Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, characterized by poor prognosis due to its high proliferative and invasive potential. Tumor metabolic reprogramming, particularly involving glucose metabolism, is essential for tumor survival. This study investigates the role of the Hippo pathway effector transcriptional co-activator with PDZ-binding motif (TAZ) in regulating gluconeogenesis and promoting tumorigenesis in HCC. Methods: TAZ expression in HCC was analyzed using The Cancer Genome Atlas data and validated in clinical samples and cell lines. TAZ was overexpressed or silenced in HCC cell lines to evaluate its effects on cell proliferation, apoptosis, migration, and invasion. The expression and prognostic relevance of the gluconeogenesis-related genes phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6-phosphatase (G6PC) were examined, along with their correlation with TAZ expression. Tumor growth was assessed in nude mice. Interactions between TAZ and the glucocorticoid receptor (GR) were investigated using co-immunoprecipitation, immunofluorescence, and chromatin immunoprecipitation assays. Results: TAZ was significantly upregulated in HCC tissues and cell lines. TAZ overexpression enhanced proliferation, reduced apoptosis, and promoted migration and invasion. In contrast, PCK1 and G6PC were downregulated in HCC and showed a negative correlation with TAZ expression. Conclusion TAZ modulates gluconeogenesis and accelerates tumor growth, whereas its knockdown attenuates tumor progression. TAZ interacts with GR, suppressing its transcriptional activity on gluconeogenic gene promoters.

Erythropoietin-producing hepatoma receptor A2 （EphA2） is a member of the erythropoietin-producing hepatoma （Eph） subfamily of receptor tyrosine kinases. As a critical regulator of cancer development and progression， EphA2 can promote tumor initiation， growth， invasion， metastasis， stemness， and angiogenesis by activating or enhancing the oncogenic signaling pathways. High expression of EphA2 in tumor tissues is closely associated with poor prognosis， thus it is a very promising potential target for cancer treatment. This article reviews the molecular mechanisms by which EphA2 promotes cancer development and progression， aiming to provide clues and theoretical basis for EphA2-targeted cancer treatment.

Objective To explore the effect of hypoxic exercise on Irisin secretion of obese rats with a palmitic acid-induced lipid accumulation in L6 myotubes and a high-fat diet-induced model.Methods L6 myotubes were treated with 750 μmol/L palmitic acid to induce lipid accumulation and subsequently divided into four groups of normoxia(N),exercise(E),hypoxia(H),and hypoxic exer-cise(HE).Hypoxic conditions(1%O2)were used to simulate a low-oxygen environment,while AICAR stimulation was applied to the E and HE groups to mimic exercise.Eighty 3-week-old Sprague-Dawley rats were fed a high-fat diet for 16 weeks to establish an obesity model.Fifty obese rats that met the criteria were then selected and randomly assigned according to their body weight into five groups of normoxia-sedentary(NC),normoxia-exercise(NE),hypoxia-sedentary(HC),high-liv-ing high-training(HH),and low-living high-training(LH),each of 10.The hypoxic environment was set at 13.6%O2(simulating 3,500 m altitude).Then the NE,HH and LH groups performed daily one-hour treadmill training(NE:20 m/min;HH and LH:16 m/min),5 days/week for 4 weeks.After the intervention,the body composition was measured using dual-energy X-ray absorptiometry(DEXA),while Irisin concentrations in cell culture media and rat serum were determined by using the enzyme-linked immunosorbent assay.Moreover,fibronectin type Ⅲ domain-containing 5(FNDC5)mRNA expression in L6 cells and rat skeletal muscle was measured by quantitative polymerase chain reaction(qPCR),while FNDC5 and silent information regulator 1-peroxisome proliferators-activated re-ceptor γ coactivator lalpha(SIRT1-PGC-1α)pathway proteins were analyzed using Western blotting.Results(1)Cell experiments:①Compared with the N group,there were significantly higher Irisin lev-els in the culture medium of the E,H,and HE groups(P<0.01,P<0.05),as well as elevated FNDC5 mRNA and protein expression in the E and HE groups(P<0.05,P<0.01).Moreover,the Iri-sin concentration and FNDC5 protein levels of group HE were significantly higher than group E(P<0.05).②Compared with group N,significantly increased SIRT1 and PGC-1α protein expression was observed in groups E and HE(P<0.05,P<0.01).(2)Animal experiments:①Compared with the NC group,body weight and fat mass were significantly lower in the NE,LH,and HH groups(P<0.01),with further reductions observed in the HH group compared with the NE group(P<0.05).② Com-pared with group NC,groups NE,LH,and HH exhibited higher serum Irisin levels and increased FNDC5 mRNA and protein expression in skeletal muscle(P<0.05,P<0.01).Furthermore,FNDC5 pro-tein expression of the HH group was significantly higher than the NE group(P<0.05).③ Compared with the NC group,SIRT1 and PGC-1α protein levels were significantly upregulated in the NE,LH,and HH groups(P<0.05,P<0.01).Conclusion Hypoxic exercise effectively alleviates obesity,reduces body weight and fat accumulation in high-fat diet-induced obese rats,and enhances FNDC5 expres-sion and Irisin secretion,which may be mediated through activation of the SIRT1-PGC-1α signaling pathway.Moreover,among the different hypoxic exercise modalities,the"high-living high-training"protocol appears to have greater benefits in promoting FNDC5/Irisin expression and facilitating weight and fat reduction in obese rats.

Clinical pharmacist training is an important way to strengthen the clinical pharmacist team's construction and improve their pharmaceutical service capabilities and levels.The Pharmacy Administration and Pharmacy Practice in Healthcare Institutions-Part 4-8-1:Pharmacy Administration-Pharmacy Training Management-Clinical Pharmacist Training was based on the relevant requirements of the current clinical pharmacist training system of the Chinese Hospital Association,and formulated by sor-ting out relevant materials,such as standards,policies and regulations,technical specifications,literature,the current situation of clinical pharmacist training in China,and expert opinions.A total of 15 key elements of clinical pharmacist training were selected and divided into three aspects(base management,training process and assessment,and the quality management,evaluation and improvement).This article mainly introduced the construction method and content of the clinical pharmacist training standard,to deepen the understanding of the standard for relevant units and to promote the implementation of the standard.

Objective:To screen bile acid-related characteristic genes in IgA nephropathy (IgAN) based on the feature gene selection algorithm in the machine learning method, aiming to exploring the molecular biological mechanisms and biomarkers of IgAN.Methods:The gene expression data and sample grouping information of GSE93798, GSE116626 and GSE35487 were downloaded from the Gene Expression Omnibus (GEO). Bile acid-related gene sequences were obtained from the Molecular Signatures Database (MSigDB). R language was used to identify differentially expressed genes between IgAN samples and healthy control samples. Candidate genes were obtained by intersecting differentially expressed genes and bile acid-related genes. The least absolute shrinkage and selection operator (LASSO) algorithm in machine learning was used to screen the feature genes in the candidate genes as biomarkers, and the feature genes in the training set and validation set were analyzed by the rate of change index. Receiver operating characteristic curve (ROC) method was used to evaluate the diagnostic value of identified bile acid related characteristic genes for IgAN. Gene set enrichment analysis (GSEA) was used to analyze the Spearman correlation between the characteristic genes and all other genes and their related metabolic pathways. The expression of disease-characteristic genes in the kidney tissues of IgAN rats was validated by real-time PCR.Results:Gene expression information from kidney tissue samples of 20 IgAN cases and 22 healthy controls were obtained from GEO database. A total of 204 bile acid-related genes including 24 pathways were obtained from MSigDB. The results of gene differential expression analysis showed that 333 genes in the kidney tissues of IgAN patients were differentially expressed compared with those of healthy controls, including 102 up-regulated genes and 231 down-regulated genes, among which 12 differentially expressed genes were related to bile acid genes, as follows: NR1H4,SLC23A1, ALDH8A1, FABP1, ALB, SLC27A2, DIO1, CYP8B1, BBOX1, PIPOX, AKR1C1 and SLC10A2. Five characteristic genes ( NR1H4, SLC23A1, FABP1, ALB and AKR1C1) were screened by LASSO regression algorithm.ROC analysis results showed that in GSE93798 cohort genes, the AUC of NR1H4, SLC23A1, FABP1 and ALB genes with differential expression was >0.95 respectively in diagnosing IgAN, and that of AKR1C1 genes with differential expression was >0.85 in diagnosing IgAN. The gene expression data of SLC23A1 in GSE35487 cohort was missing. ROC analysis results of other four genes showed that the AUC of differential expression of ALB gene for IgAN was >0.95 respectively, that of NR1H4 gene was >0.70, and that of both FABP1 and AKR1C1 gene was >0.60. In the GSE116626 cohort genes, the AUC of five disease characteristic genes ( NR1H4, SLC23A1, FABP1, ALB, AKR1C1) for diagnosing IgAN was >0.60, respectively. These results suggested that 5 characteristic genes have certain distinguishing ability between IgAN group and control group. GSEA results were displayed that the characteristic genes were related to butyric acid metabolism, propionic acid metabolism, arginine and proline metabolism, valine leucine and isoleucine degradation, fatty acid metabolism, etc. These results suggested that five characteristic genes might be related to IgAN through the above metabolic mechanisms. The verification results of five bile acid characteristic genes in the rat model of IgAN in the kidney tissue showed that the expressions of four genes, NR1H4, SLC23A1, FABP1 and ALB, were higher than those of the control group, and there was no statistical significance in the expression of AKR1C1 gene between the two groups. Conclusions:The expression of bile acid-related characteristic genes is abnormal in the kidney tissue of IgAN patients. Four bile acid-related differentially expressed genes, NR1H4, SLC23A1, FABP1 and ALB, are expected to be biomarkers for non-invasive diagnosis and therapeutic targets .

Clinical pharmacist training is an important way to strengthen the clinical pharmacist team's construction and improve their pharmaceutical service capabilities and levels.The Pharmacy Administration and Pharmacy Practice in Healthcare Institutions-Part 4-8-1:Pharmacy Administration-Pharmacy Training Management-Clinical Pharmacist Training was based on the relevant requirements of the current clinical pharmacist training system of the Chinese Hospital Association,and formulated by sor-ting out relevant materials,such as standards,policies and regulations,technical specifications,literature,the current situation of clinical pharmacist training in China,and expert opinions.A total of 15 key elements of clinical pharmacist training were selected and divided into three aspects(base management,training process and assessment,and the quality management,evaluation and improvement).This article mainly introduced the construction method and content of the clinical pharmacist training standard,to deepen the understanding of the standard for relevant units and to promote the implementation of the standard.

Objective To explore the effect of hypoxic exercise on Irisin secretion of obese rats with a palmitic acid-induced lipid accumulation in L6 myotubes and a high-fat diet-induced model.Methods L6 myotubes were treated with 750 μmol/L palmitic acid to induce lipid accumulation and subsequently divided into four groups of normoxia(N),exercise(E),hypoxia(H),and hypoxic exer-cise(HE).Hypoxic conditions(1%O2)were used to simulate a low-oxygen environment,while AICAR stimulation was applied to the E and HE groups to mimic exercise.Eighty 3-week-old Sprague-Dawley rats were fed a high-fat diet for 16 weeks to establish an obesity model.Fifty obese rats that met the criteria were then selected and randomly assigned according to their body weight into five groups of normoxia-sedentary(NC),normoxia-exercise(NE),hypoxia-sedentary(HC),high-liv-ing high-training(HH),and low-living high-training(LH),each of 10.The hypoxic environment was set at 13.6%O2(simulating 3,500 m altitude).Then the NE,HH and LH groups performed daily one-hour treadmill training(NE:20 m/min;HH and LH:16 m/min),5 days/week for 4 weeks.After the intervention,the body composition was measured using dual-energy X-ray absorptiometry(DEXA),while Irisin concentrations in cell culture media and rat serum were determined by using the enzyme-linked immunosorbent assay.Moreover,fibronectin type Ⅲ domain-containing 5(FNDC5)mRNA expression in L6 cells and rat skeletal muscle was measured by quantitative polymerase chain reaction(qPCR),while FNDC5 and silent information regulator 1-peroxisome proliferators-activated re-ceptor γ coactivator lalpha(SIRT1-PGC-1α)pathway proteins were analyzed using Western blotting.Results(1)Cell experiments:①Compared with the N group,there were significantly higher Irisin lev-els in the culture medium of the E,H,and HE groups(P<0.01,P<0.05),as well as elevated FNDC5 mRNA and protein expression in the E and HE groups(P<0.05,P<0.01).Moreover,the Iri-sin concentration and FNDC5 protein levels of group HE were significantly higher than group E(P<0.05).②Compared with group N,significantly increased SIRT1 and PGC-1α protein expression was observed in groups E and HE(P<0.05,P<0.01).(2)Animal experiments:①Compared with the NC group,body weight and fat mass were significantly lower in the NE,LH,and HH groups(P<0.01),with further reductions observed in the HH group compared with the NE group(P<0.05).② Com-pared with group NC,groups NE,LH,and HH exhibited higher serum Irisin levels and increased FNDC5 mRNA and protein expression in skeletal muscle(P<0.05,P<0.01).Furthermore,FNDC5 pro-tein expression of the HH group was significantly higher than the NE group(P<0.05).③ Compared with the NC group,SIRT1 and PGC-1α protein levels were significantly upregulated in the NE,LH,and HH groups(P<0.05,P<0.01).Conclusion Hypoxic exercise effectively alleviates obesity,reduces body weight and fat accumulation in high-fat diet-induced obese rats,and enhances FNDC5 expres-sion and Irisin secretion,which may be mediated through activation of the SIRT1-PGC-1α signaling pathway.Moreover,among the different hypoxic exercise modalities,the"high-living high-training"protocol appears to have greater benefits in promoting FNDC5/Irisin expression and facilitating weight and fat reduction in obese rats.

Objective:To screen bile acid-related characteristic genes in IgA nephropathy (IgAN) based on the feature gene selection algorithm in the machine learning method, aiming to exploring the molecular biological mechanisms and biomarkers of IgAN.Methods:The gene expression data and sample grouping information of GSE93798, GSE116626 and GSE35487 were downloaded from the Gene Expression Omnibus (GEO). Bile acid-related gene sequences were obtained from the Molecular Signatures Database (MSigDB). R language was used to identify differentially expressed genes between IgAN samples and healthy control samples. Candidate genes were obtained by intersecting differentially expressed genes and bile acid-related genes. The least absolute shrinkage and selection operator (LASSO) algorithm in machine learning was used to screen the feature genes in the candidate genes as biomarkers, and the feature genes in the training set and validation set were analyzed by the rate of change index. Receiver operating characteristic curve (ROC) method was used to evaluate the diagnostic value of identified bile acid related characteristic genes for IgAN. Gene set enrichment analysis (GSEA) was used to analyze the Spearman correlation between the characteristic genes and all other genes and their related metabolic pathways. The expression of disease-characteristic genes in the kidney tissues of IgAN rats was validated by real-time PCR.Results:Gene expression information from kidney tissue samples of 20 IgAN cases and 22 healthy controls were obtained from GEO database. A total of 204 bile acid-related genes including 24 pathways were obtained from MSigDB. The results of gene differential expression analysis showed that 333 genes in the kidney tissues of IgAN patients were differentially expressed compared with those of healthy controls, including 102 up-regulated genes and 231 down-regulated genes, among which 12 differentially expressed genes were related to bile acid genes, as follows: NR1H4,SLC23A1, ALDH8A1, FABP1, ALB, SLC27A2, DIO1, CYP8B1, BBOX1, PIPOX, AKR1C1 and SLC10A2. Five characteristic genes ( NR1H4, SLC23A1, FABP1, ALB and AKR1C1) were screened by LASSO regression algorithm.ROC analysis results showed that in GSE93798 cohort genes, the AUC of NR1H4, SLC23A1, FABP1 and ALB genes with differential expression was >0.95 respectively in diagnosing IgAN, and that of AKR1C1 genes with differential expression was >0.85 in diagnosing IgAN. The gene expression data of SLC23A1 in GSE35487 cohort was missing. ROC analysis results of other four genes showed that the AUC of differential expression of ALB gene for IgAN was >0.95 respectively, that of NR1H4 gene was >0.70, and that of both FABP1 and AKR1C1 gene was >0.60. In the GSE116626 cohort genes, the AUC of five disease characteristic genes ( NR1H4, SLC23A1, FABP1, ALB, AKR1C1) for diagnosing IgAN was >0.60, respectively. These results suggested that 5 characteristic genes have certain distinguishing ability between IgAN group and control group. GSEA results were displayed that the characteristic genes were related to butyric acid metabolism, propionic acid metabolism, arginine and proline metabolism, valine leucine and isoleucine degradation, fatty acid metabolism, etc. These results suggested that five characteristic genes might be related to IgAN through the above metabolic mechanisms. The verification results of five bile acid characteristic genes in the rat model of IgAN in the kidney tissue showed that the expressions of four genes, NR1H4, SLC23A1, FABP1 and ALB, were higher than those of the control group, and there was no statistical significance in the expression of AKR1C1 gene between the two groups. Conclusions:The expression of bile acid-related characteristic genes is abnormal in the kidney tissue of IgAN patients. Four bile acid-related differentially expressed genes, NR1H4, SLC23A1, FABP1 and ALB, are expected to be biomarkers for non-invasive diagnosis and therapeutic targets .

Objective:To develop a prognostic prediction model for patients with colorectal cancer based on a peripheral blood cell composite score (PBCS) system.Methods:This retrospective observational study included patients who had primary colorectal cancer without distant metastasis, who did not undergo radiotherapy or chemotherapy before surgery, who did not receive leukocyte or platelet-raising therapy within 1 month before surgery, and whose postoperative pathology confirmed colorectal adenocarcinoma with complete tumor resection. Patients with severe anemia, infection, or hematologic diseases before surgery, as well as those with severe heart, lung, or other important organ diseases or concurrent malignant tumors, were excluded. In total, 1021 patients with colorectal cancer who underwent surgical treatment in the Department of Gastrointestinal Surgery of the Fourth Hospital of Hebei Medical University from April 2018 to April 2020 were retrospectively included as the training set (766 patients) and the internal validation set (255 patients). Additionally, using the same criteria, 215 patients with colorectal cancer who underwent surgical treatment in another treatment group from March 2015 to December 2020 were selected as the external validation set. The "surv_cutpoint" function in R software was used to analyze the optimal cut-off values of neutrophils, lymphocytes, and platelets, and a PBCS system was established based on the optimal cut-off values. The scoring rules of the PBCS system were as follows: Neutrophils and platelets below the optimal cut-off value = 1 point, otherwise 0 points; Lymphocytes above the optimal cut-off value = 1 point, otherwise 0 points. The scores of the three cell types were added together to obtain the PBCS. Univariate and multivariate Cox regression analyses were performed to explore the correlation between patients' clinicopathological features and prognosis, and a nomogram was constructed based on the Cox regression analysis to predict patients' prognosis. The accuracy of the nomogram prediction model was validated using the C-index, calibration curve, and decision curve analysis.Results:The optimal cut-off values for neutrophils, lymphocytes, and platelets were 4.40×10 9/L, 1.41×10 9/L, and 355×10 9/L, respectively. The patients were divided into high and low groups according to the optimal cut-off values of these cells. Survival curve analysis showed that a high lymphocyte count (training set: P=0.042, internal validation: P=0.010, external validation: P=0.029), low neutrophil count (training set: P=0.035, internal validation: P=0.001, external validation: P=0.024), and low platelet count (training set: P=0.041, internal validation: P=0.030, external validation: P=0.024) were associated with prolonged overall survival (OS), with statistically significant differences in all cases. Survival analysis of different PBCS groups showed that patients with a high PBCS had longer OS than those with a low PBCS ( P<0.05). Univariate and multivariate Cox regression analysis results showed that aspirin use history, vascular thrombus, neural invasion, CA19-9, N stage, operation time, M stage, and PBCS were independent factors affecting OS (all P<0.05). The PBCS was also an independent factor affecting disease-specific survival ( P<0.05), but not progression-free survival ( P>0.05). The above independent risk or protective factors were included in R software to construct a nomogram for predicting OS. The C-index (0.873), calibration curve, and decision curve analysis (threshold probability: 0.0%–75.2%) all indicated that the nomogram prediction model had good predictive performance for OS. Conclusion:This study demonstrates that the PBCS constructed based on preoperative peripheral blood levels of neutrophils, lymphocytes, and platelets is an independent factor associated with the prognosis of patients with colorectal cancer. The nomogram model constructed based on this score system exhibits good predictive efficacy for the prognosis of these patients.

Severe infection is a significant threat to patient safety and survival.As the main treat-ment for hospital acquired infections,meropenem is limited in its effectiveness due to the emergence of drug resistance,especially after long-term use of antibiotics.Therefore,optimizing the efficacy of an-tibiotics such as meropenem and avoiding microbi-al resistance has become an urgent issue to be ad-dressed.Therapeutic drug monitoring(TDM),as an important tool for achieving personalized drug ad-ministration,is increasingly recognized as an impor-tant strategy for optimizing antibiotic concentra-tion,avoiding treatment failure and toxicity in criti-cally ill patients and patients with renal insufficien-cy.By reviewing the current application status,pharmacokinetics,and TDM guidance of meropen-em,clinical references are provided for the treat-ment of critically ill patients and patients with renal insufficiency,and guidance and support are provid-ed for optimizing antibiotic treatment.