Military Medical Research最新文献

Clonal hematopoiesis of indeterminate potential (CHIP), driven by leukemia-related somatic mutations in hematopoietic stem cells, previously recognized as a major risk factor for hematological malignancies, has now emerged as a potent risk factor for chronic inflammation and diverse non-hematologic diseases. CHIP-associated DNA methyltransferase 3 alpha (DNMT3A), tet methylcytosine dioxygenase 2 (TET2), and additional sex combs like 1 (ASXL1) mutations alter epigenetic programs, skew myelopoiesis, and increase proinflammatory cytokines, resulting in chronic inflammation and immune imbalance. This review integrates mechanistic insights with clinical evidence to delineate CHIP's roles in solid tumors, cardiovascular disorders, and metabolic dysregulation, with an extended discussion of renal dysfunction and neurodegenerative conditions. Furthermore, we also discuss CHIP's diagnostic and therapeutic impacts across multiple disease contexts, advocating for mutation-specific diagnostic paradigms to guide therapeutic interventions.

Background: Heart failure (HF) continues to be a public health issue in China with population aging and increasing disease drivers. The burden, spatial patterns, temporal trends, and underlying causes of HF in China at subnational levels remain inadequately understood. This study aims to assess the disease burden and causes of HF, and their regional disparities in China from 1990 to 2023.

Methods: Utilizing the estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, we assessed the prevalence and years lived with disability (YLDs) of HF and their trends in China at both national and subnational levels. Estimates were also compared by disease severity, sex, age group, cause, and region.

Results: In 2023, China had an estimated 14.3 million HF cases, marking a significant 208.4% increase over the past three decades. Ischemic heart disease (IHD) has become the top cause of HF, compared with 1990, with hypertensive heart disease (HHD) at the top. Alongside chronic obstructive pulmonary disease (COPD), these three leading causes accounted for 77.4% of all HF cases. The burden of HF due to IHD and COPD exhibited distinct regional patterns and substantial disparities: regions in northern China exhibited notably higher age-standardized YLDs rates for HF due to IHD, while provinces in the western regions faced the highest burden from COPD. Six provinces with the highest tertile of YLDs rates in 2023 also experienced the most pronounced increases between 1990 and 2023.

Conclusions: HF remains a significant public health challenge in China, with a marked increase in prevalence over the past three decades. The substantial regional variations highlight the need for targeted and region-specific public health strategies. Enhanced nationwide efforts should be made to reduce the geographical disparities in the burden of HF.

Background: Steroid-refractory (SR) acute graft-versus-host disease (aGVHD) is the major cause of early mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Xenopax, a novel and the only available humanized interleukin-2 (IL-2) receptor antagonist, has been approved as a category 2 biological product by the National Medical Products Administration. This study aims to evaluate the efficacy, safety, and prognostic factors of xenopax treatment for SR-aGVHD in real-world settings.

Methods: This was a multicenter, retrospective analysis that included SR-aGVHD patients who received xenopax at 17 hospitals across China. The data were collected from the electronic medical records in transplant databases. The primary endpoint was the 28-day overall response rate (ORR), encompassing both partial and complete responses. This study also included independent historical SR-aGVHD cohorts treated with best available treatments (BATs, n = 1009) as controls.

Results: In total, 172 SR-aGVHD patients were included in this study. Xenopax was administered either as monotherapy (n = 60) or in combination with other second-line treatments (n = 112). The ORR was 64.5% [95% confidence interval (CI) 57.3-71.7%] on day 28 and 82.6% (95% CI 76.9-88.3%) at any time after xenopax treatment. The 2-year probabilities of disease-free survival, overall survival, non-relapse mortality (NRM), and relapse after xenopax treatment were 57.0% (95% CI 49.9-65.0%), 68.0% (95% CI 61.4-75.4%), 24.2% (95% CI 18.0-30.9%), and 19.0% (95% CI 12.8-25.2%), respectively. The ORR and survival were similar between patients with and without prior second-line treatments. The conditioning regimen and human leukocyte antigen disparity did not impact the efficacy of xenopax treatment. According to the multivariate analysis, the presence of grade III-IV aGVHD did not adversely affect the therapeutic response or survival. Xenopax also showed some superiority over BATs in historical cohorts.

Conclusions: Our real-world findings suggest that xenopax is an effective and safe treatment for SR-aGVHD.

Despite having multiple treatment options, the overall outcomes, including the survival rates of non-small cell lung cancer (NSCLC) patients, remain relatively low, indicating the need to explore new approaches to achieve improved therapeutic responses. To that end, repurposed drugs such as metformin have been evaluated against many cancer types, including NSCLC. Metformin, a widely used oral hypoglycemic drug for type 2 diabetes, exhibits anticancer properties and synergy with several standards of care agents. In this review, we provide a comprehensive overview of the role and anticancer mechanisms of metformin-based combination approaches for the treatment of NSCLC. We logically discussed the experimental evidence from the in vitro and in vivo studies utilizing metformin alone, and then its combination with chemotherapeutic agents, targeted therapy, and immunotherapy. We also present clinical trials that underscore the beneficial and adverse outcomes of metformin use in combination with targeted therapy and chemotherapeutic agents, and emphasize the limitations and challenges for the treatment of diabetic and non-diabetic NSCLC patients. It appears that, regardless of the diverse anticancer mechanisms of this biguanide, the benefits may be confined to a specific patient subgroup, which opens new avenues to be explored for NSCLC treatment.

Background: Surface engineering has emerged as a promising strategy to enhance the performance of nanomedicines. In particular, the PEGylation levels for chemotherapy drug 7-Ethyl-10-hydroxycamptothecin (SN38) prodrug nanoparticles (NPs) play a crucial role in determining their stability, drug release kinetics, cytotoxicity, cellular uptake, in vivo pharmacokinetics, biodistribution, and antitumor efficacy. The study aims to investigate the surface engineering for chemotherapy drugs, providing new solutions for improving their in vivo delivery.

Methods: We systematically evaluated the effects of different PEGylation levels on NPs (W_DSPE-mPEG2k/W_prodrug; 0%, 5%, 20%, 40%, 60%, 80%, 100%, 150%, and 200% NPs) incorporated on SN38 prodrug NPs via surface engineering. Drug release was measured using high-performance liquid chromatography (HPLC), while cytotoxicity was assessed via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cellular uptake was accurately quantified using liquid chromatography-mass spectrometry (LC-MS). The in vivo pharmacokinetics of the NPs were evaluated in Sprague-Dawley rats, and the biodistribution and antitumor efficacy were assessed using a CT26 colon tumor-bearing BALB/c mice model. Additionally, we examined intestinal toxicity to evaluate the safety profile.

Results: All the different PEGylation levels of SN38 prodrug NPs exhibited high drug loading (> 25%) but distinct behaviors depending on the PEGylation level. Low PEGylation (20%) led to poor colloidal stability, reduced cellular uptake, and rapid clearance by the mononuclear phagocyte system (MPS), resulting in unfavorable pharmacokinetics. Moderate PEGylation (80%) improved in vitro stability and uptake but remained insufficient to prevent rapid clearance in vivo. In contrast, high PEGylation (150%) significantly enhanced pharmacokinetic profiles, prolonged circulation, and increased tumor accumulation. The 150% NPs also showed superior antitumor efficacy without triggering anti-polyethylene glycol (PEG) immune responses or accelerated blood clearance (ABC) effects. Although high PEGylation slightly reduced cellular uptake, it conferred essential stability for systemic delivery, improving in vivo therapeutic outcomes.

Conclusions: The high PEGylation (150% NPs) exhibited the best antitumor effect and the lowest degree of intestinal toxicity. Our findings underscore the critical impact of PEGylation level on enhancing the performance and safety of SN38 prodrug NPs.

Background: Lipid metabolic reprogramming has been increasingly recognized as a key factor contributing to tumor immune evasion, therapeutic resistance, and plasticity, which collectively compromise the efficacy of targeted radionuclide therapy (TRT). Overcoming the immunosuppressive and hypoxic tumor microenvironment (TME) while interfering with tumor lipid metabolism may offer a promising strategy to potentiate TRT outcomes.

Methods: In this report, a radiopharmaceutical with multienzymatic catalysis activities is developed, wherein tumor cell membrane-coated manganese single-atom nanozymes (Mn/SAE@M) as supports deliver iodine-131 (¹³¹I) to the tumor. The Mn/SAE nanozyme core was synthesized in situ within hollow mesoporous zeolitic imidazolate frame-8 (ZIF-8) nanoparticles, then coated with homologous tumor cell membranes for targeted delivery and subsequently labeled with ¹³¹I using the Chloramine-T method. A series of in vitro and in vivo experiments was performed in non-small cell lung cancer (NSCLC) models to evaluate therapeutic efficacy and immune activation.

Results: ¹³¹I-Mn/SAE@M exhibited efficient tumor targeting and internalization mediated by membrane camouflage. Within the TME, the radiopharmaceuticals initiated abundant oxygen (O₂) release through catalase (CAT)-like catalysis, thereby mitigating a hypoxic microenvironment. In particular, it produced and enriched more reactive oxygen species (ROS) through oxidase (OXD)-, peroxidase (POD)-, and glutathione oxidase (GSHOx)-like catalytic processes. Importantly, ¹³¹I-Mn/SAE@M activated the cGAS-STING pathway, interfered with the lipid metabolic homeostasis of tumor cells, and induced ferroptosis, which is unraveled to take responsibility for the potentiated antitumor immunity. In bilateral NSCLC tumor-bearing mice, the treatment suppressed both the first and the second tumors, indicating the generation of systemic antitumor immune responses and immunological memory.

Conclusions: Such SAE-based radiopharmaceuticals provide a candidate platform to elevate TRT efficiency, and the proof-of-concept rationale of disrupting lipid metabolic homeostasis through multienzyme-mimicking cascade reactions also provides a general avenue to improve TRT and synergistically magnify antitumor immunity.

Aldehyde dehydrogenase (ALDH) 2, a mitochondrial enzyme, is the main acetaldehyde dehydrogenase involved in the scavenging of alcohol-derived acetaldehyde and endogenous aldehydes. The ALDH2^rs671 mutation affects 560 million East Asians and is closely related to an increased risk of various human diseases. In addition to its well-known function in detoxifying alcohol-derived acetaldehyde and endogenous aldehydes, ALDH2 is implicated in human health through its regulation of autophagic machinery and multiple cell death pathways (e.g., apoptosis, necroptosis, pyroptosis, ferroptosis, and NETosis). This review summarizes the current knowledge of ALDH2 and the regulatory mechanism through which ALDH2 regulates autophagy and cell death. In addition, we outline the potential role of ALDH2 in the regulation of autophagy and cell death during the occurrence and progression of human diseases, aiming to provide a novel theoretical framework for human disease treatment.

Background: At present, no commercially available endoscopic system is specifically designed for use in the battlefield, disaster relief, or unique environments with biosafety concerns. Therefore, this limitation stems from challenges such as limited portability, reliance on stable power, complex disinfection processes, and the risk of incomplete sterilization. To address these challenges, we developed a novel portable endoscopic system and evaluated its safety and effectiveness in both routine settings and specialized scenarios, including the global pandemic caused by a novel coronavirus, which represents an environment with biosafety concerns.

Methods: After sample size calculation, 30 patients underwent esophagogastroduodenoscopy (EGD) or colonoscopy using the YunSendo (the experimental group) and Olympus systems (the control group) in a randomized order. Operation time, image quality, operational performance, lesion detection, and safety were assessed. Ten emergency patients with suspected upper gastrointestinal bleeding received bedside treatment using the YunSendo system during the global pandemic caused by a novel coronavirus. Clinical outcomes in emergency endoscopic treatment were assessed.

Results: No significant differences were observed between the YunSendo and Olympus groups in terms of image quality, lesion detection, and overall procedural performance. YunSendo facilitated biopsy and colonic polyp removal; no adverse endoscopy events were reported. YunSendo successfully executed diagnostic and therapeutic procedures in emergencies, with no observed mortality at 1, 7, or 30 d, no rebleeding at 1 or 30 d, and no cross-infection rates.

Conclusions: The performance of the YunSendo portable endoscopic system was comparable to the Olympus system in terms of key metrics, demonstrating its utility in urgent scenarios. This novel system is particularly promising for medical rescue and military missions and for addressing battlefield and biosafety concerns.