients beginning at 90 days (19.3% vs. 13.4%, P=0.003). Multivariable regression confirmed preoperative MME as the strongest risk factor of long-term opioid burden. Revision status was independently associated with higher MME use at 1 year (β=348.3, P=0.011) and 2 years (β=964.4, P<0.001), but not at 90 days. Revision lumbar fusion patients demonstrate a greater pre- and postoperative opioid burden, and a greater postoperative gabapentinoid burden. Multivariable analysis confirms revision status as an independent risk factor of greater long-term MME use, beginning at 1 year. Together these findings suggest a complex, possibly neuropathic pain phenotype in revision patients, underscoring the need for tailored perioperative counseling and consistent long-term, multidisciplinary pain management.

The cancer-immunity cycle represents a self-amplifying cascade that is essential for generating durable antitumor immune responses. However, disruption of any individual step can render the entire cycle ineffective, thereby limiting the efficiency of cancer immunotherapy. Nucleic acid-based nanodrugs (NANDs) elicit unique interactions with both cancerous and immune cells, showing great potential in reactivating or amplifying the cancer-immunity cycle. This review first provides a brief introduction to the cancer-immunity cycle and NANDs and then outlines the major types of nonviral nanocarriers that have been developed to construct NANDs so far. Rational design strategies for smart NANDs are summarized. The recent advances in the precise modulation of each critical step within the cancer-immunity cycle by NANDs for enhanced cancer immunotherapy are highlighted. The current challenges faced by these NANDs are also briefly discussed.

Biohybrid robots actuated by living cells/tissues, a soft robot system that integrates many advantages of life systems and mechanical systems, are promising candidates for developing a new generation of biomedical and environmental monitoring robots. However, due to the limited muscle contraction performance and lack of flexible muscle contraction modes, biohybrid robots' low speed and flexibility have become a major challenge for their application. To overcome the limitation, different from the existing contraction mode along the longitudinal axis with pulse stimulation, we firstly adopted the square wave stimulation on triceps femoris tissue with pennate fibers arrangement from bullfrogs and found a novel muscle swinging mode with high flexibility and controllability. Based on it, we developed a biomimetic crawler actuated by triceps femoris tissue. The crawler achieved fast forward movement (average speed: ∼6.19 mm/s; maximum speed: ∼7.35 mm/s) and flexible turning ability (∼14.77°/s and ∼9.55°/s for left and right turning speed, respectively) in a liquid environment at room temperature. We believe that the results provide valuable references for the development of soft robots driven by muscle tissue and pave the way to fulfill lifelike motions and break through limitations in conventional biohybrid robots.

Abnormal proliferation of vascular smooth muscle cells (VSMCs) plays a critical role in vascular remodeling associated with various cardiovascular disorders. G9a, also known as euchromatic histone methyltransferase 2 (EHMT2), is a lysine methyltransferase that influences histone modifications, particularly H3K9me1 and H3K9me2. In this study we investigated the role of G9a in promoting VSMC proliferation and vascular intimal hyperplasia and the underlying mechanisms. To induce VSMC proliferation, primary aortic VSMCs were treated with platelet-derived growth factor-BB (PDGF-BB) and 10% fetal bovine serum (FBS) in vitro. An in vivo model of carotid intimal hyperplasia was established in mice by ligating the left common carotid artery just below the bifurcation. We showed that the expression levels of G9a were significantly elevated in both in vitro and in vivo models of VSMC proliferation. In the primary aortic VSMCs, co-treatment with G9a inhibitor UNC0642 (1 μM) effectively reduced cell viability, cyclin D1 expression, and EdU incorporation induced by PDGF-BB or 10% FBS. In mouse carotid intimal hyperplasia model, administration of UNC0642 (50 mg·kg-1·d-1, i.p.) for 14 days significantly decreased the intimal area and cyclin D1 levels, whereas intravenous administration of G9a adenovirus worsened neointimal hyperplasia. RNA-seq analysis identified CCAAT/enhancer binding protein delta (CEBPδ) as the downstream target gene that was upregulated following G9a modulation. ChIP assays revealed that G9a mediated VSMC proliferation primarily by regulating H3K9me1 at the promoter of CEBPδ. Knockdown of CEBPδ counteracted the pro-proliferative effects of G9a. In conclusion, G9a serves as a positive regulator of VSMC proliferation and presents a potential therapeutic target for cardiovascular diseases concomitant with vascular remodeling.