ObjectiveTo investigate the influence of histone deacetylase 3 (HDAC3) on the occurrence, development of psoriasis-like inflammation in mice, and the relative immune mechanisms. MethodsHealthy C57BL/6 mice aged 6-8 weeks were selected and randomly divided into 3 groups: control group (Control), psoriasis model group (IMQ), and HDAC3 inhibitor RGFP966-treated psoriasis model group (IMQ+RGFP966). One day prior to the experiment, the back hair of the mice was shaved. After a one-day stabilization period, the mice in Control group was treated with an equal amount of vaseline, while the mice in IMQ group was treated with imiquimod (62.5 mg/d) applied topically on the back to establish a psoriasis-like inflammation model. The mice in IMQ+RGFP966 group received intervention with a high dose of the HDAC3-selective inhibitor RGFP966 (30 mg/kg) based on the psoriasis-like model. All groups were treated continuously for 5 d, during which psoriasis-like inflammation symptoms (scaling, erythema, skin thickness), body weight, and mental status were observed and recorded, with photographs taken for documentation. After euthanasia, hematoxylin-eosin (HE) staining was used to assess the effect of RGFP966 on the skin tissue structure of the mice, and skin thickness was measured. The mRNA and protein expression levels of HDAC3 in skin tissues were detected using reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB), respectively. Flow cytometry was employed to analyze neutrophils in peripheral blood and lymph nodes, CD4⁺ T lymphocytes, CD8⁺ T lymphocytes in peripheral blood, and IL-17A secretion by peripheral blood CD4⁺ T lymphocytes. Additionally, spleen CD4⁺ T lymphocyte expression of HDAC3, CCR6, CCR8, and IL-17A secretion levels were analyzed. Immunohistochemistry was used to detect the localization and expression levels of HDAC3, IL-17A, and IL-10 in skin tissues. ResultsCompared with the Control group, the IMQ group exhibited significant psoriasis-like inflammation, characterized by erythema, scaling, and skin wrinkling. Compared with the IMQ group, RGFP966 exacerbated psoriasis-like inflammatory symptoms, leading to increased hyperkeratosis. The psoriasis area and severity index (PASI) skin symptom scores were higher in the IMQ group than those in the Control group, and the scores were further elevated in the IMQ+RGFP966 group compared to the IMQ group. Skin thickness measurements showed a trend of IMQ+RGFP966>IMQ>Control. The numbers of neutrophils in the blood and lymph nodes increased sequentially in the Control, IMQ, and IMQ+RGFP966 groups, with a similar trend observed for CD4⁺ and CD8⁺ T lymphocytes in the blood. In skin tissues, compared with the Control group, the mRNA and protein levels of HDAC3 decreased in the IMQ group, but RGFP966 did not further reduce these expressions. HDAC3 was primarily located in the nucleus. Compared with the Control group, the nuclear HDAC3 content decreased in the skin tissues of the IMQ group, and RGFP966 further reduced nuclear HDAC3. Compared with the Control and IMQ groups, RGFP966 treatment decreased HDAC3 expression in splenic CD4⁺ and CD8⁺ T cells. RGFP966 treatment increased the expression of CCR6 and CCR8 in splenic CD4⁺ T cells and enhanced IL-17A secretion by peripheral blood and splenic CD4⁺ T lymphocytes. Additionally, compared with the IMQ group, RGFP966 reduced IL-10 protein levels and upregulated IL-17A expression in skin tissues. ConclusionRGFP966 exacerbates psoriatic-like inflammatory responses by inhibiting HDAC3, increasing the secretion of the cytokine IL-17A, and upregulating the expression of chemokines CCR8 and CCR6.

The study aimed to construct the second and third generation chimeric antigen receptor T cells (CAR-T) targeting the c-mesenchymal-epithelial transition factor (c-Met) protein, and observe their killing effect on human serous ovarian cancer cell SKOV-3. The expression of MET gene in ovarian serous cystadenocarcinoma, the correlation between MET gene expression and the abundance of immune cell infiltration, and the effect of MET gene expression on the tissue function of ovarian serous cystadenocarcinoma were analyzed by bioinformatics. The expression of c-Met in ovarian cancer tissues and adjacent tissues was detected by immunohistochemical staining. The second and third generation c-Met CAR-T cells, namely c-Met CAR-T(2G/3G), were prepared by lentivirus infection, and the cell subsets and infection efficiency were detected by flow cytometry. Using CD19 CAR-T and activated T cells as control groups and A2780 cells with c-Met negative expression as Non target groups, the kill efficiency on SKOV-3 cells with c-Met positive expression, cytokine release and cell proliferation of c-Met CAR-T(2G/3G) were explored by lactate dehydrogenase (LDH) release, ELISA and CCK-8 respectively. The results showed that MET gene expression was significantly up-regulated in ovarian cancer tissues compared with normal tissues, which was consistent with the immunohistochemistry results. However, in all pathological stages, there was no obvious difference in MET expression and no correlation between MET gene expression and the race and age of ovarian cancer patients. The second generation and third generation c-Met CAR-T cells were successfully constructed. After lentivirus infection, the proportion of CD8⁺ T cells in c-Met CAR-T(2G) was upregulated, while there was no significant change in the cell subsets of c-Met CAR-T(3G). The LDH release experiment showed that the kill efficiency of c-Met CAR-T(2G/3G) on SKOV-3 increased with the increase of effect-target ratio. When the effect-target ratio was 20:1, the kill efficiency of c-Met CAR-T(2G) reached (42.02 ± 5.17)% (P < 0.05), and the kill efficiency of c-Met CAR-T(3G) reached (51.40 ± 2.71)% (P < 0.05). ELISA results showed that c-Met CAR-T released more cytokine compared to CD19 CAR-T and activated T cells (P < 0.05). Moreover, the cytokine release of c-Met CAR-T(3G) was higher than c-Met CAR-T(2G) (P < 0.01). The CCK-8 results showed that after 48 h, the cell number of c-Met CAR-T(2G) was higher than that of c-Met CAR-T(3G) (P < 0.01). In conclusion, both the second and third generation c-Met CAR-T can target and kill c-Met-positive SKOV-3 cells, with no significant difference. c-Met CAR-T(2G) has stronger proliferative ability, and c-Met CAR-T(3G) releases more cytokines.
Humans ; Female ; Ovarian Neoplasms/immunology* ; Proto-Oncogene Proteins c-met/metabolism* ; Receptors, Chimeric Antigen/immunology* ; Cell Line, Tumor ; Cystadenocarcinoma, Serous/immunology* ; T-Lymphocytes/immunology*

OBJECTIVE: This study aimed to investigate possible serum 25-hydroxyvitamin D [25(OH)D] cutoffs for the associations between 25(OH)D and Bone turnover markers (BTMs), and how GC gene variation influences such cutoffs in Chinese women of childbearing age. METHODS: In total, 1,505 non-pregnant or non-lactating women (18-45 years) were recruited from the 2015 Chinese Adult Chronic Disease and Nutrition Surveillance. Serum 25(OH)D, osteocalcin (OC), procollagen type 1 N-terminal propeptide (P1NP), β-CrossLaps of type 1 collagen containing cross-linked C-telopeptide (β-CTX), and single nucleotide polymorphisms were determined. Locally weighted regression and smoothing scatterplot and segmented regression were performed to estimate the 25(OH)D thresholds. RESULTS: The median serum 25(OH)D was 16.63 (11.96-22.55) ng/mL and the prevalence of low serum 25(OH)D (< 12 ng/mL) was 25.2%. Women with the lowest 25(OH)D had the highest β-CTX. After adjustment for the confounders, 25(OH)D cutoffs for OC [14.04 (12.84-15.23) ng/mL], β-CTX [13.94 (12.49-15.39) ng/mL], and P1NP [13.87 (12.37-15.37) ng/mL] in the whole population, cutoffs for OC [12.30 (10.68-13.91) ng/mL], β-CTX [12.23 (10.22-14.23) ng/mL], and P1NP [11.85 (10.40-13.31) ng/mL] in women with the GC rs2282679 G allele, and cutoffs for OC [12.75 (11.81-13.68) ng/mL], β-CTX [13.05 (11.78-14.32) ng/mL], and P1NP [12.81 (11.57-14.06) ng/mL] in women with the GC rs2282679 T allele, were observed. Below these cutoffs, BTMs were negatively associated with 25(OH)D, while above these cutoffs, BTMs plateaued. CONCLUSION In Chinese women of childbearing age, there were thresholds effect of serum 25(OH)D concentrations on BTMs. The results indicated that serum 25(OH)D concentrations < 13.87 ng/mL in this population had adverse influences on maintaining bone remodeling. BTMs were suppressed at a relatively lower serum 25(OH)D in women with the GC rs2282679 G allele compared with those with the T allele.
Humans ; Female ; Vitamin D/blood* ; Adult ; Middle Aged ; Polymorphism, Single Nucleotide ; Adolescent ; Young Adult ; China ; Biomarkers/blood* ; Bone Remodeling/genetics* ; Vitamin D-Binding Protein/genetics* ; Procollagen/blood* ; Osteocalcin/blood* ; Peptide Fragments/blood* ; East Asian People

Objective: To understand the prevalence and related factors of tobacco use among junior high school students in Beijing, so as to provide evidence to effectively conduct tobacco control intervention strategy. Methods: From April to June in 2019 and 2023, 6 489 and 6 898 junior high school students were selected by the probability proportion to size(PPS) method, and a total of 13 387 questionnaires were completed. Questionnaire on tobacco monitoring among junior high school students in Beijing was completed by selffilling. The monitoring content included demographic information, secondhand smoke exposure, tobacco product use, tobacco awareness, etc. Chisquare test was used to compare the difference of various indicators in different groups, and multivariate Logistic regression analysis was adopted to analysis the influencing factors related to the current smoking among junior high school students. Results: In 2019,the current traditional cigarettes and ecigarette smoking rates among junior high school students in Beijing were 1.34%, 1.88%, respectively, and decreased to 0.81%, 1.06% in 2023 (χ2=8.36, 15.17, P＜0.01). The attempted traditional cigarettes and ecigarette smoking rates among junior high school students in Beijing decreased from 6.67%, 6.47% in 2019 to 3.93%, 4.16% in 2023 (χ2=49.99, 35.26, P＜0.01). In 2019, the secondhand smoke exposure rates of junior high school students at homes, indoor public places, and outdoor public places were 31.04%, 44.94%, and 49.88% respectively which decreased to 22.59%, 30.23%, and 36.14% in 2023 (χ2=121.63, 308.60, 257.41, P<0.01). In 2023, male students (OR=2.88), senior students (grade 2 and 3) (OR=4.37, 4.92), disposable pocket money>20 yuan/week (OR=2.01), secondhand smoke exposure at home (OR=2.74), indoor public places (OR=2.64), perception that smoking makes young people more attractive (OR=6.29), and perception that ecigarettes help quit smoking (OR=4.31) were associated with higher tobacco use (P<0.05). Conclusions Tobacco use and secondhand smoke among junior high school students in Beijing decrease significantly. Tobacco control interventions should be provided for junior high school students continuously with a focus on ecigarettes use to promote physical and mental health development among students.

Gadopiclenol was used in adults and pediatric patients 2 years of age and older during magnetic resonance imaging(MRI)to detect and view lesions of the central nervous system(brain,spine,and associated tissues)and body(head and neck,chest,abdomen,pelvis,and musculoskeletal system)with abnormal vascular properties.Gadopiclenol is a new type of macrocyclic gadolinium-based contrast agent(GBCA).In this article,the molecular structure,principle of action,pharmacodynamics,pharmacokinetics,clinical studies,safety and other aspects of Gadopiclenol were reviewed,in order to introduce the current research status and existing achievements of Gadopiclenol.

On May 27,2021,the U.S.Food and Drug Administration(FDA)officially approved Lantheus'PYLARIFY?(Piflufolastat F 18,18 F-labeled imaging agent),which can be used for positron emission computed tomography(PET)of prostate-specific membrane antigen(PSMA)-positive lesions in prostate cancer patients to accurately identify prostate cancer with suspected metastasis or recurrence.Piflufolastat F 18 is approved by FDA for two indications.The first is the initial staging for suspected metastatic lesions in men with newly diagnosed prostate cancer.The second is restaging,with the goal of identifying lesions in the setting of biochem ical recurrence.

Lennox-Gastaut syndrome(LGS)is a severe,epileptic encephalopathy.In recent years,a variety of drugs have been approved for the treatment of LGS.The U.S.Food and Drug Administration ap-proved clobazam and cannabidiol as adjunctive therapy for LGS in October 2011 and June 2018,respectively.This article provides an overview of clobazam and cannabidiol,including their chemical structures,pharmaco-logical actions,curative effects,safety profile,drug interactions,to introduce the current state of research and the achievements of both drugs.

Infantile epileptic spasm syndrome(IESS)is a new concept proposed recently.IESS is a unique and age-specific refractory epilepsy syndrome.The recent advances in molecular biology,neuroimmunol-ogy and the in-depth study of anti-epileptic mechanism in antiepileptic drugs have led to the achievements in the definition and treatment of infantile epileptic spasm.At present,the use of traditional antiepileptic drugs is de-creasing,while the use of new antiepileptic drugs is increasing.In this paper,based on the relevant literature in recent years,the authors discuss the pathogenesis,epidemiology,etiology,diagnosis,treatment,therapeutic drugs,clinical progress,efficacy,and safety of infantile epileptic spasm,hoping to introduce the latest status in research and achievements of IESS.

Objective To develop and validate a predictive model for in-hospital mortality in elderly patients with severe acute pancreatitis (SAP). Methods A total of 368 elderly SAP hospitalized patients were selected as study objects, and were divided into mortality group (96 patients, 26.09%) and survival group (272 patients, 73.91%) based on their survival status during hospitalization. Multivariable Logistic regression analysis was performed to identify influencing factors associated with in-hospital mortality in SAP patients, and a predictive model was constructed based on these factors. Receiver operating characteristic (ROC) curves were plotted, and the predictive performance of the model was evaluated using the area under the curve (AUC), accuracy, sensitivity, and specificity. Results Univariate analysis revealed that the mortality group had a higher proportion of patients aged over 60 years, with renal insufficiency, coronary heart disease, and undergoing laparoscopic surgery. Additionally, the mortality group had significantly higher levels of red blood cell distribution width, fasting blood glucose, interleukin-6, procalcitonin, neutrophil-to-lymphocyte ratio (NLR), lactate, modified CT severity index (MCTSI) score, and bedside index for severity in acute pancreatitis (BISAP) score compared to the survival group (P < 0.05). Multivariable Logistic regression analysis identified age, renal insufficiency, MCTSI score, fasting blood glucose, and NLR as independent influencing factors of in-hospital mortality in elderly SAP patients (P < 0.05). A regression equation was constructed based on these factors: C-index=-1.569+0.258×(age)+0.334×(renal insufficiency)+0.672×(MCTSI score)+0.281×(fasting blood glucose)+0.410×(NLR). The ROC curve analysis showed that the AUC of the model for predicting in-hospital mortality in elderly SAP patients was 0.877 (95%CI, 0.840 to 0.915), with an accuracy of 84.23%, sensitivity of 75.00%, and specificity of 87.50%. Conclusion Age, renal insufficiency, MCTSI score, fasting blood glucose, and NLR are independent predictors of in-hospital mortality in elderly SAP patients. The predictive model constructed based on these factors can assist in identifying high-risk patients and predicting all-cause mortality risk in SAP.

The multiple myeloma (MM), the second most common hematologic malignancy, is malignant proliferative disease of plasma cells. Although the application of many targeted drugs has significantly prolonged the survival time of MM patients, it is still an incurable disease. In recent years, the immunosuppression caused by interaction between tumor microenvironment(TME) and tumor cells has attracted people's attention gradually. As a kind of immunosuppressive cells in TME, regulatory T cells (Treg) play an important role in the progress of MM. Treg is related to the proliferation and metastasis of tumors, and can lead to the progress of MM by promoting the angiogenesis and generating immunosuppressive TME. In this review, we briefly summarized the latest research progress on the impact of Treg on the pathogenesis of MM.
Humans ; Multiple Myeloma/pathology* ; T-Lymphocytes, Regulatory/pathology* ; Immune Tolerance ; Plasma Cells/pathology* ; Immunosuppression Therapy ; Tumor Microenvironment