Objective: To explore the role and mechanism of epiregulin (EREG) in clear cell renal cell carcinoma (ccRCC)，and to find biomarkers and therapeutic targets for ccRCC. Methods: Based on the data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases，the correlation between the expression level of EREG in ccRCC tissues and the clinical staging and survival of ccRCC patients was analyzed. The samples of 6 ccRCC cases treated in the Second Affiliated Hospital of the Air Force Medical University were collected. The expression of EREG was confirmed with immunohistochemistry and quantitative real-time polymerase chain reaction (q-PCR). The effects of EREG overexpression on the proliferation，cell cycle and apoptosis of ACHN cells were verified with CCK-8 and flow cytometry. Finally，the expressions of EREG，epidermal growth factor receptor (EGFR) and the downstream pathway proteins were detected with Western blotting. Results: Based on the databases，it was found that the expression of EREG in ccRCC samples was higher than that in adjacent tissues，and there was a positive correlation with the clinical stage. Survival analysis showed that high expression of EREG was a risk factor affecting the prognosis. The results of immunohistochemical staining and qPCR revealed that EREG was highly expressed in ccRCC. Flow cytometry showed that EREG overexpression promoted the proliferation of ACHN cells，enhanced cell cycle，and inhibited apoptosis. In addition，Western blotting suggested that EREG promoted the expressions of EREG，EGFR and the downstream proteins. Conclusion: The expression of EREG is associated with the prognosis of ccRCC patients. In vitro cell experiments have shown that it can promote the proliferation of ccRCC cells and inhibit their apoptosis，thereby leading to the progression of ccRCC. It can serve as a potential biomarker for prognosis prediction and a drug development target for ccRCC patients.

BACKGROUND: Chronic kidney disease (CKD) poses a major global health challenge, often foreshadowing poor patient outcomes. The C-reactive protein to albumin ratio (CAR) serves as a pivotal biomarker, demonstrating a strong correlation with adverse outcomes in cardiovascular disease (CVD). This study sought to examine the correlation between CAR and the risk of all-cause and cardiovascular mortality in patients with CKD stages 3-5. METHODS: This study utilized data of CKD patients from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2010, with follow-up to December 31, 2019. The optimal CAR cutoff value was identified utilizing the method of maximally selected rank statistics. Multivariable Cox proportional hazards regression model, restricted cubic splines (RCS) model, and subgroup analysis were employed to assess the association between CAR and mortality among CKD patients. RESULTS: During a median (with interquartile range) follow-up period of 115 (112,117) months among 2,841 CKD individuals, 1,893 deaths were observed, including 692 deaths due to CVD events. Based on the RCS analysis, a non-linear correlation was observed between CAR and mortality. Using 0.3 as the optimal CAR cutoff value, the cohort was divided into high and low groups. In the fully adjusted model, CKD patients with high CAR values exhibited an elevated risk of all-cause mortality (hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.28-1.83, P < 0.001) and cardiovascular mortality (HR 1.48, 95% CI 1.08-2.02, P = 0.014). Compared to the population aged >65 years (HR 1.32, 95% CI 0.99-1.76, P = 0.064), the risk of cardiovascular mortality was significantly higher in those aged ≤65 years (HR 2.19, 95% CI 1.18-4.09, P = 0.014) with elevated CAR levels. CONCLUSIONS A notable correlation exists between the elevation of CAR and increased all-cause and cardiovascular mortality, suggesting its potential as an independent indicator for evaluating the prognosis of patients with CKD stages 3-5.
Humans ; Renal Insufficiency, Chronic/epidemiology* ; Cardiovascular Diseases/blood* ; Male ; Female ; Middle Aged ; C-Reactive Protein/metabolism* ; Aged ; Biomarkers/blood* ; Nutrition Surveys ; Adult ; United States/epidemiology* ; Serum Albumin/analysis*

OBJECTIVE To explore the pharmacodynamic related substances and mechanism of Weining San(WNS) against gastric ulcer(GU) according to fingerprint and network pharmacology. METHODS Twelve batches of WNS fingerprints were established by HPLC, and methodological investigation was carried out. Combined with reference substances, characteristic peaks were identified, pharmacodynamic related substances were screened, and network pharmacological analysis was carried out. Using TCMIP and Swiss Target Prediction database to retrieve component targets; Using OMIM, GeneCards and Drugbank databases to retrieve GU disease targets, taking the intersection targets of components and diseases, using String database to construct protein-protein interaction network diagram, and analyzing topological parameters; Using Cytoscape 3.8.2 software to construct "component-disease-target" network diagram; GO and KEGG enrichment analysis of intersection targets were carried out by Metascape website. Then the alcoholic GU mouse model was established by intragastric administration of absolute ethanol to verify the results of network pharmacology prediction. RESUITS　The precision, stability and repeatability of HPLC fingerprint method were good. By comparison and comprehensive analysis of control substances, notoginsenoside R1, ginsenoside Rg1, militarine, ginsenoside Rb1, schisandrin, schisandrol B, deoxyschizandrin and schisantherin A were identified as pharmacodynamic related substances in WNS, which may play their role by regulating core targets such as AKT1, IL-6, STAT3, TNF, IL1B and key signal pathways such as PI3K-Akt and JAK-STAT. The gastric ulcer index, ulcer inhibition rate and HE staining showed that WNS could improve gastric mucosal injury in GU mice. The results of ELISA, WST-1 and TBA showed that WNS could decrease the levels of TNF-α, IL-6, IL-1β and MDA, and increase the levels of SOD and PGE2, suggesting that the anti-GU effect of WNS was related to the inhibition of inflammatory reaction and oxidative stress mechanism, which further verified the prediction of network pharmacology. CONCLUSION This study combines fingerprint analysis, network pharmacology, and animal experimental validation to explore the pharmacodynamic related substances and mechanisms of WNS anti-GU efficacy, providing reference for quality control and clinical research of WNS.

The surveillance data of new cases of acute myocardial infarction (AMI) from January 1, 2013, to December 31, 2021, in Tengzhou City, Shandong Province, were used to analyze the incidence rate of AMI and its change trend among residents. The age and gender standardized incidence rate was calculated based on the 7th National Population Census 2020. The Cochran-Armitage trend test was used to analyze the trend of onset time and age. From 2013 to 2021, the crude and standardized incidence rate of total AMI in Tengzhou City declined from 130.07/100 000 and 161.12/100 000 to 76.15/100 000 and 72.77/100 000 ( Z=-13.785 and -20.822, both P<0.001). The crude and standardized incidence rates of males were higher than those of females. In 2016, males aged 45-54 years old and females aged 35-64 years old increased by 33.33%, 103.65%, 106.30%, and 95.75% compared to 2015, and the differences were statistically significant ( χ2=6.512, 4.965, 25.115, and 46.004, all P<0.05). The incidence rate of AMI in men aged<35 and 35-44 years old had an upward trend. From 2013 to 2021, the incidence rate of AMI decreased by 55.15% in urban areas and 36.59% in rural areas ( Z=-8.529 and -11.235, both P<0.001).

The surveillance data of new cases of acute myocardial infarction (AMI) from January 1, 2013, to December 31, 2021, in Tengzhou City, Shandong Province, were used to analyze the incidence rate of AMI and its change trend among residents. The age and gender standardized incidence rate was calculated based on the 7th National Population Census 2020. The Cochran-Armitage trend test was used to analyze the trend of onset time and age. From 2013 to 2021, the crude and standardized incidence rate of total AMI in Tengzhou City declined from 130.07/100 000 and 161.12/100 000 to 76.15/100 000 and 72.77/100 000 ( Z=-13.785 and -20.822, both P<0.001). The crude and standardized incidence rates of males were higher than those of females. In 2016, males aged 45-54 years old and females aged 35-64 years old increased by 33.33%, 103.65%, 106.30%, and 95.75% compared to 2015, and the differences were statistically significant ( χ2=6.512, 4.965, 25.115, and 46.004, all P<0.05). The incidence rate of AMI in men aged<35 and 35-44 years old had an upward trend. From 2013 to 2021, the incidence rate of AMI decreased by 55.15% in urban areas and 36.59% in rural areas ( Z=-8.529 and -11.235, both P<0.001).

Acute kidney injury(AKI),a clinical syndrome caused by various factors,is characterized by a rapid decline in kidney function in a short period of time.AKI affects the short-term prognosis of patients and may also induce chronic kidney disease(CKD).However,the current treatment options for AKI mainly focus on symptom management.Specific therapeutic measures available for the prevention of transition from AKI to CKD are very limited in number.Histones are basic proteins that intricately bind the DNA in chromosomes.After translation,histones undergo various modifications on their amino-terminal tails,such as methylation,acetylation,phosphorylation,ubiquitination,and lactylation,collectively forming the"histone code",which affects the expression of genes mainly by regulating the elastic structure of chromatin or recruiting specific proteins.Extensive research conducted in recent years on histone post-translational modifications(PTMs)has also sparked continuous interest in their association with the AKI-to-CKD transition.Therefore,this paper highlights the significant role of PTMs in the process of AKI developing and progressing to CKD,with a view to finding new approaches to preventing the progression of AKI to CKD.

Objective To investigate the effect of uric acid on the clinicopathological characteristics and prognosis of immunoglobulin A nephropathy(IgAN)in patients with stage 3-4 chronic kidney disease(CKD).Methods The clinical and pathological data of 263 IgAN patients who had stage 3-4 CKD and who had confrimed diagosis through renal biopsy at the First Affiliated Hospital of Air Force Medical University between December 2008 and January 2020 were retrospectively collected.According to the levels of uric acid,the patients were divided into a hyperuricemia group(n=102)and a normal uric acid group(n=161),and the clinicopathological characteristics of the two groups were compared accordingly.With progression to end-stage renal disease or death as the endpoint event,the renal survival rate of the two groups was compared by the Kaplan-Meier method and the relationship between uric acid and the prognosis was analyzed by Cox regression and LASSO regression.Results Compared with the normal uric acid group,the hyperuricemia group had a significantly higher proportion of male patients and patients with a history of hypertension,a significantly higher level of blood urea nitrogen,and lower levels of estimated glomerular filtration rate and high-density lipoprotein.In terms of pathology,patients in the hyperuricemia group had significantly higher proportion of glomerulosclerosis,higher mesangial hypercellularity,and higher tubular atrophy/interstitial fibrosis(P＜0.05).Kaplan-Meier curve showed that there was a significant difference in renal survival rate between the two groups(P＜0.000 1).LASSO regression showed that high uric acid was a risk factor for the prognosis of IgAN patients with stage 3-4 CKD.Further multivariate Cox analysis showed that,compared with the normal uric acid group,the hyperuricemia group had a higher risk of incurring composite outcomes(hazard ratio[HR]=1.61,95％confidence interval[CI]:1.10-2.34).When uric acid was used as a continuous variable,the increase of 1 mg/dL in uric acid concentration was associated with an increased HR of 1.18(95％CI:1.08-1.29)for the composite outcome.Conclusion High uric acid is a risk factor for poor renal prognosis in IgAN patients with stage 3-4 CKD and reducing uric acid levels may effectively improve the prognosis of high-risk IgAN patients.

OBJECTIVETo explore the genetic basis for a Chinese pedigree affected with congenital hypofibrinogenamia.

METHODSPeripheral blood samples were collected from 9 members from the pedigree. Routine coagulation tests including activated partial thromboplastin time (APTT), thrombin time (TT), the prothrombin time (PT) were carried out. The activity of fibrinogen (Fg: C) was measured using Clauss method, and fibrinogen antigen (Fg: Ag) was measured with immunoturbidimetry. All exons and exon-intron boundaries of the fibrinogen Aα, Bβ and γ chain genes were amplified using PCR, which was followed by direct sequencing. Suspected mutation was confirmed by reverse sequencing. The mutant fibrinogen was analyzed with Swiss-PdbViewer.

RESULTSThe proband showed prolonged APTT, PT and TT. Her functional fibrinogen (Fg: C) and antigen fibrinogen (Fg: Ag) levels were reduced to 0.69 g/L and 0.72 g/L, respectively. Her mother and grandmother also had a low levels of fibrinogen, which were 0.99 g/L and 0.83 g/L for Fg: C, 1.02 g/L and 0.87 g/L for Fg: Ag, respectively. The results of other members from the pedigree were all within the normal range. Genetic analysis reveled a heterozygous G>T mutation at nucleotide 7590 in exon 8 of γ gene in the proband, which was predicted to be a novel Ser313Ile mutation. The mutation was also found in her mother and grandmother. Model analysis showed that the Ser313Ile mutation disturbed the hydrogen bonds between Ser313, Asn319 and Asp320. Moreover, the mutation also altered the mutual electrostatic force and affected the folding and instability of the mutant fibrinogen.

CONCLUSIONThe heterozygous Ser313Ile mutation probably underlies the hypofibrinogenemia in this pedigree.

Adult ; Afibrinogenemia ; genetics ; Female ; Fibrinogen ; chemistry ; genetics ; Heterozygote ; Humans ; Male ; Middle Aged ; Mutation ; Pedigree

OBJECTIVETo detect the presence of ROS1 fusion gene in pulmonary adenocarcinoma and its clinicopathologic parameters.

METHODSFluorescence RT-PCR was used to detect the presence of ROS1 fusion gene in 369 surgical resection samples of pulmonary adenocarcinoma with known EGFR mutation status. The presence of ROS1 fusion gene in correlation with clinicopathologic features was analyzed. Sixteen positive and 20 negative samples by RT-PCR were further confirmed by direct sequencing.

RESULTSROS1 fusion gene was detected in 16 of 369 lung adenocarcinoma samples (4.3%). The presence of ROS1 fusion gene was not correlated to gender, age, smoking history, tumor site, size, histological subtype, tumor differentiation, T staging, lymph node metastasis, TNM staging and EGFR mutation (P > 0.05). The frequency of ROS1 fusion gene was similar in female and male patients, 4.4% (8/183) vs 4.3% (8/186), P > 0.05. The presence of ROS1 fusion gene in patients of ≤ 60 years of age was higher than that in patients of > 60 years, 5.1% (10/195) vs 3.4% (6/174), P > 0.05. The rate of ROS1 fusion gene of non-smokers was a slight higher than that of smokers, 4.4% (14/318) vs 3.9% (2/51), P > 0.05. Both positive and negative cases were confirmed by direct sequencing in all cases.

CONCLUSIONSROS1 fusion gene occurs more frequently in younger and non-smoking patients of pulmonary adenocarcinoma, and may coexist with EGFR mutations. ROS1 fusion gene seems to define a distinct subset of pulmonary adenocarcinoma.

Objective To investigate the expression,clinicopathological significance and correlation of S100A4,EGFR and PI3K in lung adenocarcinoma.Methods Immunohistochemical method (EnVision two steps) was used to detect the expression of S100A4,EGFR and PI3K proteins in 84 lung adenocarcinoma tissue samples and 30 normal lung tissue samples.The relationship of S100A4,EGFR and PI3K expression with clinicopathologic factors,post-operative five-year survival and the correlations among the three proteins were analyzed.Results The positive expression rates of S100A4,EGFR and PI3Kin lung adenocarcinoma tissues were higher than those in normal tissues,respectively [(69.0 ％,58/84) vs (6.7 ％,2/30),(64.3 ％,54/84) vs (16.7 ％,5/30),(52.4 ％,44/84) vs (13.3 ％,4/30),P ＜ 0.01].The expression of S100A4,EGFR and PI3K proteins were positively correlated with the differentiated degree,lymph node metastasis,clinical stages,and five-year survival (P ＜ 0.05),but not correlated with other clinicopathologic factors (P ＞ 0.05).The expression of S100A4 was positively correlated with EGFR and PI3K in lung adenocarcinoma (P ＜ 0.01),and the expression of EGFR was positively correlated with PI3K (P＜ 0.01).Conclusions S100A4,EGFR and PI3K were closely related with the occurrence,development,metastasis and prognosis of lung adenocarcinoma.S100A4 might be an important marker in estimating biological behavior and metastasis tendence of lung adenocarcinoma.S100A4 may be correlated with EGFR and PI3K.