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Comment on a case report on a challenging case of a severe spinal congenital deformity with a type I split spinal cord malformation (SSCM) in a 23-year-old with initial neurological symptoms. The patient was treated with a halo gravity traction over one month. A posterior vertebral column resection cephalad to the bony spur at T12 was done and moderate frontal and sagittal plane curve correction was achieved without resection of the bony spur. In conclusion, despite a quite clear recommendation in the current literature to first surgically address the type 1 SSCM prior to correction of any spinal deformity, the authors of the present case chose to leave the bony spur. Still it remains to be seen if in this very case the spur will become clinically apparent in the future or not. As long as larger studies on curve correction without spur resection in SSCM are not available, spur resection prior to any type of curve correction remains the golden standard.

Icariin (ICA) has a significant capacity to protect against depression and hippocampal injury, but it cannot effectively cross the blood-brain barrier and accumulate in the brain. Therefore, the mechanism by which ICA protects against hippocampal injury in depression remains unclear. In this study, we performed proteomics analysis of cerebrospinal fluid to investigate the mechanism by which ICA prevents dysfunctional hippocampal neurogenesis in depression. A rat model of depression was established through exposure to chronic unpredictable mild stress for 6 weeks, after which 120 mg/kg ICA was administered subcutaneously every day. The results showed that ICA alleviated depressive symptoms, learning and memory dysfunction, dysfunctional neurogenesis, and neuronal loss in the dentate gyrus of rats with depression. Neural stem cells from rat embryonic hippocampi were cultured in media containing 20% cerebrospinal fluid from each group of rats and then treated with 100 μM corticosterone. The addition of cerebrospinal fluid from rats treated with ICA largely prevented the corticosterone-mediated inhibition of neuronal proliferation and differentiation. Fifty-two differentially expressed proteins regulated by chronic unpredictable mild stress and ICA were identified through proteomics analysis of cerebrospinal fluid. These proteins were mainly involved in the ribosome, PI3K-Akt signaling, and interleukin-17 signaling pathways. Parallel reaction monitoring mass spectrometry showed that Rps4x, Rps12, Rps14, Rps19, Hsp90b1, and Hsp90aa1 were up-regulated by chronic unpredictable mild stress and down-regulated by ICA. In contrast, HtrA1 was down-regulated by chronic unpredictable mild stress and up-regulated by ICA. These findings suggest that ICA can prevent depression and dysfunctional hippocampal neurogenesis through regulating the expression of certain proteins found in the cerebrospinal fluid. The study was approved by the Experimental Animal Ethics Committee of Guangzhou University of Chinese Medicine of China in March 2017.

Background Patients who have breast cancer surgery are at risk of axillary web syndrome (AWS), an under-recognized postsurgical complication which can result in shoulder morbidity and functional impairment. Emerging studies have indicated that AWS may persist beyond the first few months after surgery, although few studies have assessed the prevalence and association of AWS beyond a year after diagnosis. Therefore, the aim of this study was to investigate the prevalence and associations for AWS in post-operative breast cancer patients up to 3 years after surgery. Methods This cross sectional observational study was conducted at a community-based cancer rehabilitation center. Patients were evaluated for the presence of AWS via physical examination. Disease-related data was obtained from clinical review and medical records. Descriptive statistics were utilized to illustrate patient demographics and clinical characteristics. Logistic regression analyses were used to determine associations of AWS. Results There were 111 Asian women who were recruited, who had undergone breast surgery and were referred to a national outpatient rehabilitation center. The prevalence of AWS in this population was 28.9%. In the multivariate regression model, significant factors were age p = 0.031) and ALND (OR = 6.54; 95% CI = 1.36–31.3; p = 0.019). There was reduced shoulder flexion ROM (p Conclusions A high prevalence of AWS was reported in breast cancer survivors even at 3 years after breast surgery. Our findings highlight the need to identify breast cancer survivors with AWS even in the survivorship phase, and develop strategies to raise awareness and minimize functional impairment in these patients.

BACKGROUND Idiopathic basal ganglia calcification (IBGC) is a neurodegenerative disease characterized by symmetrical calcification of basal ganglia and other brain region, also known as Fahr’s disease. It can be sporadic or familial, and there is no definite etiology at present. With the development of neuroimaging, the number of reports of IBGC has increased in recent years. However, due to its hidden onset, diverse clinical manifestations, and low incidence, it is likely to be misdiagnosed or ignored by potential patients and their family. CASE SUMMARY We report a case of a 61-year-old man who presented with symptoms of dysphagia and alalia. His computed tomography scan of the brain revealed bilateral symmetric calcifications of basal ganglia, cerebellum, thalamus, and periventricular area. The genetic test showed a new mutation sites of MYORG, c.1438T>G mutation and c.1271_1272 TGGTGCGC insertion mutation. He was finally diagnosed with IBGC. CONCLUSION It is important to detect MYORG mutation when IBGC is suspected, especially in those without an obvious family history, for better understanding of the underlying mechanism and identifying potential treatments.

Context Chinese herbal formula JiaWeiSiNiSan (JWSNS) has been widely used to prevent stress-induced neuropsychiatric ailments in clinics and proven to have therapeutic anti-stress effects on rats. However, the mechanism remains unclear. Objective Based on the proteomics of cerebrospinal fluid (CSF), this study explores the possible mechanism and target proteins of JiaWeiSiNiSan raising stress resilience and preventing stress damage. Materials and methods A 6-week Chronic Unpredictable Mild Stress (CUMS) model was applied on adult Wistar male rats to observe the effects of JWSNS on improving mental stress resilience. Tandem Mass Tag (TMT) proteomics and bioinformatics analysis were used to screen and analyze differentially expressed proteins (DEPs) in CSF. Parallel Reaction Monitoring (PRM) was used to validate target DEPs. Results Significantly decreased sucrose preference, locomotion activity level and accuracy of T-maze, as well as increased immobility time, were observed in CUMS rats compared to CON rats while JWSNS improved above depression-like behaviours. The quantitative proteomics and bioinformatics analysis showed that JWSNS decreased the expression of Rps4x, HSP90AA1, Rps12, Uba1, Rsp14, Tuba1b in CUMS rats CSF (p

Background Pleomorphic adenoma (PA) is the most common benign tumor that occurs in the salivary glands; however, tracheobronchial PA is rarely observed. To the best of our knowledge, fewer than 50 cases have been reported in the literature. We report a 49-year-old woman who had been treated for asthma for 2 years before being diagnosed with PA of the trachea. Case summary A 49-year-old woman was referred to our hospital due to dyspnea upon exertion and chronic cough with wheezing for 2 years. Laboratory tests showed an elevated white blood cell count, absolute neutrophil count, and percentage of neutrophils. A chest computerized tomography scan showed a well-defined, soft-tissue density lesion measuring 2.4 cm × 2.1 cm in the lower trachea. Flexible bronchoscopy revealed that nearly 90% of the tracheal lumen was obstructed. The histopathological and immunohistochemistry features suggested PA of the trachea. Furthermore, we review the characteristics of 29 patients with tracheobronchial PA over the last 30 years. Conclusion Tracheobronchial PA occurs without gender predominance, mostly in the lower or upper trachea, and has a low recurrence rate. The median age at diagnosis is 48 years. The most common symptoms are cough, stridor, dyspnea, and wheezing.

The relationships between interleukin (IL)-6 and cardiac myxoma remain to be clarified. This article systematically reviewed the IL-6 properties in cardiac myxoma patients based on retrieval of pertinent literature published between 1998 and 2018. Significant differences were found in circulating IL-6 values between preoperation and 1 and 6 months after operation. Preoperative circulating IL-6 correlated significantly with tumour volume (r=0.8552, p=0.003), while there were no significant correlations with maximal tumour dimension (r=0.2443, p=0.190). No correlation was found between circulating IL-6 at 1 and 6 months after tumour resection with either tumour volume or with maximal tumour dimension. The positive rate of immunostaining of IL-6 in cardiac myxoma tissues was 93.3%. Overproduction of IL-6 is responsible for the inflammatory presentations, constitutional symptoms, and recurrence and distal embolisation of cardiac myxoma. Cardiac myxoma could be a cellular source of IL-6 release. Cardiac myxoma resection is an absolute choice of eliminating IL-6 production in these patients. Key Words: Cardiac surgical procedures, Cytokines; Inflammation, Interleukin-6, Neoplasms.

BACKGROUND Recent research suggests that although prokinetic agents, acid suppressors, and radical treatment for Helicobacter pylori infection may be effective in patients with functional dyspepsia (FD), a large proportion of patients still fail to respond to these treatments or may suffer from severe adverse reactions. Many traditional Chinese medicinal herbs can regulate the status of the entire body and have special advantages in the treatment of functional diseases. The present study was designed to verify the efficacy of Biling Weitong Granules (BLWTG), a traditional Chinese medicinal herbal compound formula, in alleviating epigastric pain syndrome (EPS) in FD patients, in an attempt to provide an effective prescription for the clinical treatment of this disease. AIM To evaluate the clinical efficacy and safety of BLWTG in treating EPS in patients with FD. METHODS In this multicenter, stratified, randomized, double-blind, placebo-controlled, parallel group clinical trial, eligible patients were randomized into the BLWTG and placebo groups who were treated for 6 wk. Efficacy indicators including the severity and frequency of EPS and the time to pain resolution and safety indicators including adverse events were observed and compared. RESULTS The baseline demographic data and clinical characteristics, such as epigastric pain symptoms, pain intensity, and frequency of attacks, were matched between the two groups before randomization. After 6 wk of treatment and after the center effect was eliminated, the epigastric pain was significantly improved in 28.33% and 85.59% of the patients in the placebo and BLWTG groups, respectively (P < 0.05). At 6 wk, the resolution rate of epigastric pain was 15% and 69.49% in the placebo and BLWTG groups, respectively (P < 0.05). The differences of total FD clinical score between these two groups were significant (P < 0.05) at 2, 4, and 6 wk (P < 0.05). The scores of each item and the total score in the Functional Digestive Disorders Quality of Life Questionnaire showed significant differences between the two groups at 6 wk after both the center and interaction effects were eliminated (P < 0.05). There was no significant difference in the incidence of adverse events between the two groups, and no serious adverse event was noted during the observation. CONCLUSION Compared with placebo, BLWTG markedly improved EPS in FD patients without causing serious adverse reactions.

Anthocyanins are a type of natural pigment that have high potential for development and utilization in regions like food, pharmaceutical, and cosmetic industries, with nitrogen and phosphorus starvation possibly promoting their accumulation in grapes. However, it remains unclear whether such starvation impacts the grape callus, or how the co-starvation of nitrogen and phosphorus affects the biosynthesis of anthocyanins. Here, we investigated how nitrogen starvation, phosphorus starvation, and the co-starvation of these two elements affects the synthesis of anthocyanins in the callus of grape skin. Results showed that separate starvation of nitrogen and phosphorus, as well as nitrogen and phosphorus co-starvation, inhibited callus growth, while significantly promoting the accumulation of anthocyanins. However, co-starvation did not facilitate anthocyanin biosynthesis during the later stages of callus growth. qRT-PCR analysis showed that the expression of VvUFGT and VvMYBA1 was closely related to anthocyanin accumulation in the callus under nitrogen and phosphorus starvation. Besides, we also confirmed that the abscisic acid signaling pathway was involved in anthocyanin accumulation as well as callus resistance under adverse conditions. This study provides a basis for investigating the regulatory mechanisms of anthocyanin synthesis in grapes, as well as theoretical support for the production of anthocyanins by callus culture. Even though nitrogen and phosphorus deficiencies have been reported to promote anthocyanin biosynthesis in grapevine berries, whether the same deficiencies also induce anthocyanin accumulation in grape callus and whether nitrogen and phosphorus co-deficiency enhances this induction have yet to be reported. Therefore, the present study to investigate the effects of nitrogen starvation, phosphorus starvation, and nitrogen and phosphorus co-starvation on anthocyanin accumulation and ABA signaling in grape callus.

Primary familial brain calcification (PFBC) is a progressive neurological disorder manifesting as bilateral brain calcifications in CT scan with symptoms as parkinsonism, dystonia, ataxia, psychiatric symptoms, etc. Recently, pathogenic variants in MYORG have been linked to autosomal recessive PFBC. This study aims to elucidate the mutational and clinical spectrum of MYORG mutations in a large cohort of Chinese PFBC patients with possible autosomal recessive or absent family history. Mutational analyses of MYORG were performed by Sanger sequencing in a cohort of 245 PFBC patients including 21 subjects from 10 families compatible with a possibly autosomal-recessive trait and 224 apparently sporadic cases. In-depth phenotyping and neuroimaging features were investigated in all patients with novel MYORG variants. Two nonsense variants (c.442C > T, p. Q148*; c.972C > A, p. Y324*) and two missense variants (c.1969G>C, p. G657R; c.2033C > G, p. P678R) of MYORG were identified in four sporadic PFBC patients, respectively. These four novel variants were absent in gnomAD, and their amino acid were highly conserved, suggesting these variants have a pathogenic impact. Patients with MYORG variants tend to display a homogeneous clinical spectrum, showing extensive brain calcification and parkinsonism, dysarthria, ataxia, or vertigo. Our findings supported the pathogenic role of MYORG variants in PFBC and identified two pathogenic variants (c.442C > T, c.972C > A), one likely pathogenic variant (c.2033C > G), and one variant of uncertain significance (c.1969G>C), further expanding the genetic and phenotypic spectrum of PFBC-MYORG.

Fluorouracil (5-FU) and oxaliplatin (L-OHP) are the most commonly used chemotherapy drugs for colorectal cancer, though resistance is common. Compound Sophora injection is a traditional Chinese medicine that can protect the liver against oxidation, improve immunity, and enhance sensitivity to chemotherapy; it may have an effect of reversing resistance in 5-FU- and L-OHP-resistant gastric cancer cells (5-FU/SW480 and L-OHP/SW480, respectively). A concentration gradient experiment was performed to identify a nontoxic dose of compound Sophora injection. 5-FU/SW480 and L-OHP/SW480 cells were treated with the nontoxic dose of compound radix Sophorae injection for 48 h, and changes in drug resistance to 5-FU and L-OHP were detected. Alterations in apoptosis and the cell cycle were assessed, as were the mRNA and protein levels of permeability glycoprotein (P-gp), annexin A1 (ANXA1), and ATP-binding cassette superfamily G member 2 (ABCG2). Flow cytometry showed a reduction in the number of cells in the G1 phase and an increase of cells in the S phase (P<0.05). mRNA and protein expression of P-gp and ABCG2 was significantly higher in 5-FU/SW480 and L-OHP/SW480 cell lines, and ANXA1 expression decreased significantly (P<0.05). Compound Sophora injection can reverse the drug resistance of 5-FU/SW480 and L-OHP/SW480 cell lines to 5-FU and L-OHP, respectively, possibly through a mechanism involving reduced expression of P-gp and ABCG2 but enhanced expression of ANXA1, which is the basis for the identification of clinical drug resistance in colorectal cancer.

Obesity is considered a chronic inflammatory disease, the inflammatory factors, such as interleukin 6 (IL‐6), monocyte chemoattractant protein 1 (MCP‐1) and small inducible cytokine A5 (RANTES), are elevated in obese individuals. Pituitary adenylate cyclase‐activating polypeptide (PACAP) suppresses anti‐inflammatory cytokines and ameliorates glucose and lipid metabolism. Our previous study showed that Fas apoptosis inhibitory molecule (FAIM) is a new mediator of Akt2 signalling, increases the insulin signalling pathway and lipid metabolism. In this study, we found that PACAP promoted the expression of FAIM protein in a human hepatocyte cell line (L02). Overexpression of FAIM with lentivirus suppressed the expression of the inflammatory factor interleukin 6 (IL‐6), monocyte chemoattractant protein 1 (MCP‐1) and tumour necrosis factor alpha (TNF‐α). Following treatment of obese mice with FAIM or PACAP for 2 weeks, inflammation was alleviated and the bodyweight and blood glucose levels were decreased. Overexpression of FAIM down‐regulated the expression of adipogenesis proteins, including SREBP1, SCD1, FAS, SREBP2 and HMGCR, and up‐regulated glycogen synthesis proteins, including Akt2 (Ser474) phosphorylation, GLUT2 and GSK‐3β, in the liver of obese mice. However, down‐regulation of FAIM with shRNA promotes obesity. Altogether, our data identified that FAIM mediates the function of PACAP in anti‐inflammation, glucose regulation and lipid metabolism in obese liver.

Hereditary spastic paraplegias refer to a heterogeneous group of neurodegenerative disorders resulting from degeneration of the corticospinal tract. Clinical characterization of patients with hereditary spastic paraplegias represents progressive spasticity, exaggerated reflexes and muscular weakness. Here, to expand on the increasingly broad pools of previously unknown hereditary spastic paraplegia causative genes and subtypes, we performed whole exome sequencing for six affected and two unaffected individuals from two unrelated Chinese families with an autosomal dominant hereditary spastic paraplegia and lacking mutations in known hereditary spastic paraplegia implicated genes. The exome sequencing revealed two stop-gain mutations, c.247_248insGTGAATTC (p.I83Sfs*11) and c.526G>T (p.E176*), in the ubiquitin-associated protein 1 (UBAP1) gene, which co-segregated with the spastic paraplegia. We also identified two UBAP1 frameshift mutations, c.324_325delCA (p.H108Qfs*10) and c.425_426delAG (p.K143Sfs*15), in two unrelated families from an additional 38 Chinese pedigrees with autosomal dominant hereditary spastic paraplegias and lacking mutations in known causative genes. The primary disease presentation was a pure lower limb predominant spastic paraplegia. In vivo downregulation of Ubap1 in zebrafish causes abnormal organismal morphology, inhibited motor neuron outgrowth, decreased mobility, and shorter lifespan. UBAP1 is incorporated into endosomal sorting complexes required for transport complex I and binds ubiquitin to function in endosome sorting. Patient-derived truncated form(s) of UBAP1 cause aberrant endosome clustering, pronounced endosome enlargement, and cytoplasmic accumulation of ubiquitinated proteins in HeLa cells and wild-type mouse cortical neuron cultures. Biochemical and immunocytochemical experiments in cultured cortical neurons derived from transgenic Ubap1flox mice confirmed that disruption of UBAP1 leads to dysregulation of both early endosome processing and ubiquitinated protein sorting. Strikingly, deletion of Ubap1 promotes neurodegeneration, potentially mediated by apoptosis. Our study provides genetic and biochemical evidence that mutations in UBAP1 can cause pure autosomal dominant spastic paraplegia.

Ultrasound-assisted extraction (UAE) was used to extract procyanidins (PC) from the perilla seed hull. Four independent variables, namely, liquid-to-solid ratio, ethanol concentration, UAE time, and UAE temperature were investigated. Response surface methodology was performed on the basis of results of single-factor tests. The optimal conditions for PC extraction were as follows: a liquid-to-solid ratio of 15:1, an ethanol concentration of 62%, a UAE time of 29 min, and a UAE temperature of 53 °C. Under these conditions, the experimental yield of PC was 2.185 mg/g (n = 3), which is correlated with the predicted value of 2.2 mg/g. The extracted and purified PC showed excellent antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl, hydroxyl, and 2,2’-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radicals in vitro.

In this research, numerical analysis, response surface method (RSM) and experiments are used to investigate and verify the hot forging process for manufacturing aluminum crown forgings for shock absorber assembly. First, establish the computer aided design (CAD) model of the die and the billet, and simulate it from the finite element method (FEM). Second, a new preforming die was designed with a preformed dressing of controllable deformation zone (CDZ) by the CAD software. Third, numerical simulation was combined with RSM to optimize the processing parameters with the aim of minimizing the die wear while the integrity of forgings should be prioritized preserved. According to RSM, the billet size and preformed dressing of CDZ are important factors affecting the distance between die and workpiece (C). The optimal design factor of the preforming die: billet diameter (D), billet length (L) and flash design (F) are 40 mm, 205 mm and CDZ 1, respectively. Through the results of FEM, this study describes the distribution of microscopic grain flow lines are highly related to forming, stress, strain, and temperature as well as die design such as CDZ in preformed dressing. In order to accurately verify that the parameters analyzed by the RSM, both numerical analysis and physical experiments are carried out and optimal scheme exhibit reasonable consistency.

Previously, we established an optogenetic model to induce Amyloid-β intracellular oligomerization to model distinct disease etiologies (Limet al. 2020). Here we examine the effect of Wnt signaling on Amyloid in this model. We observe that Wnt activation rescues the detrimental effects of Amyloid expression and oligomerization. We analyze the gene expression changes downstream of Wnt that contribute to this rescue and find changes in aging related genes, protein misfolding, metabolism and inflammation. We propose that Wnt expression reduces inflammation through repression of Toll activating factors and confirm that chronic Toll activation reduces lifespan. We propose that the protective effect observed for Lithium treatment functions at least in part through Wnt activation and inhibition of inflammation.

The intestinal flora is recognized as a significant contributor to the immune system. In this research, the protective effects of oyster peptides on immune regulation and intestinal microbiota were investigated in mice treated with cyclophosphamide. The results showed that oyster peptides restored the indexes of thymus, spleen and liver, stimulated cytokines secretion and promoted the relative mRNA levels of Th1/Th2 cytokines (IL-2, IFN-γ, IL-4 and IL-10). The mRNA levels of Occludin, Claudin-1, ZO-1, and Mucin-2 were up-regulated, and the NF-κB signaling pathway was also activated after oyster peptides administration. Furthermore, oyster peptides treatment reduced the proportion of Firmicutes/Bacteroidetes, increased the relative abundance of Alistipes, Lactobacillus, Rikenell and the content of short-chain fatty acids, and reversed the composition of intestinal microflora similar to that of normal mice. In conclusion, oyster peptides effectively ameliorated cyclophosphamide-induced intestinal damage and modified gut microbiota structure in mice, and might be utilized as a beneficial ingredient in functional foods for immune regulation.

Purpose To evaluate the value of impulse oscillometry (IOS) and quantitative HRCT parameters for differentiating asthma-COPD overlap (ACO) in COPD patients. Patients and Methods We enrolled 44 controls and 66 COPD patients, divided into the pure COPD group (n=40) and the ACO group (n=26). Spearman correlation analysis was utilized to assess the relationship between the quantitative HRCT and IOS parameters. A binary logistic regression analysis was performed to analyze the associations between the different variables and the risk of ACO. Receiver operating characteristic (ROC) curves were employed to identify the optimal cutoff and assess the diagnostic value of relative volume change -856 HU to -950 HU (RVC-856 to -950), decrease in the resistance from 5 Hz to 20 Hz (R5-R20) and their combination in predicting ACO. Bootstrapping validation was used to evaluate the internal validation. The concordance index (C-index) and calibration plot were calculated to assess the discrimination and calibration of the prediction model. Results Binary logistic regression analysis indicated that RVC-856 to -950 and the IOS parameters (R5-R20, R5, X5) were independently correlated with a higher risk of developing ACO after adjusting for age, sex, body mass index (BMI), history of smoking, exacerbation and atopy or allergic rhinitis. A correlation analysis showed a good correlation between the pulmonary function parameters and RVC-856 to -950, with a weaker correlation with the % area of low attenuation (LAA%) in ACO patients. Combining RVC-856 to -950 and R5-R20 to predict ACO, the AUC was 0.909, and the optimal cutoff value was >-0.62 for RVC-856 to -950 and >0.09 for R5-R20. Good calibration and favorable discrimination were displayed with a higher C-index. Conclusion More serious small airway impairment exists in ACO patients. The combination of RVC-856 to -950 and R5-R20 could be applied to differentiate ACO from COPD patients.

Proper embryonic development requires directional axes to pattern cells into embryonic structures. In Drosophila, spatially discrete expression of transcription factors determines the anterior to posterior organization of the early embryo, while the Toll and TGFβ signalling pathways determine the early dorsal to ventral pattern. Embryonic MAPK/ERK signaling contributes to both anterior to posterior patterning in the terminal regions and to dorsal to ventral patterning during oogenesis and embryonic stages. Here we describe a novel loss of function mutation in the Raf kinase gene, which leads to loss of ventral cell fates as seen through the loss of the ventral furrow, the absence of Dorsal/NFκB nuclear localization, the absence of mesoderm determinants Twist and Snail, and the expansion of TGFβ. Gene expression analysis showed cells adopting ectodermal fates much like loss of Toll signaling. Our results combine novel mutants, live imaging, optogenetics and transcriptomics to establish a novel role for Raf, that appears to be independent of the MAPK cascade, in embryonic patterning.

Background: Proton pump inhibitors (PPIs) are validated gastric acid suppressors and have been widely used to treat patients with active duodenal ulcers. Although existing PPIs have shown great efficacy, many scientists are still devoted to developing more effective PPIs with better safety profile. Herein, we aimed to compare the safety and efficacy of anaprazole in duodenal mucosal healing, a novel PPI, to that of rabeprazole.Methods: In this multicenter, randomized, positive-controlled, double-blinded, parallel-group phase II clinical trial, a total of 150 qualified patients with endoscopically confirmed active duodenal ulcers were randomized (1:1:1) to receive rabeprazole 10 mg, anaprazole 20 mg or anaprazole 40 mg for 4 weeks. The ulcer healing rates after 4 weeks of treatment were compared between groups by independent central review and investigator review. In addition, symptoms and safety were evaluated.Results: Based on the independent central review, the ulcer healing rates of the 10 mg rabeprazole, 20 mg anaprazole and 40 mg anaprazole groups were 88.0, 85.1, and 87.5%, respectively, in the FAS population and 88.9, 86.0, and 90.9%, respectively, in the PPS population. The ulcer healing rate difference between anaprazole 20 mg and Rabeprazole 10 mg is −2.9% (95% CI, −16.5–10.7%), and −0.5% (95% CI, −13.5–12.5%) between anaprazole 40 mg and Rabeprazole 10 mg, in the FAS population. Based on the investigator review, the ulcer healing rates of the 10 mg rabeprazole, 20 mg anaprazole, and 40 mg anaprazole groups were 72.0, 70.2, and 77.1%, respectively, in the FAS population and 75.6, 72.1, and 79.5%, respectively, in the PPS population. The ulcer healing rate difference between anaprazole 20 mg and Rabeprazole 10 mg is −1.8% (95% CI, −19.8–16.3%), and 5.1% (95% CI, −12.2–22.3%) between anaprazole 40 mg and Rabeprazole 10 mg, in the FAS population. Most patients (>90%) eventually achieved complete symptom relief. The incidence rates of adverse events were of no significant differences among the treatment groups. Potential possible better liver tolerance was observed in two anaprazole dose groups than rabeprazole 10 mg group.Conclusion: Both at a dosage of 20 and 40 mg daily, anaprazole, is effective with good safety profile in the treatment of active duodenal ulcers in this Phase 2 study, which allows anaprazole to be advanced to a phase III clinical trial.Clinical Trial Registration:https://www.clinicaltrials.gov/ct2/results?cond=&term=NCT04503629&cntry=&state=&city=&dist=, Identifier: CTR20181464, NCT04503629.

Few studies have investigated the relationship between sarcopenia and mild to moderate renal decline. This study aimed to investigate the relationship between chronic kidney disease (CKD) and sarcopenia. In total, 123 patients hospitalized with CKD and 57 healthy volunteers who underwent physical examination during the same period (control group) were analyzed. Body compositions were measured by dual-energy X-ray absorptiometry, and the relative appendicular skeletal muscle index (RASMI) was calculated. Muscular strength was evaluated using a pinch meter. Walking speed within 6 m was measured for muscular function assessment. Single-photon emission computed tomography was performed to measure the glomerular filtration rate (GFR) of CKD patients, who were then divided into CKD1 (55 patients in CKD stages 1 and 2) and CKD2 (68 patients in CKD stages 3-5). The incidence rates of sarcopenia were significantly higher in the CKD1 (40.0%) and CKD2 (55.9%) groups than in the control group (19.3%) (P

The nigrostriatal dopaminergic (DA) system, which includes DA neurons in the ventral and dorsal tiers of the substantia nigra pars compacta (vSNc, dSNc) and DA terminals in the dorsal striatum, is critically implicated in motor control. Accumulating studies demonstrate that both the nigrostriatal DA system and motor function are impaired in aged subjects. However, it is unknown whether dSNc and vSNc DA neurons and striatal DA terminals age in similar patterns, and whether these changes parallel motor deficits. To address this, we performed ex vivo patch-clamp recordings in dSNc and vSNc DA neurons, measured striatal dopamine release, and analyzed motor behaviors in rodents. Spontaneous firing in dSNc and vSNc DA neurons and depolarization-evoked firing in dSNc DA neurons showed inverse V-shaped changes with age. But depolarization-evoked firing in vSNc DA neurons increased with age. In the dorsal striatum, dopamine release declined with age. In locomotor tests, 12-month-old rodents showed hyperactive exploration, relative to 6- and 24-month-old rodents. Additionally, aged rodents showed significant deficits in coordination. Elevating dopamine levels with a dopamine transporter inhibitor improved both locomotion and coordination. Therefore, key components in the nigrostriatal DA system exhibit distinct aging patterns and may contribute to age-related alterations in locomotion and coordination.

Breast cancer is the most common type of cancer diagnosed among women, and basal-like breast carcinoma (BLBC) has been associated with a more aggressive histology, poorer prognosis, and non-responsiveness to hormone therapy. In the present study, the role and molecular mechanism of circular (circ)_NOTCH3 in the development and progression for BLBC was identified. circ_RNAs array was used to screen the ectopic expression of hsa_circ_0109177 (circ_NOTCH3) in BLBC. RT-qPCR was conducted to evaluate the circ_NOTCH3 expression in BLBC tissues and paired normal tissues, as well as related cell lines. Cell function changes were analyzed following circ_NOTCH3 or micro (mi)RNA overexpression or co-expression. Bioinformatics analysis and dual-luciferase reporter assay were performed to predict and verify the binding sites between circ_NOTCH3 and miRNAs. Gene expression changes were assessed using western blotting. circ_NOTCH3 had a significantly higher expression in BLBC tissues and cell lines. The upregulation of circ_NOTCH3 promoted the proliferation, migration, invasion and inhibited the apoptosis for BLBC cells. The opposite results were observed following miR-205-5p overexpression. However, the co-expression of circ_NOTCH3 and miR-205-5p resulted in those restoration. circ_NOTCH3 is capable of binding to miR-205-5p, and upregulating its target gene KLF12, which can be downregulated by miR-205-5p overexpression and restored by the co-expression of circ_NOTCH3 and miR205-5p. circ_NOTCH3, being an protooncogene and a powerful biomarker, can function as a sponge, compete with miR-205-5p, modulate KLF12 expression, and promote the development and progression of BLBC.

A large number of colorectal cancers have a genetic background in China. However, due to insufficient awareness, the diagnostic rate remains low and merely 5-6% of colorectal cancer patients are diagnosed with hereditary colorectal cancer. Familial adenomatous polyposis (FAP) is an autosomal dominant genetic disease caused by mutations in the adenomatous polyposis coli (APC) gene. Different mutation sites in APC are associated with the severity of FAP, risks of carcinogenesis, and extraintestinal manifestations. We used next-generation sequencing (NGS) and capture techniques to screen suspected mutation points in the proband in this pedigree. Using modified Sanger sequencing, we identified members of the family who were carriers of this variant and whether this segregated well with disease occurrence. FAP family members had multiple adenomatous polyps in their gastrointestinal tracts, some of which developed into cancer with age. Two subjects presented a rare common bile duct polyp phenotype. No extraintestinal manifestations were observed. A heterozygous frameshift mutation in APC exon 16 (NM_000038.6) was observed in the proband and in other patients: c.3260_3261del (p.Leu1087GlnQfs ∗ 31) (rs587782305); the variant call format was CCT/C. Due to the deletion of two bases, a stop codon appeared after 31 amino acids, and the protein was truncated prematurely, which affected the conformation of the protein. Pedigree genetic linkage analysis showed that the clinical phenotype cosegregated with the APC mutation p.L1087fs. This mutation may be the pathogenic in this FAP family and responsible for this rare common bile duct polyp.

Simple Summary In this review, we discuss treatment strategies in biliary tract cancers (gallbladder cancer, intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma). In particular, we will describe advances in cellular therapies and cancer vaccines for biliary tract cancers, followed by our local experience with combining a melanoma-associated antigen (MAGE)-positive cell lysate-based autologous dendritic cell vaccine and anti-angiogenic therapy (bevacizumab) in a case of stage IV gallbladder cancer. Abstract Biliary tract cancer (BTC) is a rare, but aggressive, disease that comprises of gallbladder carcinoma, intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma, with heterogeneous molecular profiles. Advanced disease has limited therapeutic options beyond first-line platinum-based chemotherapy. Immunotherapy has emerged as a viable option for many cancers with a similar unmet need. Therefore, we reviewed current understanding of the tumor immune microenvironment and recent advances in cellular immunotherapy and therapeutic cancer vaccines against BTC. We illustrated the efficacy of dendritic cell vaccination in one patient with advanced, chemorefractory, melanoma-associated antigen (MAGE)-positive gallbladder carcinoma, who was given multiple injections of an allogenic MAGE antigen-positive melanoma cell lysate (MCL)-based autologous dendritic cell vaccine combined with sequential anti-angiogenic therapy. This resulted in good radiological and tumor marker response and an overall survival of 3 years from diagnosis. We postulate the potential synergism of adding anti-angiogenic therapy, such as bevacizumab, to immunotherapy in BTC, as a rational scientific principle to positively modulate the tumor microenvironment to augment antitumor immunity.

Background: Early-stage diagnosis and treatment can improve survival rates of liver cancer patients. Dynamic contrast-enhanced MRI provides the most comprehensive information for differential diagnosis of liver tumors. However, MRI diagnosis is affected by subjective experience, so deep learning may supply a new diagnostic strategy. We used convolutional neural networks (CNNs) to develop a deep learning system (DLS) to classify liver tumors based on enhanced MR images, unenhanced MR images, and clinical data including text and laboratory test results. Methods: Using data from 1,210 patients with liver tumors (N = 31,608 images), we trained CNNs to get seven-way classifiers, binary classifiers, and three-way malignancy-classifiers (Model A-Model G). Models were validated in an external independent extended cohort of 201 patients (N = 6,816 images). The area under receiver operating characteristic (ROC) curve (AUC) were compared across different models. We also compared the sensitivity and specificity of models with the performance of three experienced radiologists. Results: Deep learning achieves a performance on par with three experienced radiologists on classifying liver tumors in seven categories. Using only unenhanced images, CNN performs well in distinguishing malignant from benign liver tumors (AUC, 0.946; 95% CI 0.914–0.979 vs. 0.951; 0.919–0.982, P = 0.664). New CNN combining unenhanced images with clinical data greatly improved the performance of classifying malignancies as hepatocellular carcinoma (AUC, 0.985; 95% CI 0.960–1.000), metastatic tumors (0.998; 0.989–1.000), and other primary malignancies (0.963; 0.896–1.000), and the agreement with pathology was 91.9%.These models mined diagnostic information in unenhanced images and clinical data by deep-neural-network, which were different to previous methods that utilized enhanced images. The sensitivity and specificity of almost every category in these models reached the same high level compared to three experienced radiologists. Conclusion: Trained with data in various acquisition conditions, DLS that integrated these models could be used as an accurate and time-saving assisted-diagnostic strategy for liver tumors in clinical settings, even in the absence of contrast agents. DLS therefore has the potential to avoid contrast-related side effects and reduce economic costs associated with current standard MRI inspection practices for liver tumor patients.

Exosomes, the nano-vesicles released from living cells, were the important mediator for cell-to-cell communication. In order to clarify whether the exosomes derived from obesity adipose tissue mediate insulin resistance of hepatocytes, we extract the exosomes from the adipose tissue of different mice models. Exosomes derived from ob/ob mice (Ob-exosomes), B6 mice fed with a high-fat diet (HFD-exosomes) and normal B6 mice (WT-exosomes) displayed similar size and molecular makers, but their effect on the insulin sensitivity of hepatocytes were obviously different or opposite. Abundant exosomal miRNAs in Ob-, HFD- and WT-exosomes were detected by the Next Generation Sequencing. The levels of miR-141-3p in Ob- and HFD-exosomes were significantly lower than WT-exosomes. MiR-141-3p can be effectively delivered into AML12 cells accompanied by the absorption of exosomes, but the absorption of miR-141-3p into AML12 cells could be blocked by GW4869, an inhibitor of exosome biogenesis and release. Importantly, the Ob-exosomes or miR-141-3p knockdown in WT--exosomes obviously inhibited the insulin response and glucose uptake of AML12 cells, however, the inhibitory effects on insulin function disappeared after the overexpression of miR-141-3p in Ob-exosomes or AML12 cells. The effects of miR-141-3p on insulin function could be achieved by improving the level of phosphorylation of AKT and enhancing insulin signal transduction. Therefore, the absorption of hepatocytes for exosomes released from obesity adipose tissue containing less miR-141-3p than healthy adipose tissue can significantly inhibit the insulin sensitivity and glucose uptake. Our study may certify a novel mechanism that the secretion of “harmful” exosomes from obesity adipose tissues cause insulin resistance.

Background: miR-24-3p is a microRNA (miRNA) that is involved in the differentiation of various types of cancers and has been shown to act as an oncogene or tumor suppressor in certain cancers. However, the underlying mechanism of the miR-24-3p/TEL2 pathway has not been elucidated yet. Methods: The expression of miR-24-3p mRNA in NP69 cells and five NPC cell lines was detected. miR-24-3p mimics were transfected into S26 and 6-10B cells to explore the effect of miR-24-3p on the TEL2 mRNA and protein levels in NPC by Western blotting. In addition, tissue was collected from 116 patients with NPC, and total RNA was extracted for qRT-PCR to determine the expression of levels TEL2 and miR-24-3p. Furthermore, Transwell assays were conducted to study the effect of cancer cell migration and invasion. Results: In this study, we found that ectopic expression of miR-24-3p decreased the mRNA and protein levels of TEL2 in NPC cells, while knockdown of miR-24-3p increased the mRNA and protein levels of TEL2. Additionally, there was a negative correlation between miR-24-3p and TEL2 in NPC tissues. Mechanistically, we showed that miR-24-3p inhibits TEL2 expression via direct binding to the 3' untranslated region (3' UTR) of TEL2. Conclusions: Collectively, our results suggest that the miR-24-3p/TEL2 pathway may be a new target for treating patients with NPC.

Background Hereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. To date, more than 78 HSP loci have been mapped to cause HSP. However, both the clinical and mutational spectrum of Chinese patients with HSP remained unclear. In this study, we aim to perform a comprehensive analysis of clinical phenotypes and genetic distributions in a large cohort of Chinese HSP patients, and to elucidate the primary pathogenesis in this population. Methods We firstly performed next-generation sequencing targeting 149 genes correlated with HSP in 99 index cases of our cohort. Multiplex ligation-dependent probe amplification testing was further carried out among those patients without known disease-causing gene mutations. We simultaneously performed a retrospective study on the reported patients exhibiting HSP in other Chinese cohorts. All clinical and molecular characterization from above two groups of Chinese HSP patients were analyzed and summarized. Eventually, we further validated the cellular changes in fibroblasts of two major spastic paraplegia (SPG) patients (SPG4 and SPG11) in vitro. Results Most patients of ADHSP (94%) are pure forms, whereas most patients of ARHSP (78%) tend to be complicated forms. In ADHSP, we found that SPG4 (79%) was the most prevalent, followed by SPG3A (11%), SPG6 (4%) and SPG33 (2%). Subtle mutations were the common genetic cause for SPG4 patients and most of them located in AAA cassette domain of spastin protein. In ARHSP, the most common subtype was SPG11 (53%), followed by SPG5 (32%), SPG35 (6%) and SPG46 (3%). Moreover, haplotype analysis showed a unique haplotype was shared in 14 families carrying c.334C > T (p.R112*) mutation in CYP7B1 gene, suggesting the founder effect. Functionally, we observed significantly different patterns of mitochondrial dynamics and network, decreased mitochondrial membrane potential (Δψm), increased reactive oxygen species and reduced ATP content in SPG4 fibroblasts. Moreover, we also found the enlargement of LAMP1-positive organelles and abnormal accumulation of autolysosomes in SPG11 fibroblasts. Conclusions Our study present a comprehensive clinical spectrum and genetic landscape for HSP in China. We have also provided additional evidences for mitochondrial and autolysosomal-mediated pathways in the pathogenesis of HSP. Electronic supplementary material The online version of this article (10.1186/s13024-018-0269-1) contains supplementary material, which is available to authorized users.

Guan-Sheng Zeng,* Li-Chang Chen,* Hui-Zhen Fan, Ling-Ling Wu, Xi-Ping Wu, Ze-Kui Fang, Xi He, Hua-Peng Yu Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China *These authors contributed equally to this work Background and objective: The distance of 6-minute walk test (D6MWT) has been widely used in the assessment of functional status in patients with COPD, while very little attention has been paid to the role of steps of 6-minute walk test (S6MWT). The purpose of this study was to investigate the relationship between S6MWT and other physiologic parameters of COPD. Patients and methods: Seventy patients with stable COPD were enrolled consecutively in this cross-sectional study. Pulmonary function tests, including spirometry, impulse oscillometry (IOS) and the single-breath diffusing capacity of the lungs for carbon monoxide (DLCO), were carried out at rest. Quality of life was assessed by health-related quality of life (HRQoL) questionnaires, including modified Medical Research Council dyspnea scale (mMRC), St George’s Respiratory Questionnaire, Chronic Obstructive Pulmonary Disease Assessment Test (CAT) and Clinical Chronic Obstructive Pulmonary Questionnaire. Both steps and distance were measured in the following 6-minute walk test (6MWT). Results: Both S6MWT and D6MWT showed significant correlation with spirometry, IOS, DLCO parameters and HRQoL questionnaires score. Both pre- and post-6MWT inspiratory capacity showed significant correlation with S6MWT (ρ=0.338, P=0.004; ρ=0.359, P=0.002, respectively), whereas did not correlate with D6MWT (ρ=0.145, P=0.230; ρ=0.160, P=0.189, respectively). In stepwise multiple regression analysis, mMRC grade, age and CAT score remained as significant predictors in the final model for D6MWT (adjusted R2=0.445, P