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Background As thyroid-stimulating immunoglobulins (TSI) are a sign of Graves' disease (GD), measuring TSI titers is becoming increasingly important for GD diagnosis. This study evaluated the diagnostic accuracy of a new fully automated TSI immunoassay (Immulite™ TSI assay) in GD patients and compared it to the third generation thyroid-stimulating hormone receptor antibody (TRAb) electrochemiluminescence assay (Elecsys Anti-TSHR assay). Additionally, clinical characteristics associated with responsiveness to methimazole in patients with newly diagnosed GD were preliminarily explored. Methods This study involved 324 subjects, comprising patients with untreated GD (GD-UT), Graves’ ophthalmopathy (GO) patients, GD patients who had been treated for > 12 months (GD-T), autoimmune thyroiditis (AIT) patients, and healthy subjects (HS). The Immulite™ TSI and Elecsys Anti-TSHR assay were performed on all samples. According to their responsiveness to methimazole, the GD-UT patients were divided into rapid and slow responder groups, and their clinical characteristics were compared. Results A receiver operating characteristic (ROC) curve analysis of GD-UT patients showed that the optimal TSI cut-off value was 0.57 IU/L. Logistic regression revealed that age and initial FT4 and TSI levels in the middle-dose methimazole group were related to a rapid response, while the initial FT4 level, but not TSI, in the high-dose group was also associated with a rapid response. Conclusions The clinical diagnostic performance of the Immulite™ TSI assay for diagnosing GD was comparable to that of the Elecsys Anti-TSHR assay. The initial FT4 and TSI levels can be used as predictors of the responsiveness to methimazole in patients with newly diagnosed GD.

Background Cardiovascular disease (CVD) is a common comorbidity associated with chronic obstructive pulmonary disease (COPD), but few studies have been conducted to identify CVD risk in COPD patients. This study was to develop a predictive model of CVD in COPD patients based on the National Health and Nutrition Examination Survey (NHANES) database. Methods A total of 3,226 COPD patients were retrieved from NHANES 2007–2012, dividing into the training (n = 2351) and testing (n = 895) sets. The prediction models were conducted using the multivariable logistic regression and random forest analyses, respectively. Receiver operating characteristic (ROC) curves, area under the curves (AUC) and internal validation were used to assess the predictive performance of models. Results The logistic regression model for predicting the risk of CVD was developed regarding age, gender, body mass index (BMI), high-density lipoprotein (HDL), glycosylated hemoglobin (HbA1c), family history of heart disease, and stayed overnight in the hospital due to illness last year, which the AUC of the internal validation was 0.741. According to the random forest analysis, the important variables-associated with CVD risk were screened including smoking (NNAL and cotinine), HbA1c, HDL, age, gender, diastolic blood pressure, poverty income ratio, BMI, systolic blood pressure, and sedentary activity per day. The AUC of the internal validation was 0.984, indicating the random forest model for predicting the CVD risk in COPD cases was superior to the logistic regression model. Conclusion The random forest model performed better predictive effectiveness for the cardiovascular risk among COPD patients, which may be useful for clinicians to guide the clinical practice.

AIM To assess the performance of the apparent diffusion coefficient (ADC) and relative ADC (rADC) to differentiate benign from malignant breast lesions using the plateau pattern of the time–intensity curve (Type II TIC), including the impact of lesions-enhancement subtypes and menopausal status of patients. MATERIALS AND METHODS Between September 2016 and December 2019, 408 patients with 169 benign and 239 malignant lesions with Type II TIC underwent magnetic resonance imaging (MRI), including diffusion-weighted imaging, with b-values of 50 and 800 s/mm2. ADC and rADC values were calculated by placing regions of interest (ROIs) on the lesion, the parenchyma of the normal breast, and the pectoralis major muscle. A receiver operating characteristic (ROC) curve was generated to compare the diagnostic performance of each parameter in distinguishing between benign and malignant breast lesions. Further classification was undertaken to study the discriminatory performance of each parameter in the different lesions enhancement subtypes (mass-like enhancement [MLE] and non-MLE [NMLE]) and menopausal status of patients (pre-menopausal and post-menopausal). RESULTS There was a significant difference in the ADC and rADC values between benign and malignant lesions. The sensitivities of lesion ADC, gland rADC, and muscle rADC were 79.29%, 77.51%, and 79.29%, respectively, with specificities of 94.56%, 82.01%, and 94.98%, respectively. The area under the ROC curve (AUC) of muscle rADC was the highest (AUC=0.92), especially in the MLE subtype (AUC=0.96), and was not affected by the menopausal status. CONCLUSION Muscle rADC and lesion ADC assessment improved the diagnostic performance of breast MRI in distinguishing between benign and malignant breast lesions with Type II TIC, especially muscle rADC in the MLE subtype.

To systematically investigate the effect of imaging features at different DCE-MRI phases to optimise a radiomics model based on DCE-MRI for the prediction of tumour-infiltrating lymphocyte (TIL) levels in breast cancer. This study retrospectively collected 133 patients with pathologically proven breast cancer, including 73 patients with low TIL levels and 60 patients with high TIL levels. The volumes of breast cancer lesions were manually delineated on T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and each phase of DCE-MRI, followed by 6250 quantitative feature extractions. The least absolute shrinkage and selection operator (LASSO) method was used to select predictive feature sets for the classifiers. Four models were developed for predicting TILs: (1) single enhanced phase radiomics models; (2) fusion enhanced multi-phase radiomics models; (3) fusion multi-sequence radiomics models; and (4) a combined radiomics-based clinical model. Image features extracted from the delayed phase MRI, especially DCE_Phase 6 (DCE_P6), demonstrated dominant predictive performances over features from other phases. The fusion multi-sequence radiomics model and combined radiomics-based clinical model achieved the highest predictive performances with areas under the curve (AUCs) of 0.934 and 0.950, respectively; however, the differences were not statistically significant. The DCE-MRI radiomics model, especially image features extracted from the delayed phases, can help improve the performance in predicting TILs. The radiomics nomogram is effective in predicting TILs in breast cancer. • Radiomics features extracted from DCE-MRI, especially delayed phase images, help predict TIL levels in breast cancer. • We developed a nomogram based on MRI to predict TILs in breast cancer that achieved the highest AUC of 0.950.

We performed an up-to-date meta-analysis to quantify the overall incidence and risk of severe adverse events (AEs) associated with T-DM1 in patients with breast cancer. Pubmed, Embase, and oncology conference proceedings were searched for relevant studies. Data were extracted to calculate the summary incidence rate and relative risk (RR) of grade ≥3 AEs. A total of 5,045 patients from 7 RCTs were included in the meta-analysis. The use of T-DM1 was associated with an increased risk of severe thrombocytopenia (RR 10.66, 95% CI 3.23–35.18, P < 0.001), anemia (RR 1.68, 95% CI 1.15–2.44, P = 0.007), elevated ALT (RR 2.67, 95% CI 1.60–4.47, P < 0.001), and AST (RR 3.76, 95% CI 1.45–9.78, P = 0.007). In addition, the use of T-DM1 can increase the risk of severe hypertension (RR 1.59, 95% CI 1.03–2.45, P = 0.037) and peripheral sensory neuropathy (RR 8.13, 95% CI 1.89–35.03, P = 0.005). Treatment with T-DM1 increases the risk of severe hematologic toxicities, hepatotoxicity, hypertension, and peripheral sensory neuropathy in patients with breast cancer, while the overall incidence of these AEs is low.

Ovarian aging refers to the process by which ovarian function declines until eventual failure. The pathogenesis of ovarian aging is complex and diverse; oxidative stress (OS) is considered to be a key factor. This review focuses on the fact that OS status accelerates the ovarian aging process by promoting apoptosis, inflammation, mitochondrial damage, telomere shortening and biomacromolecular damage. Current evidence suggests that aging, smoking, high-sugar diets, pressure, superovulation, chemotherapeutic agents and industrial pollutants can be factors that accelerate ovarian aging by exacerbating OS status. In addition, we review the role of nuclear factor E2-related factor 2 (Nrf2), Sirtuin (Sirt), mitogen-activated protein kinase (MAPK), protein kinase B (AKT), Forkhead box O (FoxO) and Klotho signaling pathways during the process of ovarian aging. We also explore the role of antioxidant therapies such as melatonin, vitamins, stem cell therapies, antioxidant monomers and Traditional Chinese Medicine (TCM), and investigate the roles of these supplements with respect to the reduction of OS and the improvement of ovarian function. This review provides a rationale for antioxidant therapy to improve ovarian aging.

Breast cancer (BC) is now the most frequent and lethal cancer among women. Cuproptosis is a newly identified programmed cell death process that has been connected to tumor therapeutic sensitivity, patient outcomes, and the genesis of cancer. Cuproptosis-related genes (CRGs) are involved in breast cancer, although their roles and potential mechanisms are still unclear. First, we examined the effect of gene mutations and copy number changes on overall survival in 1168 breast cancer samples. Breast cancer patients were split into two molecular categories as determined by the variation in CRG based on clinicopathological traits, overall survival, and cell-infiltrating traits in tumor microenvironments. In addition, we created and validated a CRG score to calculate breast cancer patients' OS. Finally, we created a comprehensive nomogram for the clinical use of the CRG score. Patients whose CRG scores were low showed increased odds of developing OS, a larger mutation load, and immunological activation than those with high CRG scores. The CRG score, the cancer stem cell index, and the responsiveness to chemotherapy or targeted therapies were also shown to be statistically significantly correlated. Our thorough examination of CRGs in breast cancer patients demonstrated that they may be useful predictors of prognosis, clinical characteristics, and tumor microenvironment. These findings provide fresh insight into CRGs in breast cancer and might inspire brand-new approaches to both diagnosing and treating patients there.

BACKGROUND AND AIM Gastrointestinal submucosal tumors (SMTs) can be removed by submucosal tunneling endoscopic resection (STER). However, limited studies have evaluated STER for the removal of multiple upper gastrointestinal SMTs. The aim of this study was to evaluate the feasibility and outcomes of STER in the treatment of multiple upper gastrointestinal SMTs. METHODS From January 2011 to April 2020, the cases of patients with multiple upper gastrointestinal SMTs undergoing STER were retrospectively analyzed. Variables of clinicopathological characteristics, major adverse events (mAEs), and follow up were collected and analyzed. RESULTS Submucosal tunneling endoscopic resection was performed in 54 patients (48 male and 6 female patients) with 120 SMTs. Forty-four patients had two tumors, eight patients had three tumors, and two patients had four tumors. The median size of each patient was 1.8 cm (range 0.7 to 3.5 cm). Forty-five patients had tumors removed by one tunnel, and nine patients by two tunnels. The median procedure time was 50 min (range 14 to 120 min), and the mAE rate was 16.7% (9/54). No significant differences were found between patients with two tumors and those with > 2 tumors in terms of tunnel length, hospital stay, procedure time, and mAEs (all P > 0.05). In addition, patients with two tunnels had procedure time, hospital stay, and mAE rates comparable with those with one tunnel (all P > 0.05). No local recurrence or distant metastasis occurred during a median follow up of 64 months. CONCLUSIONS Submucosal tunneling endoscopic resection is a safe and effective technique for the resection of multiple upper gastrointestinal SMTs.

Background NOD-like receptors affect multiple stages of cancer progression in many malignancies. NACHT, LRR, and PYD domain-containing protein 7 (NLRP7) is a member of the NOD-like receptor family, although its role in tumorigenesis remains unclear. By analyzing clinical samples, we found that NLRP7 protein levels were upregulated in colorectal cancer (CRC). We proposed the hypothesis that a high level of NLRP7 in CRC may promote tumor progression. Here, we further investigated the role of NLRP7 in CRC and the underlying mechanism. Methods NLRP7 expression in human CRC and adjacent non-tumorous tissues was examined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. The effect of NLRP7 in CRC progression was investigated in vitro and in vivo. Proteins interacting with NLRP7 were identified by immunoprecipitation and mass spectrometry analysis while immunofluorescence staining revealed the cellular location of the proteins. Cellular ubiquitination and protein stability assays were applied to demonstrate the ubiquitination effect on NLRP7. Cloning and mutagenesis were used to identify a lysine acceptor site that mediates NLRP7 ubiquitination. Cytokines/chemokines affected by NLRP7 were identified by RNA sequencing, qRT-PCR, and enzyme-linked immunosorbent assay. Macrophage phenotypes were determined using qRT-PCR, flow cytometry, and immunohistochemistry. Results NLRP7 protein levels, but not mRNA levels, were upregulated in CRC, and increased NLRP7 protein expression was associated with poor survival. NLRP7 promoted tumor cell proliferation and metastasis in vivo and in vitro and interacted with ubiquitin-specific protease 10, which catalyzed its deubiquitination in CRC cells. NLRP7 stability and protein levels in CRC cells were modulated by ubiquitination and deubiquitination, and NLRP7 was involved in the ubiquitin-specific protease 10 promotion of tumor progression and metastasis in CRC. K379 was an important lysine acceptor site that mediates NLRP7 ubiquitination in CRC cells. In CRC, NLRP7 promoted the polarization of pro-tumor M2-like macrophages by inducing the secretion of C-C motif chemokine ligand 2. Furthermore, NLRP7 promoted NF-κB nuclear translocation and activation of C-C motif chemokine ligand 2 transcription. Conclusions We showed that NLRP7 promotes CRC progression and revealed an as-yet-unidentified mechanism by which NLRP7 induces the polarization of pro-tumor M2-like macrophages. These results suggest that NLRP7 could serve as a biomarker and novel therapeutic target for the treatment of CRC.

Background:. Although endovascular therapy has been widely used for focal aortoiliac occlusive disease (AIOD), its performance for extensive AIOD (EAIOD) is not fully evaluated. We aimed to demonstrate the long-term results of EAIOD treated by endovascular therapy and to identify the potential risk factors for the loss of primary patency. Methods:. Between January 2008 and June 2018, patients with a clinical diagnosis of the 2007 TransAtlantic Inter-Society Consensus II (TASC II) C and D AIOD lesions who underwent endovascular treatment in our institution were enrolled. Demographic, diagnosis, procedure characteristics, and follow-up information were reviewed. Univariate analysis was used to identify the correlation between the variables and the primary patency. A multivariate logistic regression model was used to identify the independent risk factors associated with primary patency. Five- and 10-year primary and secondary patency, as well as survival rates, were calculated by Kaplan-Meier analysis. Results:. A total of 148 patients underwent endovascular treatment in our center. Of these, 39.2% were classified as having TASC II C lesions and 60.8% as having TASC II D lesions. The technical success rate was 88.5%. The mean follow-up time was 79.2 ± 29.2 months. Primary and secondary patency was 82.1% and 89.4% at 5 years, and 74.8% and 83.1% at 10 years, respectively. The 5-year survival rate was 84.2%. Compared with patients without loss of primary patency, patients with this condition showed significant differences in age, TASC II classification, infrainguinal lesions, critical limb ischemia (CLI), and smoking. Multivariate logistic regression analysis showed age

Post-transcriptional modifications of pre-mRNAs expand the diversity of proteomes in higher eukaryotes. In the brain, these modifications diversify the functional output of many critical neuronal signal molecules. In this study, we identified a brain-specific A-to-I RNA editing that changed glutamine to arginine (Q/R) at exon 20 and an alternative splicing of exon 4 in Tmem63b, which encodes a ubiquitously expressed osmosensitive cation channel. The channel isoforms lacking exon 4 occurred in ∼80% of Tmem63b mRNAs in the brain but were not detected in other tissues, suggesting a brain-specific splicing. We found that the Q/R editing was catalyzed by Adar2 (Adarb1) and required an editing site complementary sequence located in the proximal 5′ end of intron 20. Moreover, the Q/R editing was almost exclusively identified in the splicing isoform lacking exon 4, indicating a coupling between the editing and the splicing. Elimination of the Q/R editing in brain-specific Adar2 knockout mice did not affect the splicing efficiency of exon 4. Furthermore, transfection with the splicing isoform containing exon 4 suppressed the Q/R editing in primary cultured cerebellar granule neurons. Thus, our study revealed a coupling between an RNA editing and a distant alternative splicing in the Tmem63b pre-mRNA, in which the splicing plays a dominant role. Finally, physiological analysis showed that the splicing and the editing coordinately regulate Ca2+ permeability and osmosensitivity of channel proteins, which may contribute to their functions in the brain.

We recently reported that exposure to triclosan (TCS), a broad-spectrum antibacterial agent, affects social behaviors in adult mice, however, the long-lasting effects of TCS exposure during early life on social behaviors are still elusive. The present study aimed to investigate the long-lasting impacts of adding TCS to the maternal drinking water during lactation on the social behaviors of adult mouse offspring and to explore the potential mechanism underlying these effects. The behavioral results showed that TCS exposure decreased body weight, increased depression-like behavior and decreased social dominance in both male and female offspring, as well as increased anxiety-like behavior and bedding preference in female offspring. In addition, enzyme-linked immunosorbent assay (ELISA) indicated that TCS exposure increased peripheral proinflammatory cytokine levels, altered serum oxytocin (OT) levels, and downregulated the expression of postsynaptic density protein 95 (PSD-95) in the hippocampus. Morphological analysis by transmission electron microscopy (TEM) demonstrated that exposure to TCS induced morphological changes to synapses and neurons in the hippocampus of offspring. These findings suggested that TCS exposure during lactation contributed to abnormal social behaviors accompanied by increased peripheral inflammation and altered hippocampal neuroplasticity, which provides a deeper understanding of the effects of TCS exposure during early life on brain function and behavioral phenotypes.

Increasing evidence has shown that early life events exert long-lasting effects on brain function and mental diseases. Exercise has been proven to have many positive effects on behaviors, such as reducing anxiety- and depression-like behaviors and alleviating cognitive impairment. However, the long-lasting and even short-term effects of regular swimming exercise on social dominance remain unclear. The purpose of this study was to investigate the potential effects of postweaning swimming exercise on social dominance and metabolic adaptation in adult mice. Three-week-old mice performed 1 h of swimming exercise in warm water for 4 weeks. A series of behavioral tests, such as the social dominance test (SDT), open field test (OFT), and forced swim test (FST), were conducted. Behavioral test results showed that both male and female mice in the swimming group had a higher rank than those in the sedentary group in the SDT of early adulthood, while only female mice in the swimming group maintained the social dominance in late adulthood. There was no difference between the swimming and sedentary groups in anxiety- and depression-like behaviors. Metabolomics analysis showed that there were alterations in particular metabolites and signaling pathways after one month of swimming exercise, including sphingolipid metabolism, neuroactive ligand-receptor interaction and caffeine metabolism. In conclusion, our results provide the first evidence that postweaning swimming exercise has long-lasting and sex-dependent effects on social dominance, which may be caused by metabolic adaptation.

The surgery for esophageal cancer arising after prior gastrectomy is technically difficult with high morbidity and mortality. Endoscopic submucosal dissection (ESD) is a minimally invasive endoscopic treatment for superficial SCC with high curative resection rate. But few studies are concerned about ESD under these circumstances. The aim of this study was to elucidate the short- and long-term outcomes of ESD for superficial esophageal squamous cell cancer (SCC) in patients with prior gastrectomy. From January 2009 to January 2019, 37 patients with prior gastrectomy who underwent ESD for superficial esophageal SCC were retrospectively enrolled at the Zhongshan Hospital, Fudan University in Shanghai, China. Rates of en bloc resection, complete resection, curative resection, incidence of postoperative bleeding, perforation and postoperative stricture were evaluated as short-term outcomes. Overall survival, and local recurrence-free survival were evaluated as long-term outcomes. The rate of en bloc resection, complete resection and curative resection were 94.6%, 86.5% and 78.4%, respectively. No perforation was observed. 1 (2.7%) patient experienced postoperative bleeding. During the median observation of 43 months, 3 (8.6%) patients experienced esophageal stricture, successfully managed by balloon dilation. 3(8.6%) patients had local recurrence after ESD with 5-year local recurrence-free survival rate of 91.4%. During the observation period, 4 patients died of other reasons. The 1, 3, 5-year overall survival rates were 97.1%, 97.1% and 91.4%. The short-term outcomes indicate ESD is technically difficult with lower resection completeness in patients after gastrectomy, while the long-term outcomes are rather favorable.

Objective The study aim was to examine the effects of cognitive behavioural therapy (CBT) on the pregnancy outcomes of women receiving in vitro fertilization-embryo transfer (IVF-ET) treatment. Methods A literature review was performed using the databases MEDLINE, the Cochrane Database, Embase, Chinese National Knowledge Infrastructure (CNKI) and WANFANG. Eligible studies were selected according to inclusion and exclusion criteria. Relevant data were extracted and the quality of studies assessed. Odds ratios with 95% confidence intervals were pooled to statistically analyse the difference between intervention and control groups. Results Ten studies were selected for the systematic review and meta-analysis. The findings showed that CBT and cognitive-related therapy significantly improved the pregnancy rate of women undergoing IVF-ET treatment. Subgroup analysis showed that patients who received CBT, rather than complex psychological interventions, and those who received interventions delivered by professional psychologists, were more likely to become pregnant during IVF-ET treatment. Conclusion CBT and cognitive-related interventions had significant effects on the pregnancy outcomes of women receiving IVF-ET treatment. CBT treatment (rather than complex psychological interventions) provided by professional psychologists is strongly recommended.

We recently reported that maternal exposure to bisphenol AF (BPAF), an environmental endocrine disruptor (EED), induced significant alterations in emotional behaviors in offspring mice during adolescence in a sex-dependent manner. However, the effects of adult BPAF exposure and the potential long-lasting effects of maternal exposure to BPAF on offspring mice are still unknown. The present study aimed to investigate the neurobehavioral effects of adult and maternal exposure to BPAF, intragastrically (0.4, 4 mg•kg

Sleep deprivation (SD) has adverse effects on physical and mental health. Recently increasing attention has been given to SD in the early-life stage. However, the effects and mechanisms of postweaning SD on cognitive function and social behaviors are still unclear. In this study, SD was conducted in mice from postnatal Day 21 (PND21) to PND42, 6 h a day. Meanwhile, changes in body weight, food and water intake were continuously monitored. Behavioral tests were carried out in adulthood of mice. The levels of serum corticosterone, the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), and the anti-inflammatory cytokines interleukin-10 (IL-10), vasopressin (VP) and oxytocin (OT) were measured by ELISA. Golgi staining was used to calculate neural dendritic spine density in the dorsal hippocampus (dHPC) CA1 region and medial prefrontal cortex (mPFC). We found that postweaning SD increased the food intake and the weight of female mice. Behavioral results showed that postweaning SD caused cognitive impairment and lowered social dominance in adult male mice but not in female mice. ELISA results showed that SD increased the levels of serum corticosterone, VP and OT in male mice and serum OT in female mice. Golgi staining analysis showed that SD decreased neural dendritic spine density in the dHPC in male mice. These results suggest that postweaning SD has a long-term effect on social dominance and cognitive function in male mice, which may provide a new insight into the role of SD in regulating cognitive function and social behaviors.

Triclosan (TCS), a newly identified environmental endocrine disruptor (EED) in household products, has been reported to have toxic effects on animals and humans. The effects of TCS exposure on individual social behaviors and the potential underlying mechanisms are still unknown. This study investigated the behavioral effects of 42-day exposure to TCS (0, 50, 100 mg/kg) in drinking water using the open field test (OFT), social dominance test (SDT), social interaction test (SIT), and novel object recognition task (NOR). Using 16S rRNA sequencing analysis and transmission electron microscopy (TEM), we observed the effects of TCS exposure on the gut microbiota and ultrastructure of hippocampal neurons and synapses. Behavioral results showed that chronic TCS exposure reduced the social dominance of male and female mice. TCS exposure also reduced social interaction in male mice and impaired memory formation in female mice. Analysis of the gut microbiota showed that TCS exposure increased the relative abundance of the Proteobacteria and Actinobacteria phyla in female mice. Ultrastructural analysis revealed that TCS exposure induced ultrastructural damage to hippocampal neurons and synapses. These findings suggest that TCS exposure may affect social behaviors, which may be caused by altered gut microbiota and impaired plasticity of hippocampal neurons and synapses.

Objective: Synchronous multiple primary early esophageal cancers (SMPEEC) are rare and aggressive. Early detection of esophageal cancer can improve survival rate. Endoscopic submucosal dissection (ESD) is a minimally invasive endoscopic treatment of early esophageal cancers. However, ESD for SMPEEC is little known. We aimed to clarify the clinical outcomes of simultaneous ESD treating SMPEEC. Methods: We retrospectively reviewed the medical data of 34 patients, who underwent ESD for SMPEEC at Endoscopy Center of Zhongshan Hospital, Fudan University, between May 2013 and December 2014. The data of lesion size, histopathology, en bloc resection, curative resection, complication, and tumor local recurrence were analyzed. Results: Among 34 patients, 67 lesions were removed simultaneously in 33 cases; 2 lesions were removed in 2 operations for 1 case. For the simultaneous resection, the en bloc rate was 97.01% (65/67) and the curative resection rate was 92.54% (62/67). Postoperative stricture occurred in two cases and delayed bleeding occurred in one case. There was one local recurrence, no metastasis or procedure-related death. Conclusions: Simultaneous ESD as a treatment for SMPEEC is technically feasible, benefited from reducing hospitalization time and medical expenses. For the cases with risk factors of complications, simultaneous ESD needs to be avoided.

OBJECTIVE Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although genome-wide association studies (GWAS) have identified >60 T1D loci in Caucasians, less is known in Asians. RESEARCH DESIGN AND METHODS We performed the first two-stage GWAS of T1D using 2,596 autoantibody-positive T1D case subjects and 5,082 control subjects in a Chinese Han population and evaluated the associations between the identified T1D risk loci and age and fasting C-peptide levels at T1D diagnosis. RESULTS We observed a high genetic correlation between children/adolescents and adult T1D case subjects (rg = 0.87), as well as subgroups of autoantibody status (rg ≥ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near BTN3A1 (odds ratio [OR] 1.26, P = 2.70 × 10−8) and rs3802604 in GATA3 (OR 1.24, P = 2.06 × 10−8), and two previously reported loci, rs1770 in MHC (OR 4.28, P = 2.25 × 10−232) and rs705699 in SUOX (OR 1.46, P = 7.48 × 10−20). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus P = 9.78 × 10−12), specific to the Chinese population. Based on the identified eight variants, we achieved an area under the curve value of 0.86 (95% CI 0.85–0.88). By building a genetic risk score (GRS) with these variants, we observed that the higher GRS were associated with an earlier age of T1D diagnosis (P = 9.08 × 10−11) and lower fasting C-peptide levels (P = 7.19 × 10−3) in individuals newly diagnosed with T1D. CONCLUSIONS Our results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine.

Objective Selenium deficiency is a risk factor for Kashin-Beck Disease (KBD), an endemic osteoarthropathy. Although promoter hypermethylation of glutathione peroxidase 3 (GPX3) (a selenoprotein) has been identified in several cancers, little is known about promoter methylation and expression of GPX3 and their relation to selenium in KBD. The present study was thus conducted to investigate this research question. Methods Methylation and expressions of GPX3 in whole blood drawn from 288 KBD patients and 362 healthy controls and in chondrocyte cell line were evaluated using methylation-specific PCR and qRT-PCR, respectively. The protein levels of PI3K/Akt/c-fos signaling in the whole blood and chondrocyte cell line were determined with Western blotting. Chondrocytes apoptosis were detected by Hoechst 33342 and Annexin V-FITC/PI staining. Results GPX3 methylation was increased, GPX3 mRNA was decreased, and protein levels in the PI3K/Akt/c-fos signaling pathway were up-regulated in the whole blood collected from KBD patients as compared with healthy controls. Similar results were obtained for chondrocytes injured by oxidative stress. There was a significant, decreasing trend in GPX3 expression across groups of unmethylation, partial methylation, and complete methylation for GPX3, in sequence. Compared with unmethylation group, protein levels in PI3K/Akt/c-fos pathway were enhanced in partial and complete methylation groups. Treatment of chondrocytes with sodium selenite resulted in reduced methylation and increased expression of GPX3 as well as down-regulated level of PI3K/Akt/c-fos proteins. Conclusions The methylation and expression of GPX3 and expression of PI3K/Akt/c-fos pathway are altered in KBD and these changes are reversible by selenium supplementation.

Gastric small submucosal tumors (SMTs) are becoming increasingly common. However, the fundus of stomach is regarded as a difficult area for endoscopic resection (ER). In this study, we investigated the efficacy, safety, and long-term outcomes of ER for small SMTs of the gastric fundus in a large series of patients, research that was previously lacking. 537 consecutive patients with SMTs no more than 20 mm in diameter, occurring in the gastric fundus and originating from the muscularis propria layer, which were treated with endoscopic submucosal excavation or endoscopic full-thickness resection (EFTR) were included in this retrospective study at Zhongshan Hospital of Fudan University from January 2013 to September 2016. Clinicopathological, endoscopic, and follow-up data were collected and analyzed. En bloc resection was achieved in 100% of patients, and complete resection was achieved for 530 (98.7%) lesions. Although the total rate of complications was 9.3%, few serious adverse events occurred in only three (0.6%) patients, including major pneumoperitoneum, major hydrothorax, and bleeding. Unlike lager tumor sizes and longer procedure times, endoscopist experience had a positive impact on decreasing the likelihood of complications. Based on statistical analysis, tumors with greater size near the cardia, which were treated by EFTR, were the significant contributors to longer operative times. A median follow-up of 32 months was available, and all patients were free from local recurrence or distant metastasis during the study period. Although the gastric fundus presents technical difficulties, ER is effective for the resection of small gastric SMTs with a high complete resection rate and rare serious adverse events.

Ayimukedisi Yalikong,1,2,* Xu-Quan Li,1,3,* Ping-Hong Zhou,1,2 Zhi-Peng Qi,1,2 Bing Li,1,2 Shi-Lun Cai,1,2 Yun-Shi Zhong1,2 1Endoscopy Center, Zhongshan Hospital of Fudan University, Shanghai, 200032, People’s Republic of China; 2Endoscopy Research Institute of Fudan University, Shanghai, 200032, People’s Republic of China; 3Shanghai Henlius Biopharmaceuticals Co., Ltd., Shanghai, 200033, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shi-Lun Cai; Yun-Shi ZhongZhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai, 200032, People’s Republic of ChinaEmail caishilun1988@qq.com; zhongyunshi@yahoo.comBackground: Colon cancer (CRC) was a malignant tumor and there were about 25% of patients with tumor metastasis at diagnosis stage. Chemotherapeutic agents for metastatic CRC patients were with great side effects and the clinical treatment results of advanced CRC were still not satisfactory. Human epidermal growth factor receptor 2 (HER2) is overexpressed in some CRC patients and is an effective target for CRC patient treatment. Anti-HER2 therapy had a beneficial role in the treatment of HER2-positive metastatic CRC with fewer side effects. CRC patients with BRAF mutations were resistant to HER2 antibodies treatment. Therefore, there was an urgent need to develop new therapeutic agents.Methods: HER2 targeted nanoparticles (TPLNP) drug delivery system loading triptolide (TPL) were prepared and identified. The effects of TPLNP and free TPL on cell viability, targeting and cell cycle progression on HT29 (BRAF mutation) with HER2 overexpression, were evaluated by Cell Counting Kit-8 (CCK8), Fluorescence Activating Cell Sorter (FACS) and immunofluorescence methods, respectively. The anti-tumor efficacies of TPLNP were evaluated in subcutaneous xenograft model of colon cancer and the survival rate, tumor volume, liver and kidney indexes of tumor-bearing mice were measured.Results: TPLNP was small in nanosize (73.4± 5.2nm) with narrow size distribution (PDI=0.15± 0.02) and favorable zeta potential (pH=9.6, zeta potential: − 57.3± 6.69mV; pH=7.0, zeta potential: − 28.7± 5.1mV; pH=5.6, zeta potential: − 21.1± 4.73mV). Comparing with free TPL treatment group, TPLNP developed stranger colon cancer-killing efficiency in a dose- and time-dependent manner detected with CCK8 method; achieved good in vitro colon cancer targeting detected with flow cytometry and immunofluorescence experiments; enhanced more HT29-HER2 apoptosis and induced more cell cycle arrested in G1-S phase detected with FACS in vitro. As for in vivo antitumor response, TPLNP remarkably inhibited the growth of colon cancer in the colon cancer xenograft model, significantly improved the survival rate and did not exhibit significant liver and kidney toxicity in contrast with free TPL in vivo.Conclusion: TPLNP was effectively against colon cancer with HER2 overexpression and BRAF mutation in pre-clinical models. In summary, the TPLNP appeared to be a promising treatment option for CRC in clinical application based on improved efficacy and the favorable safety profile.Keywords: colon cancer, HER2, triptolide, BRAF mutation

Metformin has been demonstrated to be beneficial for the treatment of an impaired myocardium as a result of ischemia/reperfusion (I/R) injury, and miR-34a may be involved in this process. The aim of the present study was to determine the mechanisms by which metformin attenuated myocardial I/R injury–induced apoptosis. In the in vivo I/R model using Sprague–Dawley rats, metformin reduced the area of damaged myocardium and serum creatine MB isoform (CKMB) activity resulting in protection of the myocardium. Metformin also reduced apoptosis and the expression of apoptosis associated proteins, including caspase 3 and cleaved caspase, and decreased the expression of miR-34a, which is upregulated during I/R injury, which in turn resulted in corresponding changes in expression of Bcl-2, a direct target of miR-34a both in vitro and in vivo. To further examine the role of miR-34a in this process, H9C2 cells were transfected by a miR-34a mimic and inhibitor. Overexpression of miR-34a increased apoptosis in H9C2 cells induced by oxygen–glucose deprivation/recovery and knockdown of miR-34a expression–reduced apoptosis under the same conditions. Therefore, the effect of metformin on miR-34a in vitro were assessed. Metformin decreased the deacetylation activity of silent information regulator 1 resulting in reduced Ac-p53 levels, which reduced the levels of pri-miR-34a, and thus in turn reduced miR-34a levels. To confirm these results clinically, 90 patients with ST-segment elevation myocardial infarction following percutaneous coronary intervention were recruited. Patients who took metformin regularly before infarction had lower miR-34a levels and lower serum CKMB activity. Metformin also improved the sum ST-segment recovery following I/R injury. In conclusion, metformin may be helpful in the treatment of myocardial I/R.

Background Anovulation is one of the main causes of female infertility. This study will evaluate the effectiveness and safety of Bushen Culuan Decoction for anovulatory infertility caused by six diseases, including anovulatory abnormal uterine bleeding, polycystic ovarian syndrome, hyperprolactinemia, luteinized unruptured follicle syndrome, corpus luteum insufficiency, and premature ovarian insufficiency. Methods This is a randomized, double-blinded, double-dummy, parallel, positively controlled, adaptive, multicenter clinical trial. All participants will be randomly allocated by a central randomization system to the treatment group or the control group in a 1:1 ratio. The treatment group will undergo a 14-day treatment with Bushen Culuan Decoction 13 g three times a day and a 5-day treatment with clomiphene citrate placebo tablets 50 mg once a day starting on day 5 of every menstrual period. The control group will undergo a 14-day treatment with Bushen Culuan Decoction placebo 13 g three times a day and a 5-day treatment with clomiphene citrate tablets 50 mg once a day from day 5 in every menstrual period. The whole treatment will last through 3 menstrual periods or 6 menstrual periods, depending on whether ovulation is regained in the first 3 menstrual periods. All statistical analyses will be performed in SPSS 21.0 (SPSS, Chicago, Illinois, USA), and a p value Discussion The objective of this RCT is to evaluate whether Bushen Culuan Decoction enables a higher pregnancy rate than clomiphene citrate in women with anovulatory infertility and to identify the anovulatory diseases for which Bushen Culuan Decoction has higher effectiveness .This study has been approved by the Medical Ethics Committee of Xiyuan Hospital China Academy of Chinese Medical Sciences (No. 2017XLA037-2). The results of this study will be offered for publication in peer-reviewed journals. Trial registration ClinicalTrials.gov NCT03709849. Registered on 19 November 2018.

Purpose: Previous studies suggest that a cumulative cisplatin dose of 200 mg/m2 might be adequate in the intensity-modulated radiation therapy (IMRT) era for locoregionally advanced nasopharyngeal carcinoma (LANPC). However, two cycles of once-every-3-weeks cisplatin at 100 mg/m2 has never been prospectively compared with standard once-a-week cisplatin regimen. Patients and Methods: This trial was conducted at three hospitals from 2011 to 2016. Patients who met the eligibility criteria were recruited (ChiCTR-TRC-12001979) and randomly assigned (1:1) via a computer-generated sequence to receive once-every-3-weeks cisplatin at 100 mg/m2 for two cycles or once-a-week cisplatin at 40 mg/m2 for six cycles concurrently with IMRT. Primary endpoint was failure-free survival and between-group absolute difference of 10% as the noninferiority margin. Results: A total of 510 patients were enrolled. Median follow-up time was 58.3 months with 85.4% of 3-year failure-free survival in the once-every-3-weeks group and 85.6% in the once-a-week group. An absolute difference of −0.2% (95% confidence interval, −6.3 to 5.9; Pnoninferiority = 0.0016). Acute toxicities of grade 3 or higher occurred in 55.8% in the once-every-3-weeks group and 66.3% in the once-a-week group (P = 0.015). The most common acute toxicities were hematologic abnormalities, including leukopenia (16% vs. 27%; P = 0.0022) and thrombocytopenia (1% vs. 5%; P = 0.015). The late grade 3–4 auditory loss rate was significantly lower in the once-every-3-weeks group than the once-a-week group (6% vs. 13%; P = 0.0039). Conclusions: Once-every-3-weeks cisplatin as concurrent chemoradiotherapy is noninferior to once-a-week cisplatin in the treatment efficacy in the LANPC. Although both regimens are well tolerated, severe acute toxicities and late-onset auditory loss are higher in the once-a-week group.

OBJECTIVE To evaluate the effects of the addition of preoperative hepatic and regional arterial chemotherapy (PHRAC) on prognosis of stage II and III colorectal cancer (CRC) in a multicenter setting. SUMMARY OF BACKGROUND DATA Our previous single-center pilot trial suggested that PHRAC in combination with surgical resection could reduce the occurrence of liver metastasis (LM) and improve survival in CRC patients. METHODS A prospective multi-center randomized controlled trial was conducted from December 2008 to December 2012 at 5 hospitals in China. Eligible patients with clinical stage II or III CRC who underwent curative resection were randomized to receive PHRAC plus adjuvant therapy (PHRAC arm) or adjuvant therapy alone (control arm). The primary endpoint was DFS. Secondary endpoints were cumulative LM rates, overall survival (OS), and safety (NCT00643877). RESULTS A total of 688 patients from 5 centers in China were randomly assigned (1:1) to each arm. The five-year DFS rate was 77% in the PHRAC arm and 65% in the control arm (HR = 0.61, 95% CI 0.46-0.81; P = 0.001). The 5-year LM rates were 7% and 16% in the PHRAC and control arms, respectively (HR = 0.37, 95% CI 0.22-0.63; P < 0.001). The 5-year OS rate was 84% in the PHRAC arm and 76% in the control arm (HR = 0.61, 95% CI 0.43-0.86; P = 0.005). There were no significant differences regarding treatment related morbidity or mortality between the two arms. CONCLUSIONS The addition of PHRAC could improve DFS in patients with stage II and III CRC. It reduced the incidence of LM and improved OS without compromising patient safety. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00643877.

BackgroundThe use of a self-expandable metallic stent (SEMS) as a bridge to surgery has increased for patients with obstructing colorectal cancer. However, relatively few reports have compared SEMS as a bridge to elective surgery for acute malignant obstruction of the right-sided colon (MORC) vs. emergency surgery (ES). This study aimed to evaluate the benefits of elective surgery after SEMS placement vs. ES for patients (including stage IV cases) with acute MORC.MethodsPatients with acute MORC who underwent radical resection for a primary tumour from July 2008 to November 2016 at Zhongshan Hospital of Fudan University were retrospectively enrolled. Postoperative short-term outcomes, progression-free survival (PFS), and overall survival (OS) were compared between the SEMS and ES groups.ResultsIn total, 107 patients with acute MORC (35 in the SEMS group and 72 in the ES group) were included for analysis. The Intensive Care Unit admission rate was lower (11.4% vs. 34.7%,P = 0.011), the incidence of complications was reduced (11.4% vs. 29.2%,P = 0.042), and the postoperative length of hospitalisation was significantly shorter (8.23 ± 6.50 vs. 11.18 ± 6.71 days,P = 0.033) for the SEMS group. Survival curves showed no significant difference in PFS (P = 0.506) or OS (P = 0.989) between groups. Also, there was no significant difference in PFS and OS rates between patients with stage II and III colon cancer. After colectomy for synchronous liver metastases among stage IV patients, the hepatectomy rates for the SEMS and ES groups were 85.7% and 14.3%, respectively (P = 0.029). The hazard ratio for colectomy alone vs. combined resection was 3.258 (95% CI 0.858–12.370;P = 0.041).ConclusionStent placement offers significant advantages in terms of short-term outcomes and comparable prognoses for acute MORC patients. For synchronous liver metastases, SEMS placement better prepares the patient for resection of the primary tumour and liver metastasis, which contribute to improved survival.

To date there is no effective treatment for pregnancies complicated by fetal growth restriction (FGR). Salvia miltiorrhiza, a traditional Chinese herb has been shown to promote blood flow and improve microcirculatory disturbance. In this pilot study, we evaluated whether S. miltiorrhiza can potentially become a possible therapy for FGR. Nineteen pregnant women with FGR were treated with S. miltiorrhiza and ATP supplementation for an average of 7 days, and 17 cases received ATP supplementation as controls. The estimated fetal weights (EFWs) were measured by ultrasound after treatment, and the birthweights were recorded after birth. After treatment with S. miltiorrhiza, 7 (37%) FGR cases showed an increase in EFW to above the 10th percentile, compared with 4 (23%) FGR cases in controls (odds ratio: 1.896, 95% confidence limits (CLs): 0.44–8.144). At delivery, 10 (53%) FGR cases in the treatment group delivered babies with a birthweight above the 10th percentile, compared with 6 (35%) FGR cases in the control group (odds ratio: 2.037, 95% CL: 0.532–7.793); 80 or 64% FGR cases in the treatment group showed an increase in fetal abdominal circumference (AC) or biparietal diameter (BPD) above the 10th percentile before delivery. While 44 or 30% FGR cases in the control group showed an increase in AC or BPD. No improvement of head circumference (HC) or femur length (FL) was seen. These pilot data suggest the need for multicenter randomized clinical trials on the potential of S. miltiorrhiza to improve perinatal outcome in pregnant women complicated by FGR.

We investigated the outcomes of endovascular repair for penetrating aortic ulcers (PAUs) with and without intramural hematoma (IMH).Patients with PAUs who had undergone thoracic endovascular aortic repair (TEVAR) or endovascular abdominal aortic repair (EVAR) at our center were enrolled. Patient demographics, presenting symptoms, and anatomic characteristics were collected and analyzed to investigate the TEVAR/EVAR indications, perioperative complications, and mortality.We identified 138 patients with PAU. Of the 138 patients, 58 (42.0%) had also had IMH. Compared with the patients without IMH, the patients with IMH had had significantly greater emergency admission rates (P .01), a larger aortic diameter (P = .03), and a greater incidence of stent-induced new entry development (P = .02). No significant differences were found in mortality or freedom from reintervention between patients with PAUs with and without IMH during follow-up. However, the cumulative survival rates calculated using Kaplan-Meier analysis for patients who had undergone TEVAR/EVAR during their first hospitalization were significantly greater than those who had undergone delayed TEVAR/EVAR during follow-up.TEVAR/EVAR was safe and effective, with encouraging outcomes for patients with PAUs with or without IMH, and can be used more aggressively for symptomatic patients. The presence of PAUs with IMH did not seem to adversely affect long-term mortality. However, but stent-induced new entry was more likely to develop.

Acinetobacter baumannii is one of the dominating causes of nosocomial pneumonia, however, very little is known about the host immune response associated with pathogenesis of A. baumannii infection. Here, we used a hypervirulent A. baumannii to establish an acute lethal pneumonia, supported by high bacterial burdens, severe inflammatory cells infiltration and lung damage. The lung transcriptome changes in response to A. baumannii lethal pneumonia were detected by RNA sequencing. The results showed that 6,288 host genes changed expression, with 3,313 upregulated genes and 2,975 downregulated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that genes related to TNF, cytokine-cytokine receptor interaction, Toll-like receptor, NOD-like receptor, NF-κB, Jak-STAT, HIF-1 signaling pathways, apoptosis, and phagosome were significantly upregulated. Whereas, genes associated with PI3K-AKT signaling pathway, glycolysis/gluconeogenesis, amino acid and fatty acid metabolism were downregulated. Immune cell typing highlighted the inflammatory response of innate immune cells headed by neutrophils. The reliability of RNA sequencing results were verified with selected differentially expressed genes by real-time PCR. This work provides an insight into the pathogenesis of lethal A. baumannii lung infection.

A number of studies have demonstrated that exosomes were involved in important physiological and pathological processes through cell-to-cell communication in cardiovascular disease, which contained nucleic acids, proteins, and lipid contents. In our study, we found that the protein platelet endothelial cell adhesion molecule-1 (PECAM1) was an extracellular vesicle in the blood of high blood pressure patients (HBPP). Isolated the vesicles from the blood of HBPP and health examiners and detected its size and morphology with nanoparticle tracking analysis, then we identified its surface protein CD63, CD81, and the protein expression of PECAM1 in the exosome with western blot. Furthermore, we analyzed the correlation between the expression of PECAM1 and the high blood degree with linear regression analysis. Our results showed that the morphology of extracellular vesicles was more evident in high blood pressure groups than healthy controls, and the protein expression of PECAM1 was also abundant in the vesicles of HBPP, however, there were no extracellular vesicles in the blood samples of healthy controls. Besides, linear regression showed the linear correlation coefficient R = 0.901, P

Toxoplasmosis is a parasitic zoonosis with the highest incidence in humans. Severe lesions due to acute toxoplasmosis have been recorded in the visceral organs including the liver, where hepatocytes and Kupffer cells are important innate immune cells. Arctigenin (AG) is a bioactive ingredient of Arctium lappa L. and increasing evidence suggests that AG exhibits anti-oxidant, anti-inflammatory and anti-Toxoplasma gondii (T. gondii) effects. However, the role of AG in acute liver damage induced by T. gondii infection remains unclear. In this study, we analyzed the effects of AG against T. gondii-induced liver damage by establishing an in vitro infection model using a murine liver cell line (NCTC-1469 cells) and an in vivo mouse model with acute T. gondii infection of virulent RH strain. In the current study, AG effectively attenuated hepatocytes apoptosis and inhibited the reproduction of T. gondii. The results of in vitro and in vivo studies showed that AG significantly reduced alanine aminotransferase/aspartate aminotransferase activities and lessened pathological damage of liver. Moreover, AG suppressed T. gondii-induced inducible nitric oxide synthase production. AG also attenuated liver inflammation by inhibiting T. gondii-induced activation of the high-mobility group box1/toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-κB) signaling pathway. These findings demonstrated that AG exhibited prominent hepatoprotective activities in toxoplasmic liver injury with anti-inflammatory effects by inhibiting the HMGB1/TLR4/NF-κB signaling axis. Thus, this study provides the basis for the development of new drugs to treat toxoplasmic hepatitis.

Dantrolene has been demonstrated to be neuroprotective for multiple neurodegenerative diseases. However, dantrolene's limited penetration into the CNS hampers its effectiveness as a neuroprotective agent. Here, we studied whether the intranasal administration of dantrolene provided better penetration into the brain than the commonly used oral approach. C57BL/6 mice, aged 2-4 months, received a single dose of either intranasal or oral dantrolene (5mg/kg). Inhibition of dantrolene clearance from the brain was examined by co-administration with P-gp/BCRP inhibitors, nimodipine or elacridar. The concentration of dantrolene in the brain and plasma was measured at 10, 20, 30, 50, 70, 120, 150 and 180 minutes after administration. Separate cohorts of mice were given intranasal dantrolene (5mg/kg) or vehicle, 3 times/ week, for either 3 weeks or 4 months, to examine potential adverse side effects on olfaction and motor coordination, respectively. We found that Dantrolene concentrations were sustained in the brain after intranasal administration for 180 min, while concentrations fell to zero at 120 min for oral administration. Chronic use of intranasal dantrolene did not impair olfaction or motor function in these mice. Blood brain barrier pump inhibitors did not further increase dantrolene peak concentrations in the brain. Our results suggested that Intranasal administration of dantrolene is an effective route to increase its concentration and duration in the brain compared to the oral approach, without any obvious side effects on olfaction or motor function.

Background and Aims. Gastric peroral endoscopic myotomy (G-POEM) has been regarded as a novel and minimally invasive therapy for refractory gastroparesis. This study reports the long-term outcomes and possible predictive factors for successful outcomes after G-POEM in an Asian population. Methods. This is a retrospective single-centre study of 16 patients who underwent G-POEM for refractory gastroparesis from August 2016 to October 2017. This study included 11 males and 5 females; in addition, 13 patients had postsurgical gastroparesis, and 3 patients had diabetes. The patients included had severe and refractory gastroparesis, as indicated by a Gastroparesis Cardinal Symptom Index (GCSI) score ≥20, and evidence of a delay on gastric emptying scintigraphy (GES). The primary outcome parameter was an assessment of the long-term clinical efficacy of the procedure. The secondary outcome parameter was the detection of possible predictive factors for success and the determination of cut-off values for such predictors. Results. Technical success was achieved in 100% of the patients, with a mean procedure time of 45.25±12.96 min. The long-term clinical response was assessed in all patients during a median follow-up of 14.5 months. Clinical success was achieved in 13 (81.25%) patients. There was a significant reduction in the GCSI scores and GES values after the procedure compared to the baseline values, with P values of ≤30 had a high sensitivity and a negative predictive value (NPV) of 100% for predicting a successful procedure. GES (half emptying time ≤221.6 min and 2-hour retention ≤78.6%) had a high specificity and a positive predictive value (PPV) of 100%. Conclusions. G-POEM is a safe and effective treatment option with a long-term efficacy of 81.6%. GCSI and GES could serve as good predictive measures.

Endoscopic full-thickness resection (EFTR) derived from endoscopic submucosal dissection has gradually been accepted and even promoted for the treatment of submucosal tumors (SMTs) originating from the muscularis propria (MP) layer. However, there are some difficulties when EFTR is used to treat MP lesions in the gastric fundus. This study intends to explore whether EFTR can be made simpler, safer, and more effective with the traction assistance of dental floss.The clinical data of patients (trial group) with lesions in the MP layer in the gastric fundus undergoing EFTR with traction assistance of dental floss at Zhongshan Hospital, in 2016, were reviewed retrospectively. The control group was matched with the trial group according to tumor size. The differences in tumor resection time, patient hospitalization time, and complication rate were evaluated.There was no significant difference in the average age of the two groups, each of which comprised 24 cases (58.7 ± 11.8 years versus 56.6 ± 7.9 years, t = 0.663, P = .511). However, there was a statistically significant difference in the operative time between the two groups (10.8 ± 2.8 minutes versus 19.0 ± 4.7 minutes, t = 7.298, P .05). There was no statistically significant difference in the length of the postoperative hospital stay (3.2 ± 0.5 days versus 3.2 ± 0.5 days, t = 0.291, P = .772). In the trial group, there were 19 cases of gastrointestinal stromal tumors (group 1) and 5 cases of leiomyoma. The control group had similar results. Neither group experienced postoperative delayed bleeding, perforation, or other complications.When EFTR is used to treat SMTs originating from the MP in the gastric fundus, dental floss traction assistance can relieve the tumor boundary to simplify the surgical procedure and save the operation time.

Progesterone receptor membrane component 1 (PGRMC1) mediates antimitotic and antiapoptotic actions of progesterone in granulosa cells, which indicates that PGRMC1 may play a key role in maintaining the status of granulosa cells. The current study investigated the effects of progesterone on intracellular signaling involved in differentiation, follicle development, inflammatory responses, and antioxidation, and determined the role of PGRMC1 in these processes. Our results demonstrated that progesterone slowed follicle development and inhibited p-ERK1/2, p-p38, caspase-3, p-NF-κB, and p-IκB-α signals involved in differentiation, steroidogenesis, and inflammatory responses in granulosa cells. Progesterone inhibited the steroidogenic acute regulatory protein and the cholesterol side-chain cleavage enzyme and decreased pregnenolone production. A PGRMC1 inhibitor and a PGRMC1 small interfering RNA ablated these inhibitory effects of progesterone. Interfering with PGRMC1 functions also decreased cellular antioxidative effects induced by an oxidant. These results suggest that PGRMC1 might play a critical role in maintaining the status of granulosa cells and balancing follicle numbers.

Severe pulmonary infection is a major threat to human health accompanied by substantial medical costs, prolonged inpatient requirements, and high mortality rates. New antimicrobial therapeutic strategies are urgently required to address the emergence of antibiotic resistance and persistent bacterial infections. In this study, we show that the constitutive expression of a native antimicrobial peptide LL‐37 in transgenic mice aids in clearing Pseudomonas aeruginosa (PAO1), a major pathogen of clinical pulmonary infection. Orthotopic transplantation of adult mouse distal airway stem cells (DASCs), genetically engineered to express LL‐37, into injured mouse lung foci enabled large‐scale incorporation of cells and long‐term release of the host defense peptide, protecting the mice from bacterial pneumonia and hypoxemia. Further, correlates of DASCs in adult humans were isolated, expanded, and genetically engineered to demonstrate successful construction of an anti‐infective artificial lung. Together, our stem cell‐based gene delivery therapeutic platform proposes a new strategy for addressing recurrent pulmonary infections with future translational opportunities., Using adult distal airway stem cells (DASCs) as a natural vehicle to deliver the antimicrobial peptide LL‐37 into damaged lung, this study reports a technology to restore epithelium barrier and pulmonary innate immunity, which could have applications for the treatment of infectious lung diseases.

Rationale: Donor-derived bacterial infection is a rare cause of morbidity after solid organ transplantation (SOT) but associated with significant morbidity and mortality, deaths caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) infection account for a considerable proportion of postoperation mortality rate in liver and kidney recipients. The arterial rupture as a result of fungal arteritis is occasionally described, while the rupture of graft vascular anastomosis after SOT due to donor-derived CRKP infection is rarely reported. Patients concerns: We reported 1 patient with donor-derived CRKP infection following liver transplantation and 2 patients following renal transplantation (1 liver and 2 kidneys were from the same donor), who experienced sudden abdominal pain and abdominal hemorrhage almost at the same time after organ transplantation. Diagnosis: The patients were diagnosed as graft arteries rupture due to corrosion caused by CRKP infection based on computed tomography scan, blood culture, laparotomy, and pulse-field gel electrophoresis. Interventions: Anti-shock treatment, exploratory laparotomy, broad-spectrum antibiotics, and abdominal puncture and drainage were given. Outcomes: The liver recipient survived as well as the liver graft, still under treatment of multiple abdominal infections. The 2 renal recipients were alive after resection of the renal grafts and underwent hemodialysis. Lessons: Rupture of graft artery should be foreseen when donor-derived CRKP infection was confirmed and broad-spectrum antibiotics and other interventions need to be considered.

To evaluate the efficacy and safety of Chinese medicine (CM) improving pregnancy outcomes after surgery for endometriosis-associated infertility.A multicenter, randomized, double-blind placebo parallel controlled clinical trial was designed. A total of 202 patients who had laparoscopy for endometriosis-associated infertility with qi stagnation and blood stasis syndrome were included and randomly divided into the CM treatment group and placebo control group at a ratio of 1:1 using a central block randomization from May 2014 to September 2017, 101 patients in each group. The two groups received continuous intervention at 1-5 days after surgery, for 6 menstrual cycles. Before ovulation, the CM group was treated Huoxue Xiaoyi Granule (); after ovulation, Bushen Zhuyun Granule ( was involved. The control group was treated with placebo. Transvaginal ultrasonography was performed every menstrual cycle during the treatment, and female hormone levels in the follicular and luteal phases were measured during the 1st, 3rd and 6th menstrual cycles. The analysis was continued until pregnancy. The primary outcomes were clinical pregnancy rate and pregnancy outcome, and the secondary outcomes were follicular development and endometrial receptivity. Safety evaluations were performed before and after treatment.(1) Clinical pregnancy and live birth rates: the clinical pregnancy and live birth rates of the CM group were significantly higher than those of the placebo group [44.6% (45/101) vs. 29.7% (30/101), 34.7% (35/101) vs. 20.8% (21/101), both P0.05]. (2) Follicle development: the incidence of dominant follicles, rate of cumulative cycle ovulation, and rate of cumulative cycle mature follicle ovulation were significantly higher in the CM group than those in the placebo group [93.8% (350/373) vs. 89.5% (341/381), 80.4% (275/342) vs. 69.1% (253/366), 65.8% (181/275) vs 56.1% (142/253), P0.05 or P0.01]). The incidence of cumulative cycle luteinized unruptured follicle syndrome was significantly lower in the CM group than in the placebo group [11.7% (40/342) vs. 17.8% (65/366), P0.05). (3) Endometrial receptivity: after treatment, both endometrial types and endometrial blood flow types in the CM group were mainly types A and B, while those in the placebo group were mainly types B and C, with a significant difference between the two groups (both P0.05). (4) Adverse events: the incidence of adverse events between the two groups was not significantly different (P0.05).Strategies for activating blood circulation-regulating Gan (Liver)-tonifying Shen (Kidney) sequential therapy can effectively improve the clinical pregnancy rate and live birth rate of endometriosis-associated infertility with qi stagnation and blood stasis after laparoscopy, improve follicular development, promote ovulation, improve endometrial receptivity, while being a safe treatment option. (Trial registration No. NCT02676713).

Angiitis-induced critical limb ischemia (AICLI) patients constitute a remarkable proportion of no-option critical limb ischemia (CLI) patients. Stem cell therapy has become an innovative and promising option for no-option CLI patients. As one of these promising stem cell therapies, purified CD34+ cell transplantation (PuCeT) has shown favorable short-term results. However, the long-term efficacy of PuCeT has yet to be reported. This study evaluates the long-term efficacy of PuCeT in AICLI patients. Twenty-seven AICLI patients were enrolled from May 2009 to December 2011. Granulocyte colony-stimulating factor (G-CSF) and enoxaparin sodium were administered for 5 days. On day 5, CD34+ cell isolation was performed, and cells were transplanted by intramuscular injection. The primary endpoint, major-amputation-free survival rate (MAFS), as well as secondary endpoints, such as peak pain-free walking time (PPFWT) and the Wong-Baker FACES pain rating scale score (WFPRSS), were routinely evaluated during the 5-year follow-up period. The endpoints were as follows: the MAFS was 88.89%; PPFWT increased from 3 ± 3 to 17 ± 6 minutes; WFPRSS decreased from 7 ± 2 to 0.3 ± 1.7; the ulcer healing rate was 85.71%; the recurrence rate was 11.11%; and SF-36v2 scores were significantly improved at 5 years after PuCeT. The rate of labor recovery 5 years after PuCeT was 65.38%, and no severe adverse effect was observed during the treatment. PuCeT demonstrated long-term efficacy and durability as a treatment of AICLI not only in achieving limb salvage but also in recovering the labor competence and improving the quality of life of patients.

Background According to the Japanese Esophageal Society (JES) guidelines, early esophageal squamous cell carcinoma (SCC) involving the muscularis mucosae (M3) or upper submucosal (SM1) layers are relative indications for endoscopic submucosal dissection (ESD). Additional esophagectomy or chemoradiotherapy is recommended for patients with relative indications after evaluation. However, elderly patients (≥ 60 years) with relative indications in China often refuse additional treatment because of the debilitating side effects. The aim of this study was to evaluate the long-term outcomes of elderly patients with relative indications who did not undergo additional treatment after ESD. Methods Data from elderly patients with relative indications who underwent ESD for early esophageal SCC between January 2008 and December 2013 were reviewed retrospectively. Stricture and recurrence, and 5-year progression-free survival (PFS) and overall survival rates were compared with patients with absolute indications for ESD. Results 158 elderly patients were included and analyzed (89 in the absolute indications group and 69 in the relative indications group). The baseline characteristics were balanced between the two groups. During 56 months (range 1 – 108) of follow-up, the postoperative stricture rates were similar in the absolute and relative indications groups (21.3 % vs. 31.9 %; P = 0.13). The hazard ratio (HR) for PFS in the absolute vs. the relative indications groups was 1.025 (95 % confidence interval [CI] 0.36 – 2.95; P = 0.96). The 5-year PFS rates were 90.5 % (95 %CI 83.44 – 97.56) and 90.8 % (95 %CI 83.74 – 97.86) for the absolute and relative indications groups, respectively. The HR for overall survival in the absolute vs. the relative indications groups was 0.564 (95 %CI 0.13 – 2.52; P = 0.45). The 5-year overall survival rates were 96.6 % (95 %CI 92.88 – 100) and 95.6 % (95 %CI 90.70 – 100) for the absolute and relative indications groups, respectively. Conclusions Based on this study, regular follow-up without additional treatment may be considered as another choice for elderly patients with early esophageal SCC and relative indications after ESD.

Background and Aims Endoscopic and histological healing are associated with improved clinical outcomes in ulcerative colitis [UC]. We aimed to investigate the predictive value of faecal immunochemical test [FIT] for endoscopic and histological healing in UC. Methods We measured quantitative FIT and faecal calprotectin [FC] in 140 consecutive UC patients who underwent colonoscopy. We assessed the diagnostic accuracy of FIT for predicting endoscopic healing using the Mayo endoscopic subscore [MES 0/1] and for histological healing using the Geboes score [< 2.0] and Nancy index [grade ≤ 1]. The predictive abilities of FIT were compared with those of FC. Results FIT had an area under the curve [AUC] of 0.77 (95% confidence interval [CI] 0.67-0.86, p < 0.001) for endoscopic healing, an AUC of 0.77 [95% CI 0.67-0.86, p < 0.001] using the Geboes score, and 0.77 [95% CI 0.66-0.85, p < 0.001] using the Nancy Index for histological healing. The AUC of FIT was comparable to that of FC for endoscopic healing [p = 0.773] and histological healing [p = 0.767-0.960], and was comparable to colonoscopy for histological healing [p = 0.384-0.673]. FIT < 50 ng/ml predicted endoscopic healing with a sensitivity, specificity, and positive predictive value [PPV] of 72%, 68%, and 82%, respectively, and for histological healing with a sensitivity, specificity, and PPV of 73-75%, 67%, and 78-80%, respectively. Combining FIT with FC led to a higher specificity [90%] for histological healing. Over 85% of patients with FIT < 50 ng/ml and FC < 50 μg/g achieved histological healing. Conclusions FIT is highly sensitive and accurate to predict endoscopic and histological healing in UC. It represents a promising non-invasive tool for monitoring mucosal healing in UC.

Objective To evaluate the etiologies for dense vitreous hemorrhage in adults with non-traumatic and reveal management of early vitrectomy for the disease. Methods Study included 105 eyes from 105 patients. Outcome measures were etiologies of vitreous hemorrhage, formation of retinal and/or disk neovascular membrane (NVM), incidence of retinal tear and detachment, visual acuity (VA) and postoperative complications. Results Mean time between presentation and surgery was 7.1 days. The most common etiologies were retinal vein occlusion (RVO) (58.1%), retinal tear (22.9%) and retinal vasculitis (10.4%). Most RVO (77.0%) and retinal vasculitis (72.7%) eyes were associated with retinal and/or disk NVM. Retinal tear and retinal detachment was found in 24 and 48 eyes, respectively. VA improved significantly from 1/70 to 0.6 following vitrectomy. The most common postoperative complication was cataract (28.6%). Conclusion RVO, retinal tear and retinal vasculitis were the most common causes of dense vitreous hemorrhage. Early vitrectomy has a good outcome with acceptable complication rates in this setting.

A diploid genome is necessary for normal mammalian development, thus haploid parthenogenetic embryos undergo frequent self-diploidization during preimplantation development; however, the underlying mechanism is unclear. In this study, time-lapse recording revealed that human haploid parthenotes (HPs) undergo self-diploidization via failed cytokinesis (FC) and endomitosis (EM). The frequencies of FC/EM were significantly higher in HPs than in normal fertilized embryos (26.3% vs. 1.6%, P vs. 0, P in situ hybridization of chromosome 16,18 and X in HPs identified diploid recovery after the appearance of FC/EM, and FC/EM HPs showed improved blastocyst formation compared with non-FC/EM HPs (18.8% and 40.0% vs. 15.4%, P > 0.05). In 66.7% of the 1-cell stage HPs, furrow ingression was not observed during the time for normal cleavage, and both immunostaining and gene expression analysis of 1-cell stage HPs revealed the absence or down-regulation of several key genes of the Rho pathway, which regulates cytomitosis. Our results suggested that the major mechanism for self-diploidization is Rho pathway inhibition leading to FC/EM in the first cell cycle, and fine-tuning of this signalling pathway may help to generate stable haploid embryos for stem cell biology studies.

To retrospectively investigate the clinicopathological features and prognosis of early esophageal squamous cell neoplasm (ESCN) treated with endoscopic resection (ER), especially, to compare the prognosis in patients with sm2 cancer and non-sm2 cancer. From 2007 to 2013, 368 patients were included in our analysis. The patients were 252 (68.5 %) men and 116 (31.5 %) women with a median age of 61 (range 16–84 years) years. Hyperplasia, mild dysplasia, moderate dysplasia, severe dysplasia, m1, m2, m3, sm1, and sm2 were diagnosed in 47 (12.8 %), 27 (7.3 %), 34 (9.2 %), 61 (16.6 %), 54 (14.7 %), 38 (10.3 %), 63 (17.1 %), 12 (3.3 %), and 32 (8.7 %) cases. The mean (range) follow-up time was 29 (0–84) months. The cumulative overall 1-, 3-, and 5-year metachronous esophageal lesion rates were 4.1, 12.9, and 32.6 %. The incidence of lymph node or distant metastasis was 1.54 % in m3, 6.25 % in sm2, and 0 in other subgroups. The overall 1-, 3-, and 5-year survival rates were 99.5, 97.3, and 87.5 %. There was significant difference between sm2 and non-sm2 patients in metastatic rate (P = 0.021); however, no difference existed between m3 patients and sm2 patients (P = 0.252). The difference of metachronous esophageal lesion (P = 0.401) and survival (P = 0.634) between sm2 and non-sm2 patients was not obvious. Our study showed that ER was an effective and relatively safe treatment for superficial ESCN. ER is still appropriate in select sm2 patients. To monitor the second primary cancer in sm2 is necessary during the follow-up.

Cholecystectomy is a risk factor for insulin resistance and diabetes, but the association between cholecystectomy and insulin release/sensitivity remains obscure. We investigated the association between cholecystectomy and the factors related to glycemia and glucose tolerance.A cross-sectional study was conducted in 2011 with 10,027 participants aged ≥40 in Nanjing, China. After applying exclusion criteria, 8,030 participants were divided into three groups: 1, without gallbladder disease (n = 6783); 2, with gallbladder disease but without cholecystectomy (n = 857); and 3, with cholecystectomy (n = 390).Various indexes of blood glucose and insulin level after the oral glucose tolerance test (OGTT) were assessed. The association between gallbladder disease or cholecystectomy and diabetes was evaluated with logistic regression models. Group 3 had a higher prevalence of newly diagnosed diabetes by OGTT criteria compared with groups 2 and 1, respectively (20.5% vs. 12.4% vs. 10.6%, P 0.001). The adjusted odds ratio and 95% confidence interval of diabetes associated with cholecystectomy were 1.546 (1.168, 2.046) (P = 0.002). Pattern 2, which was characterized by a lasting late insulin response, was more frequent in group 3 compared with groups 2 and 1, respectively (61.0% vs. 54.3% vs.48.3%, P 0.001). After adjusting for confounding factors, a higher total insulin release and lower Matsuda insulin sensitivity index (P 0.001) were found in group 3 compared with the other two groups.Cholecystectomized subjects demonstrated a higher prevalence of diabetes characterized by lower peripheral insulin sensitivity and higher total insulin release.

Gender-nonconforming (GN) children are often perceived less positively, which may harm their well-being. We examined the development of such perceptions and an intervention to modify them. Chinese children's appraisals were assessed using multiple measures (verbal responses, sharing, and rank order task) after viewing vignettes of gender-conforming (GC) and GN hypothetical peers. In Study 1, children (N = 210; 4-, 5-, 8-, and 9-year-olds) were less positive toward GN than GC peers, especially if they were older or if the peers were boys. In Study 2 (N = 211, 8- and 9-year-olds), showing children exemplars of GN peers who displayed positive and GC characteristics subsequently reduced bias against gender nonconformity. These findings inform strategies aimed at reducing bias against gender nonconformity.

Objective: This study was performed to explore the effects of probucol on contrast-induced acute kidney injury (CIAKI) in patients with coronary heart disease undergoing percutaneous coronary intervention (PCI). Methods: In total, 220 patients undergoing PCI were randomly assigned to either the control group (hydration from 12 hours before to 12 hours after contrast administration; n = 110) or the probucol group (hydration plus probucol 500 mg twice daily 1 day before and 3 days after the operation; n = 110). The primary endpoint was the occurrence of serum creatinine (Scr)-based CIAKI, defined as an absolute increase in Scr by 0.5 mg/dl (44.2 μmol/L) or a relative 25% increase from baseline within 48 to 72 hours after exposure to contrast medium. The secondary outcomes were composite variations in Scr, blood urea nitrogen (BUN), creatinine clearance rate (Ccr) within 48 to 72 hours, and major adverse events during hospitalization or the 7-day follow-up period after PCI. Results: The overall incidence of Scr-based CIAKI was 7.3% (16/220): 5.5% (6/110) in the control group and 9.1% (10/110) in the probucol group (χ2 = 1.078, P = .298). There were no significant differences in the occurrence rate of major adverse events during hospitalization or the 7-day follow-up period after PCI between the groups. Multivariate logistic regression analysis showed that probucol was not an independent protective factor for CIAKI (odds ratio, 1.825; 95% confidence interval, 0.639–5.212; P = .261). However, hydration was an independent protective factor (odds ratio, 0.997; 95% confidence interval, 0.995–0.999; P = .004). Conclusion: Probucol cannot effectively reduce the incidence of CIAKI through its anti-inflammatory and antioxidative stress effects.

Purpose This study is designed to develop a Chinese version of the Diabetes Strengths and Resilience Measure for Adolescents (DSTAR-Teen) and evaluate its psychometric characteristics. Design and methods One hundred and twenty adolescents with type 1 diabetes (Mean age = 16.3 ± 5.1, 51.7% male, Mean HbA1c = 7.6 ± 2.2%) were enrolled from one national endocrine center in China. Participants were administered with the DSTAR-Teen and the related psychosocial instruments to evaluate the reliability and validity. The DSTAR-Teen was adapted into Chinese version prior to data collection. Results The Chinese DSTAR-Teen demonstrated adequate reliability (Cronbach's α coefficients = 0.90, intraclass correlation coefficient = 0.98). A minimum detectable change at the 95% confidence level was 5.8 points. In exploratory and confirmatory factorial analyses, a three-factor structure emerged with a variance of 67.4%, demonstrating construct validity. Moreover, resilience was significantly associated with glycated hemoglobin, diabetes distress and self-care behavior as hypothesized, further supporting validity. Conclusion The Chinese version of the DSTAR-Teen is a psychometrically sound instrument that may capture the adaptive attitudes and behaviors associated with diabetes management. Practice implications This scale can be used in both clinical and research settings with the aim of identifying diabetes specific strengths and improving the health outcomes in adolescents with type 1 diabetes.