Human bone marrow mesenchymal stem cell-derived exosomes loaded with gemcitabine inhibit pancreatic cancer cell proliferation by enhancing apoptosis.

BACKGROUND: Pancreatic cancer remains one of the most lethal malignancies, and has limited effective treatment. Gemcitabine (GEM), a chemotherapeutic agent, is commonly used for clinical treatment of pancreatic cancer, but it has characteristics of low drug delivery efficiency and significant side effects. The study tested the hypothesis that human bone marrow mesenchymal stem cell (MSC)-derived exosomes loaded with GEM (Exo-GEM) would have a higher cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis. AIM: To investigate the cytotoxicity of MSC-derived Exo-GEM against pancreatic cancer cells in vitro. METHODS: Exosomes were isolated from MSCs and characterized by transmission electron microscopy and nanoparticle tracking analysis. Exo-GEM through electroporation, sonication, or incubation, and the loading efficiency was evaluated. The cytotoxicity of Exo-GEM or GEM alone against human pancreatic cancer Panc-1 and MiaPaca-2 cells was assessed by MTT and flow cytometry assays. RESULTS: The isolated exosomes had an average size of 76.7 nm. The encapsulation efficacy and loading efficiency of GEM by electroporation and sonication were similar and significantly better than incubation. The cytotoxicity of Exo-GEM against pancreatic cancer cells was stronger than free GEM and treatment with 0.02 µM Exo-GEM significantly reduced the viability of both Panc-1 and MiaPaca-2 cells. Moreover, Exo-GEM enhanced the frequency of GEM-induced apoptosis in both cell lines. CONCLUSION: Human bone marrow MSC-derived Exo-GEM have a potent cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis, offering a promising drug delivery system for improving therapeutic outcomes.

Change trend and attribution analysis of leaf area index in the East African Plateau from 1982 to 2020.

The ecosystems on the East African Plateau are crucial for maintaining the biodiversity, water resource balance, and ecological equilibrium of the African continent. However, the spatiotemporal variations of vegetation and the driving factors remain unclear. We analyzed leaf area index (LAI) change trends in the East African Plateau based on the GIMMS LAI4g dataset and further conducted attribution analysis combining temperature and precipitation data, as well as 10 Dynamic Global Vegetation Models (DGVMs) in TRNEDY v9. The results showed that LAI of the East African Plateau had a modest change trend from 1982 to 1999 (2.5×10-3 m2·m-2·a-1), but significantly increased from 2000 to 2020 (5.2×10-3 m2·m-2·a-1), which was 2.1 times faster than that during 1982-1999. Temperature and precipitation had weak correlations with LAI from 1982 to 1999, but showed significant correlations from 2000 to 2020. The DGVMs demonstrated consistent attribution results, with temperature and precipitation contributing significantly more to the LAI variations from 2000 to 2020 compared to the period from 1982 to 1999. The results highlighted the key role of climate change in driving vegetation greening on the East African Plateau during 2000-2020, which could provide important evidence for ecological conservation and sustainable development strategies in the region.

Endoplasmic reticulum-targeted iridium(III) photosensitizer induces pyroptosis for augmented tumor immunotherapy.

An ideal tumor treatment strategy involves therapeutic approaches that can enhance the immunogenicity of the tumor microenvironment while simultaneously eliminating the primary tumor. A cholic acid-modified iridium(III) (Ir3) photosensitizer, targeted to the endoplasmic reticulum (ER), has been reported to exhibit potent type I and type II photodynamic therapeutic effects against triple-negative breast cancer (MDA-MB-231). This photosensitizer induces pyroptotic cell death mediated by gasdermin E (GSDME) through photodynamic means and enhances tumor immunotherapy. Mechanistic studies have revealed that complex Ir3 induces characteristics of damage-related molecular patterns (DAMPs) in MDA-MB-231 breast cancer cells under light conditions. These include cell-surface calreticulin (CRT) eversion, extracellular high mobility group box 1 (HMGB1) and ATP release, accompanied by ER stress and increased reactive oxygen species (ROS). Consequently, complex Ir3 promotes dendritic cell maturation and antigen presentation under light conditions, fully activates T cell-dependent immune response in vivo, and ultimately eliminates distant tumors while destroying primary tumors. In conclusion, immune regulation and targeted intervention mediated by metal complexes represent a new and promising approach to tumor therapy. This provides an effective strategy for the development of combined targeted therapy and immunotherapy.

Deoxygenative radical cross-coupling of C(sp3)-O/C(sp3)-H bonds promoted by hydrogen-bond interaction.

Building C(sp3)-rich architectures using simple and readily available starting materials will greatly advance modern drug discovery. C(sp3)-H and C(sp3)-O bonds are commonly used to strategically disassemble and construct bioactive compounds, respectively. However, the direct cross coupling of these two chemical bonds to form C(sp3)-C(sp3) bonds is rarely explored in existing literature. Conventional methods for forming C(sp3)-C(sp3) bonds via radical-radical coupling pathways often suffer from poor selectivity, severely limiting their practicality in synthetic applications. In this study, we present a single electron transfer (SET) strategy that enables the cleavage of amine α-C - H bonds and heterobenzylic C - O bonds to form C(sp3)-C(sp3) bonds. Preliminary mechanistic studies reveal a hydrogen bond interaction between substrates and phosphoric acid facilitates the cross-coupling of two radicals with high chemoselectivity. This methodology provides an effective approach to a variety of aza-heterocyclic unnatural amino acids and bioactive molecules.

Factors influencing the prognosis of patients with cardiogenic shock treated with extracorporeal membrane oxygenation: A protocol for systematic review and meta-analysis.

BACKGROUND: Cardiogenic shock is a clinical syndrome caused by primary heart disease that results in decreased cardiac output and insufficient systemic perfusion. A study was conducted to determine what factors affect survival in patients with cardiogenic shock treated with extracorporeal membrane oxygenation (ECMO). METHODS: A systematic search was conducted across various databases, including CKNI, VIP, Wan Fang, CBM, Embase, PubMed, Cochrane Library, and Web of Science databases, to gather factors linked to the prognosis of patients with cardiogenic shock who underwent ECMO treatment. The search period for each database was set to conclude on April 30, 2024. RESULTS: The findings suggest that, in comparison to the death group, the lactic acid levels of the survival group after treatment were significantly lower (95% confidence interval [CI]: -0.79, -0.58). In addition, the creatinine levels of the survival group after treatment were also significantly lower than those of the death group (95% CI: -0.39, -0.14). Furthermore, the troponin levels in the survival group after treatment were lower than those in the death group (95% CI: -0.32, 0.04), and the total bilirubin levels in the survival group after treatment were also lower than those in the death group (95% CI: -0.62, -0.23). CONCLUSIONS: According to the study, total bilirubin, creatinine, and lactic acid levels were lower in the survival group than in the death group when ECMO was used to treat cardiogenic patients, suggesting a better prognosis for patients with cardiogenic shock. Therefore, total bilirubin, creatinine, and lactic acid could be influential factors in the prognosis of survival in patients with cardiogenic shock.

Prediction model of pressure injury occurrence in diabetic patients during ICU hospitalization--XGBoost machine learning model can be interpreted based on SHAP.

BACKGROUND: The occurrence of pressure injury in patients with diabetes during ICU hospitalization can result in severe complications, including infections and non-healing wounds. AIMS: The aim of this study was to predict the occurrence of pressure injury in ICU patients with diabetes using machine learning models. STUDY DESIGN: In this study, LASSO regression was used for feature screening, XGBoost was employed for machine learning model construction, ROC curve analysis, calibration curve analysis, clinical decision curve analysis, sensitivity, specificity, accuracy, and F1 score were used for evaluating the model's performance. RESULTS: Out of the 503 ICU patients with diabetes included in the study, pressure injury developed in 170 cases, resulting in an incidence rate of 33.8 %. The XGBoost model had a higher AUC for predicting pressure injury in patients with diabetes during ICU hospitalization (train: 0.896, 95 %CI: 0.863 to 0.929; test: 0.835, 95 % CI: 0.761-0.908). The importance of SHAP variables in the model from high to low was: 'Days in ICU', 'Mechanical Ventilation', 'Neutrophil Count', 'Consciousness', 'Glucose', and 'Warming Blanket'. CONCLUSION: The XGBoost machine learning model we constructed has shown high performance in predicting the occurrence of pressure injury in ICU patients with diabetes. Additionally, the SHAP method enables the interpretation of the results provided by the machine learning model. RELEVANCE TO CLINICAL PRACTICE: Improve the ability to predict the early occurrence of pressure injury in diabetic patients in the ICU. This will enable clinicians to intervene early and reduce the occurrence of complications.

Arthroscopic treatment of osteoid osteoma in the posterior proximal tibia: A case report and literature review.

BACKGROUND: Osteoid osteoma (OO) is a benign lesion characterized by an increased fibrous component in the bone marrow, presence of bone-like structures within the medullary cavity, and a surrounding sclerotic bone rim. Reports on OO located in the posterior proximal tibia are rare. CASE SUMMARY: Herein, we report the case of an 18-year-old male, admitted for the evaluation of right knee pain. The right knee pain had started 6 months prior without any apparent cause, which was notably severe at night, affecting sleep, and was exacerbated while climbing stairs or bearing weight. The patient also experienced pain on flexion. Three-dimensional computed tomography and magnetic resonance imaging revealed a nodular lesion beneath the cortical bone of the posterior medial plateau of the right tibia and an abnormal signal focus on the posterior lateral aspect of the right tibial plateau associated with extensive bone marrow edema. A small amount of fluid was present in the right knee joint capsule. The patient subsequently underwent arthroscopic excision of the OO. Postoperatively, there was significant relief of pain, and the knee range of motion returned to normal. CONCLUSION: Although OO in the posterior proximal tibia is a rare occurrence, it can be effectively excised through minimally invasive arthroscopic visualization.

Enantioselective Tsuji-Trost α-Fluoroallylation of Amino Acid Esters with Gem-Difluorinated Cyclopropanes.

A novel enantioselective Tsuji-Trost-type cross coupling reaction between gem-difluorinated cyclopropanes and N-unprotected amino acid esters enabled by synergistic Pd/Ni/chiral aldehyde catalysis is presented herein. This transformation streamlined the diversity-oriented synthesis (DOS) of optically active α-quaternary α-amino acid esters bearing a linear 2-fluoroallylic motif, which served as an appealing platform for the construction of other valuable enantioenriched compounds. The key intermediates were confirmed by HRMS detection, while DFT calculations revealed that the excellent enantioselectivity was attributed to the stabilizing non-covalent interactions between the Pd(II)-π-fluoroallyl species and the Ni(II)-Schiff base complex.

Targeting PRSS23 with tipranavir induces gastric cancer stem cell apoptosis and inhibits growth of gastric cancer via the MKK3/p38 MAPK-IL24 pathway.

Gastric cancer stem cells (GCSCs) contribute to the refractory features of gastric cancer (GC) and are responsible for metastasis, relapse, and drug resistance. The key factors drive GCSC function and affect the clinical outcome of GC patients remain poorly understood. PRSS23 is a novel serine protease that is significantly up-regulated in several types of cancers and cancer stem cells, and related to tumor progression and drug resistance. In this study, we investigated the role of PRSS23 in GCSCs as well as the mechanism by which PRSS23 regulated the GCSC functions. We demonstrated that PRSS23 was critical for sustaining GCSC survival. By screening a collection of human immunodeficiency virus (HIV) protease inhibitors (PIs), we identified tipranavir as a PRSS23-targeting drug, which effectively killed both GCSC and GC cell lines (its IC50 values were 4.7 and 6.4 µM in GCSC1 cells and GCSC2 cells, respectively). Administration of tipranavir (25 mg·kg-1·d-1, i.p., for 8 days) in GCSC-derived xenograft mice markedly inhibited the growth of subcutaneous GCSC tumors without apparent toxicity. In contrast, combined treatment with 5-FU plus cisplatin did not affect the tumor growth but causing significant weight loss. Furthermore, we revealed that tipranavir induced GCSC cell apoptosis by suppressing PRSS23 expression, releasing MKK3 from the PRSS23/MKK3 complex to activate p38 MAPK, and thereby activating the IL24-mediated Bax/Bak mitochondrial apoptotic pathway. In addition, tipranavir was found to kill other types of cancer cell lines and drug-resistant cell lines. Collectively, this study demonstrates that by targeting both GCSCs and GC cells, tipranavir is a promising anti-cancer drug, and the clinical development of tipranavir or other drugs specifically targeting the PRSS23/MKK3/p38MAPK-IL24 mitochondrial apoptotic pathway may offer an effective approach to combat gastric and other cancers.

Identification and bioactivity evaluation of miliusanes from Miliusa sinensis.

Miliusanes are a class of anticancer lead molecules belonging to meroterpenoids with an 18-carbon skeleton isolated from Miliusa plants. A phytochemical study of the plant M. sinensis was carried out to discover new miliusanes with diverse structural features in order to better understand their structure-activity relationship. As a result, 20 compounds including 12 new ones (7-14 and 17-20) belonging to two sub-classes of miliusanes were isolated and identified from the twigs and leaves of this plant. Their structures, including absolute configurations, were determined by spectroscopic analyses and electronic circular dichroism. The absolute stereochemistry of miliusane structures has also been confirmed for the first time through the single crystal X-ray diffraction analysis of miliusol (1). Bioactivity evaluation showed that some of the miliusane isolates potently inhibit cell growth of several human derived cancer cell lines with IC50 values ranging from 0.52 to 23.5 µM. Compound 11 demonstrated more potent cytotoxic activity than the known miliusol (1) in stomach cancer cells though its structure contains an unconjugated 1, 4-diketone system, which added a new structure-activity feature to miliusanes. The preliminary mechanism of action studies revealed that they could be a class of dual cell migration inhibitor and senescence inducer.

Tough and stretchable all-κ-carrageenan hydrogel based on the cooperative effects between chain conformation transition and stepwise mechanical training.

The traditional κ-carrageenan (κCG)-based hydrogel obtained from hot water can rupture easily under mechanical loading. To address this vulnerability, here we presented a robust all-κCG hydrogel without employing the second synthetic network. By simply regulating the polymer chains from random coil to stiff chain conformation in NaOH/urea solvent system via the freeze-thawing process, the as-prepared hydrogel with homogeneous structure can display an enhanced stretchability from 42.1 to 156 %, while maintaining the similar fracture stress. Moreover, upon the stepwise mechanical training and subsequent incubation in KCl aqueous solution, more helical segments of κCG were aligned and involved into the association domains, thus leading to the increment in both the crystallinity and anisotropy. Consequently, a fast self-strengthening behavior occurred, and a more stretchable (fracture strain up to 396 %), strong (stress âˆ¼ 0.55 MPa) and tough (∼1.52 MJ m-3) κCG hydrogel was obtained. In comparison to the traditional one, the fracture strain and toughness are increased by 8.5 and 11.5 times, respectively. In addition, this κCG hydrogel can demonstrate good recovery and shape-memory behaviors under medium deformation. Hence, this tough all-κCG hydrogel is expected to be tailored into the biomaterials as the wearable device, artificial tendon, and cartilage in the future.

Improved Domain Adaptation Network Based on Wasserstein Distance for Motor Imagery EEG Classification.

Motor Imagery (MI) paradigm is critical in neural rehabilitation and gaming. Advances in brain-computer interface (BCI) technology have facilitated the detection of MI from electroencephalogram (EEG). Previous studies have proposed various EEG-based classification algorithms to identify the MI, however, the performance of prior models was limited due to the cross-subject heterogeneity in EEG data and the shortage of EEG data for training. Therefore, inspired by generative adversarial network (GAN), this study aims to propose an improved domain adaption network based on Wasserstein distance, which utilizes existing labeled data from multiple subjects (source domain) to improve the performance of MI classification on a single subject (target domain). Specifically, our proposed framework consists of three components, including a feature extractor, a domain discriminator, and a classifier. The feature extractor employs an attention mechanism and a variance layer to improve the discrimination of features extracted from different MI classes. Next, the domain discriminator adopts the Wasserstein matrix to measure the distance between source domain and target domain, and aligns the data distributions of source and target domain via adversarial learning strategy. Finally, the classifier uses the knowledge acquired from the source domain to predict the labels in the target domain. The proposed EEG-based MI classification framework was evaluated by two open-source datasets, the BCI Competition IV Datasets 2a and 2b. Our results demonstrated that the proposed framework could enhance the performance of EEG-based MI detection, achieving better classification results compared with several state-of-the-art algorithms. In conclusion, this study is promising in helping the neural rehabilitation of different neuropsychiatric diseases.

Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions.

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is one of the most important intracellular pathways involved in cell proliferation, growth, differentiation, and survival. Therefore, this route is a prospective biological target for treating various human diseases, such as tumors, neurodegenerative diseases, pulmonary fibrosis, and diabetes. An increasing number of clinical studies emphasize the necessity of developing novel molecules targeting the PI3K/AKT/mTOR pathway. This review focuses on recent advances in ATP-competitive inhibitors, allosteric inhibitors, covalent inhibitors, and proteolysis-targeting chimeras against the PI3K/AKT/mTOR pathway, and highlights possible solutions for overcoming the toxicities and acquired drug resistance of currently available drugs. We also provide recommendations for the future design and development of promising drugs targeting this pathway.

Clinical Characteristics and Outcomes of Chronic Kidney Disease in People Living with HIV in a Resource-Limited Center of Central China.

Clinical management and optimal treatment are essential to improving outcomes for people living with HIV (PLWH). We assessed trends and outcomes of chronic kidney disease (CKD) in PLWH in a resource-limited center of central China. All PLWH who were followed up in a tertiary referral center in Wuhan, China, from July 2016 to June 2021 were evaluated. CKD was defined as glomerular filtration rate (GFR) <60 mL/min/1.73 m2 during two consecutive measurements 3 months apart. Baseline characteristics of the participants were extracted from the hospital medical records. The prevalence rate and associated risk factors of CKD were analyzed. A total of 863 PLWH with normal kidney function at baseline were analyzed. The median age was 33 (interquartile ranges: 26-49) years, and 778 (90.2%) were male and 85 (9.8%) were female. Among them, 50 (5.8%) had their GFR falling below 60 mL/min/1.73 m2 after a median of 54 months. Adjusted multivariate logistic regression revealed older age [adjusted odds ratio (aOR) = 1.04, 95% confidence interval (95% CI): 1.01-1.07], female sex (aOR = 3.17, 95% CI: 1.14-8.84), lower body weight (aOR = 0.95, 95% CI: 0.91-1.00), lower hemoglobin (aOR = 3.54, 95% CI: 1.51-8.30), longer duration of antiretroviral therapy exposure (aOR = 1.02, 95% CI: 1.00-1.04), and a baseline GFR between 60 and 90 mL/min/1.73 m2 (aOR = 3.89, 95% CI: 1.21-12.46) were associated with the development of CKD. Our findings showed that CKD is not infrequent in PLWH with a combination of traditional and HIV-specific risk factors for kidney disease, highlighting the suboptimal monitoring and treatment options of CKD in PLWH in resource-limited settings. Scalable monitoring strategy to improve care for this population is warranted.

PgtE Enzyme of Salmonella enterica Shares the Similar Biological Roles to Plasminogen Activator (Pla) in Interacting With DEC-205 (CD205), and Enhancing Host Dissemination and Infectivity by Yersinia pestis.

Yersinia pestis, the cause of plague, is a newly evolved Gram-negative bacterium. Through the acquisition of the plasminogen activator (Pla), Y. pestis gained the means to rapidly disseminate throughout its mammalian hosts. It was suggested that Y. pestis utilizes Pla to interact with the DEC-205 (CD205) receptor on antigen-presenting cells (APCs) to initiate host dissemination and infection. However, the evolutionary origin of Pla has not been fully elucidated. The PgtE enzyme of Salmonella enterica, involved in host dissemination, shows sequence similarity with the Y. pestis Pla. In this study, we demonstrated that both Escherichia coli K-12 and Y. pestis bacteria expressing the PgtE-protein were able to interact with primary alveolar macrophages and DEC-205-transfected CHO cells. The interaction between PgtE-expressing bacteria and DEC-205-expressing transfectants could be inhibited by the application of an anti-DEC-205 antibody. Moreover, PgtE-expressing Y. pestis partially re-gained the ability to promote host dissemination and infection. In conclusion, the DEC-205-PgtE interaction plays a role in promoting the dissemination and infection of Y. pestis, suggesting that Pla and the PgtE of S. enterica might share a common evolutionary origin.

RUNX3-mediated circDYRK1A inhibits glutamine metabolism in gastric cancer by up-regulating microRNA-889-3p-dependent FBXO4.

BACKGROUND: Targeting glutamine metabolism is previously indicated as a potential and attractive strategy for gastric cancer (GC) therapy. However, the underlying mechanisms responsible for the modification of glutamine metabolism in GC cells have not been fully elucidated. Accordingly, the current study sought to investigate the physiological mechanisms of RUNX3-mediated circDYRK1A in glutamine metabolism of GC. METHODS: Firstly, GC tissues and adjacent normal tissues were obtained from 50 GC patients to determine circDYRK1A expression in GC tissues. Next, the binding affinity among RUNX3, circDYRK1A, miR-889-3p, and FBXO4 was detected to clarify the mechanistic basis. Moreover, GC cells were subjected to ectopic expression and knockdown manipulations of circDYRK1A, miR-889-3p, and/or FBXO4 to assay GC cell malignant phenotypes, levels of glutamine, glutamic acid, and α-KG in cell supernatant and glutamine metabolism-related proteins (GLS and GDH). Finally, nude mice were xenografted with GC cells to explore the in vivo effects of circDYRK1A on the tumorigenicity and apoptosis. RESULTS: circDYRK1A was found to be poorly expressed in GC tissues. RUNX3 was validated to bind to the circDYRK1A promoter, and circDYRK1A functioned as a miR-889-3p sponge to up-regulate FBXO4 expression. Moreover, RUNX3-upregulated circDYRK1A reduced levels of glutamine, glutamic acid, and α-KG, and protein levels of GLS and GDH, and further diminished malignant phenotypes in vitro. Furthermore, in vivo experimentation substantiated that circDYRK1A inhibited the tumorigenicity and augmented the apoptosis in GC. CONCLUSION: In conclusion, these findings highlighted the significance and mechanism of RUNX3-mediated circDYRK1A in suppressing glutamine metabolism in GC via the miR-889-3p/FBXO4 axis.