Bulk anda single-cell transcriptome profiling reveals the molecular characteristics of T cell-mediated tumor killing in pancreatic cancer.

Background: Despite the potential of immune checkpoint blockade (ICB) as a promising treatment for Pancreatic adenocarcinoma (PAAD), there is still a need to identify specific subgroups of PAAD patients who may benefit more from ICB. T cell-mediated tumor killing (TTK) is the primary concept behind ICB. We explored subtypes according to genes correlated with the sensitivity to TKK and unraveled their underlying associations for PAAD immunotherapies. Methods: Genes that control the responsiveness of T cell-induced tumor destruction (GSTTK) were examined in PAAD, focusing on their varying expression levels and association with survival results. Moreover, samples with PAAD were separated into two subsets using unsupervised clustering based on GSTTK. Variability was evident in the tumor immune microenvironment, genetic mutation, and response to immunotherapy among different groups. In the end, we developed TRGscore, an innovative scoring system, and investigated its clinical and predictive significance in determining sensitivity to immunotherapy. Results: Patients with PAAD were categorized into 2 clusters based on the expression of 52 GSTTKs, which showed varying levels and prognostic relevance, revealing unique TTK patterns. Survival outcome, immune cell infiltration, immunotherapy responses, and functional enrichment are also distinguished among the two clusters. Moreover, we found the CATSPER1 gene promotes the progression of PAAD through experiments. In addition, the TRGscore effectively predicted the responses to chemotherapeutics or immunotherapy in patients with PAAD and overall survival. Conclusions: TTK exerted a vital influence on the tumor immune environment in PAAD. A greater understanding of TIME characteristics was gained through the evaluation of the variations in TTK modes across different tumor types. It highlights variations in the performance of T cells in PAAD and provides direction for improved treatment approaches.

Hybrid approach for accurate water demand prediction using socio-economic and climatic factors with ELM optimization.

This study proposes a hybrid approach for accurately predicting water demand by integrating socio-economic variables, such as population and GDP (per capita), with climatic variables, including temperature and precipitation. The prediction model utilizes an Extreme Learning Machine (ELM), effectively capturing the dynamic relationships between the input variables and water demand. The Improved Ant Nesting Algorithm is employed to fine-tune the weights and biases to optimize the network's performance. To evaluate the predictive accuracy of the model, a comprehensive dataset consisting of socio-economic and climatic factors is utilized for training and testing purposes. Performance metrics, namely Root Mean Square Error (RMSE) and Correlation Coefficients (R2), are employed as evaluation criteria. The results demonstrate that the hybrid approach achieves accurate water supply predictions, showcasing its potential to contribute significantly to effective water resource management and decision-making processes. Based on the results, IANA-ELM is considered the best model due to its high R2 values. Specifically, in the training data, the R2 values are 0.693 for population, 0.624 for GDP per capita, 0.607 for temperature, and 0.708 for rainfall. Similarly, in the test data, the R2 values are 0.672 for population, 0.608 for GDP per capita, 0.592 for temperature, and 0.708 for rainfall. This integrated approach provides a robust tool for policymakers, water utility companies, and researchers in the field of water managements, enabling them to make informed decisions based on accurate predictions of water demand.

Novel immune checkpoint-related gene model to predict prognosis and treatment responsiveness in low-grade gliomas.

Recently, studies have shown that immune checkpoint-related genes (ICGs) are instrumental in maintaining immune homeostasis and can be regarded as potential therapeutic targets. However, the prognostic applications of ICGs require further elucidation in low-grade glioma (LGG) cases. In the present study, a unique prognostic gene signature in LGG has been identified and validated as well based on ICGs as a means of facilitating clinical decision-making. The RNA-seq data as well as corresponding clinical data of LGG samples have been retrieved utilizing the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. ICG-defined non-negative matrix factorization (NMF) clustering was performed to categorize patients with LGG into two molecular subtypes with different prognoses, clinical traits, and immune microenvironments. In the TCGA database, a signature integrating 8 genes has been developed utilizing the LASSO Cox method and validated in the GEO database. The signature developed is superior to other well-recognized signatures in terms of predicting the survival probability of patients with LGG. This 8-gene signature was then subsequently applied to categorize patients into high- and low-risk groups, and differences between them in terms of gene alteration frequency were observed. There were remarkable variations in IDH1 (91% and 64%) across low-as well as high-risk groups. Additionally, various analyses like function enrichment, tumor immune microenvironment, and chemotherapy drug sensitivity revealed significant variations across high- and low-risk populations. Overall, this 8-gene signature may function as a useful tool for prognosis and immunotherapy outcome predictions among LGG patients.

MiR-9-1 controls osteoblastic regulation of lymphopoiesis.

The highly conserved MicroRNA-9 (miR-9) family consists of three members. We discovered that miR-9-1 deletion reduced mature miR-9 expression, causing 43% of the mice to display smaller size and postweaning lethality. MiR-9-1-deficient mice with growth defects experienced severe lymphopenia, but other blood cells were unaffected. The lymphopenia wasn't due to defects in hematopoietic progenitors, as mutant bone marrow (BM) cells underwent normal lymphopoiesis after transplantation into wild-type recipients. Additionally, miR-9-1-deficient mice exhibited impaired osteoblastic bone formation, as mutant mesenchymal stem cells (MSCs) failed to differentiate into osteoblastic cells (OBs). RNA sequencing revealed reduced expression of master transcription factors for osteoblastic differentiation, Runt-related transcription factor 2 (Runx2) and Osterix (Osx), and genes related to collagen formation, extracellular matrix organization, and cell adhesion, in miR-9-1-deficient MSCs. Follistatin (Fst), an antagonist of bone morphogenetic proteins (BMPs), was found to be a direct target of miR-9-1. Its deficiency led to the up-regulation of Fst, inhibiting BMP signaling in MSCs, and reducing IL-7 and IGF-1. Thus, miR-9-1 controls osteoblastic regulation of lymphopoiesis by targeting the Fst/BMP/Smad signaling axis.

Gut microbiota and bile acids partially mediate the improvement of fibroblast growth factor 21 on methionine-choline-deficient diet-induced non-alcoholic fatty liver disease mice.

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, inflammation, and fibrosis, as well as gut dysbiosis. Fibroblast growth factor 21 (FGF21), which regulates glucose and lipid metabolism, has been proven to have a good effect on NAFLD. However, the modulating process between FGF21 and gut microbiota remains unclear in treating NAFLD. Here, the fecal microbiota composition of 30 patients with NAFLD who had undergone liver biopsy and 29 matched healthy participants were studied, together with the fecal bile acid (BA) profile. Treatment with FGF21 was given in methionine-choline-deficient (MCD) diet-induced NAFLD model C57BL/6 mice. An antibiotic cocktail and fecal microbiota transplantation were used to further confirm the benefits of FGF21 that were partially attributable to the change in gut microbiota. Patients with NAFLD had higher serum FGF21 levels and dysregulated fecal microbiota compositions and fecal BA profiles. In NAFLD mice, FGF21 significantly reduced steatohepatitis and collagen deposition in vivo and restored intestinal structure. FGF21 treatment also changed gut microbiota composition and regulated dysbiosis in BA metabolism. After treatment with an antibiotic cocktail, FGF21 partially alleviated hepatic and intestinal damage in NAFLD mice. Furthermore, fecal microbiota transplantation from FGF21-treated mice showed benefits similar to FGF21 therapy. The improvement using FGF21 in MCD diet-induced NAFLD mice is partially mediated via gut microbiota and BA. Gut microbiota-regulated BA metabolism may be a potential target of FGF21 in improving NAFLD.

Immune regulatory effects of microRNA9-3.

MicroRNAs are known to regulate cell proliferation, differentiation, and apoptosis. However, the immunological mechanism and role of microRNA9-3 (miR9-3) are unknown. This study used CRISPR/cas9 technology to knock out miR9-3 to modulate its expression level. FACS results showed that the absolute number of total B cells declined in miR9-3-deficiency in the spleen (Sp), bone marrow (BM), and lymph node (LN) to different levels compared to the wild-type. Also, the absolute numbers of Fo, T1, and T2 cells decreased both in Sp and LN. The absolute numbers of total T cells in Sp and LN declined sharply; CD4+ and CD8+ T cells showed a dramatic decrease in Sp, LN, and Th (thymus) of the miR9-3- group. In BM, the cells number of immature B cells, pro-pre-B cells, pro-B cells, and pre-B cells reduced to different levels, while mature B cells were comparable to wild-type. These data illustrated that miR9-3-deficiency impaired the development of B cells in BM. Also, the development of T cells was severely impaired. In Th, the numbers of DN and DP cells were remarkably reduced in the miR9-3 mutant mice. Also, the numbers of DN-1, DN-3, and DN-4 cells decreased. The absolute number of cells in the hematopoietic stem cell (HSC) system such as LT-HSC (long-term HSC), ST-HSC (short-term HSC), MPP (multipotent progenitor), GMP (granulocyte-macrophage progenitor), CMP (common myeloid progenitors), MEP (megakaryocyte-erythroid progenitor), and CLP (common lymphoid progenitor) all were decreased in miR9-3 deficient mice. These results showed that miR9-3 deficiency initiated the damage to the entire hematopoietic system. Moreover, the absolute number of myeloid cells in both Sp and BM decreased in mutant mice. The cells number of NK cells showed a sharp reduction in Sp whereas the change was not significant in BM. The above results suggest that miR9-3 participates in the immune regulation of B cells, T cells, and the HSC system, highlighting its regulatory roles.

Fibroblasts in Scar Formation: Biology and Clinical Translation.

Scarring, which develops due to fibroblast activation and excessive extracellular matrix deposition, can cause physical, psychological, and cosmetic problems. Fibroblasts are the main type of connective tissue cells and play important roles in wound healing. However, the underlying mechanisms of fibroblast in reaching scarless wound healing require more exploration. Herein, we systematically reviewed how fibroblasts behave in response to skin injuries, as well as their functions in regeneration and scar formation. Several biocompatible materials, including hydrogels and nanoparticles, were also suggested. Moreover, factors that concern transformation from fibroblasts into cancer-associated fibroblasts are mentioned due to a tight association between scar formation and primary skin cancers. These findings will help us better understand skin fibrotic pathogenesis, as well as provide potential targets for scarless wound healing therapies.

FGF21 alleviates acute liver injury by inducing the SIRT1-autophagy signalling pathway.

Liver injury can lead to different hepatic diseases, which are the mainly causes of high global mortality and morbidity. Autophagy and Sirtuin type 1 (SIRT1) have been shown protective effects in response to liver injury. Previous studies have showed that Fibroblast growth factor 21 (FGF21) could alleviate acute liver injury (ALI), but the mechanism remains unclear. Here, we verified the relationship among FGF21, autophagy and SIRT1 in carbon tetrachloride (CCl4 )-induced ALI. We established CCl4 -induced ALI models in C57BL/6 mice and the L02 cell line. The results showed that FGF21 was robustly induced in response to stress during the development of ALI. After exogenous FGF21 treatment in ALI models, liver damage in ALI mice was significantly reduced, as well as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Consistently, FGF21 also greatly reduced the levels of ALT, AST, pro-inflammatory cytokines interleukin 6 (IL6) and tumour necrosis factor-alpha (TNFα) in ALI cell lines. Mechanistically, exogenous FGF21 treatment efficiently upregulated the expression of autophagy marker microtubule-associated protein light chain-3 beta (LC3 II) and autophagy key molecule coiled-coil myosin-like BCL2-interacting protein (Beclin1), which was accompanied by alleviating hepatotoxicity in CCl4 -treated wild-type mice. Then, we examined how FGF21 induced autophagy expression and found that SIRT1 was also upregulated by FGF21 treatment. To further verify our results, we constructed an anti-SIRT1 lentit-RNAi to inhibit SIRT1 expression in mice and L02 cells, which reversed the protective effect of FGF21 on ALI. In summary, these results indicate that FGF21 alleviates ALI by enhancing SIRT1-mediated autophagy.

Mechanism of action and therapeutic effects of oxidative stress and stem cell-based materials in skin aging: Current evidence and future perspectives.

Aging is associated with multiple degenerative diseases, including atherosclerosis, osteoporosis, and Alzheimer's disease. As the most intuitive manifestation of aging, skin aging has received the most significant attention. Skin aging results from various intrinsic and extrinsic factors. Aged skin is characterized by wrinkles, laxity, elastosis, telangiectasia, and aberrant pigmentation. The underlying mechanism is complex and may involve cellular senescence, DNA damage, oxidative stress (OS), inflammation, and genetic mutations, among other factors. Among them, OS plays an important role in skin aging, and multiple antioxidants (e.g., vitamin C, glutathione, and melatonin) are considered to promote skin rejuvenation. In addition, stem cells that exhibit self-replication, multi-directional differentiation, and a strong paracrine function can exert anti-aging effects by inhibiting OS. With the further development of stem cell technology, treatments related to OS mitigation and involving stem cell use may have a promising future in anti-skin aging therapy.

Fibroblast Growth Factor 21 Augments Autophagy and Reduces Apoptosis in Damaged Liver to Improve Tissue Regeneration in Zebrafish.

Regeneration of a part of the diseased liver after surgical resection is mainly achieved by the proliferation of the remaining healthy liver cells. However, in case of extreme loss of liver cells or in the final stages of chronic liver disease, most liver cells are depleted or lose their ability to proliferate. Therefore, to foster liver regeneration, it is of great clinical and scientific significance to improve the survival and proliferation ability of residual hepatocytes. In this study, we conducted experiments on a zebrafish model of targeted ablation of liver cells to clarify the role of fibroblast growth factor 21 (FGF21). We found that FGF21 increased the regeneration area of the damaged liver and improved the survival rate of damaged liver cells by inhibiting cell apoptosis and reducing oxidative stress. Our results also showed that administration of FGF21 upregulated autophagy, and the beneficial effects of FGF21 were reversed by the well-known autophagy inhibitor chloroquine (CQ), indicating that FGF21-activated autophagy played a central role in the treatment. We further showed that the enhancement of autophagy induced by FGF21 was due to the activation of the AMPK-mTOR signaling pathway. Taken together, these data provide new evidence that FGF21 is an effective autophagy regulator that can significantly improve the survival of damaged livers.

Circulating tumor cells: biology and clinical significance.

Circulating tumor cells (CTCs) are tumor cells that have sloughed off the primary tumor and extravasate into and circulate in the blood. Understanding of the metastatic cascade of CTCs has tremendous potential for the identification of targets against cancer metastasis. Detecting these very rare CTCs among the massive blood cells is challenging. However, emerging technologies for CTCs detection have profoundly contributed to deepening investigation into the biology of CTCs and have facilitated their clinical application. Current technologies for the detection of CTCs are summarized herein, together with their advantages and disadvantages. The detection of CTCs is usually dependent on molecular markers, with the epithelial cell adhesion molecule being the most widely used, although molecular markers vary between different types of cancer. Properties associated with epithelial-to-mesenchymal transition and stemness have been identified in CTCs, indicating their increased metastatic capacity. Only a small proportion of CTCs can survive and eventually initiate metastases, suggesting that an interaction and modulation between CTCs and the hostile blood microenvironment is essential for CTC metastasis. Single-cell sequencing of CTCs has been extensively investigated, and has enabled researchers to reveal the genome and transcriptome of CTCs. Herein, we also review the clinical applications of CTCs, especially for monitoring response to cancer treatment and in evaluating prognosis. Hence, CTCs have and will continue to contribute to providing significant insights into metastatic processes and will open new avenues for useful clinical applications.

A Promising Future of Ferroptosis in Tumor Therapy.

Currently, mechanisms and therapeutic approaches have been thoroughly studied in various prevalent malignant tumors, such as breast and lung cancer. However, there is inevitable tumor progression and drug resistance. Uncovering novel treatment strategies to inhibit tumor development is important. Ferroptosis, a form of cell death associated with iron and lipid peroxidation, has drawn extensive attention. In this paper, we reviewed the underlying mechanisms of ferroptosis (i.e., iron, glutathione, and lipid metabolism) and its role in various tumors (i.e., lung cancer, liver carcinoma, breast cancer, and pancreatic cancer). Moreover, we summarized ferroptosis-related anti-tumor drugs and emphasized the potential of combined treatment of anti-tumor drugs and radiotherapy in an effort to provide novel anti-tumor treatments.

Is Ferroptosis a Future Direction in Exploring Cryptococcal Meningitis?

Cryptococcal meningitis (CM) is the leading cause of mortality among patients infected with human immunodeficiency virus (HIV). Although treatment strategies for CM are continually being developed, the mortality rate is still high. Therefore, we need to explore more therapeutic strategies that are aimed at hindering its pathogenic mechanism. In the field of CM, several studies have observed rapid iron accumulation and lipid peroxidation within the brain, all of which are hallmarks of ferroptosis, which is a type of programmed cell death that is characterized by iron dependence and lipid peroxidation. In recent years, many studies have confirmed the involvement of ferroptosis in many diseases, including infectious diseases such as Mycobacterium tuberculosis infection and coronavirus disease-2019 (COVID-19). Furthermore, ferroptosis is considered as immunogenic and pro-inflammatory as the ferroptotic cells release damage-associated molecular pattern molecules (DAMPs) and alarmin, both of which regulate immunity and pro-inflammatory activity. Hence, we hypothesize that there might be a relationship between this unique cell death modality and CM. Herein, we review the evidence of ferroptosis in CM and consider the hypothesis that ferroptotic cell death may be involved in the cell death of CM.

Oxidative Stress at the Crossroads of Aging, Stroke and Depression.

Epidemiologic studies have shown that in the aging society, a person dies from stroke every 3 minutes and 42 seconds, and vast numbers of people experience depression around the globe. The high prevalence and disability rates of stroke and depression introduce enormous challenges to public health. Accumulating evidence reveals that stroke is tightly associated with depression, and both diseases are linked to oxidative stress (OS). This review summarizes the mechanisms of OS and OS-mediated pathological processes, such as inflammation, apoptosis, and the microbial-gut-brain axis in stroke and depression. Pathological changes can lead to neuronal cell death, neurological deficits, and brain injury through DNA damage and the oxidation of lipids and proteins, which exacerbate the development of these two disorders. Additionally, aging accelerates the progression of stroke and depression by overactive OS and reduced antioxidant defenses. This review also discusses the efficacy and safety of several antioxidants and antidepressants in stroke and depression. Herein, we propose a crosstalk between OS, aging, stroke, and depression, and provide potential therapeutic strategies for the treatment of stroke and depression.

Is DNA Methylation a Ray of Sunshine in Predicting Meningioma Prognosis?

Meningioma is the most common intracranial tumor, and recent studies have drawn attention to the importance of further research on malignant meningioma. According to the World Health Organization (WHO) grading, meningioma is classified into 15 subtypes with three grades of malignancy. However, due to a lack of descriptions of molecular subtypes, genetic mutations, or other features, there were deficiencies in the WHO classification. The DNA methylation-based meningioma classification published in 2017 used DNA copy number analysis, mutation profiling, and RNA sequencing to distinguish six clinically relevant methylation classes, which contributed to a better prediction of tumor recurrence and prognosis. Further studies indicated that gene variation and gene mutations, such as those in neurofibromin 2 (NF2) and BRCA1, were related to the high WHO grade, malignant invasion, and recurrence. Among the mutant genes described above, some have been associated with differential DNA methylation. Herein, we searched for articles published in PubMed and Web of Science from January 2000 to May 2020 by entering the keywords "meningioma," "methylation," and "gene mutation," and found a number of published studies that analyzed DNA methylation in meningiomas. In this review, we summarize the key findings of recent studies on methylation status and genetic mutations of meningioma and discuss the current deficits of the WHO grading. We also propose that a methylation-based meningioma classification could provide clues in the assessment of individual risk of meningioma recurrence, which is associated with clinical benefits for patients.

A protein fragment of Rv3194c located on mycobacterial cell surface efficiently prevents adhesion of recombinant Mycobacterium smegmatis, and promises a new anti-adhesive drug.

Adhesins are virulence factors expressed on the surfaces of pathogenic bacteria that mediate pathogen-host interactions, a critical step in the infection process. Here, we show that the Mycobacterium tuberculosis protease Rv3194c functions not only as an enzyme but as an adhesin. The heterologous Rv3194c protein was purified from Escherichia coli and was shown to bind to hyaluronic acid (HA). The HA-binding site was identified as a 20 amino acid peptide between residues 91 and 110 (P91-110). Rv3194c bound to A549 alveolar basal epithelial cells and the interaction was abolished by the addition of hyaluronidase or P91-110. Experimental infection in vitro revealed that Rv3194c participates in the attachment of recombinant Mycobacterium smegmatis (Rv3194c/MS) to A549 cells, and P91-110 treatment of A549 cells largely inhibited the Rv3194c/MS-A549 cell interaction. To provide in vivo evidence, we constructed a reporter strain of M. smegmatis that expressed a derivative of the firefly luciferase that is shifted to red (FFlucRT) in combination with Rv3194c (Rv3194c + FFlucRT/MS) to infect mice and monitor the progression of the disease. In mice, Rv3194c dramatically enhanced M. smegmatis persistence and induced lesions in the lungs. In addition, treatment of intratracheal Rv3194c + FFlucRT/MS- infected mice with P91-110 significantly suppressed the growth of Rv3194c + FFlucRT/MS in vivo and reduced pathological injury caused by infection of the lung with Rv3194c + FFlucRT/MS. Taken together, these results demonstrate that Rv3194c functions as an HA-binding adhesin and that P91-110 may have the potential for treating and preventing mycobacterial infection.

Ferroptosis in Acute Central Nervous System Injuries: The Future Direction?

Acute central nervous system (CNS) injuries, such as stroke, traumatic brain injury (TBI), and spinal cord injury (SCI) present a grave health care challenge worldwide due to high morbidity and mortality, as well as limited clinical therapeutic strategies. Established literature has shown that oxidative stress (OS), inflammation, excitotoxicity, and apoptosis play important roles in the pathophysiological processes of acute CNS injuries. Recently, there have been many studies on the topic of ferroptosis, a form of regulated cell death characterized by the accumulation of iron-dependent lipid peroxidation. Some studies have revealed an emerging connection between acute CNS injuries and ferroptosis. Ferroptosis, induced by the abnormal metabolism of lipids, glutathione (GSH), and iron, can accelerate acute CNS injuries. However, pharmaceutical agents, such as iron chelators, ferrostatin-1 (Fer-1), and liproxstatin-1 (Lip-1), can inhibit ferroptosis and may have neuroprotective effects after acute CNS injuries. However, the specific mechanisms underlying this connection has not yet been clearly elucidated. In this paper, we discuss the general mechanisms of ferroptosis and its role in stroke, TBI, and SCI. We also summarize ferroptosis-related drugs and highlight the potential therapeutic strategies in treating various acute CNS injuries. Additionally, this paper suggests a testable hypothesis that ferroptosis may be a novel direction for further research of acute CNS injuries by providing corresponding evidence.

Efferocytosis and Its Associated Cytokines: A Light on Non-tumor and Tumor Diseases?

Billions of cells undergo turnover and die via apoptosis throughout our lifetime. A prompt clearance of these apoptotic cells and debris by phagocytic cells, a process known as efferocytosis, is important in maintaining tissue homeostasis. Accordingly, impaired efferocytosis due to the defective clearance and disrupted stages can lead to a growing number of inflammation- and immune-related diseases. Although numerous studies have shown the mechanisms of efferocytosis, its role in disorders, such as non-tumor and tumor diseases, remains poorly understood. This review summarizes the processes and signal molecules in efferocytosis, and efferocytosis-related functions in non-tumor (e.g., atherosclerosis, lung diseases) and tumor diseases (e.g., breast cancer, prostate cancer), as well as describes the role of involved cytokines. Of note, there is a dual role of efferocytosis in the abovementioned disorders, and a paradoxical effect among non-tumor and tumor diseases in terms of inflammation resolution, immune response, and disease progression. Briefly, intact efferocytosis and cytokines promote tissue repair, while they contribute to tumor progression via the tumor microenvironment and macrophage politzerization. Additionally, this review provides potential targets associated with TAM (TYRO3, AXL, MERTK) receptors and cytokines, such as tumor necrosis factor α and CXCL5, suggesting potential novel therapeutic ways in treating diseases.

The "Plan-Do-Check-Action" Plan Helps Improve the Quality of the "Standardized Training of Resident Physicians": An Analysis of the Results of the First Pass Rate.

Background: Medical education is a demanding lifelong learning process, which includes three tightly connected stages: college education, post-graduate education, and continuous education. Residency, the first several years after a college education, is a pivotal time in the development of a qualified doctor. Additionally, residents are the main force that undertakes much of the clinical work in hospitals. Therefore, guaranteeing and improving residents' clinical skills and abilities through the standardized training of resident physicians (STRP) is important. However, compared with other hospitals in the Zhejiang Province, the STRP assessment results of residents in our hospital were not satisfactory in recent years. Therefore, the objective of this study was to find the problems causing the unsatisfactory performance and identify the role of the "Plan-Do-Check-Action" (PDCA) plan in providing a valuable framework for future training. Methods: Relevant studies of STRP in China and abroad were investigated by the literature review. According to published data by the Health Commision of Zhejiang Province, we collected the STRP assessment rsults of a total number of 12,036 residents. The inclusion cretria of these residents include: (1) 3rd-year residents. (2) taking STRP in the Zhejiang Province during 2016-2018 or 2017-2019. (3) the first time taking the clinical practice ability examination (CPAE) in 2018 or 2019. The results of 634 3rd-year residents from The Second Affiliated Hospital of Zhejiang University (SAHZU) were provided by the Department of Medical Education and were analyzed in depth. Three hundred and eight residents from SAHZU received normal training and took the CPAE in 2018, whereas 326 residets received PDCA and took the CPAE in 2019. PDCA is a program designed to improve the performance of residency in SAHZU. It includes the formulation and implementation of specific training plans, the check of effects, and continuous improvements. There was no change in the STRP assessment in these 2 years and the indicator of performance in the STRP assessment was the first pass rate (FPR). Statistical analyses were performed using Pearson's chi-squared test, Yates-corrected chi-square test, or Fisher's exact test (SPSS Statistics, version 25). A P-value of < 0.05 was considered significant. Results: A total number of 6,180 and 5,856 examinees in the Zhejiang Province took the clinical practice ability examination in 2018 and 2019, respectively. In 2018, a total of 308 residents from 20 departments of the SAHZU took the STRP assessment. In 2019, a total of 326 residents from 22 departments of the SAHZU underwent the PDCA plan and took the STRP assessment. Compared with the results in 2018, the average FPR in the Zhejiang Province increased by 2.92% from 87.87 to 90.79% (P < 0.001). The FPR of the SAHZU increased by 7.88% from 85.06 to 92.94% (P = 0.001). In the SAHZU, the FPRs of the Department of Emergency and Department of Anesthesiology improved 34.51% (P = 0.024) and 20.36% (P = 0.004), respectively. There were no significant differences between the performances in the 2 years of the other 20 departments. There were improved results in the "Clinical Thinking and Decision-Making" and "Operation of Basic Skills" assessment stations with increases of 3.01% (P = 0.002) and 3.94% (P = 0.002), respectively. No statistically significant differences in the FPRs of the other six stations were found. The performances in all the stations in the final tests were better than in the stimulation tests (P < 0.001). Conclusions: Although our sample size was relatively small, our results showed a small success of the PDCA plan in improving the quality of the STRP, especially for the residents in the Departments of Emergency and Anesthesiology. The PDCA plan also contributed to enhancing residents' abilities in the "Clinical Thinking and Decision-Making" and "Operation of Basic Skills" stations. Taken together, the PDCA plan may provide a practical framework for developing future training plans.

The Role of Oxidative Stress in Common Risk Factors and Mechanisms of Cardio-Cerebrovascular Ischemia and Depression.

The public health sector faces a huge challenge as a result of the high prevalence and burden of disability caused by ischemic cardio-cerebrovascular disease (CVD) and depression. Although studies have explored the underlying mechanisms and potential therapies to address conditions, there is no treatment breakthrough, especially for depression which is highly influenced by social stressors. However, accumulating evidence reveals that CVD and depression are correlated and share common risk factors, particularly obesity, diabetes, and hypertension. They also share common mechanisms, including oxidative stress (OS), inflammation and immune response, cell death signaling pathway, and microbiome-gut-brain axis. This review summarizes the relationship between ischemic CVD and depression and describes the interactions among common risk factors and mechanisms for these two diseases. In addition, we propose that OS mediates the crosstalk between these diseases. We also reveal the potential of antioxidants to ameliorate OS-related injuries.