OBJECTIVE To investigate the influence of CYP2C19 gene polymorphism on platelet function and inflammatory cytokines in elderly patients with ischemic stroke， and to analyze potential factors associated with poor prognosis. METHODS A retrospective study was conducted on elderly patients with ischemic stroke admitted to our hospital from June 2024 to June 2025， wh o underwent CYP2C19 genotype testing and received antiplatelet therapy with clopidogrel. The levels of platelet function indicators and inflammatory cytokines before and after treatment were compared among patients with different metabolic phenotypes. Based on the prognosis at 6 months post-treatment， patients were divided into poor prognosis group and good prognosis group. Univariate analysis was performed on general data， metabolic phenotype， the levels of platelet function indicators and inflammatory cytokines. Variables with P ＜0.05 and the levels of inflammatory cytokines before treatment were included in a multivariate Logistic regression analysis to identify independent risk factors for poor prognosis. Multiple linear regression was used to further analyze the relationship between metabolic phenotypes and inflammatory cytokines. RESULTS A total of 448 elderly patients with ischemic stroke were included； among them， 162 cases were normal metabolic phenotype， 218 were intermediate metabolic phenotype， and 68 were poor metabolic phenotype. No rapid or ultrarapid metabolic phenotypes were observed. After treatment， platelet aggregation rate， the levels of P-selectin and platelet activated complex-1 （PAC-1）， high-sensitivity C-reactive Protein （hs-CRP）， interleukin-1β （IL-1β）， IL-6 and tumor necrosis factor-α （TNF-α） in the normal metabolic phenotype group， intermediate metabolic phenotype group， and poor metabolic phenotype group （except for platelet aggregation rate， and the levels of P-selectin and PAC-1 in the poor metabolic phenotype group） were significantly lower than those before treatment in the same group. Moreover， the above indicators in the normal metabolic phenotype group were significantly lower than those in the intermediate and poor metabolic phenotype groups at the corresponding time， and the levels of platelet function indicators in the intermediate metabolic phenotype group were significantly lower than those in the poor metabol ic phenotype group at the corresponding time （ P ＜0.05）. Univariate and multivariate Logistic regression analyses showed that combined with hypertension， combined with diabetes mellitus， and intermediate or poor metabolic genotypes were independent risk factors for poor prognosis in elderly patients with ischemic stroke （ P ＜0.05）. Multiple linear regression analysis showed that serum levels of hs-CRP， IL-1β， IL-6 and TNF-α before treatment were significantly higher in patients with intermediate and poor metabolic genotypes compared to those with normal metabolic genotype （ P ＜0.05）， with a greater magnitude of increase in inflammatory cytokines observed in the patients with poor metabolic genotype. CONCLUSIONS The elderly ischemic stroke patients with CYP2C19 intermediate and poor metabolic genotypes have poor inhibition effect on platelet and higher levels of inflammatory cytokines than normal metabolic genotype； CYP2C19 gene polymorphism， and in combination with hypertension and diabetes， can be used as independent predictors of poor prognosis.

AIM: To analyze the changes in binocular visual function before and after small incision lenticule extraction(SMILE)in patients with different degrees of myopia.METHODS:A prospective non-randomized controlled study was conducted. A total of 94 patients(188 eyes)who visited the refractive outpatient department of the ophthalmology department of the General Hospital of the PLA from June 2022 to June 2023 and voluntarily chose SMILE were consecutively included. They were grouped according to the degree of myopia, including 24 cases(48 eyes)in the low myopia group(-3.00 D

OBJECTIVES: To investigate the inhibitory effect of pirfenidone (PFD) on growth of bladder cancer xenograft and its regulatory effect on Treg cells in tumor-bearing mice. METHODS: Thirty-two C57BL/6 mice bearing ectopic bladder tumors were randomized into control and PFD groups (n=16). In PFD group, PFD was administered orally at the daily dose of 500 mg/kg, and tumor growth and survival of the mice were monitored. After treatment for 21 days, the tumors and vital organs were harvested for analysis. Immunohistochemistry was used to assess CD3, CD4, CD8, and FOXP3 expressions in the tumors. Flow cytometry and RT-qPCR were used to analyze the percentage of CD4⁺CD25⁺FOXP3⁺ Treg cells and IL-2, IL-10, and IL-35 expressions in the tumors and spleens; organ damage of the mice was examined with HE staining. RESULTS: Compared with the control group, the PFD-treated mice exhibited significantly lower tumor growth rate with smaller tumor volumes at day 21, along with improved survival at day 28. Immunohistochemistry revealed no significant differences in the infiltration of CD3⁺ and CD8⁺ cells between the two groups, but the percentages of CD4⁺ and FOXP3⁺ cells were significantly lower in the tumors of PFD-treated mice. Flow cytometric analysis confirmed a decrease in CD4⁺CD25⁺FOXP3⁺ Treg cells in the tumors from PFD-treated mice, which also had reduced expression levels of IL-2, IL-10 and IL-35 mRNAs in the tumors. No significant differences were found in Treg cell populations or cytokine expressions in the spleen tissues between the two groups. HE staining showed obvious organ damage in neither of the groups. CONCLUSIONS PFD inhibits bladder cancer growth and enhances survival of tumor-bearing mice possibly by suppressing Treg cells in the tumor microenvironment.
Animals ; Urinary Bladder Neoplasms/drug therapy* ; Mice ; T-Lymphocytes, Regulatory/metabolism* ; Mice, Inbred C57BL ; Interleukins/metabolism* ; Interleukin-10/metabolism* ; Cell Line, Tumor ; Interleukin-2/metabolism* ; Xenograft Model Antitumor Assays ; Female

Hypoxia and aberrant activation of epidermal growth factor receptor (EGFR) are considered important features of various malignancies. However, whether hypoxia can directly trigger EGFR activation and its clinical implications remain unclear. In this study, we demonstrated that in oral cancer, a typical hypoxic tumor, hypoxia can induce chronic but constitutive phosphorylation of wild-type EGFR in the absence of ligands. Oral cancer cell lines exhibit different EGFR phosphorylation responses to hypoxia. In hypoxic HN4 and HN6 cells, ubiquitination-mediated endocytosis, lysosomal sorting, and degradation lead to low levels of EGFR phosphorylation. However, in CAL-27 and HN30 cells, a novel HIF-1α-induced long noncoding RNA (lncRNA), EUDAL, can compete with the E3 ligase/adaptor complex c-Cbl/Grb2 for binding to EGFR, stabilizing phosphorylated EGFR (pEGFR) and resulting in sustained activation of EGFR and its downstream STAT3/BNIP3 signaling. STAT3/BNIP3-mediated autophagy leads to antitumor drug resistance. A high EUDAL/EGFR/STAT3/autophagy pathway activation predicts poor response to chemotherapy in oral cancer patients. Collectively, hypoxia can induce noncanonical ligand-independent EGFR phosphorylation. High EUDAL expression facilitates sustained EGFR phosphorylation in hypoxic tumor cells and leads to autophagy-related drug resistance.
Humans ; ErbB Receptors/metabolism* ; Mouth Neoplasms/pathology* ; RNA, Long Noncoding/genetics* ; Drug Resistance, Neoplasm/genetics* ; Cell Line, Tumor ; Phosphorylation ; Signal Transduction ; STAT3 Transcription Factor/metabolism* ; Cell Hypoxia ; Autophagy ; Proto-Oncogene Proteins c-cbl/metabolism*

Objective:To investigate the current level of awareness among Chinese gastroenterologists regarding small intestinal bacterial overgrowth (SIBO).Methods:From March 7th to April 14th, 2024, an online survey questionnaire was sent to qualified clinical physicians specializing in gastroenterology in various levels of general hospitals across the country through the official channels of national academic organizations such as the Gastroenterology Branch of the Chinese Medical Association, the Gastrointestinal Motility Group of the Gastroenterology Branch of the Chinese Medical Association, and the Functional Gastrointestinal Disorders Collaborative Group of the Gastroenterology Branch of the Chinese Medical Association, as well as through the national medical continuing education project cooperation platform. The questionnaire content includes basic information, awareness of consensus guidelines on functional gastrointestinal disorders (FGID) and SIBO, understanding of SIBO and its diagnosis and treatment strategies, et al. The influencing factors of physicians′ cognitive level regarding SIBO were analyzed based on the questionnaire results. Statistical methods employed descriptive statistical method and partial correlation analysis.Results:A total of 511 valid questionnaires were collected, among them, 78.1% (399/511) of the respondents practiced in tertiary hospitals, and 90.2% (461/511) of the respondents were aware of the definition of SIBO. However, only 9.0% (46/511) could accurately identify all the key points of the relevant consensus guidelines. Educational background (undergraduate and master′s degree vs. doctor degree, OR=0.265, 0.528, 95% confidence interval(95% CI): 0.155 to 0.454, 0.322 to 0.865), professional title (junior title vs. senior title, OR=0.577, 95% CI: 0.344 to 0.968), and the number of SIBO cases handled per year (less than 50 cases vs. more than 200 cases, OR=0.144, 95% CI: 0.043 to 0.479) were independent influencing factors that affect the cognitive level of specialist physicians regarding SIBO and the guidelines (all P<0.05). The results of hydrogen and methane breath test (HMBT) was the main reference indicator for diagnosing SIBO in the respondents (79.8%, 408/511), but only 8.4%(43/511) of the specialists were familiar with the principle of HMBT, and 65.9% (337/511) were not clear about the differences in diagnostic thresholds among different consensus or guidelines. Rifaximin was the most commonly used therapy (87.5%, 447/511), but there was significant heterogeneity in the selection of dosage and treatment course. According to the survey, 17.6% (90/511) of the clinicians believed that comprehensive assessment of the patient′s clinical condition was not necessary for the diagnosis and treatment of FGID. Conclusion:Gastroenterologists are familiar with the basic concepts of SIBO, but their understanding of the diagnostic criteria application and the latest research progress is limited.

One female patient with cancer pain due to bone metastasis from breast cancer was initially treated with Xinhuang tablets,diclofenac sodium double-release enteric-soluble capsules,paracetamol dihydrocodeine tablets and paracetamol oxycodone tablets,before being switched to controlled-release oxycodone hydrochloride tablets.She regularly took oxycodone hydrochloride sustained-release tablets 20 mg,q12h,no abnormalities were observed,and the dosage was increased to 40 mg,q12h due to poor pain control.The patient was diagnosed with 5-hydroxytryptamine syndrome after 1 d of intermittent recurrent tremor,myotonia,scalp sweating,restlessness and elevated blood pressure.When oxycodone hydrochloride sustained release tablet was adjusted to 20 mg,q12h and gabapentin capsule was added to 0.1 g,tid,the frequency of tremor and myotonia attacks slightly decreased,and sweating and agitation symptoms were not relieved.After 14 days,oxycodone hydrochloride sustained release tablets were stopped and morphine sulfate sustained release tablets 60 mg,q12h were replaced.Three days later,the patient's symptoms disappeared.During 5-month follow-up,the patient's pain was well-contrdled,with no change in the dose of morphine sulfate sustained-release tablets,and no adverse drug reactions observed.Using the Naranjo's Assessment Scale,the association between the patient's serotonin syndrome and the suspected drug oxycodone hydrochloride sustained-release tablets was evaluated as"probable".Thiscase highlights the importance for clinicians to closely monitor adverse reactions induced by rapid opioid dose escalation to ensure medication safety in patients.

Objective:To explore the clinical phenotype and genetic characteristics of a patient with Progressive pseudorheumatoid dysplasia (PPRD) due to compound heterozygous variants of CCN6 gene. Methods:A patient who was admitted to Qilu Hospital of Shandong University due to " bilateral finger joint deformity, bilateral hip and knee joint movement limitation for 19 years" was selected as the study subject. Clinical data of the patient were retrospectively collected. Peripheral blood samples were collected from the patient and her parents and subjected to whole exome sequencing (WES). Long-read sequencing (LRS) and Sanger sequencing were used to verify the candidate variants. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was classified. This study was approved by the Medical Ethics Committee of Qilu Hospital of Shandong University (Ethics No.: KYLL-202502 061).Results:The patient, a 23-year-old female, presented with progressive polyarticular deformity, limited movement and abnormal growth and development since childhood. She was initially misdiagnosed as Ankylosing spondylitis and had poor response to sulphasalazine and etoricoxib treatment. WES revealed that she has harbored two heterozygous variants of the CCN6 gene (NM_198239.2), namely c. 348C>A and c. 676G>C. LRS confirmed that the two variants are located on two homologous chromosomes and constitute compound heterozygous variants. Based on the ACMG guidelines, both variants were rated as pathogenic (PVS1+ PM2_Supporting+ PM3; PM1+ PM2_Supporting+ PM3_Supporting+ PM5+ PP3_Strong). The c. 676G>C variant has not been recorded by the HGMD and ClinVar databases. Conclusion:The c. 348C>A and c. 676G>C compound heterozygous variants of the CCN6 gene probably underlay the pathogenesis of PPRD in this patient. Above finding has enriched the mutational spectrum of PPRD and provided a basis for the clinical diagnosis and genetic counseling.

⁶³Ni is predominantly generated through neutron activation in nuclear reactors and is classified as a pure beta-emitting radionuclide with a half-life of 101.1 a. During decay, ⁶³Ni emits a beta ray with an energy of 65.87 keV. ⁶³Ni can be used in the manufacture of beta radiation sources, which are utilized as reference and working sources for beta activity measurement and beta energy response calibration. Additionally, it is used in electron capture detectors for chromatography, ionization sources in electron tubes, and electron capture probes in gas chromatography. These instruments have extensive applications in food safety, public health and epidemic prevention, soil pollution monitoring, and security. ⁶³Ni is an artificial radionuclide not commonly found in the natural environment under normal conditions. However, the ⁶³Ni generated during routine operations of nuclear power plants, as well as residual materials and wastes contaminated with ⁶³Ni during plant decommissioning, may be released into the environment through liquid effluents or solid wastes. This can pose potential radiation risks to both the public and the environment. Hence, it is necessary to monitor the activity concentration of ⁶³Ni. Currently, reports on this subject are limited in China, and there is a lack of established standards for the determination of ⁶³Ni in nuclear power plants. This article reviews the global literature on the pretreatment and purification measurement processes of ⁶³Ni. The merits and demerits are summarized for pretreatment methods such as acid leaching, mixed acid digestion, ashing acid leaching/dissolution, and alkali fusion, and for separation and purification methods like solvent extraction, precipitation, and extraction chromatography. The article also highlights the advantages of measurement using liquid scintillation counters. This review provides a reference for the establishment of the determination method of ⁶³Ni in liquid effluents and solid wastes from nuclear power plants.

OBJECTIVE To analyze and identify the metabolites of pirtobrutinib （PTN） in rats， and clarify the possible metabolic pathways of PTN in rats. METHODS Six rats were intragastrically administered with 10 mg/kg PTN suspension. Blood samples were collected from the rats 30 minutes before administration and at 0.25， 0.5， 1， 2， 4， 6， 8， 12， 24 hours after administration. Urine and feces samples were collected 12 hours before administration and 24 hours after administration. UHPLC- Orbitrap Exploris 240 system combined with Compound Discoverer 3.0 and Xcalibur 2.0 software were adopted for structural identification and metabolic pathway analysis of PTN metabolites in rat plasma， urine， and feces. RESULTS A total of 29 PTN metabolites were identified， including 17， 19 and 22 metabolites in plasma， urine and feces， respectively. The metabolic pathways of PTN mainly included oxidation， sulfation， glucuronidation， etc.， and its metabolites were mostly combination products of two or more different metabolic forms. In detail， a total of 26 metabolites were associated with phase Ⅰ metabolic reactions （14 oxidation metabolites， 9 reduction/dehydrogenation metabolites， 8 demethylation metabolites， and 5 hydrolysis metabolites）. Meanwhile， a total of 20 products were involved in phase Ⅱ metabolites （14 sulfation metabolites and 8 glucuronic acid binding metabolites）. CONCLUSIONS PTN exhibits a diverse range of metabolites in rat fecal samples， with the primary metabolic pathways being oxidation， sulfation， glucuronidation， and others.

Background/Aims: Reflux symptoms frequently present in patients diagnosed with functional dyspepsia (FD). This investigation sought to elucidate the contribution of gastroesophageal reflux in the overlap relationship. Methods: Consecutive patients presenting with reflux symptoms and/or FD symptoms were prospectively included. Comprehensive assessments, including symptoms evaluation, endoscopy, esophageal functional examinations (high-resolution manometry and reflux monitoring), and proton pump inhibitor (PPI) treatment efficacy evaluation, were conducted in these patients. Results: The study enrolled 315 patients, 43.2% of which had concurrent FD symptoms and overlapping reflux symptoms. Notably, a mere 28.7% of patients in the overlap symptoms group had objective gastroesophageal reflux disease evidences (the grade of esophagitis≥ B or the acid exposure time ≥ 4.2%). Functional heartburn was demonstrated to be the main cause of overlapping reflux symptoms(55.1%). Reflux parameters analysis revealed that the reflux burden in the overlap symptoms group paralleled that of the FD symptoms group, with both registering lower levels than the reflux symptoms group (P < 0.05). Furthermore, PPI response rates were notably diminished in the overlap symptoms group (P < 0.001), even for those with objective gastroesophageal reflux disease evidences. Conclusions The study illuminated that overlapping reflux symptoms in FD was common. Strikingly, these symptoms primarily diverged from reflux etiology and exhibited suboptimal responses to PPI intervention. These findings challenge prevailing paradigms and accentuate the imperative for nuanced therapeutic approaches tailored to the distinctive characteristics of overlapping reflux symptoms in the context of FD.