Targeted Delivery of Mesenchymal Stem Cell-Derived Bioinspired Exosome-Mimetic Nanovesicles with Platelet Membrane Fusion for Atherosclerotic Treatment.

Purpose: Accumulating evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes hold significant potential for the treatment of atherosclerosis. However, large-scale production and organ-specific targeting of exosomes are still challenges for further clinical applications. This study aims to explore the targeted efficiency and therapeutic potential of biomimetic platelet membrane-coated exosome-mimetic nanovesicles (P-ENVs) in atherosclerosis. Methods: To produce exosome-mimetic nanovesicles (ENVs), MSCs were successively extruded through polycarbonate porous membranes. P-ENVs were engineered by fusing MSC-derived ENVs with platelet membranes and characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. The stability and safety of P-ENVs were also assessed. The targeted efficacy of P-ENVs was evaluated using an in vivo imaging system (IVIS) spectrum imaging system and immunofluorescence. Histological analyses, Oil Red O (ORO) staining, and Western blot were used to investigate the anti-atherosclerotic effectiveness of P-ENVs. Results: Both ENVs and P-ENVs exhibited similar characteristics to exosomes. Subsequent miRNA sequencing of P-ENVs revealed their potential to mitigate atherosclerosis by influencing biological processes related to cholesterol metabolism. In an ApoE-/- mice model, the intravenous administration of P-ENVs exhibited enhanced targeting of atherosclerotic plaques, resulting in a significant reduction in lipid deposition and necrotic core area. Our in vitro experiments showed that P-ENVs promoted cholesterol efflux and reduced total cholesterol content in foam cells. Further analysis revealed that P-ENVs attenuated intracellular cholesterol accumulation by upregulating the expression of the critical cholesterol transporters ABCA1 and ABCG1. Conclusion: This study highlighted the potential of P-ENVs as a novel nano-drug delivery platform for enhancing drug delivery efficiency while concurrently mitigating adverse reactions in atherosclerotic therapy.

Platelet-inspired targeting delivery for coronary heart disease.

Platelets play a pivotal role in many physiological and pathological processes, with their special targeting/adhering properties towards infarcted myocardium, injured or dysfunctional endothelium, and growing thrombus. Leveraging the site-targeting/adhering property, a variety of platelet-inspired targeting delivery（PITD）designs have been developed, the majority of which are reached by hitchhiking live platelets, cloaking nanoparticles with platelet membranes and mimicking platelet functions. With PITD, drugs or regenerative cells can directly reach targeted sites with minimized systematical distribution thus being of great clinical benefits. Coronary heart disease (CHD) is a major health burden worldwide. Plenty of PITD designs have shown promising outcomes for the treatment of CHD in preclinical models, especially in thrombolysis and post-percutaneous coronary intervention (post-PCI) anti-restenosis. Besides, PITD applications in cardiac protection and atherosclerotic plaque imaging are also under investigation. What's more, the potential benefits of PITD in the field of cell-based therapy are also attracting growing attention since it may resolve the problem of low arriving and retention efficiency, which are also particularly discussed in this review. In brief, our focus is putting on PITD strategies designed for the treatment of CHD, which hopefully can facilitate further optimization of this direction.

OBIA: An Open Biomedical Imaging Archive.

With the development of artificial intelligence (AI) technologies, biomedical imaging data play an important role in scientific research and clinical application, but the available resources are limited. Here we present Open Biomedical Imaging Archive (OBIA), a repository for archiving biomedical imaging and related clinical data. OBIA adopts five data objects (Collection, Individual, Study, Series, and Image) for data organization, and accepts the submission of biomedical images of multiple modalities, organs, and diseases. In order to protect personal privacy, OBIA has formulated a unified de-identification and quality control process. In addition, OBIA provides friendly and intuitive web interfaces for data submission, browsing, and retrieval, as well as image retrieval. As of September 2023, OBIA has housed data for a total of 937 individuals, 4136 studies, 24,701 series, and 1,938,309 images covering 9 modalities and 30 anatomical sites. Collectively, OBIA provides a reliable platform for biomedical imaging data management and offers free open access to all publicly available data to support research activities throughout the world. OBIA can be accessed at https://ngdc.cncb.ac.cn/obia.

Assessing the clinical utility of multi-omics data for predicting serous ovarian cancer prognosis.

Ovarian cancer (OC) is characterised by heterogeneity that complicates the prediction of patient survival and treatment outcomes. Here, we conducted analyses to predict the prognosis of patients from the Genomic Data Commons database and validated the predictions by fivefold cross-validation and by using an independent dataset in the International Cancer Genome Consortium database. We analysed the somatic DNA mutation, mRNA expression, DNA methylation, and microRNA expression data of 1203 samples from 599 serous ovarian cancer (SOC) patients. We found that principal component transformation (PCT) improved the predictive performance of the survival and therapeutic models. Deep learning algorithms also showed better predictive power than the decision tree (DT) and random forest (RF). Furthermore, we identified a series of molecular features and pathways that are associated with patient survival and treatment outcomes. Our study provides perspective on building reliable prognostic and therapeutic strategies and further illuminates the molecular mechanisms of SOC.Impact statementWhat is already known on this subject? Recent studies have focussed on predicting cancer outcomes based on omics data. But the limitation is the performance of single-platform genomic analyses or the small numbers of genomic analyses.What do the results of this study add? We analysed multi-omics data, found that principal component transformation (PCT) significantly improved the predictive performance of the survival and therapeutic models. Deep learning algorithms also showed better predictive power than did decision tree (DT) and random forest (RF). Furthermore, we identified a series of molecular features and pathways that are associated with patient survival and treatment outcomes.What are the implications of these findings for clinical practice and/or further research? Our study provides perspective on how to build reliable prognostic and therapeutic strategies and further illuminates the molecular mechanisms of SOC for future studies.

Impact of Marital Status on Management and Outcomes of Patients With Acute Myocardial Infarction: Insights From the China Acute Myocardial Infarction Registry.

Background Acute myocardial infarction (AMI) is one of the leading causes of mortality worldwide, whereas social support is a known predictor of the prognosis after AMI. As a common factor influencing social support, the impact of marital status on care quality, in-hospital mortality, and long-term prognosis of patients with AMI remains largely unknown. Methods and Results The present study analyzed data from the CAMI (China Acute Myocardial Infarction) registry involving 19 912 patients with AMI admitted at 108 hospitals in China between January 2013 and September 2014 and aimed to evaluate marital status-based differences in acute management, medical therapies, and short-term and long-term outcomes. The primary end point was 2-year all-cause death. The secondary end points included in-hospital death and 2-year major adverse cardiac and cerebrovascular events (a composite of all-cause death, myocardial infarction, or stroke). After multivariable adjustment, 1210 (6.1%) unmarried patients received less reperfusion treatment in patients with both ST-segment-elevation myocardial infarction and non-ST-segment-elevation myocardial infarction (adjusted odds ratio [OR], 0.520 [95% CI, 0.437-0.618]; P<0.0001; adjusted OR, 0.489 [95% CI, 0.364-0.656]; P<0.0001). Being unmarried was not associated with poorer in-hospital outcome but with long-term all-cause mortality and major adverse cardiac and cerebrovascular events in both ST-segment-elevation myocardial infarction (adjusted hazard ratio [HR], 1.225 [95% CI, 1.031-1.456]; P=0.0209; adjusted HR, 1.277 [95% CI, 1.089-1.498]; P=0.0027) and non-ST-segment-elevation myocardial infarction (adjusted HR, 1.302 [95% CI, 1.036-1.638]; P=0.0239; adjusted HR, 1.368 [95% CI, 1.105-1.694]; P=0.0040) populations. Conclusions The present study suggests that being unmarried is independently related to less reperfusion received, but could not explain the higher in-hospital mortality rate after covariate adjustment. Being unmarried is associated with a substantially increased risk of adverse events over at least the first 24 months after AMI. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01874691.

Direct mechanisms of SARS-CoV-2-induced cardiomyocyte damage: an update.

Myocardial injury induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is reportedly related to disease severity and mortality, attracting attention to exploring relevant pathogenic mechanisms. Limited by insufficient evidence, myocardial injury caused by direct viral invasion of cardiomyocytes (CMs) is not fully understood. Based on recent studies, endosomal dependence can compensate for S protein priming to mediate SARS-CoV-2 infection of CMs, damage the contractile function of CMs, trigger electrical dysfunction, and tip the balance of the renin-angiotensin-aldosterone system to exert a myocardial injury effect. In this review, we shed light on the direct injury caused by SARS-CoV-2 to provide a comprehensive understanding of the cardiac manifestations of coronavirus disease 2019 (COVID-19).

The influence of pre-existing hypertension on coronavirus disease 2019 patients.

Hypertension represents one of the most common pre-existing conditions and comorbidities in Coronavirus disease 2019 (COVID-19) patients. To explore whether hypertension serves as a risk factor for disease severity, a multi-centre, retrospective study was conducted in COVID-19 patients. A total of 498 consecutively hospitalised patients with lab-confirmed COVID-19 in China were enrolled in this cohort. Using logistic regression, we assessed the association between hypertension and the likelihood of severe illness with adjustment for confounders. We observed that more than 16% of the enrolled patients exhibited pre-existing hypertension on admission. More severe COVID-19 cases occurred in individuals with hypertension than those without hypertension (21% vs. 10%, P = 0.007). Hypertension associated with the increased risk of severe illness, which was not modified by other demographic factors, such as age, sex, hospital geological location and blood pressure levels on admission. More attention and treatment should be offered to patients with underlying hypertension, who usually are older, have more comorbidities and more susceptible to cardiac complications.

Pathogenesis and management of myocardial injury in coronavirus disease 2019.

The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has become a major health crisis and a worldwide pandemic. COVID-19 is characterized by high infectivity, long incubation period, diverse clinical presentations, and strong transmission intensity. COVID-19 can cause myocardial injury as well as other cardiovascular complications, particularly in senior patients with pre-existing medical conditions. The current review summarizes the epidemiological characteristics, potential mechanisms, clinical manifestations, and recent progress in the management of COVID-19 cardiovascular complications.

Investigational pharmacotherapy and immunotherapy of pulmonary arterial hypertension: An update.

Pulmonary arterial hypertension (PAH) is a progressive disease with limited effective therapies that can be lethal in the terminal stage. Since the universal use of traditional PAH-specific drugs affecting the nitric oxide pathway, endothelin pathway and prostacyclin pathway, major advances to treat this devastating condition have been made. For example, it has been recently demonstrated that PAH is associated with various dysfunctional genes and molecular signaling pathways, abnormal metabolism and endocrine systems, inflammation and immune dysfunction. Numerous descriptions of novel mechanisms in PAH have been presented, and some new drugs targeted to ease, reverse or cure PAH have been developed at the laboratory-level and/or tested in clinical trials. There are also some investigated drugs that have shown promising efficacy and safety in animal models but have failed in human beings. Inspiringly, immunotherapies also seem to be valuable therapies for PAH patients. In this review, we update the advances in investigational pharmacotherapy and immunotherapy of PAH. Hopefully this work can help promote more non-invasive treatment for PAH patients.

Pathophysiological characteristics and therapeutic approaches for pulmonary injury and cardiovascular complications of coronavirus disease 2019.

The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a major health crisis, with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) having infected over a million people around the world within a few months of its identification as a human pathogen. Initially, SARS-CoV-2 infects cells in the respiratory system and causes inflammation and cell death. Subsequently, the virus spreads out and damages other vital organs and tissues, triggering a complicated spectrum of pathophysiological changes and symptoms, including cardiovascular complications. Acting as the receptor for SARS-CoV entering mammalian cells, angiotensin converting enzyme-2 (ACE2) plays a pivotal role in the regulation of cardiovascular cell function. Diverse clinical manifestations and laboratory abnormalities occur in patients with cardiovascular injury in COVID-19, characterizing the development of this complication, as well as providing clues to diagnosis and treatment. This review provides a summary of the rapidly appearing laboratory and clinical evidence for the pathophysiology and therapeutic approaches to COVID-19 pulmonary and cardiovascular complications.

IL-24 inhibits endometrial cancer cell proliferation by promoting apoptosis through the mitochondrial intrinsic signaling pathway.

BACKGROUND: Endometrial cancer is a type of malignant tumor of the female reproductive system. Preserving fertility in endometrial cancer patients is currently a formidable challenge. Interleukin-24 (IL-24) is a unique cytokine tumor suppressor gene belonging to the IL-10 cytokine family. IL-24 has broad-spectrum antitumor activity through different signaling pathways but does not affect normal cells. IL-24 gene therapy may provide a new method for the treatment of endometrial cancer. METHODS: Transfection was used for gene transfer. The expression of IL-24 and related pathway proteins in endometrial cancer tissue and the Ishikawa cell line was detected by immunohistochemistry and Western blotting, respectively. The antitumor function of IL-24 was examined in vitro and in vivo. Cell proliferation was determined by CCK-8 assay, cell migration was shown by wound-healing assay, and cell invasion was detected by Transwell assay. Apoptosis was analyzed by TUNEL assay, and HE staining was performed to observe the morphology of the samples. RESULTS: Immunohistochemical analysis showed different expression levels of IL-24 in human endometrial cancer tissues and normal endometrial tissues. IL-24 increased protein expression of BAX and Cytochrome C, while BCL-2, MMP-3, VEGF, Caspase-9 and Caspase-3 expression was decreased. Overexpression of IL-24 inhibited cell proliferation, migration and invasion, but increased cell apoptosis in endometrial cancer. Mechanistically, we demonstrated that IL-24 inhibited endometrial cancer cell growth by inducing cell apoptosis through the mitochondrial intrinsic signaling pathway. In addition, IL-24 inhibited tumor development by inducing cell apoptosis and inhibiting angiogenesis, as shown in xenograft tumor experiments. CONCLUSIONS: Our study demonstrates the antitumor effect of IL-24 on endometrial cancer and shows that IL-24 may be a promising therapeutic gene for endometrial cancer gene therapy.

Pre-existing Health Conditions and Epicardial Adipose Tissue Volume: Potential Risk Factors for Myocardial Injury in COVID-19 Patients.

Background: Myocardial injury is a life-threatening complication of coronavirus disease 2019 (COVID-19). Pre-existing health conditions and early morphological alterations may precipitate cardiac injury and dysfunction after contracting the virus. The current study aimed at assessing potential risk factors for COVID-19 cardiac complications in patients with pre-existing conditions and imaging predictors. Methods and Results: The multi-center, retrospective cohort study consecutively enrolled 400 patients with lab-confirmed COVID-19 in six Chinese hospitals remote to the Wuhan epicenter. Patients were diagnosed with or without the complication of myocardial injury by history and cardiac biomarker Troponin I/T (TnI/T) elevation above the 99th percentile upper reference limit. The majority of COVID-19 patients with myocardial injury exhibited pre-existing health conditions, such as hypertension, diabetes, hypercholesterolemia, and coronary disease. They had increased levels of the inflammatory cytokine interleukin-6 and more in-hospital adverse events (admission to an intensive care unit, invasive mechanical ventilation, or death). Chest CT scan on admission demonstrated that COVID-19 patients with myocardial injury had higher epicardial adipose tissue volume ([EATV] 139.1 (83.8-195.9) vs. 92.6 (76.2-134.4) cm2; P = 0.036). The optimal EATV cut-off value (137.1 cm2) served as a useful factor for assessing myocardial injury, which yielded sensitivity and specificity of 55.0% (95%CI, 32.0-76.2%) and 77.4% (95%CI, 71.6-82.3%) in adverse cardiac events, respectively. Multivariate logistic regression analysis showed that EATV over 137.1 cm2 was a strong independent predictor for myocardial injury in patients with COVID-19 [OR 3.058, (95%CI, 1.032-9.063); P = 0.044]. Conclusions: Augmented EATV on admission chest CT scan, together with the pre-existing health conditions (hypertension, diabetes, and hyperlipidemia) and inflammatory cytokine production, is associated with increased myocardial injury and mortality in COVID-19 patients. Assessment of pre-existing conditions and chest CT scan EATV on admission may provide a threshold point potentially useful for predicting cardiovascular complications of COVID-19.

Efficacy and safety of laparoscopy versus local injection with absolute ethanol in the management of tubal ectopic pregnancy.

OBJECTIVE: To compare the efficacy and safety between laparoscopy and local injection with absolute ethanol (AE) for treating tubal ectopic pregnancy (EP). STUDY DESIGN: Retrospective cohort study of ectopic pregnancies in the fallopian tube from two tertiary hospitals between January 2015 and December 2017. Clinical information such as presenting symptoms, reproductive history, possible risk factors, initial diagnosis, serum beta-human chor-ionic gonadotropin (ß-HCG) level, transvaginal ultrasonography findings, methods of treatment and outcomes were reviewed and analyzed. RESULTS: A total of 119 patients were identified for this study. The diagnosis was based on clinical manifestations, ultrasonography scan and dynamic serum ß-HCG. 71.4% of women (85/119) had at least one risk factor for ectopic pregnancy, with the most common risk factors being a history of induced labor, uterine curettage, spontaneous abortion or tubal pregnancy. 64 patients were managed by laparoscopic surgery (Group A) and 2 subjects were failure and followed by a systemic methotrexate (MTX) prescription. The other 55 patients had local injection with absolute ethanol, of which 9 cases failed, followed by a second local injection and intramuscular MTX. The HCG decrease rate post absolute ethanol injection was a value predictive factor for prognosis. Moreover, the pregnancy rate one-year post treatment in local injection subjects (10/55, 18.2%) was higher than that of surgical subjects (5/64, 7.8%). CONCLUSION: Local injection of absolute ethanol and laparoscopic surgery for tubal ectopic pregnancy are both effective and relatively safe, but laparoscopic surgery has better efficacy and shorten hospitalization day. Local injection may be less invasiveness and thus beneficial to fertility preservation.

G-CSF-mobilized peripheral blood mononuclear cells combined with platelet-rich plasma accelerate restoration of ovarian function in cyclophosphamide-induced POI rats†.

Peripheral blood mononuclear cells (PBMCs) are rich in hematopoietic cells and mesenchymal stem cells. Platelet-rich plasma (PRP) is rich in various growth factors. PBMCs and PRP have been suggested, individually, to restore ovarian function by improving the local microenvironment. The current study investigated the effect of granulocyte colony-stimulating factor (G-CSF)-mobilized PBMCs combined with PRP on restoring ovarian function in rats with primary ovarian insufficiency (POI). Thirty adult female rats were randomly subdivided into five groups: normal control (control), cyclophosphamide (CTX) plus subsequent PBS (POI + PBS), CTX plus subsequent PRP (POI + PRP), CTX plus subsequent G-CSF-mobilized PBMCs (POI + PBMCs), and CTX plus subsequent G-CSF-mobilized PBMCs combined with PRP (POI + PBMCs + PRP). CTX exposure induced the typical POI phenotype with increased diestrus; shortened estrus; follicle arrest at all stages; decreased serum levels of estradiol-17ß (E2) and anti-Mullerian hormone (AMH); and increased levels of follicle-stimulating hormone (FSH). Transplantation of mobilized PBMCs with PRP resulted in a much earlier restoration of the estrous cycle, sex hormone levels, and preantral follicle growth in POI rats. Expression of the male-specific Sry gene in the ovarian tissues of POI + PBMCs + PRP female recipient rats was evident at 5, 10, and 20 days posttransplantation along with significant increases in the expression of angiogenesis markers CD34+ and VEGF and folliculogenesis markers AMH and FSHR. Additionally, PBMCs in combination with PRP mitigated granulosa cell apoptosis by downregulating BAX and upregulating BCL-2. These results demonstrate that G-CSF-mobilized PBMCs combined with PRP accelerate the restoration of ovarian function in POI rats by increasing ovarian neovascularization, reducing granulosa cell apoptosis, and promoting folliculogenesis.

A case-control study of using carbon nanoparticles to trace decision-making lymph nodes around inferior mesenteric artery in rectal cancer.

BACKGROUND: Accurate identification of lymph nodes localized around inferior mesenteric artery (IMA), with or without metastasis, is of crucial importance for surgeons when dissecting D2 or D3 lymph nodes in patients with rectal cancer (RC). The following study evaluates whether carbon nanoparticles can be used for detection of decision-making lymph nodes (DLNs) in station 253 lymph nodes found around IMA during RC surgery. METHODS: A total of 66 patients with rectal adenocarcinomas were recruited between January 2014 and August 2017. Patients were divided into carbon nanoparticle (CN) group and control (CL) group; for the CN group, 1 ml nanoparticles were endoscopically injected into submucosal layer of primary tumor 1 day before surgery. DLNs were defined as black-dyed nodes in CN group or macroscopic lymph nodes in CL group localized along the IMA, proximal to the origin of the left colic artery. D3 lymph nodes were dissected using laparoscopic radical resection, and then examined using pathological approach. Intra-operative and post-operative data were compared between the two groups. RESULTS: In CN group, black-dyed DLNs were easily found under laparoscopy; the median number of DLNs was 3 (range 1-9). In CL group, the median number of DLNs was 0 (range 0-3). Consistency between intra-operative DLNs and post-operative station 253 nodes were confirmed by pathological examination. Significant higher number of DLNs in station 253 nodes (2.91 ± 2.47 vs 0.58 ± 0.75, p < 0.001), number of station 251 nodes (12.85 ± 8.99 vs 8.09 ± 5.85, p = 0.014), number of station 253 nodes (5.21 ± 5.26 vs 3.15 ± 2.32, p = 0.045), and the number of total lymph nodes (24.06 ± 13.20 vs 16.21 ± 9.09, p = 0.007) were found in the CN group compared to CL group. CONCLUSIONS: Carbon nanoparticles are useful for identifying DLNs in station 253 LNs around IMA in RC. It is not necessary to perform D3 lymph node dissection if there are no intra-operative DLNs metastases in RC.