Objective To identify the independent predictors of programmed death-1 (PD-1) inhibitor-related endocrine adverse events and construct a clinically usable risk prediction model. Methods A total of 302 patients with solid tumors treated with PD-1 inhibitors were retrospectively enrolled. According to the presence or absence of endocrine immune-related adverse events (irAEs), the patients were divided into case group and control group. The clinical and laboratory indexes were compared between the two groups. Multivariable logistic regression was used to confirm independent predictors of endocrine irAEs. The nomogram was constructed, while the receiver operating characteristic (ROC) curve was used to test the prediction performance of the model. Results The overall incidence of endocrine irAEs was 21.9% (66/302), and the incidence of hypothyroidism was 19.5% (59/302). The age, PD-1 inhibitors, free thyroxine, thyroid peroxidase antibody (TPOAb), thyroglobulin, amylase, lymphocyte subset CD3 expression were statistically different between the two groups (P＜0.05). Multivariable logistic regression showed that higher expression of lymphocyte subset CD3 was a protective factor to prevent endocrine irAEs occurrence (P＝0.004), while age＜60 years, higher TPOAb and use of pembrolizumab were independent risk factors of endocrine irAEs (P＜0.05). The nomogram model thus constructed, and when the threshold probability of the model exceeded 0.1, its net benefit was higher. ROC curve showed that the AUC of the model to predict endocrine irAEs was 0.760. The prediction result of the model was highly consistent with the actual result. Conclusions The age, type of PD-1 inhibitor, baseline TPOAb level, and baseline CD3 expression can independently predict endocrine irAEs occurrence or not. The nomogram model based on this model has good predictive efficiency, which can provide reference for early identification of high-risk patients and immunotherapy management.

Objective:To study the mechanistic role of myeloid-specific Notch1 knockout inhibiting STING signaling to regulate hepatocyte lipophagy.Methods:A mouse model of nonalcoholic steatohepatitis (NASH) was established using a high-fat diet (HFD) and mouse bone marrow-derived macrophages (BMMs). Primary hepatocytes were isolated to construct a co-culture system. Twelve Notch1 FL/FL mice were randomly divided into two groups: the Notch1 FL/FL + normal diet (NCD) and the Notch1 FL/FL + HFD group. Further, 12 Notch1 M-KO mice were randomly divided into two groups: Notch1 M-KO + NCD, and Notch1 M-KO + HFD group.Serum alanine aminotransferase (sALT), total cholesterol (TC) and triglyceride (TG) were collected from mice serum samples. Liver tissue samples were collected for H&E staining, immunofluorescence (IF), Western blot and qRT-PCR. Tumor necrosis factor (TNF)-α was detected in the supernatant by enzyme-linked immunosorbent assay (ELISA). The comparison of inter group data was conducted using a t-test. Results:The mouse NASH model, mouse BMMs co-culture system, and primary hepatocytes were successfully constructed. Compared with the Notch1 FL/FL + HFD group, the Notch1 M-KO + HFD group showed a significant increase in serum ALT [(250.02 ± 58.21) U/L vs (370.70 ± 54.57) U/L, t = 3.705, P = 0.004], TG [(29.90 ± 3.54) mg/g vs (43.83 ± 8.56) mg/g, t = 3.685, P = 0.004], and TC [(33.70 ± 8.43) mg/g vs (90.53 ± 12.53) mg/g, t = 9.917, P < 0.001]. HE staining of liver tissue showed remarkable balloon-like alterations in liver cells, while IF staining demonstrated increased macrophage infiltration ( t = 7.346, P < 0.001). Compared with the hepatocyte group co-cultured with Notch1 FL/FL BMMs, the BODIPY probe showed a significant increase in lipid droplet (LDs) deposition in liver cells in the Notch1 M-KO group ( t = 3.835, P < 0.001). The co-localization of lysosomal associated membrane protein 1 (LAMP1), LDs ( t = 7.103, P < 0.001), microtubule-associated protein light chain 3 (LC3) -II/LC3-I ( t = 5.0, P = 0.007), and autophagy associated gene 12 (Atg12) ( t = 28.36, P < 0.001) had decreased expression, while P-62 had increased expression ( t = 3.253, P = 0.03), indicating a decrease in autophagic flow. Additionally, LC3 and LDs colocalization decreased ( t = 5.24, P = 0.0003), indicating reduced lipophagy. Compared with the Notch1 FL/FL group, the Notch1 M-KO BMMS mouse group showed an increase in the expression of p-STING ( t = 5.318, P = 0.006), p-TANK1 binding kinase 1 (TKB1) ( t = 6.467, P = 0.002), p-interferon regulatory factor 3 (IRF3) ( t = 14.61, P < 0.001), and p-P65 ( t = 12.7, P = 0.002) protein, accompanied by mRNA expression of the inflammatory mediators interferon (IFN)-β ( t = 7.978, P < 0.001), TNFα ( t = 8.496, P = 0.001), interleukin-1 β (IL-1 β) ( t = 4.7, P < 0.001), and CXCL-10 ( t = 4.428, P = 0.001). The STING gene was knocked out in the BMMs Notch1 M-KO mice using CRISPR/Cas9. Compared with the CRISPR-Control group, the expression of P-TKB1 ( t = 2.909, P = 0.044), p-IRF3 ( t = 10.96, P < 0.001), p-IRF3 ( t = 10.96, P < 0.001), and p-P65 ( t = 7.091, P = 0.002) proteins was lower in the STING-KO BMMs group. The release of TNF-α in the supernatant was decreased (732.3 ± 129.35 pg/ml vs. 398.17 ± 47.15 pg/ml, t = 4.204, P = 0.014). However, in hepatocytes co-cultured with STING-KO BMMs, LC3-II/LC3-I ( t = 7.546, P = 0.001) increased, p-62 ( t = 10.96, P < 0.001) expression decreased, autophagic flow increased, and the colocalization of LC3 and LDs increased, lipophagy increased, and LDs deposition decreased. Conclusion:Myeloid-specific Notch1 knockout can activate macrophages STING signaling, increase the expression of inflammatory mediator genes, inhibit the occurrence of autophagy flow and lipophagy in hepatocyte cells, and aggravate LDs deposition and NASH progression.

Objective To establish a dual wavelength HPLC method to compare the content changes of seven active components:monoglycoside,loganin,swertin,paeoniflorin,gallic acid,5-hydroxymethyl furfural and paeonol in Liuwei Dihuang Decoction(hereinafter referred to as"Liuweidihuang Decoction")before and after the preparation of Cornus wine;To explore the effect and mechanism of Liu(Shan)and Liu(Jiu)on 90 days after ovariectomy in postmenopausal osteoporosis model rats.Methods ①The contents of seven active ingredients in the Cornus wine mixed with Liuwei Dihuang Decoction were determined by dual wavelength HPLC.Chromatographic conditions:hypersil C18 chromatography(4.6 mm×250 mm,5 μm),mobile phase acetonitrile-0.3%phosphoric acid,gradient elution(0-7 min,0%-8%acetonitrile;7-15 min,8%-10%;15-20 min,10%-15%;20-30 min,15%-23%;30-50 min,23%-45%),flow rate 0.6 mL·min-1,detection wavelength:240 nm(monoglycoside,loganin,swertin,paeoniflorin),274 nm(gallic acid,5-hydroxymethyl furfural,paeonol),column temperature 30℃,injection volume 20 μL.②6-8 month old SD rats,divided into sham-operated group,model group,positive drug group,shanshuang flesh with Liuwei Dihuang Decoction group(liu(shan)group)and wine cornelian flesh withLiuwei Dihuang Decoction group(liu(wine)group),dosing started on the 5 d after ovariectomy,weighed weekly,and 5 rats from each group were taken at 90 d after surgery,weighed,anaesthetized,serum taken,bilateral femurs,and organs(uterus,spleen,liver,both kidneys and heart)were weighed.Serum calcium(Ca),phosphorus(P)and estradiol(E2)levels were measured using a fully automated biochemical instrument and chemiluminescent microparticle immunoassay,respectively;bone mineral density(BMD)values were measured using a dual-energy X-ray bone densitometer.HE staining was used to observe the morphological changes of bone tissue in rats.Results ①All the seven potent ingredients mentioned above were contained in the Liuwei Dihuang Decoction before and after the wine preparation of Cornu Cervi Pantotrichum,and the total content of the seven potent ingredients in liu(wine)was higher than that in liu(shan)(P<0.01).Among them,gallic acid and 5-hydroxymethylfurfural were higher in Liu(Jiu)than in Liu(Shan)(P<0.01),while the content of monosidine was lower than in Liu(Shan)(P<0.01).②Comparison with the sham-operated group:90 d after surgery,the serum Ca,P,E2 levels and uterine index of rats in the model group decreased(P<0.01),the BMD value decreased(P<0.01),and the degree of structural damage to bone tissue The degree of damage to the bone tissue structure was deepened,manifested by enlargement of the bone marrow cavity,gradual increase of adipocytes,dilution of the bone trabeculae arrangement,reduction of the number of bone trabeculae or even fracture.③Compared with the model group,90 d after surgery,the serum E2,Ca,P levels and uterine index of the rats in the liu(shan)and liu(wine)groups increased(P<0.05),the bone tissue structure of the liu(shan)and liu(wine)groups improved significantly,and the BMD value increased significantly(The liver and spleen indices of the liu(wine)groups increased(P<0.05).Conclusion The combination of the wine preparation of Cornus officinalis and its use in the formula of LiuWei Di Huang Decoction both contain monosidine,strychnine,sweretin,paeoniflorin,gallic acid,5-hydroxymethyl furfural(5-HMF)and tannin,and can effectively interfere with PMOP.Among them,the anti-osteoporotic effect of Liu Wei Di Huang Tang,which was formulated with wine and dogwood,was better than that of Liu Wei Di Huang Tang,which was formulated with Cornus officinalis,and the former contained more 5-HMF and gallic acid than the latter,which may provide some experimental basis for the selection of wine and dogwood in the 2020 edition of the Pharmacopoeia and the clinical application of Liu Wei Di Huang Tang in the prevention and treatment of PMOP.

OBJECTIVES: This study examined the associations between adverse childhood experiences (ACEs) and diabetes within a social-ecological framework, incorporating personal and environmental unfavorable conditions during childhood from family, school, and community contexts. METHODS: Data were obtained from the China Health and Retirement Longitudinal Study (2014 life history survey and 2015 survey), including 9,179 participants aged ≥45 years. ACEs were collected through self-report questionnaires, and participants were categorized based on the number of distinct ACEs experienced (0, 1, 2, 3, or ≥4 ACEs). Diabetes was defined by biomarkers, self-reported diagnosis, and treatment status. Logistic regression was conducted to explore the associations between ACEs and diabetes. Subgroup analyses were conducted by gender, age, and obesity status. RESULTS: Compared with participants without ACEs, those exposed to any ACE (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.01 to 1.40), 3 ACEs (OR, 1.32; 95% CI, 1.07 to 1.62) and ≥4 ACEs (OR, 1.29; 95% CI, 1.07 to 1.56) had an increased risk of diabetes. For each additional ACE, the risk of diabetes increased by about 5%. Regarding the source of ACEs, those originating from the family (OR, 1.23; 95% CI, 1.08 to 1.41) were associated with diabetes. In terms of specific ACE types, family members with substance abuse (OR, 1.23; 95% CI, 1.01 to 1.52), emotional abuse (OR, 1.28; 95% CI, 1.12 to 1.46), and poor parental relationship (OR, 1.25; 95% CI, 1.09 to 1.43) were associated with diabetes. CONCLUSIONS ACEs, particularly those originating from the family, were associated with diabetes. Interventions aimed at preventing and mitigating ACEs are essential for the early prevention of diabetes.

Humans ; Female ; Prevalence ; Breast Neoplasms ; Cancer Survivors ; Non-alcoholic Fatty Liver Disease ; Liver

Objective:To compare the clinical outcomes and safety of haploidentical donor (HID)and HLA-matched sibling donor(MSD)hematopoietic stem cell transplantation(HSCT)for severe aplastic anemia(SAA).Methods:From January 1, 2012 to December 31, 2019, retrospective review of clinical data was performed for 75 SAA patients undergoing HSCT at Department of Hematology, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.Based upon donor sources, they were divided into two groups of MSD(49 cases)and HID (26 cases). And two groups were compared with regards to hematopoietic recovery, graft-versus-host disease(GVHD)infection and overall survival(OS).Results:Time of platelet and neutrophil engraftment of two groups was comparable(11 d vs.11 d, P=0.84; 11 d vs.12 d, P=0.08). Compared with HID group, MSD group had a lower incidence of acute GVHD(46.2% vs.18.4%, P=0.01)with a comparable incidence of grade Ⅱ-Ⅳ acute GVHD(26.9% vs.14.3%, P=0.24), grade Ⅲ-Ⅳ acute GVHD(15.4% vs.4.1%, P=0.09)and chronic GVHD(23.9% vs.23.1 %, P=0.71). A reactivation of CMV occurred in 27(55.1%)MSD and 22(84.6%)HID recipients( P=0.01). And the incidence of EB viremia was 69.4% and 61.5% respectively.After a median follow-up period of 54.0 and 18.5 months, the estimated 3-year OS rate of MSD and HID groups were 94.0% and 88.0% respectively ( P=0.35). Conclusions:HID HSCT is an effective and relatively safe option for SAA patients, especially for those in urgent need of treatment without MSD or refractory/relapse to immunosuppressive therapy.

Objective:To investigate the effect of different cleaning methods on the cleaning effect of Da Vinci robotic electrosurgical instruments and the feasibility of adenosine triphosphate(ATP) fluorescence detection technology for evaluating the cleaning effect of Da Vinci robotic electrosurgical instruments.Methods:A total of 180 electrosurgical instruments were divided into control group and test group by random digits table method from June 2018 to June 2019 after robotic surgery. For the control group, 90 cases were manually cleaned to complete the device cleaning process, and for the test group, 90 cases were mechanically cleaned to complete the device cleaning process. Through visual observation, magnifying glass examination and ATP fluorescence detection technology, the cleaning effect of the two methods and the correlation between the evaluation results obtained by ATP fluorescence detection technique and traditional inspection method were compared.Results:The qualified rate of visual observation, magnifying lens examination and ATP fluorescence detection in the control group were 95.56%(85/90), 86.67% (78/90) and 84.44% (76/90), respectively, and that in the test group were 100.00% (90/90), 97.78% (88/90) and 98.89% (89/90), respectively. The test group was higher than the control group. The difference between the two groups was statistically significant ( χ2 values were 4.310, 7.745, 12.291, P<0.05 or 0.01). In the control group, there was a positive correlation between the qualified rate of ATP fluorescence detection and visual observation ( r value was 0.374, P < 0.01), and a significant positive correlation between the qualified rate of magnifying lens examination ( r value was 0.538, P < 0.01). In the test group, There was also a significant positive correlation between the qualified rate of ATP fluorescence detection and visual observation ( r value was 0.754, P < 0.01), and between the qualified rate of magnifying lens examination( r value was 0.556, P < 0.01). Conclusions:Mechanical cleaning is used to clean Da Vinci robotic electrosurgical instruments, which is superior to traditional manual cleaning. ATP fluorescence detection technology is feasible for evaluating the cleaning effect of Da Vinci robotic electrosurgical instruments.

B cell linker (BLNK) is a key linker protein of B cell receptor (BCR) signaling pathway. BLNK participates in the regulation of PLC-γactivity and the activation of Ras pathway through its typical structure and interaction network with other proteins, and is thus widely involved in the regulation of B cell proliferation, differentiation, apoptosis and signal transduction. Furthermore, it is closely related to anaphylactic diseases, multiple sclerosis, chromosomal aneuploidy, aneuglobulinemia, B lymphocytic leukemia and lymphoma. Herein we review the structure and biological function of BLNK and its role in B cell-related diseases. BLNK can cooperate with a series of effective proteins to activate BCR signaling pathway, thereby regulating the development, maturation and function of B cells. The functional mutation of BLNK can destroy the homeostasis of B cells and affect the development and maturation of B cells, which leads to the occurrence of B cell related diseases. A comprehensive understanding of the biological functions of BLNK not only provides insights into the pathogenesis of B cell-related diseases, but also inspires new ideas and helps to find breakthroughs for the treatment of these diseases with BLNK as the therapeutic target.
Adaptor Proteins, Signal Transducing ; chemistry ; genetics ; physiology ; Apoptosis ; B-Lymphocytes ; cytology ; physiology ; Cell Differentiation ; Cell Proliferation ; Humans ; Mutation ; Receptors, Antigen, B-Cell ; chemistry ; physiology ; Signal Transduction ; Structure-Activity Relationship

Acoustic resolution photoacoustic microscopy (ARPAM) combines the advantages of high optical contrast, and high ultrasonic spatial resolution and penetration. However, in photoacoustic microscopy (PAM), the information from deep regions can be greatly affected by the shallow targets, and most importantly, the irreconcilable conflict between the lateral resolution and depth of fields has always be a major factor that limits the imaging quality. In this work, an ARPAM system was developed, in which a non-coaxial arrangement of light illumination and acoustic detection was adopted to alleviate the influence of the tissue surface on the deep targets, and a novel focal zone integral algorithm was applied with multiple axial scanning to improve the lateral resolution. Phantom experiment results show that, the build system can maintain a consistent high lateral resolution of 0.6 mm over a large range in axial direction, which is close to the theoretical calculations. The following tumor imaging results on nude mice indicate that, the proposed method can provide more in-depth information compared with the conventional back detection ARPAM method. With the development of fast repetition lasers and image scanning technologies, the proposed method may play an important role in cerebral vascular imaging, cervical cancer photoacoustic endoscopic detection, and superficial tumor imaging.

Objective To confirm the correlation between pre or post processing semen parameters and clinical pregnancy rate in infertile couples with male factors undergoing intrauterine insemination (IUI) .Methods The pregnancy rate based on ovulation in‐ducing agent in infertile couples with male factors infertility per the 2010 world health organization criteria treated with IUI was e‐valuated .One hundred and twenty eight cycles were divided into pregnant group (16 cycles) and non‐pregnant group(112 cycles) . The pre or post processing semen parameters were retrospectively evaluated .Results The overall pregnancy rate was 12 .5% .All parameters in this study has no statistically significant difference between the two groups (P>0 .05) .Logistic multivariate analysis showed that there was no significant correlation between semen parameters and clinical pregnancy rate (P> 0 .05) .Conclusion There are no significant correlations between semen parameters and clinical pregnancy rate when the normal forms of patients with male infertility was 4% or higher .No semen parameters could predict results of clinical pregnancy .