Journal of Translational Internal Medicine最新文献

Background and objectives: Hemostasis factors affecting clot patterns, particularly fibrinogen, may influence the effectiveness of intravenous thrombolysis (IVT). We aimed to investigate the impact of differences in fibrinogen plasma levels on the efficacy and safety of tenecteplase versus alteplase in an acute ischemic cerebrovascular events-II (TRACE-II) trial.

Methods: In a multi-center, prospective, open-label, end-point blinded, randomized, controlled trial. Adults with acute ischemic stroke (AIS) were enrolled. Patients received intravenous tenecteplase (0-25 mg/kg) or alteplase (0-9 mg/kg) within 4-5 h. Patients were divided into three groups according to their plasma fibrinogen level: low fibrinogen level (< 2 g/L), normal fibrinogen level (2-4 g/L), and high fibrinogen level (> 4 g/L). The Modified Rankin Score (mRS) from 2 to 6 was used to define the efficacy outcome. The safety outcomes were the occurrence of symptomatic intracranial hemorrhage (sICH) within 36 h and 90 days, parenchymal hematoma 2 (PH₂) within 36 h, any intracranial hemorrhage (ICH), other significant hemorrhagic events, and death at 3 months. SAS software version 9.4 was used for statistical analysis. Binary logistic regression was used to evaluate the efficacy and safety outcomes differences between tenecteplase and alteplase in the three fibrinogen groups. The interaction between treatment and fibrinogen subgroups was used to assess the effect of fibrinogen levels on the efficacy and safety of different treatments. All P-values are two-tailed and significance was defined as P < 0.05.

Results: The trial enrolled 1409 patients with AIS. Among them, 705 patients received tenecteplase treatment and 704 patients received alteplase treatment. Six percent of all patients had a low plasma fibrinogen level ( < 2 g/L), 81% had a normal fibrinogen level (2-4 g/L), and 13% had a high plasma fibrinogen level ( > 4 g/L). The efficacy of tenecteplase compared to alteplase remained consistent across varying fibrinogen levels (interaction P = 0.30). Additionally, the safety outcomes were comparable between the two treatments across all fibrinogen levels [sICH at 36 h (interaction P = 0.94); sICH at 90 days (interaction P = 0.77); PH₂ICH at 36 h (interaction P = 0.84); Other symptomatic hemorrhagic events within 90 days (interaction P = 0.54)]. Similarly, there was no significant difference in mortality rates between patients treated with tenecteplase and alteplase across different plasma fibrinogen levels (interaction P = 0.58).

Conclusion: The results of the study suggest that the efficacy and safety of tenecteplase in treated AIS patients within 4.5 h are comparable to those of alteplase, regardless of plasma fibrinogen levels.

Background and objectives: Nidogen 1 (NID1) is a highly conserved structural component of the extracellular matrix (ECM), which interacts with different basement membrane (BM) proteins to form a stabilized meshwork. The promoting ability of NID1 in cancer development and metastasis has been demonstrated in multiple cancer types, including ovarian cancer, breast cancer, and hepatocellular carcinoma (HCC). This suggests that NID1 holds great potential as a therapeutic target for cancer treatment. However, currently, there is a lack of commercially available neutralizing antibody for clinical testing and treatment.

Methods: To address this, we utilized hybridoma technology to develop a monoclonal neutralizing antibody which targets the critical G2 region of NID1. The therapeutic effect of this NID1 neutralizing antibody against a wide range of human cancer cells was evaluated.

Results: The results showed that NID1 neutralizing antibody effectively attenuated the growth, motility and metastasis of HCC, lung cancer, breast cancer and nasopharyngeal carcinoma cells in vitro. The proof-of-concept of targeting NID1 using neutralizing antibody was further demonstrated in various animal models. Mechanistically, our findings indicate that treatment with NID1 neutralizing antibody leads to the deregulation of hypoxia-inducible factor-1 (HIF-1α) pathway in cancer cells.

Conclusions: Taken together, this study offers promising prospects for a new pan-cancer monoclonal antibody-based strategy by targeting the tumor-associated membrane protein NID1.

Background and objectives: This study aimed to elucidate the role of the glymphatic system-a crucial pathway for clearing waste in the brain-in the aging process and its contribution to cognitive decline. We specifically focused on the diffusion tensor imaging analysis along the perivascular space (ALPS) index as a noninvasive biomarker of glymphatic function.

Methods: Data were drawn from the Alzheimers Disease Neuroimaging Initiative (ADNI) database and a separate validation cohort to analyze the ALPS index in cognitively normal older adults. The relationships among the ALPS index, brain morphometry, and memory performance were examined.

Results: As a biomarker of glymphatic function, the ALPS index appeared to decline with age in both cohorts. According to the brain morphology analysis, the ALPS index was positively correlated with the thickness of the left entorhinal cortex (r = 0.258, P _{false discovery rate (FDR)} = 2.96 × 10^-4), and it played a mediating role between aging and left entorhinal cortex thinning. The independent cohort further validated the correlation between the ALPS index and the left entorhinal cortex thickness (r = 0.414, P _FDR = 0.042). Additionally, in both the primary and validation cohorts, the ALPS index played a significant mediating role in the relationship between age and durable or delayed memory decline.

Conclusion: This study highlights the ALPS index as a promising biomarker for glymphatic function and links it to atrophy of the core memory brain regions during aging. Furthermore, these results suggest that targeting glymphatic dysfunction could represent a novel therapeutic approach to mitigate age-related memory decline.

In the evolving landscape of cancer treatment, the strategic manipulation of regulated cell death (RCD) pathways has emerged as a crucial component of effective anti-tumor immunity. Evidence suggests that tumor cells undergoing RCD can modify the immunogenicity of the tumor microenvironment (TME), potentially enhancing its ability to suppress cancer progression and metastasis. In this review, we first explore the mechanisms of apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis, along with the crosstalk between these cell death modalities. We then discuss how these processes activate antigen-presenting cells, facilitate the cross-priming of CD8+ T cells, and trigger anti-tumor immune responses, highlighting the complex effects of novel forms of tumor cell death on TME and tumor biology. Furthermore, we summarize potential drugs and nanoparticles that can induce or inhibit these emerging RCD pathways and their therapeutic roles in cancer treatment. Finally, we put forward existing challenges and future prospects for targeting RCD in anti-cancer immunity. Overall, this review enhances our understanding of the molecular mechanisms and biological impacts of RCD-based therapies, providing new perspectives and strategies for cancer treatment.

Background and objectives: Recently, a series of publications discuss what kind of clinical and technical information is important to know before performing endoscopic ultrasound (EUS) examinations. This paper aims to investigate variations in the performance of EUS examinations in different countries worldwide to present views and experiences on the use of pre-EUS investigations.

Methods: In a multinational and multidisciplinary survey, more than 100 practicing EUS endoscopists were surveyed by a questionnaire asking for their level of education and training, their experience in diagnostic and therapeutic procedures, preferred technical use and procedural steps before EUS examination. Substantial geographic variation not only in the level of training and mandatory imaging prior to EUS, but consequently also in the standards and practice of EUS examinations and advanced EUS guided therapeutic procedures were observed. The participants' preferences regarding technical use and procedural steps prior to EUS examinations were assessed according to their level of education and training experience.

Results: Transabdominal ultrasound (TUS) is performed prior to EUS by the EUS endoscopists themselves in most European countries but not in North and South Americas where non-invasive pre-EUS imaging is delegated to other specialties such as radiology. Different training backgrounds, cultural beliefs, infrastructures, available equipment and access to training programs have a strong impact on the EUS workforce and EUS procedural practice across the continents.

Conclusions: The study results suggest existence of relevant geographical differences that reflect not only the different levels of education in different settings but also differences regarding technical standards for the performance of EUS and TUS examinations worldwide.

Aging and age-related diseases are major drivers of multimorbidity and mortality worldwide. Cellular senescence is a hallmark of aging. The accumulation of senescent cells is causally associated with pathogenesis of various age-associated disorders. Due to their promise for alleviating age-related disorders and extending healthspan, therapeutic strategies targeting senescent cells (senotherapies) as a means to combat aging have received much attention over the past decade. Among the conventionally used approaches, one is the usage of small-molecule compounds to specifically exhibit cytotoxicity toward senescent cells or inhibit deleterious effects of the senescence-associated secretory phenotype (SASP). Alternatively, there are immunotherapies directed at surface antigens specifically upregulated in senescent cells (seno-antigens), including chimeric antigen receptor (CAR) therapies and senolytic vaccines. This review gives an update of the current status in the discovery and development of senolytic therapies, and their translational progress from preclinical to clinical trials. We highlight the current challenges faced by senotherapeutic development in the context of senescence heterogeneity, with the aim of offering novel perspectives for future anti-aging interventions aimed at enhancing healthy longevity.