Current status and continuing medical education need for general practitioners in Tibet, China: a cross-sectional study.

BACKGROUND: The Tibetan area is one of China's minority regions with a shortage of general practice personnel, which requires further training and staffing. This research helps to understand the current condition and demand for general practitioner (GP) training in Tibetan areas and to provide a reference for promoting GP education and training. METHODS: We conducted a cross-sectional survey using stratified sampling targeting 854 GPs in seven cities within the Tibetan Autonomous Region, utilizing an online questionnaire. Achieving a high response rate of 95.1%, 812 GPs provided invaluable insights. Our meticulously developed self-designed questionnaire, available in both Chinese and Tibetan versions, aimed to capture a wide array of data encompassing basic demographics, clinical skills, and specific training needs of GPs in the Tibetan areas. Prior to deployment, the questionnaire underwent rigorous development and refinement processes, including expert consultation and pilot testing, to ensure its content validity and reliability. In our analysis, we employed descriptive statistics to present the characteristics and current training needs of GPs in the Tibetan areas. Additionally, chi-square tests were utilized to examine discrepancies in training needs across various demographic groups, such as age, job positions, and educational backgrounds of the participating GPs. RESULTS: The study was completed by 812 (812/854, 95.1%) GPs, of whom 62.4% (507/812) were female. The top three training needs were hypertension (81.4%, 661/812), pregnancy management (80.7%, 655/812), and treatment of related patient conditions and events (80.5%, 654/812). Further research shows that the training required by GPs of different ages in "puncturing, catheterization, and indwelling gastric tube use" (64.6% vs. 54.8%, p = 9.5 × 10- 6) varies statistically. GPs in various positions have different training needs in "community-based chronic disease prevention and management" (76.6% vs. 63.9%, p = 0.009). The training needs of GPs with different educational backgrounds in "debridement, suturing, and fracture fixation" (65.6% vs. 73.2%, p = 0.027) were also statistically significant. CONCLUSIONS: This study suggests the need for targeted continuing medical education activities and for updating training topics and content. Course developers must consider the needs of GPs, as well as the age, job positions, and educational backgrounds of GPs practicing in the Tibetan Plateau region. TRIAL REGISTRATION: Not applicable.

TMED3 promotes the development of malignant melanoma by targeting CDCA8 and regulating PI3K/Akt pathway.

BACKGROUND: Transmembrane emp24 domain containing (TMED) proteins are known to play pivotal roles in normal development, but have been reported to be implicated in pancreatic disease, immune system disorders, and cancers. As far as TMED3 is concerned, its roles in cancers are controversial. However, evidence describing TMED3 in the context of malignant melanoma (MM) is scarce. RESULTS: In this study, we characterized the functional significance of TMED3 in MM and identified TMED3 as a tumor-promoting factor in MM development. Depletion of TMED3 arrested the development of MM in vitro and in vivo. Mechanistically, we found that TMED3 could interact with Cell division cycle associated 8 (CDCA8). Knocking down CDCA8 suppressed cell events associated with MM development. On the contrary, elevating CDCA8 augmented cell viability and motility and even reversed the inhibitory effects of TMED3 knockdown on MM development. On the other hand, we found that the levels of P-Akt and P-PI3K were decreased in response to TMED3 downregulation, which was partially abolished following SC79 treatment. Thus, our suspicion was that TMED3 exacerbates MM progression via PI3K/Akt pathway. More notably, previously decreased P-Akt and P-PI3K in TMED3-depleted cells were rescued after overexpressing CDCA8. Also, previously impaired cell events due to CDCA8 depletion were ameliorated after SC79 addition, implying that TMED3 regulates PI3K-AKT pathway via CDCA8, thereby promoting MM development. CONCLUSIONS: Collectively, this study established the link between TMED3 and MM, and provides a potential therapeutic intervention for patients with MM harboring abundant TMED3.

Multiomics Analysis Reveals Cuproptosis-Related Signature for Evaluating Prognosis and Immunotherapy Efficacy in Colorectal Cancer.

Cuproptosis is a copper-induced form of mitochondrial cell death which is engaged in the proliferation and migration of a variety of tumors. Nevertheless, the role of cuproptosis in tumor microenvironment (TME) remodeling and antitumor therapy is still poorly understood. We characterized two diverse cuproptosis-associated molecular isoforms in CRC which exhibit distinct prognostic and TME characteristics. Subsequently, we constructed a cuproptosis-associated prognostic model containing five genes and divided the patients into a high CPS-score group and a low CPS-score group. Univariate and multivariate Cox analyses showed that the CPS score could be used as an independent prognostic factor. The nomogram, and its consequent calibration curves, indicated that this prognostic signature had good predictive power for CRC. The analysis of single-cell sequencing data showed the significant expression of HES4 and SPHK1 in various immune and stromal (including fibroblasts) cells. Further studies showed that tumor mutational burden (TMB), high microsatellite instability (MSI-H) ratio, immune checkpoint blockade (ICB), and human leukocyte antigen (HLA) gene expression all positively correlated with the CPS score, predicting a better reaction to immunotherapy in high CPS-core patients. The CPS score constructed from cuproptosis subtypes can be used as a predictive tool to evaluate the prognosis of CRC patients and their response to immunotherapy.

[Mechanism of Xianglian Pills in improving dyslipidemia in obese mice induced by high-fat diet based on network pharmacology and intestinal flora].

The present study aimed to investigate the effect of Xianglian Pills(XLP) on lipid metabolism in obese mice and explore the underlying mechanism based on network pharmacology and intestinal flora. Firstly, network pharmacology was used to predict the possible effect of XLP on obesity. Secondly, an obese mouse model induced by a high-fat diet was established to observe changes in mouse body weight, adiposity index, liver and adipose tissue pathology. Lipid profiles, liver and kidney function markers, insulin content, and the expression of recombinant uncoupling protein 1(UCP-1) and PR structural domain protein 16(PRDM16) were measured. The 16S rRNA gene sequencing technology was used to analyze the changes in the intestinal flora. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis showed that XLP mainly played a role in improving obesity by regulating lipolysis, type 2 diabetes mellitus, and insulin resistance. The results of animal experiments showed that XLP significantly reduced body weight, adiposity, blood lipid levels, and serum insulin levels in obese mice, while enhancing the expression of UCP-1 and PRDM16 in adipose tissue without causing damage to the liver or kidneys. The 16S rRNA gene sequencing results showed that XLP decreased the Firmicutes/Bacteroidetes(F/B) ratio at the phylum level, increased the relative abundance of Akkermansia and Bacteroides at the family and genus levels, and reduced the abundance of Allobaculum. Therefore, XLP can effectively improve lipid metabolism disorders in high-fat diet-induced obese mice, and the mechanism is related to the improvement of brown adipose function, the browning of white fat, the accelerated lipid metabolism, and the improvement of intestinal flora. However, its effect on promoting the conversion of white adipose to brown adipose still needs to be further studied.

Comparison of clinical outcomes and risk factors for COVID-19 infection in cancer patients without anticancer treatment and noncancer patients.

Background: Previous studies have shown that cancer patients have higher rates of coronavirus disease 2019 (COVID-19) infection and mortality than noncancer patients. However, the differences between cancer patients undergoing regular follow-up without anticancer treatment and noncancer patients with COVID-19 have remained insufficiently investigated. Methods: A retrospective case-control study of 52 patients with COVID-19 infection was performed with a 1:3 matched proportion of cancer patients undergoing regular follow-up without anticancer treatment and noncancer patients. The demographic characteristics, clinical data, laboratory tests, treatment, and complications of patients were collected from medical records. Chi-square tests and univariate and multivariate regressions were performed to assess the differences between these two cohorts of COVID-19 patients with and without cancer and risk factors for severe events in COVID-19 patients. Results: Increased C-reactive protein (CRP) (>4 mg/L) (p = 0.015) and lactate dehydrogenase (LDH) (>243 IU/L) (p = 0.038) were identified as risk factors for severe events in all enrolled COVID-19 patients based on multivariate analysis, but cancer as a chronic disease (p = 1.000) was not identified as an independent risk factor for severe events in COVID-19 patients. Compared with noncancer patients, cancer patients had a significantly longer median hospitalization time (29 days vs. 19 days, p = 0.048) and a higher incidence of hypoalbuminemia complications (84.6 vs. 46.2%, p = 0.016). Conclusions: Increased CRP and LDH were risk factors for severe events in all enrolled COVID-19 patients, and an increased incidence of hypoalbuminemia complications and longer hospitalization were noted in COVID-19 cancer patients undergoing regular follow-up without anticancer treatment compared with noncancer patients.

Synthesis and anti-inflammatory activity of paeonol derivatives with etherized aryl urea by regulating TLR4/MyD88 signaling pathway in RAW264.7 cell.

Thirty-three novel paeonol etherized aryl urea derivatives (PEUs) were synthesized via a bromination-Williamson Ether Synthesis-deprotection-nucleophilic addition reaction sequence. The structures of PEUs were characterized by LC-MS, HRMS, 1H NMR and 13C NMR spectra. The levels of nitric oxide (NO), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages were initially employed to evaluate the anti-inflammatory effects of all compounds. Remarkably, b16 exhibited a good anti-inflammatory activity at 2.5 µm which is the same as the potency of paeonol at 20 µm. The results of mechanism research displayed that the anti-inflammatory effect of b16 was ascribed to the inhibition of the TLR4/MyD88 signaling pathway and inflammatory factors. Additionally, b16 distinctly reduced the generation of free radicals in macrophages and strikingly increased the mitochondrial membrane potential. According to the structure-activity relationships (SAR) of PEUs, the incorporation of halogens on the benzene ring and the hydrogen of phenol hydroxyl substituted by aryl urea, were beneficial to enhance the anti-inflammatory activities. Molecular docking results illustrated that the binding ability of b16 to TLR4 was stronger than that of paeonol. In summary, the novel aryl urea-derivied paeonol b16 could be a new promising candidate for the treatment of inflammation-related diseases.

Fouling and chemically enhanced backwashing performance of low-pressure membranes during the treatment of shale gas produced water.

The treatment of shale gas produced water (SGPW) for beneficial reuse is currently the most dominant and economical option. Membrane filtration is one preferred method to deal with SGPW, but membrane fouling is an unavoidable problem. In this study, two types of ultrafiltration (UF) membranes and one type of microfiltration (MF) membrane were investigated to treat SGPW from Sichuan basin. Results showed that increased total dissolved solid (31-40 g/L) and UV254 (10-42.9 m-1) were observed for the same shale gas plays, and the primary fluorescent organic substances were humic acid-like components. Compared to UF membranes with the flux decline by 2% to 60%, MF membranes with larger pore size were more likely to be fouled with the flux decline by 43% to 95%. Cake layer filtration was verified to be the primary membrane fouling mechanism. Statistical analysis showed that UV254 played the most significant role in membrane fouling which had the highest correlation (0.76 to 0.93). Compared to permeate backwashing (13%), deionized water backwashing and chemically enhanced backwashing (CEB) using NaClO, H2O2 and citric acid improved the cleaning efficiencies (31%-95%). CEB using NaOH prepared by deionized water aggravated membrane fouling, while excellent cleaning efficiencies (39%-79%) were observed for CEB using NaOH prepared by permeate. The difference in cleaning behaviors for fouled membranes by SGPW was verified by morphology observation and element composition analysis.

Oncolytic adenovirus H101 ameliorate the efficacy of anti-PD-1 monotherapy in colorectal cancer.

BACKGROUND: Immune checkpoint blockade therapy with anti-programmed cell death (PD)-1 antibodies provides therapeutic effect for many patients of various cancers but remains inadequate in colorectal cancer (CRC) patients. The present study aims to assess the efficacy of oncolytic adenovirus (OncoAd ) in enhancing the anti-PD-1 treatment of CRC. METHODS: The estimating relative subsets of RNA transcripts algorithm was used for estimating the infiltrated immune cells in melanoma and CRC tissues. The efficacy of OncoAd with anti-PD-1 monotherapy was performed in a CT26 CRC mouse model in vivo. Flow cytometric analysis of peripheral blood and tumor tissues determined the difference anti-tumor immune efficacy of OncoAd with anti-PD-1 monotherapy. RESULTS: The Cancer Genome Atlas database indicated that CD8+ T cells and regulatory T cells were significantly elevated in melanoma compared to CRC cohorts. Moreover, intratumor injection of oncolytic adenovirus enhanced T cell infiltration and decreased Treg percentages in the CT26 CRC colorectal cancer mouse model. Combinatorial OncoAd with anti-PD-1 antibody treatment markedly enhanced the anti-tumor efficacy of anti-PD-1 by significantly decreasing the tumor volume and reducing tumor growth in a CRC mouse model. To the end, OncoAd treatment increased the CD8/Treg ratio, indicating that OncoAd intratumor injection ameliorate the anti-tumor immune response of anti-PD-1 therapy. CONCLUSION: The present study elucidates that OncoAd promotes intratumor T cell infiltration and improves anti-PD-1 immunotherapy, thereby providing a potent combinatorial therapeutic strategy for CRC.

Enhancement of Fe-C micro-electrolysis in water by magnetic field: Mechanism, influential factors and application effectiveness.

Fe-C micro-electrolysis system has been widely used in filters, or as an advanced treatment process in some water treatment plants to treat various wastewater. In this study, Fe-C micro-electrolysis process was enhanced by an economical and environmentally friendly method, applied magnetic field. Batch kinetic experiments and scanning electron micrographs demonstrated a more effective micro-electrolysis and more severely corroded on the surface of Fe-C after applying a magnetic field at pH 3.0. An applied magnetic field reduced the charge-transfer resistance and increased the current density in micro-electrolysis system and Fe-C became more prone to electrochemical corrosion. Corrosion products were proved to be Fe2+, Fe3O4, and C-O, moreover, the formation of them were also increased in the presence of a magnetic field. Base on that, some influential factors like magnetic field flux intensity, Fe-C particle size, pH, Fe-C dosage and its reusability were investigated in this paper. Since Fe2+ release was accelerated in micro-electrolysis system by an applied magnetic field, combination of various advanced oxidation processes were designed to explore the application effectiveness of the system. The degradation rate of target contaminant was significantly improved in the presence of a magnetic field, suggesting it could be a reliable method for wastewater treatment.

Pd(ii)-Catalyzed decarboxylative meta-C-H difluoromethylation.

A palladium(ii)-catalyzed decarboxylative meta-selective C-H difluoromethylation of arenes has been developed from easily accessible difluoroacetic acids. Initial mechanistic studies disclosed that a reasonable migratory insertion is involved in this meta-C-H functionalization.

Structure confirmation and thermal kinetics of the inclusion of cis-jasmone in ß-cyclodextrin.

In this study, inclusion complex of cis-jasmone in ß-CD (ß-CD-CJ) was synthesized to improve cis-jasmone stability. The structure and thermal kinetics of the inclusion complex was investigated by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TG) and differential scanning calorimetry (DSC). DSC studies showed that the stability of cis-jasmone after ß-cyclodextrin encapsulation was improved. The dissociation kinetics of ß-CD-CJ at different heating rates was studied by TG, and the activation energy E of ß-CD-CJ thermal decomposition kinetic parameters was defined by Flynn-Wall-Ozawa method. The results showed that the average activation energy E was 121.16 kJ mol-1.

The traditional Chinese medicinal formula BDL301 suppresses tumor growth by inhibiting STAT3 pathway and inducing apoptosis in colorectal cancer cells.

The traditional Chinese medicinal formula BDL301 has been used to inhibit inflammation for hundreds of years. The development of colorectal cancer and chronic inflammation are closely related. In this study, we investigated whether BDL301 could inhibit tumor growth. We found that angiogenesis and tumor growth were both inhibited in vivo. In addition, apoptosis was induced and the signal transducer and activator of transcription-3 (STAT3) pathway were suppressed in the colorectal cancer cells in vitro and in vivo by BDL301. This study demonstrates that BDL301 exerted significant anticancer activity by inhibiting the STAT3 pathways and inducing apoptosis in colorectal cancer cells.

JAK2 inhibitor blocks the inflammation and growth of esophageal squamous cell carcinoma in vitro through the JAK/STAT3 pathway.

Recent research indicates that the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway may play an important role in chronic inflammation which promotes cancer progression, yet the mechanism is not clear. The present study aimed to investigate the role of the JAK/STAT3 pathway in the growth and cancer-related inflammation (CRI) of esophageal squamous cell carcinoma (ESCC) by studying the crosstalk between the JAK/STAT3 pathway and nuclear factor-κB (NF-κB) and cyclooxygenase-2 (COX-2) which are important inflammatory factors associated with tumorigenesis. Cell growth and the cell cycle were assessed by CCK-8 assays and flow cytometry, respectively. The protein levels of STAT3, phosphorylated STAT3, VEGF, NF-κB p65, phosphorylated NF-κB p65 and COX-2 in ESCC cells following treatment with JAK2 inhibitor for 48 h or interleukin-6 (IL-6) for 24 h were detected. RT-PCR was performed to study the interaction among STAT3, NF-κB and COX-2 by transfection of siRNAs targeted at STAT3 and NF-κB. STAT3 was activated in 3 ESCC cell lines at different levels. Blocking the JAK/STAT3 pathway inhibited cancer growth through regulation of cell growth, cell cycle and angiogenesis. Likewise, abrogation of the JAK/STAT3 pathway decreased CRI by downregulating levels of NF-κB p65 phosphorylation, COX-2 and IL-6 concentration. In addition, CRI and cancer growth were accelerated by IL-6 through stimulation of the JAK/STAT3 and NF-κB p65 pathway. Moreover, STAT3 and NF-κB both regulated COX-2 as a downstream gene. The JAK/STAT3 pathway is an important pathway which links CRI and cancer growth through IL-6 and crosstalk with the NF-κB p65 subunit and COX-2. The STAT3 pathway could be a novel target both for cancer treatment and prevention in ESCC.

Prognostic role of C-reactive protein in prostate cancer: a systematic review and meta-analysis.

Several studies have reported that C-reactive protein (CRP), an inflammation biomarker, may be associated with the prognosis of prostate cancer (PCa). The objective of this systematic review is to summarize the predictive role of CRP for survival in PCa as reported in previous studies. Related studies were identified, and evaluated for quality through multiple search strategies. Data was collected from studies comparing overall and cancer-specific survival (CSS) in patients with elevated CRP levels and those having lower levels. However, for progression-free survival (PFS), data were collected according to the log of CRP. The hazard ratio (HR) and its 95% confidence interval (CI) were used to assess the strength of associations. A total of nine studies (n = 1,497) were evaluated in this meta-analysis (five for overall survival (OS), four for CSS and two for PFS). For OS and PFS, the pooled HR of CRP was statistically significant at 1.51 (95% CI, 1.28-1.79) and 1.50 (95% CI, 1.25-1.81), respectively. For CSS, the pooled HR was 1.91 (95% CI, 1.36-2.69) with higher CRP expression in PCa, which strongly indicates poorer survival in PCa. This study demonstrates that CRP may have a critical prognostic value in patients with prostatic cancer.

Prognostic value of human equilibrative nucleoside transporter1 in pancreatic cancer receiving gemcitabin-based chemotherapy: a meta-analysis.

BACKGROUND: The potential prognostic value of human equilibrative nucleoside transporter1 in pancreatic cancer receiving gemcitabine-based chemotherapy is variably reported. OBJECTIVE: The objective of this study was to conduct a systematic review of literature evaluating human equilibrative nucleoside transporter1 expression as a prognostic factor in pancreatic cancer receiving gemcitabine-based chemotherapy and to conduct a subsequent meta-analysis to quantify the overall prognostic effect. METHODS: Related studies were identified and evaluated for quality through multiple search strategies. Only studies analyzing pancreatic cancer receiving gemcitabine-based chemotherapy were eligible for inclusion. Data were collected from studies comparing overall, disease-free and progression-free survival (OS, DFS and PFS) in patients with low human equilibrative nucleoside transporter1 levels and those having high levels. The hazard ratio (HR) and its 95% confidence interval (95%CI) were used to assess the strength of associations. Hazard ratios greater than 1 reflect adverse survival associated with low human equilibrative nucleoside transporter1 levels. RESULTS: A total of 12 studies (n = 875) were involved in this meta-analysis (12 for OS, 5 for DFS, 3 for PFS). For overall and disease-free survival, the pooled HRs of human equilibrative nucleoside transporter1 were significant at 2.93 (95% confidence interval [95% CI], 2.37-3.64) and 2.67 (95% CI, 1.87-3.81), respectively. For progression-free survival, the pooled HR in higher human equilibrative nucleoside transporter1 expression in pancreatic cancer receiving gemcitabine-based chemotherapy was 2.76 (95% CI, 1.76-4.34). No evidence of significant heterogeneity or publication bias was seen in any of these studies. CONCLUSION: These results support the case for a low human equilibrative nucleoside transporter1 level representing a significant and reproducible marker of adverse prognosis in pancreatic cancer receiving gemcitabine-based chemotherapy.

[Impact of NF-kappaB inhibitor on STAT3 translocation in PC-3 prostate cancer cell line].

OBJECTIVE: To observe the changes in the expressions of STAT3 and NF-KB in PC-3 cells after IL-6 stimulation and to verify the effects of the NF-KB inhibitor caffeic acid phenethyl ester (CAPE) on the expressions of p-STAT3 and IL-6 in the PC-3 prostate cancer cell line. METHODS: PC-3 prostate cancer cells were treated with IL-6 at 20 ng/ml for 5, 10, 20, 30 and 45 min. The protein and mRNA expressions of STAT3 and NF-kappaB were measured by Western blot and real time PCR, respectively, and the cell cycle was detected by flow cytometry. The PC-3 cells were exposed to TNF-alpha or TNF-alpha + CAPE, followed by determination of the IL-6 expression in the supernatant of the cells by ELISA and the expression of p-STAT3 by Western blot. RESULTS: After IL-6 stimulation, both the expression of p-STAT3 protein and the proliferation index of the PC-3 cells were significantly increased, and so were the expressions of IL-6 and p-STAT3 protein in the supernatant after TNF-alpha treatment (P < 0.05). TNF-alpha + CAPE induced statistically lower expressions of IL-6 and p-STAT3 than TNF-alpha alone (P < 0.05). CONCLUSION: CAPE can inhibit IL-6 secretion induced by TNF-alpha in PC-3 cells and thus suppress STAT3 translocation. Therefore, by inhibiting the expression of NF-kappaB and affecting STAT3 and other related cell signaling pathways, CAPE may become a new therapeutic option for prostate cancer.