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Background & aims Nonalcoholic fatty liver disease (NAFLD) is a key component of metabolic syndrome ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and is now becoming the leading cause of cirrhosis and hepatocellular carcinoma worldwide. However, due to the complex and unclear pathophysiological mechanism, there are no specific approved agents for treating NASH. Breviscapine, a natural flavonoid prescription drug isolated from the traditional Chinese herb Erigeron breviscapus, exhibits a wide range of pharmacological properties, including effects on metabolism. However, the anti-NASH efficacy and mechanisms of breviscapine have not yet been characterized. Approach & results We evaluated the effects of breviscapine on the development of hepatic steatosis, inflammation and fibrosis in vivo and in vitro under metabolic stress. Breviscapine treatment significantly reduced lipid accumulation, inflammatory cell infiltration, liver injury and fibrosis in mice fed a high-fat diet (HFD), a high-fat/high-cholesterol (HFHC) diet, or a methionine- and choline-deficient (MCD) diet. In addition, breviscapine attenuated lipid accumulation, inflammation and lipotoxicity in hepatocytes undergoing metabolic stress. RNA sequencing and multiomics analyses further indicated that the key mechanism linking the anti-NASH effects of breviscapine was inhibition of TAK1 phosphorylation and the subsequent MAPK signaling cascade. Treatment with the TAK1 inhibitor 5Z-7-oxozeaenol abrogated breviscapine-mediated hepatoprotection under metabolic stress. Molecular docking illustrated that breviscapine directly bound to TAK1. Conclusion Breviscapine prevents metabolic stress-induced NASH progression through direct inhibition of TAK1 signaling. Breviscapine might be a novel therapeutic candidate for the treatment of NASH.

Patients with persistent ulcerative colitis (UC) are at a higher risk of developing colitis-associated cancer (CAC). Previous studies have reported that intestinal microbiota disturbance plays an important role in the process of CAC development in patients with UC, indicating that targeted intervention of intestinal microbiota and its metabolites may be a potential therapeutic strategy. Gut microbiota in the process of colorectal cancer development in UC patients was analyzed using the gutMEGA database and verified in fecal samples. The abundance of Bacteroides fragilis reduced significantly in the process of colitis associated cancer development. Broad-spectrum antibiotics (BSAB) intervene with the intestinal microbiota of mice and accelerate the process of colon cancer development. However, gavage transplantation with B. fragilis can effectively reverse the effects of BSAB. In the intestinal tract, B. fragilis promotes the secretion of short-chain fatty acids (SCFAs). Subsequently, SCFAs, especially butyrate, negatively regulate the inflammatory signaling pathway mediated by NLRP3 to inhibit the activation of macrophages and the secretion of proinflammatory mediators such as IL-18 and IL-1β, reducing the level of intestinal inflammation and restricting CAC development. In conclusion, colonization with B. fragilis has been shown to be effective in ameliorating intestinal epithelial damage caused by chronic inflammation and preventing the development of colonic tumors. Thus, it can be a therapeutic intervention strategy with good clinical application prospects.

BACKGROUND Jaundice is a major manifestation of posthepatectomy liver failure, a feared complication after hepatic resection. Herein, we report a case of posthepatectomy jaundice that was not caused by liver failure but by paroxysmal nocturnal hemoglobinuria (PNH)-induced hemolysis. CASE SUMMARY A 56-year-old woman underwent right hepatectomy and biliary tract exploration surgery due to hepatic duct stones. Prior to surgery, the patient was mildly anemic. The direct antiglobulin test was negative. A bone marrow biopsy showed mild histiocyte hyperplasia. After surgery, the patient suffered a progressive increase in serum bilirubin. Meanwhile, the patient developed hemolytic symptoms after blood transfusion. She was ultimately diagnosed with PNH. PNH is a rare bone marrow failure disorder that manifests as complement-dependent intravascular hemolysis with varying severity. After steroid treatment, the patient’s jaundice gradually decreased, and the patient was discharged on the 35th postoperative day. CONCLUSION PNH-induced hemolysis is a rare cause of posthepatectomy jaundice. It should be suspected in patients having posthepatectomy hyperbilirubinemia without other signs of liver failure. Steroid therapy can be considered for the treatment of PNH in such cases.

The human microbiome has a role in the development of multiple diseases. Individual microbiome profiles are highly personalized, though many species are shared. Understanding the relationship between the human microbiome and disease may inform future individualized treatments. We hypothesize the blood microbiome signature may be a surrogate for some lung microbial characteristics. We sought associations between the blood microbiome signature and lung-relevant host factors. Based on reads not mapped to the human genome, we detected microbial nucleic acids through secondary use of peripheral blood RNA-sequencing from 2,590 current and former smokers with and without chronic obstructive pulmonary disease (COPD) from the COPDGene study. We used the Genome Analysis Toolkit (GATK) microbial pipeline PathSeq to infer microbial profiles. We tested associations between the inferred profiles and lung disease relevant phenotypes and examined links to host gene expression pathways. We replicated our analyses using a second independent set of blood RNA-seq data from 1,065 COPDGene study subjects and performed a meta-analysis across the two studies. The four phyla with highest abundance across all subjects were Proteobacteria, Actinobacteria, Firmicutes and Bacteroidetes. In our meta-analysis, we observed associations (q-value Acinetobacter, Serratia, Streptococcus and Bacillus inferred abundances and Modified Medical Research Council (mMRC) dyspnea score. Current smoking status was associated (q Acinetobacter, Serratia and Cutibacterium abundance. All 12 taxa investigated were associated with at least one white blood cell distribution variable. Abundance for nine of the 12 taxa was associated with sex, and seven of the 12 taxa were associated with race. Host-microbiome interaction analysis revealed clustering of genera associated with mMRC dyspnea score and smoking status, through shared links to several host pathways. This study is the first to identify a bacterial microbiome signature in the peripheral blood of current and former smokers. Understanding the relationships between systemic microbial signatures and lung-related phenotypes may inform novel interventions and aid understanding of the systemic effects of smoking.

Steroid receptor coactivators (SRCs) possess specific and distinct oncogenic roles in the initiation of cancer and in its progression to a more aggressive disease. These coactivators interact with nuclear receptors and other transcription factors to boost transcription of multiple genes, which potentiate cancer cell proliferation, migration, invasion, tumor angiogenesis and epithelial–mesenchymal transition (EMT). Targeting SRCs using small molecule inhibitors (SMIs) is a promising approach to control cancer progression and metastasis. By high-throughput screening analysis, we recently identified SI-2 as a potent SRC SMI. To develop therapeutic agents, SI-10 and SI-12, the SI-2 analogs are synthesized that incorporate the addition of F atoms to the SI-2 chemical structure. As a result, these analogs exhibit a significantly prolonged plasma half-life, minimal toxicity and improved hERG activity. Biological functional analysis showed that SI-10 and SI-12 treatment (5–50 nM) can significantly inhibit viability, migration and invasion of breast cancer cells in vitro and repress the growth of breast cancer PDX organoids. Treatment of mice with 10 mg/kg/day of either SI-10 or SI-12 was sufficient to repress the growth of xenograft tumors derived from MDA-MB-231 and LM2 cells. Furthermore, in spontaneous and experimental metastasis mouse models developed from MDA-MB-231 and LM2 cells, respectively, SI-10 and SI-12 effectively inhibited the progression of breast cancer lung metastasis. These results demonstrate that SI-10 and SI-12 are promising therapeutic agents and are specifically effective in blocking tumor metastasis, a key point in tumor progression to a more lethal state that results in patient mortality in the majority of cases.

Relationships among autonomic nervous system, diabetes and metabolic syndrome.

Yadi Zhu,1,2,* Lingling Dai,1,2,* Hongru Zhao,3,* Boan Ji,4 Yang Yu,1,2 Hui Dai,1,2 Chunhong Hu,1,2 Ximing Wang,1,2 Jun Ke1,2 1Department of Radiology, The First Affiliated Hospital of Soochow University, Soochow, Jiangsu Province, People’s Republic of China; 2Institute of Medical Imaging, Soochow University, Soochow, Jiangsu Province, People’s Republic of China; 3Department of Neurology, The First Affiliated Hospital of Soochow University, Soochow, Jiangsu Province, People’s Republic of China; 4Medical School of Soochow University, Soochow, Jiangsu Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ximing Wang; Jun KeDepartment of Radiology, The First Affiliated Hospital of Soochow University, No. 188 Shizi Road, Soochow, 215000, Jiangsu Province, People’s Republic of ChinaTel +86-512-67973062Fax +86-512-67973061Email wangximing1998@163.com; fmrikej@126.comPurpose: Neuroimaging studies on migraine have revealed structural and functional alterations in the hippocampus, a region involved in pain processing and stress response. This study was designed to investigate whether effective connectivity of this region is disrupted in migraine and relates to chronicity of this disease.Patients and Methods: In 39 episodic migraine (EM) patients, 17 chronic migraine (CM) patients, and 35 healthy controls, we investigated differences in the directional influences between the hippocampus and the rest of the brain by combining resting-state functional magnetic resonance imaging and Granger causality analysis (GCA), with bilateral hippocampus as seed regions. The associations between directional influences and the clinical variables were also examined.Results: Comparing each patient group to the control group, we found increased and decreased negative influence on the hippocampus exerted by the bilateral visual areas and right dorsolateral prefrontal cortex (dlPFC), respectively. The hippocampus showed increased positive influence on the right posterior insula and medial prefrontal cortex (mPFC), as well as increased negative influence on the left cerebellum in CM patients relative to EM patients and healthy controls. Furthermore, across all patients, the migraine frequency exhibited a positive and negative association with causal influence from the hippocampus to mPFC and left cerebellum, respectively.Conclusion: Migraine patients have abnormal effective connectivity between the hippocampus and multiple brain regions involved in the sensory and cognitive processing of pain. Disrupted directional influences to the hippocampus exerted by dlPFC and bilateral visual areas were common features of EM and CM patients. Directional influences from the hippocampus to mPFC and left cerebellum may be useful imaging biomarkers for assessing migraine frequency.Keywords: migraine, hippocampus, effective connectivity, resting-state, functional magnetic resonance imaging

Background Aggressive malignant primary orbital tumors are extremely rare in newborns. The current cases further clarify the clinical features of malignant primary orbital tumors in neonates. Case summary At the time of presentation at the Seventh Center of People's Liberation Army General (PLAG) Hospital, the children were 1-, 2- and 5-mo-old, respectively, and included 2 boys and 1 girl. All three cases had unilateral proptosis at birth, and underwent mass excision and histopathologic examination. A peripheral primary neuroectodermal tumor, an aggressive infantile fibromatosis and an embryonic rhabdomyosarcoma were diagnosed, respectively. The first case underwent routine chemotherapy following surgery but died within three months due to worsening condition as the tumor spread throughout the body. The other two children were treated by surgery, and at the follow-up visits 6 mo and 1 year after surgery, respectively, the wound was completed healed, and they had normal growth and development without radiotherapy or chemotherapy. A review of highly uncommon orbital tumors in newborns is also provided. Conclusion Malignant primary tumors should be considered in the presence of unilateral proptosis in newborns.

Yang Yu,1,* Wenfeng Wang,2,* Zuquan Xiong,3 Zhenyu Yang,1 Jun Li,1 Yifan Shen,1 Bin Gu1 1Urology Department, Shanghai Pudong New Area People’s Hospital, Shanghai, People’s Republic of China; 2Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, People’s Republic of China; 3Urology Department, Shanghai Huashan Hospital, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bin GuUrology Department, Shanghai Pudong New Area People’s Hospital, 490 Chuanhuan South Road, Shanghai, 201200, People’s Republic of ChinaTel/Fax +86-2120509000Email ibippan3998@163.comPurpose: This study aimed to compare perioperative outcomes of open partial nephrectomy (OPN) and laparoscopic partial nephrectomy (LPN) from a retrospective single-center dataset.Patients and Methods: A retrospective single-center analysis of 210 patients who underwent open (n=91) or laparoscopic (n =119) partial nephrectomy for RCC was conducted between 2012 and 2015. All patients were grouped into low complexity, moderate complexity, and high complexity according to the R.E.N.A.L. Nephrometry Score, respectively. The rates of intraoperative and postoperative complications estimated blood loss, warm ischemia time, operative time, conversion of laparoscopic procedure to open surgery, and postoperative length of stay were assessed for both procedures.Results: In low complexity group (n=93), patients undergoing LPN (n=52) under ischemia conditions had significantly longer renal artery clamp time (p < 0.001) and operative time (p = 0.001) compared with OPN (n=41). However, patients undergoing LPN had a significantly less postoperative length of stay (p=0.005) and estimated blood loss (p < 0.001) compared with OPN. There was no statistically significant difference in the rates of complications between LPN and OPN. In the moderate complexity group (n=114), 67 and 47 patients underwent LPN and OPN, respectively. LPN had notably longer warm ischemia time (p < 0.001) and operative time (p < 0.001) compared with OPN. There were no statistically significant differences in the rates of complications, estimated blood loss, and postoperative length of stay between LPN and OPN. In the high complexity group (n=3), all patients underwent OPN.Conclusion: OPN and LPN procedures performed in patients with low and moderate complexity tumors based on the RENAL Nephrometry score offer acceptable and comparable results. When applied to low complexity tumors, our data suggest that laparoscopic NSS is an effective, minimally invasive therapeutic approach with the advantages of less blood loss, earlier hospital discharge, and more rapid convalescence.Keywords: renal cell carcinoma, open partial nephrectomy, laparoscopic partial nephrectomy, R.E.N.A.L. Nephrometry Score

BackgroundInfertility is a widespread global challenge. Currently, the most effective treatment strategy for infertility is in vitro fertilization (IVF), which is an assisted reproductive technique (ART). The use of IVF for assisted pregnancy dates back to the last 41 years when the first IVF baby was born. During IVF, many oocytes are obtained in an IVF cycle, and more than one embryo is formed. Subsequently, frozen-thawed embryo transfer (FET) is increasingly being used in IVF cycles for women in whom a fresh embryo transfer fails to result in a pregnancy, or in those who return for a second baby. However, the pregnancy success rates following FET treatment cycles are reportedly lower than in fresh embryo transfers. Therefore, recent related studies are increasing determining mechanisms of improving the sustained pregnancy rate of FET and reducing the rate of early abortion.The Gushen’antai pill (GSATP), which contains a mixture of 10 herbs, has been widely used in traditional Chinese medicine (TCM) as a pharmacological option to prevent miscarriage. However, randomized controlled trials (RCT) have never been conducted to provide high-level clinical evidence on the clinical efficacy of GSATP. The objective of this study is to investigate the effect of GSATP of hormone therapy (HT) FET cycles on pregnancy rate.MethodsA total of 300 subjects aged between 18 and 40 years which prepared for HT cycle FET will be enrolled in the study. The patients were from five different hospitals, with 60 patients from each hospital. Patients were randomly divided into two groups, and medication was started on the day of endometrial transformation. After FET 28 days, B-ultrasound was done to determine whether to continue the medication. Baseline assessments were carried out before the trial and outcomes were collected 4, 6, 8, 10, and 12 weeks of each gestational cycle.DiscussionDifferences in ongoing pregnancy rate, clinical pregnancy rate, implantation rate, and threatened abortion rate between the two groups will be statistically analyzed. We can finally have an objective evaluation of the efficacy of the traditional Chinese medicine Gushen’antai pills.Trial registrationChiCTR1900026737. Registered October 20, 2019.

A biological research framework to define Alzheimer’ disease with dichotomized biomarker measurement was proposed by National Institute on Aging–Alzheimer’s Association (NIA–AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic 18F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline 18F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal β-amyloid in neocortical regions but prompt cognitive decline by interacting with β-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer’s disease could be illustrated with biomarker measurement under NIA–AA framework. Clinical–neuroimaging–neuropathological studies in other cohorts are needed to validate these findings.

Background and aims Nonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis (NASH), has become a major cause of liver transplantation and liver-associated death. NASH is the hepatic manifestation of metabolic syndrome and is characterized by hepatic steatosis, inflammation, hepatocellular injury, and different degrees of fibrosis. However, there is no US Food and Drug Administration-approved medication to treat this devastating disease. Therapeutic activators of the AMP-activated protein kinase (AMPK) have been proposed as a potential treatment for metabolic diseases such as NASH. Cordycepin, a natural product isolated from the traditional Chinese medicine Cordyceps militaris, has recently emerged as a promising drug candidate for metabolic diseases. Approach and results We evaluated the effects of cordycepin on lipid storage in hepatocytes, inflammation, and fibrosis development in mice with NASH. Cordycepin attenuated lipid accumulation, inflammation, and lipotoxicity in hepatocytes subjected to metabolic stress. In addition, cordycepin treatment significantly and dose-dependently decreased the elevated levels of serum aminotransferases in mice with diet-induced NASH. Furthermore, cordycepin treatment significantly reduced hepatic triglyceride accumulation, inflammatory cell infiltration, and hepatic fibrosis in mice. In vitro and in vivo mechanistic studies revealed that a key mechanism linking the protective effects of cordycepin were AMPK phosphorylation-dependent, as indicated by the finding that treatment with the AMPK inhibitor Compound C abrogated cordycepin-induced hepatoprotection in hepatocytes and mice with NASH. Conclusion Cordycepin exerts significant protective effects against hepatic steatosis, inflammation, liver injury, and fibrosis in mice under metabolic stress through activation of the AMPK signaling pathway. Cordycepin might be an AMPK activator that can be used for the treatment of NASH.

Comprehensive investigations on the incidence and prognosis of pituitary tumors are still lacking. The present study aims to summarize the incidence, demographics, and survival outcome of pituitary adenoma on a population-based level. This study includes all pituitary adenomas reported in the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2016 in the United States. Extensive clinical and demographic characteristics were extracted and submitted to group comparisons. The standardized incidence rate was calculated and stratified by year at diagnosis, age/sex and age/treatment groups. The Kaplan–Meier analysis and multivariable regressions were performed to identify the factors associated with overall survival. A total of 47,180 pituitary tumors were identified, including 47,030 typical adenomas, 111 uncertain behavior pituitary adenomas, and 39 pituitary carcinomas. The overall standardized incidence rate was 4.8 cases per 100,000 person-years and the annual incidence rate continually trended upwards, with a peak seen in 2015. We noticed a bimodal age-related distribution in females and a unimodal distribution in males. In the multivariate regression analysis, the factors associated with prolonged survival included typical adenoma, younger age, and smaller tumor size. Whereas, black and male patients had worse overall survival. Our study provides a reliable estimate on the incidence of pituitary adenoma and confirms that the annual standardized incidence rate is increasing. Pituitary adenomas have a satisfactory long-term prognosis and age, tumor size, and tumor subtypes are related to overall survival. Though statistically significant, our inferential findings should be constrained within the limitations of SEER database.

Purpose To investigate the relationship between obstructive sleep apnea (OSA) severity and high-sensitivity C-reactive protein (Hs-CRP), and their respective impact on the clinical outcomes in patients undergoing off-pump cardiac artery bypass grafting (OPCABG). Methods We enrolled consecutive eligible patients listed for elective OPCABG who underwent cardiorespiratory polygraphy before surgery between January 2019 and December 2019 in this prospective observational single-center study. Baseline, intraoperative, and postoperative clinical data were compared between absent-mild and moderate-severe OSA groups. Regression analysis investigated the relationship between Hs-CRP level and severity of OSA, and further assessed the factors influencing postoperative atrial fibrillation, duration of hospitalization, and hospital cost. Results Patients with moderate-severe OSA accounted for 42.3% (52/123) of the cohort. Partial pressure of carbon dioxide (PCO2), Hs-CRP, apnea hypopnea index (AHI), mean apnea time, maximum apnea time, and oxygen desaturation index ODI ≥ 3% were significantly higher in the moderate-severe OSA group than in the absent-mild OSA group. Left ventricle ejection fraction (LVEF), lowest arterial oxygen saturation (SaO2), and mean SaO2 were significantly lower in the moderate-severe OSA group. Moderate-severe OSA was associated with elevated Hs-CRP level (OR = 2.356, 95% CI 1.101–5.041, P = 0.027). Hs-CRP was an independent risk factor for post-CABG atrial fibrillation (POAF) (OR = 1.212, P = 0.01). Hs-CRP level independently correlated with duration of hospitalization (B = 0.456, P = 0.001) and hospital cost (B = 1.111, P = 0.044). Conclusion Hs-CRP level was closely related to OSA severity and have potential utility in predicting POAF, duration of hospitalization, and hospital costs in patients undergoing OPCABG.

Background Deep brain stimulation (DBS) has proved effective for Parkinson’s disease (PD), but the identification of stimulation parameters relies on doctors’ subjective judgment on patient behavior. Methods Five PD patients performed 10-meter walking tasks under different brain stimulation frequencies. During walking tests, a wearable functional near-infrared spectroscopy (fNIRS) system was used to measure the concentration change of oxygenated hemoglobin (△HbO2) in prefrontal cortex, parietal lobe and occipital lobe. Brain functional connectivity and global efficiency were calculated to quantify the brain activities. Results We discovered that both the global and regional brain efficiency of all patients varied with stimulation parameters, and the DBS pattern enabling the highest brain efficiency was optimal for each patient, in accordance with the clinical assessments and DBS treatment decision made by the doctors. Conclusions Task fNIRS assessments and brain functional connectivity analysis promise a quantified and objective solution for patient-specific optimization of DBS treatment. Trial registration Name: Accurate treatment under the multidisciplinary cooperative diagnosis and treatment model of Parkinson’s disease. Registration number is ChiCTR1900022715. Date of registration is April 23, 2019.

Rationale: The conserved long non-coding RNA (lncRNA) myocardial infarction associate transcript (Miat) was identified for its multiple single-nucleotide polymorphisms that are strongly associated with susceptibility to MI, but its role in cardiovascular biology remains elusive. Here we investigated whether Miat regulates cardiac response to pathological hypertrophic stimuli. Methods: Both an angiotensin II (Ang II) infusion model and a transverse aortic constriction (TAC) model were used in adult WT and Miat-null knockout (Miat-KO) mice to induce pathological cardiac hypertrophy. Heart structure and function were evaluated by echocardiography and histological assessments. Gene expression in the heart was evaluated by RNA sequencing (RNA-seq), quantitative real-time RT-PCR (qRT-PCR), and Western blotting. Primary WT and Miat-KO mouse cardiomyocytes were isolated and used in Ca2+ transient and contractility measurements. Results: Continuous Ang II infusion for 4 weeks induced concentric hypertrophy in WT mice, but to a lesser extent in Miat-KO mice. Surgical TAC for 6 weeks resulted in decreased systolic function and heart failure in WT mice but not in Miat-KO mice. In both models, Miat-KO mice displayed reduced heart-weight to tibia-length ratio, cardiomyocyte cross-sectional area, cardiomyocyte apoptosis, and cardiac interstitial fibrosis and a better-preserved capillary density, as compared to WT mice. In addition, Ang II treatment led to significantly reduced mRNA and protein expression of the Ca2+ cycling genes Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) and ryanodine receptor 2 (RyR2) and a dramatic increase in global RNA splicing events in the left ventricle (LV) of WT mice, and these changes were largely blunted in Miat-KO mice. Consistently, cardiomyocytes isolated from Miat-KO mice demonstrated more efficient Ca2+ cycling and greater contractility. Conclusions: Ablation of Miat attenuates pathological hypertrophy and heart failure, in part, by enhancing cardiomyocyte contractility.

IL-6 is reported to be the main upstream activator, instead of the downstream target of JAK2/STAT3. This study is intended to explore the correlation of IL-6 and JAK2/STAT3 signaling pathway with clinicopathological features and prognosis in nasopharyngeal carcinoma (NPC). First, NPC tissues and normal nasopharyngeal epithelial tissues were obtained from 117 NPC patients. Next, we detected expression levels of IL-6 in serum and those of STAT3, p-STAT3, JAK2, p-JAK2 and CyclinD1 in tissues. A follow-up was conducted in all the patients and the survival was analyzed. To verify the correlation of IL-6 and JAK2/STAT3 pathway, CNE-1 and SUNE1 NPC cells were interpreted with IL-6 and JAK2/STAT3 signaling pathway inhibitor AG490 to detect cell viability, migration and invasion. We observed thatIL-6 increased in serum of NPC patients. The expressions of IL-6, STAT3, p-STAT3, JAK2, p-JAK2 and CyclinD1 in NPC tissues were higher and correlated with TNM stage and lymph node metastasis (LNM). Survival rates were reduced in patients with positive expressions of IL-6, STAT3, p-STAT3, JAK2, p-JAK2 and CyclinD1. LNM and positive expressions of IL-6 and p-STAT3 were risk factors for poor prognosis of NPC. Besides, recombinant human IL-6 promoted cell proliferation, invasion and migration while AG490 inhibited cell proliferation, invasion and migration in CNE-1 and SUNE1 NPC cells. The results demonstrated that increased IL-6 expression and the activated JAK2/STAT3 signaling pathway had effects on prognosis and reduced the survival time in NPC patients, which provide a potential target for the treatment of NPC.

Background:. Andersson lesions (ALs) are not uncommon in ankylosing spondylitis (AS). Plain radiography (PR) is widely used for the diagnosis of ALs. However, in our practice, there were some ALs in AS patients that could not be detected on plain radiographs. This study aimed to propose the concept of occult ALs and evaluate the prevalence and radiographic characteristics of the occult ALs in AS patients. Methods:. A total of 496 consecutive AS patients were admitted in the Affiliated Drum Tower Hospital, Medical School of Nanjing University between April 2003 and November 2019 and they were retrospectively reviewed. The AS patients with ALs who met the following criteria were included for the investigation of occult ALs: (1) with pre-operative plain radiographs of the whole-spine and (2) availability of pre-operative computed tomography (CT) and/or magnetic resonance imaging (MRI) of the whole-spine. The occult ALs were defined as the ALs which were undetectable on plain radiographs but could be detected by CT and/or MRI. The extensive ALs involved the whole discovertebral junction or manifested as destructive lesions throughout the vertebral body. Independent-samples t test was used to compare the age between the patients with only occult ALs and those with only detectable ALs. Chi-square or Fisher exact test was applied to compare the types, distribution, and radiographic characteristics between detectable and occult ALs as appropriate. Results:. Ninety-two AS patients with a mean age of 44.4 ± 10.1 years were included for the investigation of occult ALs. Twenty-three patients had occult ALs and the incidence was 25% (23/92). Fifteen extensive ALs were occult, and the proportion of extensive ALs was significantly higher in detectable ALs (97% vs. 44%, χ2 = 43.66, P

Chenlu Liang, Liuyi Li, Meizhen Zhu, Jiejie Hu, Yang Yu Department of Breast Tumor Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, People’s Republic of ChinaCorrespondence: Yang YuDepartment of Breast Tumor Surgery, Zhejiang Cancer Hospital, No. 1, Banshan Road, Hangzhou, 310022, Zhejiang Province, People’s Republic of ChinaTel/Fax +86 571 8812 2011Email yuyangkaiyu@163.comPurpose: The results of large randomised trials have changed the treatment strategy of axillary lymph nodes. Axillary lymph node dissection (ALND) can be avoided in some patients with one to two sentinel lymph nodes (SLNs) metastasis based on final paraffin section (FPS) results which called into question the need for intraoperative frozen section (FS). This study aims to assess the guiding value of the number of positive SLN detected via FS for intraoperative ALND.Patients and Methods: This study retrospectively analyzed data from 3303 patients with breast cancer who underwent SLN biopsy between 2015 and 2019. Combined with the FPS results, FS sensitivity, specificity, and false negative rate (FNR) were calculated and the difference in the number of positive SLNs between FS and FPS was analyzed.Results: The overall FNR of FS was 23.21%, which was 76.47% in isolated tumor cells, 62.28% in micrometastasis, and 12.09% in macrometastatic disease. The size of SLN metastasis were significantly associated with a higher FNR (p< 0.001). The accuracy rate of the number of positive SLNs detected via FS was 92.62%. Human epidermal growth factor receptor 2 (HER2) (p< 0.03) and Ki67 (p< 0.02) were significant factors affecting the accuracy rate.Conclusion: FS is a effective method for SLN biopsy, ALND can be avoided in patients with one or two positive SLNs detected via FS.Keywords: breast neoplasms, sentinel lymph node, frozen section, false negative rate, axillary lymph node dissection

Background Tuberculosis (TB) is a widespread infectious disease, with an incidence that is increasing worldwide. Cutaneous TB (CTB) occurs rarely, accounting for less than 1% of all TB cases. Due to the clinical presentation and diagnostic difficulties, CTB is often clinically neglected and misdiagnosed. Case summary A 32-year-old man underwent several debridement surgeries and skin flap transplantation after trauma. The wound remained unhealed, accompanied by sinus formation. According to empirical judgment, T-cell spot of TB test, and bacterial culture of pyogenic fluids, he was diagnosed with CTB due to infection with exogenous Mycobacterium tuberculosis. A comprehensive anti-TB regimen that included isoniazid, rifampicin, ethambutol, and pyrazinamide was applied. The sinus was filled with a hydrophilic fiber-containing silver dressing, and wound-protecting sponges were applied to part of the wound. The wound healed after 40 d. No ulceration was found within 2 mo after discharge; further follow-up will be conducted. Conclusion A non-healing wound may be caused by TB infection. Comprehensive treatment of CTB is effective.

The role of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer with peritoneal metastasis (GCPM) is still controversial, mainly due to the limited survival benefit and uncertain patient selection. This study aims to construct a selecting strategy in GCPM for CRS + HIPEC.From a prospective established database, 125 patients were enrolled. All these patients were pathologically confirmed as GCPM and treated with CRS + HIPEC with or without preoperative or postoperative chemotherapy. The clinical documents and follow-up results were collected and analyzed with the primary endpoint of overall survival (OS) and the secondary endpoint of perioperative serious adverse events (SAEs).The median OS of 125 GCPM patients treated with CRS + HIPEC was 10.7 months, with 1-, 2-, 3-, and 5-year survival rates of 43.8%, 24.7%, 18.6%, and 15.7%, respectively. The multivariate analysis identified completeness of cytoreduction (CC), SAEs, HIPEC drugs, and adjuvant chemotherapy as independent prognostic factors on OS. The median OS was 30.0 (95%CI: 16.8-43.3) months in CC-0 group, significantly better than 7.3 (95%CI: 5.8-8.8) months in CC1-3 group (P 0.001). The median OS showed no significant difference among CC-1 (8.5, 95%CI: 6.7-10.2, months), CC-2 (5.6, 95%CI: 3.0-8.2, months) and CC-3 (6.5, 95%CI: 5.2-7.7, months) groups (P 0.05 for all pairwise comparations). The nomogram based on peritoneal metastasis timing, preoperative tumor marker (TM), and peritoneal cancer index (PCI), with AUC of 0.985, showed a good accuracy and consistency between actual observation and prediction of the probability of complete CRS. The cutoffs of PCI were 16 for synchronous GCPM with normal TM, 12 for synchronous GCPM with abnormal TM, 10 for metachronous GCPM with normal TM, and 5 for metachronous GCPM with abnormal TM, setting the probability to achieve complete CRS as 50%.Only complete CRS + HIPEC (CC-0) could improve survival for high selected GCPM patients with acceptable safety. An incomplete CRS (CC1-3) should be avoided for GCPM patients. Synchronous GCPM with PCI ≤16 and normal TM, synchronous GCPM with PCI ≤12 and abnormal TM, metachronous GCPM with PCI ≤10 and normal TM, or metachronous GCPM with PCI ≤5 and abnormal TM maybe potential indications for complete CRS + HIPEC treatment.

A 43‐year‐old man with a 23‐year history of type II diabetes presented with uncontrolled hyperglycemia with frequent episodes of ketoacidosis. He was diagnosed with exogenous insulin antibody syndrome, and received high‐dose methylprednisolone to treat insulin resistance. Ketoacidosis relapsed 2 years later, and the patient showed an incomplete response to glucocorticoids. We decided to administer therapeutic plasma exchange, which resulted in rapid lowering of the daily insulin requirement and improved glycemic control.

Although immunotherapy has achieved great clinical success in clinical outcomes, especially the anti-PD-1 or anti-PD-L1 antibodies, not all patients respond to anti-PD-1 immunotherapy. It is urgently required for a clinical diagnosis to develop non-invasive imaging meditated strategy for assessing the expression level of PD-L1 in tumors. In this work, a 68Ga-labeled single-domain antibody tracer, 68Ga-NOTA-Nb109, was designed for specific and noninvasive imaging of PD-L1 expression in an MC38 tumor-bearing mouse model. Comprehensive studies including Positron Emission Tomography (PET), biodistribution, blocking studies, immunohistochemistry, and immunotherapy, have been performed in differences PD-L1 expression tumor-bearing models. These results revealed that 68Ga-NOTA-Nb109 specifically accumulated in the MC38-hPD-L1 tumor. The content of this nanobody in MC38 hPD-L1 tumor and MC38 Mixed tumor was 8.2 ± 1.3, 7.3 ± 1.2, 3.7 ± 1.5, 2.3 ± 1.2%ID/g and 7.5 ± 1.4, 3.6 ± 1.7, 1.7 ± 0.6, 1.2 ± 0.5%ID/g at 0.5, 1, 1.5, 2 hours post-injection, respectively. 68Ga-NOTA-Nb109 has the potential to further noninvasive PET imaging and therapy effectiveness assessments based on the PD-L1 status in tumors. To explore the possible synergistic effects of immunotherapy combined with chemotherapy, MC38 xenografts with different sensitivity to PD-L1 blockade were established. In addition, we found that PD-1 blockade also had efficacy on the PD-L1 knockout tumors. RT-PCR and immunofluorescence analysis were used to detect the expression of PD-L1. It was observed that both mouse and human PD-L1 expressed among three types of MC38 tumors. These results suggest that PD-L1 on tumor cells affect the efficacy, but it on host myeloid cells might be essential for checkpoint blockade. Moreover, anti-PD-1 treatment activates tumor-reactive CD103+ CD39+ CD8+T cells (TILs) in tumor microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide. However, the mechanisms underlying the acquisition of the metastatic potential in PDAC has not been well understood. In this study, we identified a total of 154 genes upregulated in primary tissues of PDAC with liver metastasis using the Genome Cancer Atlas (TCGA) and GSE151580 cohorts. The epithelial-mesenchymal transition and glycolysis were enriched by the liver metastasis-related genes, indicating that the liver metastasis-related genes might be functionally relevant to liver metastasis in PDAC. Moreover, we also found that the liver metastasis-related genes were primarily regulated at epigenetic level. Particularly, SFN, a cell cycle checkpoint protein, and KRT19, a marker gene for ductal cells, were predicted to be regulated by multiple methylation sites at the promoter. Clinically, we for the first time defined a liver metastasis score (LMS), which was derived from liver metastasis-related genes, and closely associated with clinical characteristics such as disease type and tumor grade, in PDAC. Furthermore, we also divided the samples into high and low LMS groups using three cohorts with long-term follow-up (TCGA, GSE71729, and E-MTAB-6134), which exhibited significantly different prognostic outcomes across three PDAC cohorts, suggesting that the LMS might be a good indicator for risk stratification in PDAC. Furthermore, we also found that the liver metastasis-related genes were primarily expressed in malignant ductal cells by integrative analysis of the bulk and single-cell gene expression data. Moreover, the malignant ductal cells and M0 macrophages were highly correlated with LMS, indicating that the two cell types might function as tumor-promoting cells in PDAC. In summary, the systematic analysis for the first time defined an LMS score to evaluate the risk of liver metastasis in PDAC and revealed that malignant ductal cells might promote PDAC liver metastasis, which greatly improves our understanding of the liver metastasis-related genes, their underlying mechanisms, and association with prognosis in PDAC.

Background/Purpose Hemophagocytic lymphohistiocytosis (HLH), a rarely occurring syndrome with various triggers, is associated with early mortality. Owing to a lack of sufficient corresponding data in Taiwan, this study aimed to identify the outcome and potential factors associated with 180-day mortality in pediatric HLH. Methods This retrospective study analyzed clinical and laboratory data on pediatric patients diagnosed with HLH at our institute (1995–2019). Logistic regression analysis was conducted to determine the associations between various factors and 180-day mortality. Results Overall, 48 patients had HLH; their median age at diagnosis was 5 years (interquartile range: 2–11 years). Clinical presentations and laboratory parameters required for diagnosis included fever (98%), splenomegaly (79%), hyperferritinemia (98%), hemophagocytosis (94%), thrombocytopenia (90%), anemia (63%), hypertriglyceridemia (68%), and neutropenia (57%). The 5-year overall survival (OS) rate was 49%. Of 22 patients who had died at the last follow-up, 15 (68%) died within 180 days after diagnosis. In the multivariate analysis, hemoglobin (odds ratio [OR]: 0.564, p = 0.024) and triglyceride (OR: 1.004, p = 0.049) were significantly associated with 180-day mortality. Higher triglyceride levels at diagnosis were related to significantly lower 180-day OS rates (52.9% vs. 86.1%, p = 0.018). Conclusion The overall outcome in our cohort was similar to that reported in some of the largest international cohorts. Hypertriglyceridemia and anemia may be indicative of poor prognoses in pediatric HLH patients independently and may be used to guide treatment strategy formulations for better outcomes.

Background It is reported that appropriately 50% of early breast cancer patients with 1–2 positive sentinel lymph node (SLN) micro-metastases could not benefit from axillary lymph node dissection (ALND) or breast-conserving surgery with whole breast irradiation. However, whether patients with 1–2 positive SLN macro-metastases could benefit from ALND remains unknown. The aim of our study was to develop and validate nomograms for assessing axillary non-SLN metastases in patients with 1–2 positive SLN macro-metastases, using their pathological features alone or in combination with STMs. Methods We retrospectively reviewed pathological features and STMs of 1150 early breast cancer patients from two independent cohorts. Best subset regression was used for feature selection and signature building. The risk score of axillary non-SLN metastases was calculated for each patient as a linear combination of selected predictors that were weighted by their respective coefficients. Results The pathology-based nomogram possessed a strong discrimination ability for axillary non-SLN metastases, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.727 (95% CI: 0.682–0.771) in the primary cohort and 0.722 (95% CI: 0.653–0.792) in the validation cohort. The addition of CA 15–3 and CEA can significantly improve the performance of pathology-based nomogram in the primary cohort (AUC: 0.773 (0.732–0.815) vs. 0.727 (0.682–0.771), P P Conclusion The nomograms based on pathological features can be used to identify axillary non-SLN metastases in breast cancer patients with 1–2 positive SLN. In addition, the combination of STMs and pathological features can identify patients with patients with axillary non-SLN metastases more accurately than pathological characteristics alone.

Purpose. To investigate the vascular density of the optic nerve head (ONH) and macula using optical coherence tomography angiography (OCTA) in patients undergoing vitrectomy for rhegmatogenous retinal detachment (RRD) and to evaluate associations with visual outcomes. Methods. Patients with RRD, successfully treated with a pars plana vitrectomy (PPV) and a minimum three-month follow-up were included in this study. The vessel density (VD) of the ONH and peripapillary regions, foveal avascular zone (FAZ), foveal flow density (FFD), and parafoveal flow density (PFD) were evaluated using OCTA and compared to the fellow eye. Multivariate linear regression analysis was performed to determine correlations with visual outcomes. Results. Thirty-one patients with macula-off RRD were included in the study. Compared with the fellow eyes, eyes after RRD surgery had a lower peripapillary VD ( P < 0.01 ). No significant difference in superficial and deep FFD, PFD, and FAZ area was found compared to the fellow eyes. Postoperative peripapillary VD and baseline BCVA were significantly associated with BCVA three months after PPV ( P < 0.05 ). Conclusion. Rhegmatogenous retinal detachment eyes successfully treated with PPV had lower peripapillary vessel density than fellow healthy eyes. Postoperative BCVA was related to postoperative peripapillary VD.

Due to the advantages of easy harvesting and escaping from immune rejection, autologous bone marrow-derived mesenchymal stem cells (BMSCs) are promising in immunosuppressive therapy against inflammation and autoimmune diseases. However, it is still a challenge because the immunomodulatory properties of BMSCs always are impaired by the immunopathogenesis in patients. Because of reliable and extensive multiple biological activities, osthole have got more and more clinical attention. In this article, we found that BMSCs derived from osteoporosis donors was ineffective in cell therapy for experimental inflammatory colitis and osteoporosis.In vivo and in vitro tests showed that due to the downregulated Fas and FasL expression, the ability of osteoporotic BMSCs to induce T cell apoptosis decreased. Through the application of osthole, we successfully restored the immunosuppressive ability of osteoporotic BMSCs and improved its treatment efficacy in experimental inflammatory colitis and osteoporosis. In addition, we found the immunomodulatory properties of BMSCs were enhanced after osthole pretreatment. In this study, our data unravel a new approach that pharmacological modification (i.e., osthole) can improve the immune regulatory performance of BMSCs from a healthy or inflammatory microenvironment. The development of targeted strategies to enhance the immunosuppressive therapy of BMSCs might be significantly improved by these findings. Funding Statement: This work was supported by Nature Science Foundation of China (81800979 to Yang Yu.， 31970783 to Deqin Yang, 81700958 to Liang Chen, 32000577 to Bingyi Shao,81800958 to Dou Lei). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: All the animal experiments were conducted under the experimental animal guidelines of the National Institutes of Health and approved by the Animal Care and Use Committee of Chongqing Medical University.

Background Neuromyelitis optica spectrum disorders (NMOSD) are associated with recurrent episodes of optic neuritis and transverse myelitis, often resulting in high attack-related disability. Therapeutic apheresis has been recommended as a second-line treatment for steroid-refractory NMOSD. To assess the efficacy and safety of two apheresis techniques, lymphoplasmapheresis (LPE) and therapeutic plasma exchange (TPE), in refractory NMOSD and to provide a new treatment option for patients with refractory NMOSD. Methods This retrospective study examined NMOSD patients who had undergone either LPE or TPE treatment between January 2015 and January 2018. The patients were monitored for improvements in disabilities, incidences of adverse reactions, and safety of the procedure over a one-year follow-up period. The primary outcome measures included changes in the visual outcome scale (VOS) score, the expanded disability status scale (EDSS), and the annualized relapse rate (ARR). Results Neurological function and objective response rates were significantly improved in 76.5% of patients treated with LPE and 83.3% of patients treated with TPE. There were no significant differences in the two treatment groups (P=0.392). Similarly, there were no differences in the reduction in the relative relapse rate between the two groups (P=0.494). Adverse reactions, mostly of mild or moderate intensity, were recorded in 9.3% of procedures in 38% of patients. The most commonly observed adverse events (AEs) were similar between the two treatment cohorts. Conclusions Patients treated with LPE showed improved neurological function comparable to that reported with TPE treatment. No superiority was shown for either of the apheresis techniques.

Rationale and Objectives The purpose of this study was to investigate the role of computed tomography (CT) radiomics for the prediction of the human epidermal growth factor 2 (HER2) status in patients with gastric cancer. Methods One hundred and thirty two consecutive patients with advanced gastric cancer undergoing radical gastrectomy were retrospectively reviewed. All patients received preoperative contrast CT examination, and immunohistochemistry results of their HER2 status were available. All the subjects were randomly divided into a training cohort (n = 90) and a test cohort (n = 42). Arterial phase (AP) and portal phase (PP) contrast CT images were retrieved for tumor segmentation and feature extraction. Receiver operating characteristics (ROC) curves and area under the curve (AUC) were used to evaluate the performance of the radiomics classifiers. Results Among the 132 patients, a total of 99 patients were HER2 negative, and the remaining 33 patients were border line or positive. The AP radiomics model could distinguish HER2-negative cases with an AUC of 0.756 (95% confidence interval [CI]: 0.656–0.840) in the training cohort, which was confirmed in the test cohort with AUC of 0.830 (95% CI: 0.678–0.930). The PP radiomics model showed AUCs of 0.715 (95% CI: 0.612–0.804) and 0.718 (95% CI: 0.554–0.849) in the training and test cohort for distinction of negative HER2 cases, respectively. Conclusion Radiomics models based on standard-of-care CT images hold promise for distinguishing HER2-negative gastric cancer.

The model provided by the International Classification of Functioning, Disability and Health (ICF) is used to describe, classify and measure function in both health care practice and research. ICF for Children and Youth (ICF-CY) has not been applied to the rehabilitation of patients with visual impairment. The purpose of this case report is to describe the process of evaluation and treatment of low vision patients based on ICF-CY models. The patient was a 9-year-old girl. The diagnosis included retinopathy of prematurity (ROP) (OU), secondary glaucoma after iridectomy (OD), keratoleukoma (OD), retinal detachment (OS), strabismus postoperation (OU), nystagmus. The patient complained of being unable to see clearly, of fear of falling down stairs and of being unable to study normally. The ICF-CY framework is used to assess the overall function and disability of this girl. We provided visual devices and instruction to improve the body structure and function, mobility restriction and environmental factors associated with the cognitive function of patients. The results showed that with the help of devices and the guidance of her parents, friends and health professionals, the patient's cognitive function, learning ability and social ability were significantly improved and her psychological conditions had also been improved. As a result, using the ICF-CY model to evaluate and intervene in patients is helpful for accurately dealing with different functional problems and their correlations.

Current clinical treatment targeting osteosarcoma (OS) are limited for OS patients with pulmonary metastasis or relapse, which led to high mortality (70%-85%) for advanced osteosarcoma patients. Although ongoing efforts have been made to illustrate the mechanisms of tumorigenesis and progression in OS; however, it was far for us to learn a comprehensive molecular mechanism implies in OS development. In our study, we implicated a circRNA hsa_circ_0002137, which was higher expressed in osteosarcoma tumours compared with paracancerous tissue. The dysregulated expression pattern was also found in osteosarcoma cell lines. The role of circ_0002137 was explored via down- or up-regulated experiments. It was proved that down-regulation of circ_0002137 suppressed the progress of OS, including cell invasion, cell cycle and cell apoptosis. Furthermore, the correlation between circ_0002137 and miR-433-3p was predicted using bioinformatic tools and verified utilizing RNA pull-down assay and luciferase reporter assay. Interestingly, we found that the inhibitory effect of circ_0002137 on OS was dependent of insulin-like growth factor-1 receptor (IGF1R). In conclusion, it was demonstrated that circ_0002137 could restrain the progression of OS through regulating miR-433-3p/IGF1R axis, providing a comprehensive landscape of circ_0002137 in the generation and development of OS.

Axillary lymph node dissection is an indispensable step in modified radical mastectomy for breast cancer. It is the most reliable method and the golden standard to determine the status of axillary lymph nodes. It is also of great importance to evaluate the prognosis and develop treatment plans for breast cancer patients. Axillary lymph node dissection can be anatomically divided into levels I, II, and III. Level I and Level II axillary lymph dissection is the standard clinical treatment of axillary lymph nodes positive breast cancer, whereas level III axillary lymph node dissection has been controversial. Level III axillary lymph node metastasis is one of the important factors that can easily cause distant metastasis and recurrence. It is also an important index to estimate the prognosis of breast cancer patients. To facilitate the decision of whether or not to perform level III lymph node dissection, we reviewed the indications, complications, and surgical procedures of level III lymph node dissection.

Objective To investigate the therapeutic efficacy of titanium elastic intramedullary nail (TEN) and open reduction and internal fixation with plate (ORIF) in the treatment of humeral fracture in children. Methods A retrospective study was carried out in a total of 69 patients who were admitted to the hospital from January 2013 to December 2018. These patients, including 41 males and 28 females, were aged from 6 to 12 years old with a median of 8 years. These patients were diagnosed with humeral fracture and underwent the surgery of ORIF (n = 22) or TEN (n = 47). The intraoperative bleeding, operation time, length of stay (LOS), and fracture healing time were compared between the two groups. The therapeutic effect was assessed by the shoulder range of motion, the elbow range of motion, the UCLA shoulder function score, and the Mayo elbow performance score (MEPS) 6 months after the surgery. Results The intraoperative bleeding (97.20 ± 27.83 mL vs 185.60 ± 37.50 mL, P, Compared with the open reduction and internal fixation with plate, titanium elastic intramedullary nail can be a good technique for the treatment of humeral fracture in children, with the advantages of less intraoperative bleeding, shorter operative time, quicker healing, and better recovery of shoulder mobility and range of motion.

Genome‐wide 5hmC profiling in cell‐free DNA acquired from CRC patients, adenoma patients, and healthy individuals revealed that the differential 5hmC‐modified regions were gathered into four clusters with no overlap, although there are a few overlapped genes shared between the different clusters. CRC patients with adenoma history showed exclusive 5hmC‐gain characteristics, which was consistent with the ‘parallel’ evolution hypothesis in adenoma., Approximately 85% colorectal cancers (CRCs) are thought to evolve through the adenoma‐to‐carcinoma sequence associated with specific molecular alterations, including the 5‐hydroxymethylcytosine (5hmC) signature in circulating cell‐free DNA (cfDNA). To explore colorectal disease progression and evaluate the use of cfDNA as a potential diagnostic factor for CRC screening, here, we performed genome‐wide 5hmC profiling in plasma cfDNA and tissue genomic DNA (gDNA) acquired from 101 samples (63 plasma and 38 tissues), collected from 21 early‐stage CRC patients, 21 AD patients, and 21 healthy controls (HC). The gDNA and cfDNA 5hmC signatures identified in gene bodies and promoter regions in CRC and AD groups were compared with those in HC group. All the differential 5hmC‐modified regions (DhMRs) were gathered into four clusters: Disease‐enriched, AD‐enriched, Disease‐lost, and AD‐lost, with no overlap. AD‐related clusters, AD‐enriched and AD‐lost, displayed the unique 5hmC signals in AD patients. Disease‐enriched and Disease‐lost clusters indicated the general 5hmC changes when colorectal lesions occurred. Cancer patients with a confirmable adenoma history segmentally gathered in AD‐enriched clusters. KEGG functional enrichment and GO analyses determined distinct differential 5hmC‐modified profiles in cfDNA of HC individuals, AD, and CRC patients. All patients had comprehensive 5hmC signatures where Disease‐enriched and Disease‐lost DhMR clusters demonstrated similar epigenetic modifications, while AD‐enriched and AD‐lost DhMR clusters indicated complicated subpopulations in adenoma. Analysis of CRC patients with adenoma history showed exclusive 5hmC‐gain characteristics, consistent with the ‘parallel’ evolution hypothesis in adenoma, either developed through the adenoma‐to‐carcinoma sequence or not. These findings deepen our understanding of colorectal disease and suggest that the 5hmC modifications of different pathological subtypes (cancer patients with or without adenoma history) could be used to screen early‐stage CRC and assess adenoma malignancy with large‐scale follow‐up studies in the future.

Pharmacological stimulation of adipose tissue remodeling and thermogenesis to increase energy expenditure is expected to be a viable therapeutic strategy for obesity. Berberine has been reported to have pharmacological activity in adipose tissue to anti-obesity, while the mechanism remains unclear. Here, we observed that berberine significantly reduced the body weight and insulin resistance of high-fat diet mice by promoting the distribution of brown adipose tissue and thermogenesis. We have further demonstrated that berberine activated energy metabolic sensing pathway AMPK/SIRT1 axis to increase the level of PPARγ deacetylation, which leads to promoting adipose tissue remodeling and increasing the expression of the thermogenic protein UCP-1. These findings suggest that berberine that enhances the AMPK/SIRT1 pathway can act as a selective PPARγ activator to promote adipose tissue remodeling and thermogenesis. This study proposes a new mechanism for the regulation of berberine in adipose tissue and offers a great prospect for berberine in obesity treatment.

Because chondrocytes are the only resident cells in articular cartilage, the steady state of these cells is important for the maintenance of joint function. In various osteoarthritis diseases, chondrocytes undergo a series of pathophysiologic changes, leading to the loss of chondrocytes and the degradation of extracellular matrix (ECM). This study found that Cytoplasmic localized histone deacetylase 6 (HDAC6) is up-regulated on the articular surface in a destabilization of the medial meniscus-induced mouse osteoarthritis model. Because HDAC6 is highly related to the acetylation of tubulin and the function of the microtubule system is closely related to material transport and signal transduction, the relationship between the expression level or activity of HDAC6 and the fate of chondrocytes in vitro and in vivo were confirmed. Primary chondrocytes overexpressing DNA-HDAC6 with plasmid were constructed in vitro, and HDAC6 inhibitor Tubastatin A was selected to inhibit HDAC6 enzyme activity in vivo and in vitro. Subsequently, mitochondrial spatial arrangement, degradation of ECM, and pathological changes in joint were defined. The results indicate that overexpression of HDAC6 causes mitochondrial dysfunction and promotes reactive oxygen species production, leading to degradation of ECM. Tubastatin A treatment after osteoarthritis ameliorates the degradation of cartilage and improves the microenvironment and function of the joint. HDAC6 may be targeted to treat osteoarthritis.

Pancreatic cancer has been becoming the second cause of cancer death in the western world, and its disease burden has increased. Neoadjuvant therapy is one of the current research hotspots in the field of pancreatic cancer, aiming to improve the surgical rate and prognosis of pancreatic cancer. Based on the latest evidence, this review discussed neoadjuvant therapy in pancreatic cancer from the following three aspects: patient selection, protocols selection of neoadjuvant therapy, and treatment response evaluation and resectability prediction. A big controversy existed on the indications of neoadjuvant treatment, but it was agreed that any patient who is likely to achieve R0 resection due to neoadjuvant therapy should be the targeted population. A variety of chemotherapy regimens were tried for neoadjuvant therapy in pancreatic cancer, and FOLFIRINOX and Nab-Paclitaxel plus Gemcitabine are two preferred regimens at present. It was challenging to evaluate treatment response and predict resectability after neoadjuvant therapy, although imaging by CT is widely used. Based on new findings of the remarkable performance of several chemotherapy regimens with or without radiotherapy, the neoadjuvant indications of pancreatic cancer have extended in recent years. However, it is still a challenge to assess the neoadjuvant treatment response and determine the timing of surgery.

Background Apathy is common in Alzheimer's disease (AD) patients. However, its relation with other clinical symptoms in AD and brain structural changes in magnetic resonance imaging is unclear. Results Compared with AD with no apathy group, cognitive function and activities of daily living were significantly impaired and neuropsychiatric symptoms were obviously presented in AD with apathy group (P 0.05). Correlation analyses and multiple linear analyses revealed that thickness of left temporal pole and volume of posterior corpus callosum were significantly and negatively correlated with Modified Apathy Estimation Scale score in AD patients (P Conclusions Apathy with AD is positively correlated with cognitive impairment, neuropsychiatric symptoms and poor activities of daily living. Atrophy of left temporal pole and posterior corpus callosum presented by MRI is positively related with apathy of AD. Methods In this study, 137 AD patients were recruited and divided into AD with apathy group and AD with no apathy group according to Modified Apathy Estimation Scale score. We evaluated patients' cognitive function, neuropsychiatric symptoms and activities of daily living, detected the frequency of Apolipoprotein E genotypes and measured cortical thickness and volume by magnetic resonance imaging (MRI).

The aim of this study was to explore the epidemiology of Toxoplasma gondii infection in patients with colorectal cancer (CRC) in eastern China. Therefore, 287 primary CRC patients and 287 age-matched healthy control subjects were recruited to estimate the seroprevalence of T. gondii and identify the risk factors of infection. Enzyme-linked immunoassays were used to test for anti-T. gondii immunoglobulin G (IgG) and IgM antibodies. Forty-six (16%) samples were positive for anti-T. gondii IgG antibodies in patients with CRC, compared with 26 (9.1%) in the healthy controls, a significant difference ( P = 0.007 ). By contrast, eight (2.8%) patients tested positive for T. gondii IgM antibodies, compared with three (1.1%) in the controls, a difference that was not significant ( P = 0.13 ). Multivariable backward stepwise logistic regression analysis revealed that a rural residence (OR 2.83; 95% CI 1.15–7.01; P = 0.024 ) and treatment with chemotherapy (OR 2.16; 95% CI 1.02–4.57; P = 0.045 ) were risk factors for T. gondii infection in patients with CRC. Thus, T. gondii infection is serious in patients with CRC, and a rural residence and treatment with chemotherapy are independent risk factors for infection by this parasite. Therefore, medical professionals should be aware of this pathogen in patients with CRC, and the causes of T. gondii infection in these patients need to be explored further.

Highlights • AKT overexpression correlates with poor prognosis in neuroblastoma patients. • BX-795 inhibits PDK1 and abrogates the AKT signaling pathway activation. • BX-795 demonstrates strong efficacy in neuroblastoma spheroid tumor model. • Combination with BX-795 synergistically enhances doxorubicin antitumor activity. • BX-795 synergistically sensitized ALK mutated neuroblastoma cell lines to crizotinib., High-risk neuroblastoma (NB) represents a major clinical challenge in pediatric oncology due to relapse of metastatic, drug-resistant disease, and treatment-related toxicities. An analysis of 1235 primary NB patient dataset revealed significant increase in AKT1 and AKT2 gene expression with cancer stage progression. Additionally, Both AKT1 and AKT2 expression inversely correlate with poor overall survival of NB patients. AKT1 and AKT2 genes code for AKT that drive a major oncogenic cell signaling pathway known in many cancers, including NB. To inhibit AKT pathway, we repurposed an antiviral inhibitor BX-795 that inhibits PDK1, an upstream activator of AKT. BX-795 potently inhibits NB cell proliferation and colony growth in a dose-dependent manner. BX-795 significantly enhances apoptosis and blocks cell cycle progression at mitosis phase in NB. Additionally, BX-795 potently inhibits tumor formation and growth in a NB spheroid tumor model. We further tested dual therapeutic approaches by combining BX-795 with either doxorubicin or crizotinib and found synergistic and significant inhibition of NB growth, in contrast to either drug alone. Overall, our data demonstrate that BX-795 inhibits AKT pathway to inhibit NB growth, and combining BX-795 with current therapies is an effective and clinically tractable therapeutic approach for NB., Graphical abstract Image, graphical abstract

BackgroundThe clinical guidelines related to the primary prevention of Alzheimer’s disease (AD) have focused on the management of vascular risk factors. However, the link between vascular risk factors and AD in older adults remains unclear. This study aimed to determine the association between vascular risk factors and subsequent AD in 178,586 older adults (age ≥ 65 years).MethodsParticipants were recruited from 2009 through 2010 and followed up for 6 years. We assessed various vascular risk factors (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], triglycerides [TG], fasting glucose [FG], systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse pressure [PP], and body mass index [BMI]) and their association with AD incidence, categorizing each vascular factor using current clinical guidelines.ResultsAD was observed in 6.0% of participants at follow-up. All lipid profiles (TC, LDL-C, HDL-C and TG) were positively associated with the risk of AD. SBP and PP were in negative associations with AD, and DBP was positively associated with AD. BMI exhibited a negative association with AD incidence. We found no significant association between FG and AD risk. The sex difference was observed to have effects on vascular risk factors.ConclusionsIn this study, we comprehensively investigated the association between eight vascular risk factors and the risk of incident AD. Our findings suggest that multiple vascular risk factors are related to the development of AD in older adults. These results can help inform future guidelines for reducing AD risk.

Aims/Objective The development of type 2 diabetes is a result of insulin resistance in various tissues, including skeletal muscle and liver. Apolipoprotein M (ApoM) plays an important role in the function of high‐density lipoprotein, and also affects hepatic lipid and glucose metabolism. In this study, we aimed to investigate whether ApoM overexpression modulates glucose metabolism and improves insulin sensitivity. Materials and Methods The Goto‐Kakizaki (GK) rats were transfected with adeno‐associated virus (AAV) encoding rat ApoM gene or control blank. The oral glucose tolerance test (OGTT) and hyperinsulinemic‐euglycemic clamp (HEC) experiment were used to assess the insulin sensitivity of GK rats. Results The results show that ApoM messenger ribonucleic acid and protein were significantly overexpressed in the pancreatic tissues. Overexpression of ApoM decreased fasting blood glucose and random blood glucose, improved glucose tolerance, and increased bodyweight and insulin levels in GK rats. The glucose infusion rate of rats in the AAV encoding rat ApoM gene group during HEC test was 1.04‐, 1.23‐ and 1.95‐fold higher than that in the AAV control blank group at 1–3 weeks after injection of AAV, respectively. A Wes‐ProteinSimple assay and quantification was carried out to assess phosphorylated protein kinase B/protein kinase B protein levels in the muscle tissues of ApoM‐overexpressing GK rats, and they were found to be higher than those of the control group at the seventh week after AAV injection. Conclusions ApoM overexpression through adeno‐associated virus gene transfer might improve insulin secretion and insulin sensitivity in GK rats., Apolipoprotein M overexpression decreased fasting blood glucose and random blood glucose, and increased insulin in Goto‐Kakizaki rats. Apolipoprotein M overexpression increased the phosphorylated protein kinase B/protein kinase B protein levels in the muscle tissues of Goto‐Kakizaki rats. Apolipoprotein M overexpression might improve insulin sensitivity in Goto‐Kakizaki rats.

Purpose The predictive value of anti-Mullerian hormone (AMH) for ovarian dysfunction postchemotherapy is controversial. This study aimed to evaluate the value of serum AMH levels clinically and theoretically. Patients animals and methods We detected the serum estradiol, follicular stimulating hormone (FSH), luteinizing hormone (LH), and AMH levels in 144 premenopausal women with breast cancer receiving cyclophosphamide-based chemotherapy. The hormone levels before and postchemotherapy were compared; the correlations among the hormones and amenorrhea and menstrual recovery were analyzed. In addition, the serum AMH levels were detected randomly in 177 normal healthy women and 36 normal female C57BL/6J mice of different ages; meanwhile, the status of ovarian follicles was also examined. Furthermore, 72 Balb/c nude mice with breast cancer were randomly assigned to three groups that received different doses of cyclophosphamide (CTX) (control, 100 mg/kg, and 200 mg/kg), and the alterations in serum AMH levels and ovarian follicles were recorded and analyzed. Results Chemotherapy-induced amenorrhea was associated with prechemotherapy AMH levels, E2 levels, and FSH levels (P 0.05). In patients with breast cancer treated with chemotherapy, the serum AMH levels did not differ significantly between the pre- and post-chemotherapy periods in patients aged 0.05), whereas a dramatic reduction was detected in patients aged >35 years (P Conclusion Our results indicate that AMH is an efficient marker for predicting postchemotherapy ovarian function exclusively in premenopausal female patients with breast cancer aged >35 years.

It has been increasingly evident that pulse pressure (PP) is associated with Alzheimer's disease (AD) but whether PP increases AD risk and the mechanism responsible for this association remains unclear. To investigate the effects of PP in the process of AD, we have evaluated the cross-sectional and longitudinal associations of PP with AD biomarkers, brain structure and cognition and have assessed the effect of PP on AD risk in a large sample (n= 1,375) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Multiple linear regression and mixed-model regression were employed in cross-sectional and longitudinal analyses respectively. Clinical disease progression was assessed using Cox proportional hazards models. High PP was associated with lower β-amyloid 42 (Aβ42) (P= .015), and higher total tau (T-tau) (P= .011), phosphorylated tau (P-tau) (P= .003), T-tau/Aβ42 (P= .004) and P-tau/Aβ42 (P = .001), as well as heavier cortical amyloid-beta burden (P= .011). Longitudinally, baseline high PP was significantly associated with hippocampal atrophy (P= .039), entorhinal atrophy (P= .031) and worse memory performance (P= .058). Baseline high PP showed more rapid progression than those with normal PP (P

Objective: Thyroglobulin antibodies (TgAb), principally comprising immunoglobulin G (IgG), are frequently found in healthy individuals. Previously, we showed that the glycosylation levels of TgAb IgG differed across various thyroid diseases, suggesting an important role of glycosylation on antibodies in the pathogenesis of thyroid diseases. Since IgG1 and IgG4 are the primary TgAb IgG subclasses, this study aimed to investigate the glycosylation of TgAb IgG1 and IgG4 subclasses in thyroid diseases. Methods: TgAb IgG was purified by affinity chromatography from the serum of patients with Hashimoto’s thyroiditis (HT) (n = 16), Graves’ disease (GD) (n = 8), papillary thyroid carcinoma (PTC) (n = 6), and PTC with histological lymphocytic thyroiditis (PTC-T) (n = 9) as well as healthy donors (n = 10). TgAb IgG1 and IgG4 concentrations were determined by enzyme-linked immunosorbent assay, and a lectin microassay was used to assess TgAb IgG1 and IgG4 glycosylation. Results: Significantly elevated mannose, sialic acid, and galactose levels on TgAb IgG1 were found in HT and PTC patients compared to GD patients and healthy controls (all p < 0.05). The mannose, sialic acid, and core fucose levels on TgAb IgG1 in PTC-T patients were higher than in healthy controls (all p < 0.05). Additionally, TgAb IgG1 from PTC-T patients exhibited lower sialylation than that from patients with PTC and higher fucosylation than that from patients with HT (both p < 0.05). However, TgAb IgG4 glycosylation did not differ among the five groups (p < 0.05). Conclusion: Our study describes different distributions of TgAb IgG1 glycosylation in various thyroid diseases. The aberrantly increased glycosylation levels of TgAb IgG1 observed in HT, PTC, and PTC-T might be indicative of immune disorders and participate in the pathogenesis of these diseases.

BACKGROUND The increase of triglyceride (TG) can induce coronary heart disease, atherosclerosis, pancreatitis and other diseases and is the most common inducing factor of acute pancreatitis (AP) second only to biliary tract disease and drinking. The pathogenesis of hyperlipidemic acute pancreatitis (HLAP) is not exactly clear, but it may be related to the toxic effect of the increase of free fatty acids produced by TG decomposition on the pancreas itself, microcirculation disorder of the pancreas, and calcium overload. At present, non-surgical therapy is the main treatment for HLAP. The key to preventing recurrence is to reduce blood lipids, change the diet structure, and reduce weight. This study aimed to treat HLAP with modified Dachengqi decoction combined with conventional therapy, based on the "six-hollow-organs to be unblocked" theory. METHODS Forty patients with HLAP who received treatment in the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine and Puding County Hospital of Traditional Chinese Medicine from September 2016 to August 2019 were selected and divided into a control group and an intervention group, each with 20 cases, following a random number table. The control group was treated with conventional therapy while the intervention group was treated with modified Dachengqi decoction combined with conventional therapy. RESULTS After treatment, the cure rate and the total effective rate were 60% and 95% respectively in the intervention group, and 25% and 75% respectively in the control group (P

Background Pre-treatment PLR (platelet-lymphocyte ratio) was reported to be associated with the prognosis in gastric cancer (GC), but the results remain inconclusive. This meta-analysis aimed to investigate the prognostic potential of the pre-treatment PLR in gastric cancer. Methods We performed a systematic literature search in PubMed, Embase, and the Cochrane Library to identify eligible publications. The hazard ratio (HR)/odds ratio (OR) and its 95% confidence (CI) of survival outcomes and clinicopathological parameters were calculated. Results A total of 49 studies (51 cohorts), collecting data from 28,929 GC patients, were included in the final analysis. The pooled results demonstrated that the elevated pre-treatment PLR was significantly associated with poor overall survival (OS) (HR 1.37, 95% CI 1.26–1.49, p < 0.001; I2 = 79.90%, Ph < 0.001) and disease-free survival (DFS) (HR 1.52, 95% CI 1.22–1.90, p < 0.001, I2 = 88.6%, Ph < 0.001). Furthermore, the patients with the elevated PLR had a higher risk of lymph node metastasis (OR = 1.17, 95% CI 1.02–1.33, p = 0.023), serosal invasion (T3+T4) (OR = 1.34, 95% CI 1.10–1.64, p = 0.003), and increased advanced stage (III+IV) (OR = 1.20, 95% CI 1.06–1.37, p = 0.004). Conclusions An elevated pre-treatment PLR was a prognostic factor for poor OS and DFS and associated with poor clinicopathological parameters in GC patients.

Amplicon-based next generation sequencing (NGS) approaches have been preferentially adopted by the clinical laboratories on the basis of a short turnaround time (TAT) and small DNA input needs. However, little work has been done to assess the amplicon-based NGS methods for copy number variation (CNV) detection in comparison with current standard methods like immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The correlation between NGS based CNV detection and the later standard methods has remained unexplored. We developed an amplicon-based panel to detect human epidermal receptor growth factor (HER2) amplification in formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 280 breast cancer and 50 gastric cancer patients. Assessment by IHC and FISH was conducted in parallel, and descriptive statistics were used to assess the concordance. The copy number detected by NGS was correlated with either the average HER2 copy number (signals/cell) (r = 0.844; p