Identification of a novel cancer-associated fibroblasts gene signature based on bioinformatics analysis to predict prognosis and therapeutic responses in breast cancer.

Cancer-associated fibroblasts (CAFs) provide suitable conditions for growth of tumor cell and facilitate tumor progression. Hence, we aimed to identify a CAFs-related gene signature associated with the prognosis of patients with breast cancer (BRCA). We downloaded datasets from Gene Expression Omnibus (GEO) and confirmed the correlation between CAFs infiltration scores and prognosis. By performing weighted gene co-expression network analysis (WGCNA) and Lasso Cox regression analysis, we constructed a four-gene (COL5A3, FN1, POSTN, and RARRES2) prognostic CAFs signature model. Based on the median risk score of CAFs, patients with BRCA were divided into high- and low-risk groups. Compared with low-risk group, patients in high-risk group exhibited a poor prognosis and limited response to immunotherapy. Furthermore, patients with high CAFs risk scores were found to have a detrimental prognosis due to the induction of immunosuppressive cell infiltration, resulting in an immunosuppressive tumor microenvironment. Importantly, we found that CAFs overexpressing FN1 and POSTN significantly promoted the wound healing and invasion ability of tumor cells in vitro validation. Taking together, we identified a four-gene prognostic CAFs signature, which was proven to be a reliable indicator for prognosis and therapeutic efficacy in patients with BRCA. This study provided evidence for novel CAFs-based stromal therapy.

Antipyretic effects of Xiangqin Jiere granules on febrile young rats revealed by combining pharmacodynamics, metabolomics, network pharmacology, molecular biology experiments and molecular docking strategies.

Xiangqin Jiere granules (XQJRG) is a proprietary Chinese medicine treating children's colds and fevers, but its mechanism of action is unclear. The aim of this study was to explore the antipyretic mechanisms of XQJRG based on pharmacodynamics, non-targeted metabolomics, network pharmacology, molecular biology experiments, molecular docking, and molecular dynamics (MD) simulation. Firstly, the yeast-induced fever model was constructed in young rats to study antipyretic effect of XQJRG. Metabolomics and network pharmacology studies were performed to identify the key compounds, targets and pathways involved in the antipyretic of XQJRG. Subsequently, MetScape was used to jointly analyze targets from network pharmacology and metabolites from metabolomics. Finally, the key targets were validated by enzyme-linked immunosorbent assay (ELISA), and the affinity and stability of key ingredient and targets were evaluated by molecular docking and MD simulation. The animal experimental results showed that after XQJRG treatment, body temperature of febrile rats was significantly reduced, 13 metabolites were significantly modulated, and pathways of differential metabolite enrichment were mainly related to amino acid and lipid metabolism. Network pharmacology results indicated that quercetin and kaempferol were the key active components of XQJRG, TNF, AKT1, IL6, IL1B and PTGS2 were core targets. ELISA confirmed that XQJRG significantly reduced the plasma concentrations of IL-1ß, IL-6, and TNF-α, and the hypothalamic concentrations of COX-2 and PGE2. Molecular docking demonstrated that the binding energies of kaempferol to the core targets were all below -5.0 kcal/mol. MD simulation results showed that the binding free energies of TNF-kaempferol, IL6-kaempferol, IL1B-kaempferol and PTGS2-kaempferol were -87.86 kcal/mol, -70.41 kcal/mol, -69.95 kcal/mol and -106.67 kcal/mol, respectively. In conclusion, XQJRG has antipyretic effects on yeast-induced fever in young rats, and its antipyretic mechanisms may be related to the inhibition of peripheral pyrogenic cytokines release by constituents such as kaempferol, the reduction of hypothalamic fever mediator production, and the amelioration of disturbances in amino acid and lipid metabolism.Communicated by Ramaswamy H. Sarma.

Effects of coagulation function indicators and tumor markers on diagnosis and clinicopathological characteristics of endometrial cancer.

BACKGROUND: Endometrial cancer is currently the prevalent malignant cancer worldwide. Diagnostic efficiency of tumor markers is limited, and coagulation function indicators in endometrial cancer are less concerned. METHODS: This study attempted to evaluate the effects of coagulation function indicators and tumor markers on the clinical diagnosis and clinicopathological characteristics of patients with endometrial cancer. The retrospective analysis compared the differences in coagulation function indicators and tumor markers among 175 patients with endometrial cancer and 170 healthy women from January 2020 to October 2022. RESULTS: Compared to the healthy control, the levels of D-dimer, fibrinogen, human epididymis protein 4 (HE4), carbohydrate antigen 125 (CA125), CA153, and CA199 in patients with endometrial cancer were significantly higher (P < 0.05). Univariate and multivariate regression analyses revealed that abnormal levels of D-dimer, fibrinogen, HE4, CA125, CA153, and CA199 were related risk factors affecting the incidence of endometrial cancer. Receiver operating characteristic curve analysis exhibited that the area under the curve (0.931) and accuracy (85.2%) of combined diagnosis of coagulation function indicators (D-dimer, fibrinogen) and tumor markers (HE4, CA125, CA153, CA199) were the highest, and its sensitivity (82.3%) and specificity (88.2%) were higher than any single or combined indicators of four tumor markers. Moreover, relative expression levels of the combined indicators were significantly different among clinicopathological characteristics that had the highest predictive value in the FIGO stage (P < 0.001). CONCLUSIONS: D-dimer and fibrinogen represent potential diagnostic factors for endometrial cancer. The combination of coagulation function indicators and tumor markers exhibited high diagnostic value in endometrial cancer, as well as predictive value for clinicopathological characteristics.

Melatonin blunts the tumor-promoting effect of cancer-associated fibroblasts by reducing IL-8 expression and reversing epithelial-mesenchymal transition.

BACKGROUND: Most studies on melatonin have focused on tumor cells but have ignored the tumor microenvironment (TME), especially one of its important components, the cancer-associated fibroblasts (CAFs). Therefore, we attempted to explore the role of melatonin in TME. METHODS: We investigated the regulatory role of melatonin in the tumor-promoting effect of CAFs and its underlying mechanism by using cell and animal models. RESULTS: CAFs promoted tumor progression, but melatonin weakened the tumor-promoting effect of CAFs. Compared with tumor cells, IL-8 was mainly expressed in CAFs. CAFs-overexpressing IL-8 induced the epithelial-mesenchymal transition (EMT) of tumor cells, and a positive crosstalk was observed between CAFs and tumor cells undergoing EMT, thereby further promoting the IL-8 expression. Melatonin suppressed this crosstalk by inhibiting the NF-κB pathway, thereby impeding the IL-8 expression from CAFs. Importantly, melatonin reversed CAFs-derived IL-8-mediated EMT by inhibiting the AKT pathway. Melatonin was found to directly and indirectly inhibit tumor progression. CONCLUSION: Our research reveals the potential action mechanism of melatonin in regulating the CAF-tumor cell interaction and suggests the potential of melatonin as an adjuvant of tumor therapy.

Expression of the prognostic marker IL-8 correlates with the immune signature and epithelial-mesenchymal transition in breast cancer.

BACKGROUND: IL-8 has been implicated in the malignant progression of various types of cancers; however, the precise molecular mechanisms associated with IL-8 in breast cancer (BRCA) are unclear. METHODS: We analyzed the clinical signature and immune characteristics of BRCA patients and its correlation with IL-8 expression using The Cancer Genome Atlas (TCGA) datasets. The role of IL-8 in epithelial-mesenchymal transition (EMT) was verified through Western blotting, Cell Counting Kit-8 assay, and wound healing assays, as well as cell invasion experiments. RESULTS: Through a comprehensive bioinformatics study, we determined that high IL-8 expression was associated with poor prognosis. Enrichment analysis revealed that high IL-8 expression was enriched in immune-related processes and cancer-related signaling pathways. In addition, IL-8 was associated with most of the immune-infiltrating cells, and high IL-8 expression indicated poor response to immunotherapy. Importantly, we found that IL-8 induced EMT in vitro. CONCLUSIONS: Taken together, our data indicate that IL-8 may be a potential and valuable prognostic marker in BRCA, which may induce adverse outcomes by modulating the immune response and promoting EMT in BRCA patients.

Prevalence of psychological symptoms and associated risk factors among nurses in 30 provinces during the COVID-19 pandemic in China.

Background: With the outbreak of the coronavirus disease 2019 (COVID-19), nurses have won well-deserved recognition for their indispensable roles in providing humane and professional healthcare for patients. However, by the nature of their role working at the forefront of patient care, nurses are prone to experiencing mental health consequences. Therefore, we pay attention to measuring the magnitude of psychological symptoms and identifying associated factors among nurses in China. Methods: We launched a nationwide, cross-sectional survey of nurses who worked in secondary or tertiary hospitals and public or private hospitals from 30 provinces in China. The prevalence and severity of symptoms of burnout, depression, and anxiety were investigated, respectively. Multivariable logistic regression analyses were performed to identify factors associated with each psychological symptom. Findings: A total of 138 279 respondents who worked in 243 hospitals completed this survey. A substantial proportion of nurses reported symptoms of burnout (34%), depression (55·5%), and anxiety (41·8%). In line with the disproportionality of economic development, we noted that the middle or western region was an independent risk factor for depression and anxiety. Compared with those working in the secondary hospital, nurses who worked in tertiary hospitals were associated with a higher likelihood of burnout and depression. Interpretation: Nurses are experiencing emotional, physical, and mental exhaustion during the COVID-19 epidemic. Governments and health policymakers need to draw attention to reinforcing prevention and ameliorating countermeasures to safeguard nurses' health. Funding: The strategic consulting project of the Chinese Academy of Engineering [2021-32-5]. Advanced Institute of Infomation Technology, Peking University, Zhejiang Province [2020-Z-17].

A single cell death is disruptive to spontaneous Ca2+ activity in astrocytes.

Astrocytes in the brain are rapidly recruited to sites of injury where they phagocytose damaged material and take up neurotransmitters and ions to avoid the spreading of damaging molecules. In this study we investigate the calcium (Ca2+) response in astrocytes to nearby cell death. To induce cell death in a nearby cell we utilized a laser nanosurgery system to photolyze a selected cell from an established astrocyte cell line (Ast1). Our results show that the lysis of a nearby cell is disruptive to surrounding cells' Ca2+ activity. Additionally, astrocytes exhibit a Ca2+ transient in response to cell death which differs from the spontaneous oscillations occurring in astrocytes prior to cell lysis. We show that the primary source of the Ca2+ transient is the endoplasmic reticulum.

Thrombo-Inflammation and Immunological Response in Ischemic Stroke: Focusing on Platelet-Tregs Interaction.

Strokes are mainly caused by thromboembolic obstruction of a major cerebral artery. Major clinical manifestations include paralysis hemiplegia, aphasia, memory, and learning disorders. In the case of ischemic stroke (IS), hyperactive platelets contribute to advancing an acute thrombotic event progression. Therefore, the principal goal of treatment is to recanalize the occluded vessel and restore cerebral blood flow by thrombolysis or mechanical thrombectomy. However, antiplatelets or thrombolytic therapy may increase the risk of bleeding. Beyond the involvement in thrombosis, platelets also contribute to the inflammatory process induced by cerebral ischemia. Platelet-mediated thrombosis and inflammation in IS lie primarily in the interaction of platelet receptors with endothelial cells and immune cells, including T-cells, monocytes/macrophages, and neutrophils. Following revascularization, intervention with conventional antiplatelet medicines such as aspirin or clopidogrel does not substantially diminish infarct development, most likely due to the limited effects on the thrombo-inflammation process. Emerging evidence has shown that T cells, especially regulatory T cells (Tregs), maintain immune homeostasis and suppress immune responses, playing a critical immunomodulatory role in ischemia-reperfusion injury. Hence, considering the deleterious effects of inflammatory and immune responses, there is an urgent need for more targeted agents to limit the thrombotic-inflammatory activity of platelets and minimize the risk of a cerebral hemorrhage. This review highlights the involvement of platelets in neuroinflammation and the evolving role of Tregs and platelets in IS. In response to all issues, preclinical and clinical strategies should generate more viable therapeutics for preventing and managing IS with immunotherapy targeting platelets and Tregs.

Inhalation Aromatherapy via Brain-Targeted Nasal Delivery: Natural Volatiles or Essential Oils on Mood Disorders.

Mood disorders, also often referred to as affective disorders, are a group of psychiatric illnesses that severely impact mood and its related functions. The high medical expenditures have placed a significant financial burden on patients and their families. Aromatherapy is an alternative and complementary treatment that utilizes essential oils (EOs) or volatile oils (VOs) to achieve major therapeutic goals. In general, EOs are volatile chemicals that enter the body primarily through skin absorption and/or nasal inhalation. In addition, they can work through oral administration. Inhalation aromatherapy has shown unique advantages for treating mood disorders, especially depression, anxiety and mental disorders such as sleep disorder, which have been validated over the last decade through clinical and animal studies. Accumulating evidence has shown that EOs or VOs can bypass the blood-brain barrier to target brain tissue through the nasal-brain pathway. Subsequently, they act on the cerebral cortex, thalamus, and limbic system in the brain to improve symptoms of anxiety, depression and improve sleep quality. Here, we review the natural aromatic plants' volatiles or essential oils used commonly as adjuncts to manage mood disorders and illustrate the mechanisms of inhalation aromatherapy, and mainly summarized the application of transnasal inhalation aromatherapy in depression, anxiety, and sleep disorders. We conclude that aromatherapy does not cause side-effects, which is vastly different from commonly used psychotropic drugs. Inhalation aromatherapy via brain-targeted nasal delivery offers potentially efficacious treatment for mental disorders and merits further study.

Reconstructable Uterus-Derived Materials for Uterus Recovery toward Efficient Live Births.

Uterine factor infertility is increasingly common in modern society and has severely affected human life and health. However, the existing biomaterial scaffold-mediated systems remain limited in efficient uterus recovery, leading to low pregnancy rate and live births. Here, reconstructable uterus-derived materials (RUMs) are demonstrated by combining uterus-derived extracellular matrix and seeded chorionic villi mesenchymal stem cells for uterus recovery, achieving highly efficient live births in rats with severe uterine injury. The RUMs can be designed into different states (such as, liquid RUMs and solid RUMs) and shapes (such as, cuboid, triangular-prism, and cube) in terms of requirements. The RUMs can effectively prevent intrauterine adhesion, and promote endometrial regeneration and muscle collagen reconstruction, as well as, accelerate wound healing by constructing a physical barrier and secreting cytokines, allowing efficient uterus recovery. The injured uterus nearly achieves complete recovery after treating with the RUMs and has normal pregnancies for supporting fetal development and live births, similar to the normal rats. The study provides a regenerative medicine therapeutics for uterine factor infertility.

Expression and clinical significance of pyruvate kinase M2 in breast cancer: A protocol for meta-analysis and bioinformatics validation analysis.

BACKGROUND: Breast cancer is a common malignant tumor in women. In recent years, its incidence is increasing year by year, and its morbidity and mortality rank the first place among female malignant tumors. Some key enzymes and intermediates in glycolysis are closely related to tumor development. Pyruvate kinase M2 (PKM2) is an important rate-limiting enzyme in glycolysis pathway. Meanwhile, it is highly expressed in proliferative cells, especially in tumor cells, and plays an important role in the formation of Warburg effect and tumorigenesis. Previous studies have explored the effects of PKM2 expression on the prognosis and clinical significance of breast cancer patients, while the results are contradictory and uncertain. This study uses controversial data for meta-analysis to accurately evaluate the problem. We collected relevant Oncomine and The Cancer Genome Atlas (TCGA) data to further verify the results. Through bioinformatics analysis, the mechanism and related pathways of PKM2 in breast cancer are explored. METHODS: We searched Wanfang, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database, PubMed, Embase, and Web of Science databases from inception to March 2021. The language restrictions are Chinese and English. The published literatures on PKM2 expression and prognosis or clinicopathological characteristics of breast cancer patients were statistically analyzed. Combined hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (95% CIs) were used to evaluate the effects of PKM2 on the prognosis and clinicopathological features of breast cancer. Stata 14.0 software was applied for meta-analysis. Oncomine and TCGA databases were used to meta-analyze the differences of PKM2 mRNA expression between breast cancer and normal breast tissues. The expression of PKM2 protein was verified by Human Protein Atlas (HPA) database. The relationship between the gene and the survival of breast cancer patients was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA). The relationship between PKM2 gene and clinicopathological characteristics was analyzed by using LinkedOmics, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis was performed by using Metascape. Protein-protein interaction (PPI) network was constructed by String website. RESULTS: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication. CONCLUSION: This study provides high-quality medical evidence for the correlation between the expression of PKM2 and the prognosis and clinicopathological features of breast cancer. Through bioinformatics analysis, this study further deepens the understanding of the mechanism and related pathways of PKM2 in breast cancer. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also should not damage participants' rights. Ethical approval is not available. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/W52HB.

Calcium Dynamics in Astrocytes During Cell Injury.

The changes in intracellular calcium concentration ([Ca2+]) following laser-induced cell injury in nearby cells were studied in primary mouse astrocytes selectively expressing the Ca2+ sensitive GFAP-Cre Salsa6f fluorescent tandem protein, in an Ast1 astrocyte cell line, and in primary mouse astrocytes loaded with Fluo4. Astrocytes in these three systems exhibit distinct changes in [Ca2+] following induced death of nearby cells. Changes in [Ca2+] appear to result from release of Ca2+ from intracellular organelles, as opposed to influx from the external medium. Salsa6f expressing astrocytes displayed dynamic Ca2+ changes throughout the phagocytic response, including lamellae protrusion, cytosolic signaling during vesicle formation, vesicle maturation, and vesicle tract formation. Our results demonstrate local changes in [Ca2+] are involved in the process of phagocytosis in astrocytes responding to cell corpses and/or debris.

The role of the Patient-Generated Subjective Global Assessment (PG-SGA) and biochemical markers in predicting anemia patients with cancer.

PURPOSE: The causes of anemia and the common side effects of cancer are multifactorial. Malnutrition is one of the alleged components of the aforementioned complications. This study planned to investigate the relationship among biochemical markers, Patient-Generated Subjective Global Assessment (PG-SGA), and anemia in cancer patients. METHODS: This analysis consisted of 234 patients who were enlisted in the Department of Oncology of the First Hospital of Shanxi Medical University between December 2016 and October 2017. The groups were divided into anemic and non-anemic patients. The gathered data primarily discussed the patients' basic information, specifically the age, gender, smoking, alcohol consumption, and nutritional status based on levels of serum biochemical markers and PG-SGA scores. RESULTS: Among the participants, 31.2% of the cancer patients were diagnosed with anemia whereas, according to the scores of PG.SGA, 65.0% of patients experienced malnourishment. The anemia was significantly associated with biochemical markers, expecting a transferrin in univariable analyses. Binary logistic regression analysis between anemic cancer patients and non-anemic cancer patients suggested that high PG-SGA score (odds ratio 1.082; 95% CI 1.027-1.141) implied the risk factor for anemia, and high PG-SGA scores could potentially increase the risk of anemia. The multiple regression analysis showed that hemoglobin concentration (OR 0.575; 95% CI 0.450-0.736) and PG-SGA score (OR 1.231; 95% CI 1.013-1.496) were linked to anemia. However, total protein, albumin, prealbumin, serum iron, transferrin, and transferrin saturation lacked a strong relationship with anemia. CONCLUSION: Anemia prevailed in cancer patients, as nutritionally assessed by PG-SGA, while hemoglobin established a linkage with anemia as they could provide extra predictive information about anemia in patients diagnosed with cancer.

Well-child care delivery in the community in China: Related factors and quality analysis of services.

Well-child health care services are essential for maintaining optimum child health and development. This study's aim was to evaluate the quality of such services and identify factors affecting service quality from the perspective of well-child health care providers located in China's Hunan Province. To achieve this, a qualitative descriptive method was employed, with 22 well-child health care providers being recruited, using purposive sampling, from among the provinces' government community health centers. The participants completed individual semi-structured interviews lasting approximately 25-30 minutes that were designed to obtain their views on well-child health care administration in the province. Then, the interview transcripts were analyzed thematically. The main finding was that participants felt that the delivery of well-child health care services in Hunan Province is insufficient. Factors they mentioned as negatively affecting the delivery of such services included the region's fragmented primary health care system, inadequate attention to this issue from parents and community health care center managers, and a lack of specialized well-child care knowledge. Thus, currently, well-child health care is not being successfully implemented in Hunan Province; consequently, in order to successfully implement well-child health care in this region, community health care centers should invest more resources and funding, particularly into education programs for well-child health care providers.

Synuclein impairs trafficking and signaling of BDNF in a mouse model of Parkinson's disease.

Recent studies have demonstrated that hyperphosphorylation of tau protein plays a role in neuronal toxicities of α-synuclein (ASYN) in neurodegenerative disease such as familial Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease. Using a transgenic mouse model of Parkinson's disease (PD) that expresses GFP-ASYN driven by the PDGF-ß promoter, we investigated how accumulation of ASYN impacted axonal function. We found that retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF) in DIV7 cultures of E18 cortical neurons was markedly impaired at the embryonic stage, even though hyperphosphorylation of tau was not detectable in these neurons at this stage. Interestingly, we found that overexpressed ASYN interacted with dynein and induced a significant increase in the activated levels of small Rab GTPases such as Rab5 and Rab7, both key regulators of endocytic processes. Furthermore, expression of ASYN resulted in neuronal atrophy in DIV7 cortical cultures of either from E18 transgenic mouse model or from rat E18 embryos that were transiently transfected with ASYN-GFP for 72 hrs. Our studies suggest that excessive ASYN likely alters endocytic pathways leading to axonal dysfunction in embryonic cortical neurons in PD mouse models.

[Localization of the assessment of chronic illness care and item evaluation].

OBJECTIVE: To translate the English version of the assessment of chronic illness care (ACIC) to Chinese, to conduct a trial in Hunan province and to develop a Chinese version ACIC. METHODS: According to the WHO rules, we translated the English version of the ACIC to Chinese and took the culture factor into account. Three hundred and ninety persons, who engaged in the work of chronic disease management in primary medical and health services in Hunan province, were enrolled for this study. One hundred and eighty three valid questionnaires were randomly selected. Six methods including discrete tendency method, good-poor analysis, correlation analysis, stepwise regression analysis, Cronbach's alpha coefficient and factor analysis were used for evaluation the questionnaire items. RESULTS: The items in Chinese version ACIC showed as follows: 1) good sensitivity. The standard deviation of each item was more than 2 and the P value from the t test between the good and poor group was less than 0.001; 2) good representation. The correlation coefficients range of each item with the total score and each dimension score was 0.588-0.916; 3) high internal consistency. Cronbach's alpha coefficient for the total scale was 0.975, and for each dimension range was 0.854-0.936; 4) independent. Factor loadings were greater than 0.40 entries, and factor loadings ranged from 0.487-0.798; 5) importance. Stepwise regression analysis α(in)=0.01, α(out)=0.05) showed 34 items were kept in the equation. CONCLUSION: Items of Chinese version ACIC retains ACIC 7 dimensions of 34 items in the original English version, which are sensitivity and typical with the internal consistency, independence and importance.

[A brief review of research on chronic disease management based on collaborative care model in China].

OBJECTIVE: To evaluate the situation for chronic disease management in China, and to seek the method for improving the collaborative management for chronic diseases in community. METHODS: We searched literature between January 2008 and November 2013 from the Database, such as China Academic Journal Full-Text Database, and PubMed. The screening was strictly in accordance with the inclusion and exclusion criteria and a summary was made among the selected literature based on a collaboration model. RESULTS: We got 698 articles after rough screen and finally selected 33. All studies were involved in patient's self-management support, but only 9 studies mentioned the communication within the team, and 11 showed a clear team division of labor. CONCLUSION: Chronic disease community management in China displays some disadvantages. It really needs a general service team with clear roles and responsibilities for team members to improve the service ability of team members and provide patients with various forms of self management services.