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Background Annexin A1 might be neuroprotective and serum annexin A1 concentrations were markedly declined after severe traumatic brain injury. We determine dthe ability of serum annexin A1 to assess severity and predict prognosis after aneurysmal subarachnoid hemorrhage (aSAH). Methods We included 157 aSAH patients and 157 healthy subjects. Serum annexin A1 measurements were measured. A poor outcome was designated as Glasgow outcome scale score of 1–3. Multivariate logistic regression analysis was applied to identify predictors of a poor 6-month outcome. Results Serum annexin A1 concentrations were significantly lower in patients than in controls. Annexin A1 concentrations were strongly correlated with the World Federation of Neurological Surgeons scale (WFNS) score, Hunt-Hess score, Glasgow coma scale score and modified Fisher score. A total of 59 patients (37.6%) experienced a poor outcome. Serum annexin A1, WFNS score and modified Fisher score emerged as the 3 independent predictors for a poor outcome after aSAH. Under ROC curve analysis, serum annexin A1 had a fair accuracy to predict a poor outcome, AUC of serum annexin A1 concentration was equivalent to those of WFNS score and modified Fisher score and AUC of combination of the 3 factors significantly exceeded that of each one alone. Conclusions Annexin A1 may be involved in the occurrence and progression of secondary brain injury after aSAH. Detection of serum annexin A1 may have certain ability for assessment of severity and prediction of long-term prognosis following aSAH.

Parkinson’s disease (PD) is the second most common neurodegenerative disease, characterised by the loss of dopaminergic neurons in the substantia nigra. Mounting evidence indicates a crucial role of inflammation and concomitant oxidative stress in the disease progression. Therefore, the aim of this study was to investigate the ability of systemically administered lipopolysaccharide (LPS) to induce motor and non-motor symptoms of PD, inflammation, oxidative stress and major neuropathological hallmarks of the disease in regions postulated to be affected, including the olfactory bulb, hippocampus, midbrain and cerebellum. Twenty-one male C57BL/6 mice, approximately 20 weeks old, received a dose of 0.3 mg/kg/day of LPS systemically on 4 consecutive days and behavioural testing was conducted on days 14–18 post-treatment, followed by tissue collection. Systemically administered LPS increased latency time in the buried food seeking test (indicative of olfactory impairment), and decreased time spent in central zone of the open field (anxiety-like behaviour). However, there was no change in latency time in the rotarod test or the expression of tyrosine hydroxylase (TH) in the midbrain. Systemically administered LPS induced increased glial markers GFAP and Iba-1 and oxidative stress marker 3-nitrotyrosine (3- NT) in the olfactory bulb, hippocampus, midbrain and cerebellum, and there were region specific changes in the expression of NFκB, IL-1β, α-synuclein, TH and BDNF proteins. The model could be useful to further elucidate early non-motor aspects of PD and the possible mechanisms contributing to the non-motor deficits. Refereed/Peer-reviewed

Alzheimer’s disease (AD) is the most common cause of dementia among elderly people. Majority of AD cases are sporadic (SAD) with unknown cause. Transgenic animal models closely reflect the familial (genetic) aspect of the disease but not the sporadic type. However, most new drug candidates which are tested positive in transgenic animal models failed in clinical studies so far. Herein, we aim to develop an AD animal model that combines most of the neuropathological features seen in sporadic AD in humans with amyloid plaques observed in transgenic mice. Four-month-old wild-type and APP/PS1 AD mice were given a single intracerebroventricular (ICV) injection of 3 mg/kg streptozotocin (STZ), a diabetogenic agent. Three weeks later, their cognitive behavior was assessed, and their brain tissues were collected for biochemical and histological analysis. STZ produced cognitive deficits in both non-transgenic mice and AD mice. Biochemical analysis showed a severe decline in synaptic proteins, increase in tau phosphorylation, oxidative stress, disturbed brain insulin signaling with extensive neuroinflammation, and cell death. Significant increase was also observed in the level of the soluble beta amyloid precursor protein (APP) fragments and robust accumulation of amyloid plaques in AD mice compared to the control. These results suggest that STZ ICV treatment causes disturbance in multiple metabolic and cell signaling pathways in the brain that facilitated amyloid plaque accumulation and tau phosphorylation. Therefore, this animal model can be used to evaluate new AD therapeutic agents for clinical translation Refereed/Peer-reviewed

Exercise has been recommended as an important strategy to improve glucose metabolism in obesity. Adipose tissue fibrosis is associated with inflammation and is implicated in glucose metabolism disturbance and insulin resistance in obesity. However, the effect of exercise on the progression of adipose tissue fibrosis is still unknown. The aim of the present study was to investigate whether exercise retarded the progression of adipose tissue fibrosis and ameliorated glucose homeostasis in diet-induced obese mice. To do so, obesity and adipose tissue fibrosis in mice were induced by high-fat diet feeding for 12 weeks and the mice subsequently received high-fat diet and exercise intervention for another 12 weeks. Exercise alleviated high-fat diet-induced glucose intolerance and insulin resistance. Continued high-fat diet feeding exacerbated collagen deposition and further increased fibrosis-related gene expression in adipose tissue. Exercise attenuated or reversed these changes. Additionally, PPARγ, which has been shown to inhibit adipose tissue fibrosis, was observed to be increased following exercise. Moreover, exercise decreased the expression of HIF-1α in adipose fibrosis, and adipose tissue inflammation was inhibited. In conclusion, our data indicate that exercise attenuates and even reverses the progression of adipose tissue fibrosis, providing a plausible mechanism for its beneficial effects on glucose metabolism in obesity.

Elbow pipe is one of the components in pipeline transportation. The impact force caused by the liquid flow in the pipe elbow produces the strain on the wall. So, the monitoring of impact force can be realized by measuring strain. This article developed a new nonintrusive method to detect the impact force on the 90° horizontal bend pipe by measuring the axial strain and the hoop strain on the outer wall of the pipe elbow. Taking three typical cross-sections (i.e. $\theta = 0^{\circ }$ , $\theta = 45^{\circ }$ , and $\theta = 90^{\circ }$ ) of the pipe elbow as examples, the impact forces were adjusted by the inlet velocity in the bend pipe based on a specific relationship. The nonintrusive method was based on fiber Bragg grating (FBG) sensors, measuring the axial strain and hoop strain on the outer wall of the elbows caused by the impact force accurately. In this article, the theoretical study and numerical analysis by ANSYS Fluent based on the finite-element method were detailed in our initial work. Then, strain gauges were used to verify the effectiveness and accuracy of FBG monitoring. The results demonstrated that the FBG sensors had good performance on the strain measurement and were sensitive to the variation of the impact force caused by different velocity levels. The lightweight and easy networking of this method make it have a wide range of application prospects.

Rationale: Brain-derived neurotrophic factor precursor (proBDNF) is expressed in the central nervoussystem (CNS) and the immune system. However, the role of proBDNF in the pathogenesis of multiplesclerosis (MS) is unknown. Methods: Peripheral blood and post-mortem brain and spinal cord specimens were obtained from multiple sclerosis patients to analyze proBDNF expression in peripheral lymphocytes and infiltrating immune cells in the lesion site. The proBDNF expression profile was also examined in the experimental autoimmune encephalomyelitis (EAE) mouse model, and polyclonal and monoclonal anti-proBDNF antibodies were used to explore their therapeutic effect in EAE. Finally, the role of proBDNF in the inflammatory immune activity of peripheral blood mononuclear cells (PBMCs) was verified in vitro experiments. Results: High proBDNF expression was detected in the circulating lymphocytes and infiltrated inflammatory cells at the lesion sites of the brain and spinal cord in MS patients. In the EAE mouse model, proBDNF was upregulated in CNS and in circulating and splenic lymphocytes. Systemic but not intracranial administration of anti-proBDNF blocking antibodies attenuated clinical scores, limited demyelination, and inhibited proinflammatory cytokines in EAE mice. Immuno-stimulants treatment increased the proBDNF release and upregulated the expression of p75 neurotrophic receptors (p75NTR) in lymphocytes. The monoclonal antibody against proBDNF inhibited the inflammatory response of PBMCs upon stimulations. Conclusion: The findings suggest that proBDNF from immune cells promotes the immunopathogenesis of MS. Monoclonal Ab-proB may be a promising therapeutic agent for treating MS. Refereed/Peer-reviewed

Up-regulation of proBDNF in ischemic brain and the detrimental role of proBDNF on cellular survival has already been established. We propose that the up-regulated proBDNF may trigger the harmful events and evoke a secondary ischemic damage after ischemia. This study aimed to establish the neuroprotective effects of anti-proBDNF antibody in a rat photothrombotic ischemic model. Photothrombotic ischemic model was performed on Sprague Dawley rats and anti-proBDNF antibodies were administered intraperitoneally to the ischemic rats at a dose of 5 mg/kg after 6 hours (6 h) and on 3 days (3d) after ischemia. Behavioural tests were performed for sensorimotor functional analyses. Animals were euthanized at 7d for histochemical and biochemical studies. We observed higher proBDNF expression around the ischemic infarct. Higher level of apoptosis and inflammation was evident at 7d after ischemia on brain sections. Interestingly, the anti-proBDNF treatment instigated significant reduction of the infarction size as detected by Haematoxylin and Eosin (H&E) staining. Similar reduction of apoptotic signaling proteins in western blot and immunostaining after anti-proBDNF treatment was found. Up-regulation of synaptic protein expression was also observed after this treatment. Significant sensorimotor functional improvements were also noticed at 7d after anti-proBDNF treatment. We conclude that anti-proBDNF treatment is anti-apoptotic and anti-inflammatory, and plays advantageous role in promoting cellular growth and improving sensorimotor function after ischemic insult. Taken together, our study suggests that this anti-proBDNF treatment can be considered as a therapeutic approach for ischemic recovery. Refereed/Peer-reviewed

The processing errors for columns of heavy-duty machine tools are affected by deformation induced by a variety of force loads and thermal loads. In general, error reduction usually uses method of error compensation. However, the precondition of error compensation is to accurately obtain the machine full-field displacement. The inverse finite element method (iFEM) is an efficient tool for the real-time reconstruction of deformation. It obtains nodal degree of freedoms (DOFs) by solving the minimum value of the error least-squares function, which constitutes the relationship between the DOFs and analytical strain. Although double-sided strain rosettes are widely used in the iFEM to obtain strain information, the strain rosettes have some shortcomings, including the internal installation being difficult and measurement size being large. Fiber Bragg grating (FBG) sensors have the advantages of being lightweight, small geometric profile and being easy to installation. Therefore, this study utilizes distributed single-sided and unidirectional strain data obtained from FBG sensors. To further improve the possibility of this practical application, cubic spline interpolation is used to reduce the number of sensors and further extend the practical usefulness. Considering coordinate transformation and boundary conditions, the total deformation of the column is determined. The superior accuracy and practical applicability of the improved formulation is demonstrated after comparing the results of analytic solutions and that of the FEM. Therefore, new direction method for supporting the machining precision of heavy-duty machine tools is proposed.

Image information security is an important research direction in the field of information security. In existed image encryption schemes, original image is transformed to meaningless random noise si...

Background B3GNT3 (β1, 3-N-acetylglucosaminyltransferase-3) belongs to the β3GlcNAcT family and is essential to form extended core 1 oligosaccharides. Previous studies revealed that B3GNT3 expression was dysregulated in multiple cancers. Here, we aimed to understand the expression profile and function of B3GNT3 in lung cancer. Materials and methods The expression of B3GNT3 was measured by immunohistochemistry and public database analysis. B3GNT3 was knocked down to evaluate the lung cancer cell proliferation, migration and invasion in in vitro and in vivo tumor formation experiments. miR-149-5p targeting B3GNT3 was identified with TargetScan analysis and confirmed with reporter assay. Overexpression of miR-149-5p was achieved using microRNA mimics and function of microRNA-149-5p/B3GNT3 axis was tested in vitro. Results B3GNT3 was upregulated in lung cancer, and B3GNT3 overexpression was associated with poor prognosis of lung cancer patients. High expression of B3GNT3 was associated with advanced TNM stages, larger tumor size, tumor metastasis and recurrence. Functionally, we demonstrated that knockdown of B3GNT3 suppressed lung cancer cell growth and invasion in vitro. Knockdown of B3GNT3 suppressed lung cancer development in a xenograft tumor model. Moreover, miR-149-5p was validated to negatively regulate B3GNT3 expression through directly targeting B3GNT3 3'-UTR. Overexpression of miR-149-5p could antagonize the tumorigenesis effect of B3GNT3 in vitro. Conclusion In summary, our study demonstrated that B3GNT3 overexpression was correlated with poor prognosis of lung cancer patient, indicating that B3GNT3 could be a promising prognostic biomarker for lung cancer. miR-149-5p negatively regulated B3GNT3 expression, which might be utilized for therapeutic target in lung cancer.

Intrahepatic cholangiocarcinoma (ICC) remains a highly heterogeneous disease with poor prognosis. Tumor-infiltrating lymphocytes were predictive in various cancers, but their prognostic value in ICC is less clear. A total of 168 ICC patients who had received liver resection were enrolled and assigned to the derivation cohort. Sixteen immune markers in tumor and peritumor regions were examined by immunohistochemistry. A least absolute shrinkage and selection operator model was used to identify prognostic markers and to establish an immune signature for ICC (ISICC ). An ISICC -applied prediction model was built and validated in another independent dataset. Five immune features, including CD3peritumor (P) , CD57P , CD45RAP , CD66bintratumoral (T) and PD-L1P , were identified and integrated into an individualized ISICC for each patient. Seven prognostic predictors, including total bilirubin, tumor numbers, CEA, CA19-9, GGT, HBsAg and ISICC , were integrated into the final model. The C-index of the ISICC -applied prediction model was 0.719 (95% CI, 0.660-0.777) in the derivation cohort and 0.667 (95% CI, 0.581-0.732) in the validation cohort. Compared with the conventional staging systems, the new model presented better homogeneity and a lower Akaike information criteria value in ICC. The ISICC -applied prediction model may provide a better prediction performance for the overall survival of patients with resectable ICC in clinical practice.

Noninvasive laser lipolysis exhibits a considerable potential in the treatment of obesity, but laser absorption by water may lead to dermal thermal damage. A novel multi-pulsed cryogen spra...

Stroke is a leading disease for morbidity and the second leading cause of mortality following ischemic heart disease. The health burden for stroke ranks the fourth of all diseases as measured in disability-adjusted life years [1]. Worldwide annual new stroke incidence is approximately 16 million with the increasing trend of an epidemic due to the aging population [2]. Despite significant progress in the management of stroke with the introduction of thrombolytic and endovascular thrombectomy therapies in recent years, a large number of patients are still left without any effective treatment due to delayed time windows and contraindications. Furthermore, these therapeutic interventions can only be used in a small fraction of stroke patients in centralized hospitals. For these reasons, neuroprotective therapy is urgently needed. However, even though thousands of neuroprotective drugs have been tested preclinically and clinically, there is no effective neuroprotective drug available for stroke [3]. The failure in neuroprotective drug development for stroke is frustrating and the hopeless situation has forced scientists shift attention from early neuroprotection to delayed mechanisms of stroke-related co-morbidities, regeneration, and plasticity. Refereed/Peer-reviewed

Background Mixed evidence challenges preoperative alpha-fetoprotein (AFP) as an independent prognostic factor for patients with hepatocellular carcinoma (HCC) after hepatectomy. Results Daily post-operative decrease of AFP by 9% as compared to the preoperative level (A09) were selected as the Cut-off. The Kaplan-Meier curve showed that A09 was significantly different for OS (P=0.043) and RFS (P=0.03). A decrease in risk by 54% was observed for OS and 32% for RFS in the at-risk population (A09>9%). A better concordance was observed after adding A09 into TNM and BCLC staging systems. Moreover, a consistent concordance was observed in the internal (FDZS5:0.63; FDZS3:0.608) and external (FDZS5:0.85; FDZS3:0.762) validation cohorts, suggesting its prognostic value in HCC population with elevated AFP. Conclusions Decrease in perioperative serum AFP rather than preoperative AFP is an independent prognostic factor for HCC patients after hepatectomy. Cut-off A09 significantly discriminates overall and recurrence-free survival and could be interpret into TNM and BCLC staging systems to improve the stratification power for HCC patients with elevated AFP. Methods Kaplan-Meier curve depicted the differences of overall survival (OS) and recurrence-free survival (RFS). Nomogram and concordance were employed to evaluate the superiority of the current staging system.

Introduction and aims Age-related severity and distribution of haemophilic arthropathy (HA) among Chinese patients with haemophilia using the Haemophilia Early Detection with Ultrasound (HEAD-US) system have not been extensively studied. Methods In our study, 89 patients with moderate and severe haemophilia were recruited. A total of 534 joints (knees, ankles and elbows on both sides included) were evaluated using musculoskeletal ultrasound (MSKUS) and scored using the HEAD-US system. Results Prevalence and average number of HA were 39.1% and 0.7, 90.6% and 3.2, 94.1% and 4.5, and 100% and 4.3 for ages ≤10, 11-20, 21-30 and 31-40 years, respectively. Prevalence and mean number of knee, ankle and elbow arthropathies also increased with age, although joint damages progressed in unparallel patterns. A significant difference in synovium subscores was observed between patients aged 10 years. An increasing tendency was observed in cartilage and subchondral bone subscores along with age before 30 years. No significant difference in mean joint scores was found between patients receiving on-demand therapy and those receiving on-demand to low-dose prophylactic therapy. Conclusions Haemophilic arthropathy developed in early childhood and progressed mainly before 30 years of age among Chinese patients with haemophilia, although in different ways among the knee, ankle and elbow.

Background/Aims Cholangiocytes are capable of reabsorbing bile salts from bile, but the pathophysiological significance of this process is unclear. To this end, we detected the expression and distribution of bile acid transport proteins in cholangiocytes from normal rat liver and analyzed the possible pathophysiological significance. Methods Bile duct tissues of Sprague-Dawley rats were isolated by enzymatic digestion and mechanical isolation, and then divided into large and small bile duct tissues. Immunohistochemistry, real-time polymerase chain reaction and Western blotting were used to determine the expression of the apical sodium-dependent bile acid transporter (ASBT), ileal bile acid binding protein (IBABP), and basolateral organic solute transporter α (Ostα) in the biliary tract system of rats. Differences in the expression and distribution of these proteins were analyzed. Results In cholangiocytes, ASBT and IBABP were mainly expressed in cholangiocytes of the large bile ducts, in which the expression of both was significantly higher than that in the small ducts (p0.05). Conclusions Bile acid transporters are expressed and heterogeneously distributed in rat bile ducts, indicating that bile acid reabsorption by cholangiocytes might mainly occur in the large bile ducts. These findings may help explore the physiology of bile ducts and the pathogenesis of various cholangiopathies.

Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy with poor prognosis. The evaluation of recurrence risk after liver resection is of great importance for ICCs. We aimed to assess the prognostic value of intra- and peritumoral immune infiltrations and to establish a novel histopathology-related immunoscore (HRI) associated with ICC recurrence. A total of 280 ICC patients who received curative resection between February 2005 and July 2011 were enrolled in our study. Patients were randomly assigned to the derivation cohort (n = 176) or the validation cohort (n = 104). Sixteen immune biomarkers in both intra- and peritumoral tissues were examined by immunohistochemistry. The least absolute shrinkage and selection operator (LASSO) Cox model was used to establish the HRI score. Cox regression analysis was used for multivariate analysis. Nine recurrence-related immune features were identified and integrated into the HRI score. The HRI score was used to categorize patients into low-risk and high-risk groups using the X-tile software. Kaplan–Meier analysis presented that the HRI score showed good stratification between low-risk and high-risk groups in both the derivation cohort (P

Purpose: To develop and validate a decision aid to help make individualized estimates of tumor recurrence for patients with resected combined hepatocellular cholangiocarcinoma (CHC). Patients and methods: Risk factors of recurrence were identified in the derivation cohort of 208 patients who underwent liver resection between 1995 and 2014 at Zhongshan Hospital to develop a prediction score. The model was subsequently validated in an external cohort of 101 CHC patients using the C concordance statistic and net reclassification index (NRI). Results: On multivariate analysis, five independent predictors associated with tumor recurrence were identified, including sex, γ-glutamyl transferase, macrovascular invasion, hilar lymphoid metastasis and adjuvant transcatheter arterial chemoembolization. The prediction score was constructed using these 5 variables, with scores ranging from 0 to 5. A patient with a score of 0 had a predicted 1- and 5-year recurrence risk of 11.1% and 22.2%, respectively. In the validation cohort, the NRIs of prediction score vs American Joint Committee on Cancer 7th TNM staging system at 1-year and 5-year were 0.185 (95% CI, 0.090-0.279, P

Objective The protective effects of exercise against glucose dysmetabolism have been generally reported. However, the mechanism by which exercise improves glucose homeostasis remains poorly understood. The FGF21–adiponectin axis participates in the regulation of glucose metabolism. Elevated levels of FGF21 and decreased levels of adiponectin in obesity indicate FGF21–adiponectin axis dysfunction. Hence, we investigated whether exercise could improve the FGF21–adiponectin axis impairment and ameliorate disturbed glucose metabolism in diet-induced obese mice. Methods Eight-week-old C57BL/6J mice were randomly assigned to three groups: low-fat diet control group, high-fat diet group and high-fat diet plus exercise group. Glucose metabolic parameters, the ability of FGF21 to induce adiponectin, FGF21 receptors and co-receptor levels and adipose tissue inflammation were evaluated after 12 weeks of intervention. Results Exercise training led to reduced levels of fasting blood glucose and insulin, improved glucose tolerance and better insulin sensitivity in high-fat diet-induced obese mice. Although serum FGF21 levels were not significantly changed, both total and high-molecular-weight adiponectin concentrations were markedly enhanced by exercise. Importantly, exercise protected against high-fat diet-induced impaired ability of FGF21 to stimulate adiponectin secretion. FGF21 co-receptor, β-klotho, as well as receptors, FGFR1 and FGFR2, were upregulated by exercise. We also found that exercise inhibited adipose tissue inflammation, which may contribute to the improvement in the FGF21–adiponectin axis impairment. Conclusions Our data indicate exercise protects against high-fat diet-induced FGF21–adiponectin axis impairment, and may thereby exert beneficial effects on glucose metabolism.

The neurotrophin receptor p75 (p75NTR) plays important roles in regulating amyloid-beta (Aβ) metabolism in the brain. The expression of p75NTR is altered in the brain of patients with Alzheimer's disease (AD). In this study, we aimed to evaluate whether p75NTR mRNA level in the peripheral blood cells is changed among AD patients and its potential to be a biomarker for AD. The study subjects included 26 patients with AD (PiB-PET positive) and 28 cognitively normal controls (PiB-PET negative). RNA was extracted from peripheral blood cells of fast blood. p75NTR mRNA was measured using quantitative real-time PCR assay. p75NTR mRNA levels in blood cells were comparable between AD patients and controls. p75NTR mRNA levels in blood cells were not correlated with MMSE scores, ApoE genotypes, gender, and age. p75NTR mRNA expression in blood cells is not changed in AD patients and is unlikely to be a biomarker for AD Refereed/Peer-reviewed

Stroke is accompanied by severe inflammation in the brain. The role of mature brain-derived neurotrophic factor (mBDNF) in ischemic stroke has received intensive attention, but the function of its precursor proBDNF is less understood. Recent studies showed that mBDNF and proBDNF in the ischemic brain are upregulated, but the significance of mBDNF and proBDNF in the lymphocytes in ischemic stroke is not known. Here, we propose that the expression levels of mBDNF and proBDNF in lymphocytes correlate with those in the brain after ischemic stroke and therefore can be surrogate markers for the ischemic brain. Using a photothrombotic model in rats and ELISA assay technique, we found that proBDNF and mBDNF in peripheral lymphocytes were upregulated but produced differential time courses after ischemia. The levels of mBDNF and proBDNF in lymphocytes at early stages of stroke (1 day), showed a strong positive correlation with those in the brain. The levels of p75, sortilin, were also increased in a time-dependent manner after ischemic stroke; however, the levels of p-TrkB in the ischemic brain at 6 h, 1 and 3 days were significantly reduced in the brain. The present study suggests that the levels of proBDNF and mBDNF in the blood lymphocytes in acute ischemic stroke reflect those in the brain at early stages. Refereed/Peer-reviewed

Background Multiple myeloma (MM) is a heterogeneous disease characterized by chromosomal translocation, deletion, and amplification in plasma cells, resulting in a huge heterogeneity in its outcomes. In the era of novel agents such as bortezomib, thalidomide, and the cycles of treatment, risk stratification by chromosomal aberrations may enable a more rational risk-stratification selection of therapeutic approaches in patients with MM. Patients and Methods We performed a retrospective study in 63 patients with MM; 29 (46.03%) with 1q21 gain and 34 (53.97%) without gain. Result In all patients, we did not find that the patients with 1q21 gain had significantly better survival compared with patients without 1q21 gain (overall survival, P = .6916; progression-free survival, P = .8740). However, in 1q21 gain patients, we found that the bortezomib group had significantly better survival compared with the non-bortezomib group in terms of both the 3-year estimated overall survival (82.3% vs. 18.8%; P = .0154) and progression-free survival (62.8% vs. 8.75%; P = .0385). Conclusion 1q21 gain detected by fluorescence in situ hybridization is not as high risk for poor prognosis with regard to time for overall survival. And the clinical outcome of patients with 1q21 gain can be improved in those who received no less than 4 cycles of bortezomib-based therapy (bortezomib, thalidomide, and dexamethasone).

In the critical period of the new coronary disease, prevention and control, the problems of how to resist the disease, prevent and control the spread of the new coronary disease infection and ensure the health of more than 40 million college students who are confined at home have attracted the attention of education authorities at all levels. In the post-epidemic era, college health education network teaching should be paid more attention to and further improved and promoted. The key work should focus on teaching content arrangement, teaching team formation, teaching form selection and teaching effect evaluation. Especially after the epidemic, we must do a good job in establishing rules and regulations, updating ideas, tapping potential, cultural construction and other aspects.

Objective To present a retrospective review of a single-institute experience with bypass surgery of complex anterior cerebral artery aneurysm. Methods Eight patients (5 females and 3 males; mean age, 34.2 years) with complex anterior cerebral artery aneurysms were treated with bypass. There were 3 precommunicating aneurysms, 1 communicating artery aneurysm, and 4 postcommunicating aneurysms (2 in A2 and 2 in A3). A3-A3 side-to-side in situ bypass was performed in 6 cases. A3–radial artery–A3 interpositional bypass was performed in 1 case with A3 segments located far apart, and A3-A3 transplantation was performed in 1 case with nonparallel aligned A3 segments. Of the 8 aneurysms, 3 were secured with proximal clipping, 1 was secured with distal clipping, 1 was secured with direct clipping, 1 was secured with isolation, and 2 were secured with embolization. Results Aneurysm obliteration was achieved in all cases. Only 1 in situ bypass from a smaller donor artery to a larger recipient artery failed with minor postoperative infarction. Intraoperative bleeding from the site of anastomosis occurred in 1 case during embolization. All patients had complete recovery with normal neurological function during follow-up at outpatient clinics. Conclusions We established a simplified surgical algorithm for complex anterior cerebral artery aneurysms based on the geometrical and spatial relationship between efferent arteries. The reasons for bypass failure and hemorrhagic complication were also discussed.

The problem of low accuracy and low convenience in the existing state of health (SOH) estimation method for vehicle lithium-ion batteries has become one of the important problems in the electric vehicle field. This paper proposes an improved cuckoo search particle filter (ICS-PF) algorithm based on a charging time segment from equal voltage data to estimate battery health status. Appropriate voltage ranges of charging time segments are selected according to the battery charging law, and in the meantime, the charging time segments are collected as a health indicator to establish the corresponding relationship with battery capacity attenuation value. An improved cuckoo search particle filter algorithm based on the traditional particle filter (PF) and cuckoo search (CS) algorithm is proposed by enhancing the search step size and discovery probability to estimate the capacity attenuation. The estimation result shows that this method is superior to the traditional particle filter and cuckoo search particle filter (CS-PF) method, as the maximum estimation error is less than 2%.

Refereed/Peer-reviewed Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder characterized by the pathological hallmarks of β-amyloid plaque deposits, tau pathology, inflammation, and cognitive decline. Hyperoside, a flavone glycoside isolated from Rhododendron brachycarpum G. Don (Ericaceae), has neuroprotective effects against Aβ both in vitro and in vivo. However, whether hyperoside could delay AD pathogenesis remains unclear. In the present study, we observed if chronic treatment with hyperoside can reverse pathological progressions of AD in the APP/PS1 transgenic mouse model. Meanwhile, we attempted to elucidate the molecular mechanisms involved in regulating its effects. After 9 months of treatment, we found that hyperoside can improve spatial learning and memory in APP/PS1 transgenic mice, reduce amyloid plaque deposition and tau phosphorylation, decrease the number of activated microglia and astrocytes, and attenuate neuroinflammation and oxidative stress in the brain of APP/PS1 mice. These beneficial effects may be mediated in part by influencing reduction of BACE1 and GSK3β levels. Hyperoside confers neuroprotection against the pathology of AD in APP/PS1 mouse model and is emerging as a promising therapeutic candidate drug for AD.

ObjectiveProlonged excessive ethanol intake impairs learning, memory and also causes brain atrophy. Brain-derived neurotrophic factor (BDNF) plays pivotal roles in the pathology of alcohol dependence. Our previous work found that chronic ethanol exposure altered the metabolism of BDNF, leading to the imbalance of proBDNF and mature BDNF (mBDNF). In this study, we hypothesized that early alcohol withdrawal would reverse the abnormal levels of proBDNF, mBDNF and their receptors.Method30 male alcohol dependence patients were recruited. Peripheral blood was sampled from all the subjects before and one week after alcohol withdrawal. The lymphocyte protein levels of proBDNF, p75NTR, sortilin and TrkB were analyzed by western blots and the serum level of mBDNF and TrkB was assayed by sandwich enzyme-linked immunosorbent assay (ELISA) at two different time points. ResultsThe levels of mBDNF and its receptor (TrkB) increased, oppositely the levels of proBDNF and its receptors (p75NTR and sortilin) decreased one week after alcohol withdrawal. ConclusionsEarly alcohol withdrawal reversed the abnormal levels of proBDNF, mBDNF and their receptors. The shift levels of proBDNF and mBDNF were both taken in the pathology of alcohol withdrawal.

The purpose of this study is to investigate the significance of alpha-enolase (ENO1) expression in squamous cell carcinoma of the lung (LUSC), its prognostic value, and prospective molecular mechanism. Using multiplatforms data, including in-house immunohistochemistry, in-house real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), in-house microarray, and public high-throughput data, the expression significance and prognostic role of ENO1 in LUSC tissues were analyzed comprehensively. With the combination of all eligible cases, compared with 941 non-LUSC lung tissues, ENO1 was significantly overexpressed in 1163 cases of LUSC (standardized mean difference (SMD) = 1.23, 95% confidence interval (CI) = 0.76–1.70, P P = 0.043). ENO1 and its related genes mainly participated in the pathways of cell division and proliferation. In conclusion, the upregulation of ENO1 could affect the carcinogenesis and unfavorable outcome of LUSC.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Evidence suggests that people can benefit from consumption of diets rich in plant phenolics because they can attenuate AD symptoms. The phenolic glucoside gastrodin is the main bioactive compound of Rhizoma Gastrodiae and is widely used for treating various neurological disorders. In this study, we assess whether long term oral administration of gastrodin can improve cognitive impairment and AD-like pathology. Our results showed that chronic gastrodin administration inhibits aggregation and disaggregate oligomeric and fibrillar species of A beta 42, prevents A beta 42 induced neurotoxicity in cell SH-SY5Y, decreases the levels of A beta plaques and hyperphosphorylated tau, alleviates activation of glial cells and proinflammatory cytokines, attenuates oxidative stress in the APP/PS1 transgenic mice. The mechanisms underlying can be attributed to the inhibition levels of enzymes of A beta and prevention GSK3 beta activity. Our results suggest that gastrodin might be a potential agent for the treatment of AD. Refereed/Peer-reviewed

Brain-derived neurotrophic factor (BDNF) regulates many neurological functions and plays a vital role during the recovery from central nervous system injuries. However, the changes in BDNF expression and associated factors following hypoxia-ischemia induced neonatal brain damage, and the significance of these changes are not fully understood. In the present study, a rat model of hypoxic-ischemic brain damage was established through the occlusion of the right common carotid artery, followed by 2 hours in a hypoxic-ischemic environment. Rats with hypoxic-ischemic brain damage presented deficits in both sensory and motor functions, and obvious pathological changes could be detected in brain tissues. The mRNA expression levels of BDNF and its processing enzymes and receptors (Furin, matrix metallopeptidase 9, tissue-type plasminogen activator, tyrosine Kinase receptor B, plasminogen activator inhibitor-1, and Sortilin) were upregulated in the ipsilateral hippocampus and cerebral cortex 6 hours after injury; however, the expression levels of these mRNAs were found to be downregulated in the contralateral hippocampus and cerebral cortex. These findings suggest that BDNF and its processing enzymes and receptors may play important roles in the pathogenesis and recovery from neonatal hypoxic-ischemic brain damage. This study was approved by the Animal Ethics Committee of the University of South Australia (approval No. U12-18) on July 30, 2018 Refereed/Peer-reviewed

Oxidative stress is a key factor in the pathogenesis of several neurodegenerative disorders and is involved in the accumulation of amyloid beta plaques and Tau inclusions. Edaravone (EDR) is a free radical scavenger that is approved for motor neuron disease and acute ischemic stroke. EDR alleviates pathologies and cognitive impairment of AD via targeting multiple key pathways in transgenic mice. Herein, we aimed to study the effect of EDR on Tau pathology in P301L mice; an animal model of frontotemporal dementia (FTD), at two age time points representing the early and late stages of the disease. A novel EDR formulation was utilized in the study and the drug was delivered orally in drinking water for 3 months. Then, behavioral tests were conducted followed by animal sacrifice and brain dissection. Treatment with EDR improved the reference memory and accuracy in the probe trial as evaluated in Morris water maze, as well as novel object recognition and significantly alleviated motor deficits in these mice. EDR also reduced the levels of 4-hydroxy-2-nonenal and 3-nitrotyrosine adducts. In addition, immunohistochemistry showed that EDR reduced tau phosphorylation and neuroinflammation and partially rescued neurons against oxidative neurotoxicity. Moreover, EDR attenuated downstream pathologies involved in Tau hyperphosphorylation. These results suggest that EDR may be a potential therapeutic agent for the treatment of FTD. Refereed/Peer-reviewed

Background and Objective: p75ECD-Fc is a novel antagonist of toxic amyloid beta protein and other neurodegenerative factors with potential for the treatment of Alzheimer’s disease (AD). Preclinical studies showed that it can alleviate the AD pathologies in animal models of dementia. In a previous paper, we used non-compartmental pharmacokinetic analysis to obtain preliminary pharmacokinetic data for p75ECD-Fc in Sprague Dawley (SD) rats. We also studied the tissue distribution in terms of drug metabolism that helped us to understand possible mechanisms of action. Here, we aim to develop population pharmacokinetic models that can describe the pharmacokinetics of p75ECD-Fc in serum and tissues. Methods: p75ECD-Fc was delivered to SD rats via two routes (intravenous and subcutaneous) at a single dose of 3 mg/kg (n = 15). Blood (n = 12) and tissue samples (n = 10–15) were then separated at different time points for a total duration of 42 days post dosage. The concentration of p75ECD-Fc in serum and tissues was measured using an enzyme-linked immunosorbent assay. Results: Data were best fitted to a 2-compartment model with linear elimination kinetics. The population parameter estimates for clearance, and volume of central and peripheral compartments were 0.000176 L/h, 0.0145 L and 0.0263 L, respectively. The presence of anti-drug antibodies was added to the final model as a covariate on clearance. The subcutaneous bioavailability was estimated to be 53.5% with a first-order absorption rate constant of 0.00745 1/h. By modeling of individual tissue concentrations, p75ECD-Fc was found to exhibit modest tissue distribution with estimated tissue/plasma partition coefficients (R) ranging from 0.004 to 0.2. Conclusion: This is the first report of a pharmacokinetic model for p75ECD-Fc and these results may facilitate the ongoing development of p75ECD-Fc and translation to clinical studies. Refereed/Peer-reviewed

Neonatal hypoxic ischemic encephalopathy (HIE) due to birth asphyxia is common and causes severe neurological deficits, without any effective therapies currently available. Neuronal death is an important driving factors of neurological disorders after HIE, but the regulatory mechanisms are still uncertain. Long non-coding RNA (lncRNA) or ceRNA network act as a significant regulator in neuroregeneration and neuronal apoptosis, thus owning a great potential as therapeutic targets in HIE. Here, we found a new lncRNA, is the most functional in targeting the Igfbp3 gene in HIE, which enriched in the cell growth and cell apoptosis processes. In addition, luciferase reporter assay showed competitive regulatory binding sites to the target gene Igfbp3 between TCONS00044054 (Vi4) and miR-185-5p. The change in blood miR-185-5p and Igfbp3 expression is further confirmed in patients with brain ischemia. Moreover, Vi4 overexpression and miR-185-5p knock-out promote the neuron survival and neurite growth, and suppress the cell apoptosis, then further improve the motor and cognitive deficits in rats with HIE, while Igfbp3 interfering got the opposite results. Together, Vi4-miR-185-5p-Igfbp3 regulatory network plays an important role in neuron survival and cell apoptosis and further promote the neuro-functional recovery from HIE, therefore is a likely a drug target for HIE therapy. Refereed/Peer-reviewed

There were many reports published on the relationship between glutathione S-transferase T1 (GSTT1) null/presence gene polymorphism and the risk of lung cancer in these years. In previous, we conducted a meta-analysis to evaluate the relationship between GSTT1 null/presence gene polymorphism and the risk of lung cancer. This study was conducted to update it.The association studies were identified from PubMed and Cochrane Library on March 1, 2016.Sixty-three reports were recruited into this meta-analysis for the association of null genotype of GSTT1 with lung cancer susceptibility, consisting of 21,220 patients with lung cancer and 21,496 controls. There was a marked association between GSTT1 null genotype and lung cancer risk in overall populations and in Asians (overall populations: Odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.07-1.28, P = 0.006; Asians: OR = 1.41, 95% CI: 1.23-1.62, P0.00001). However, GSTT1 null genotype was not associated with the risk of lung cancer in Caucasians, Brazilian population, and Africans.GSTT1 null genotype is associated with the lung cancer risk in overall populations and in Asians.

Background: The aim of this study was to establish a precise prognostic model, based on significant clinical parameters, for predicting the overall survival (OS) of adult patients with primary gastrointestinal diffuse large B cell lymphoma (GI DLBCL). Materials and Methods: The data of 7,121 GI DLBCL patients, diagnosed between 1997 and 2015, were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. These patients were randomly divided into two sequential cohorts: training (n = 5,697) set and validation (n = 1,424) set. ROC methodology and calibration curves were explicitly used to evaluate the predictive performance of nomogram. Results: The median OS in the training cohort was 76 months (1–239 months), and 3, 5, and 10-year OS rates were 60.3, 53.9, and 39.5%, respectively. Age at diagnosis, Ann Arbor stage, and marital status were important clinical predictors of OS. These characteristics were used to build a nomogram. The AUC of the nomogram for predicting 3, 5, and 10-year OS were 0.669, 0.692, and 0.740, respectively. All RUC and calibration curves revealed good accuracy in predicting prognosis of GI DLBCL. Conclusion: In summary, the established nomogram was validated to predict OS for adult patients with GI DLBCL. This predictive model could help clinicians identify high-risk patients to improve their prognosis.

Spinal cord injury (SCI) is a fatal disease that can cause severe disability. Cortical reorganization subserved the recovery of spontaneous function after SCI, although the potential molecular mechanism in this remote control is largely unknown. Therefore, using proteomics analysis, RNA interference/overexpression, and CRISPR/Cas9 in vivo and in vitro, we analyzed how the molecular network functions in neurological improvement, especially in the recovery of motor function after spinal cord transection (SCT) via the remote regulation of cerebral cortex. We discovered that the overexpression of pyridoxal kinase (PDXK) in the motor cortex enhanced neuronal growth and survival and improved locomotor function in the hindlimb. In addition, PDXK was confirmed as a target of miR-339 but not miR-124. MiR-339 knockout (KO) significantly increased the neurite outgrowth and decreased cell apoptosis in cortical neurons. Moreover, miR-339 KO rats exhibited functional recovery indicated by improved Basso, Beattie, and Bresnehan (BBB) score. Furthermore, bioinformatics prediction showed that PDXK was associated with GAP43, a crucial molecule related to neurite growth and functional improvement. The current research therefore confirmed that miR-339 targeting PDXK facilitated neurological recovery in the motor cortex of SCT rats, and the underlying mechanism was associated with regulating GAP43 in the remote cortex of rats subjected to SCT. These findings may uncover a new understanding of remoting cortex control following SCI and provide a new therapeutic strategy for the recovery of SCI in future clinical trials.

Background Substance P (SP) is implicated in brain inflammation. We clarified relationship between serum SP concentrations and functional outcome of acute intracerebral hemorrhage (ICH). Methods We quantified admission serum SP concentrations in 106 ICH patients. The primary outcome measure was a poor outcome at 90 days (modified Rankin Scale score ≥ 3) after onset. Results Patients with a poor outcome compared with the rest had substantially higher serum SP concentrations. The area under the curve for serum SP concentrations with regard to discriminating a poor outcome was 0.795 (95% CI, 0.706 to 0.867). Serum SP concentrations >449 pg/ml predicted the risk of a poor outcome with 63.0% sensitivity and 78.9% specificity, and were independently associated with a poor outcome (odds ratio, 5.437; 95% CI, 2.156 to 13.715). There were the positive associations between serum SP concentrations, National Institutes of Health Stroke Scale score (r = 0.480), hematoma volume (r = 0.464) and serum C-reactive protein concentrations (r = 0.398). Conclusions Higher serum SP concentrations in the acute phase of ICH were intimately associated with aggravated inflammation response, rising severity and increased risk of a poor functional outcome, suggesting that serum SP could be an inflammatory prognostic factor for ICH.

Objective We investigated the “BURP” maneuver’s effect on the association between difficult laryngoscopy and difficult intubation, and predictors of a difficult airway. Methods Adult patients who underwent general anesthesia and tracheal intubation from September 2016 to May 2018 were included. The “BURP” maneuver was performed when glottic exposure was classified as Cormack–Lehane grade 3 or 4, suggesting difficult laryngoscopy. The thyromental distance, modified Mallampati score, and interincisor distance were assessed before anesthesia. Results Among this study’s 2028 patients, the “BURP” maneuver decreased difficult laryngoscopies from 428 (21.1%) to 124 (6.1%) cases and increased the difficult intubation to difficult laryngoscopy ratio from 53/428 (12.4%) to 52/124 (41.9%). For laryngoscopies classified as difficult without the “BURP” maneuver, the area under the curve (AUC) of the thyromental distance, modified Mallampati score, and interincisor distance was 0.60, 0.57, and 0.66, respectively. In difficult laryngoscopies using the “BURP” maneuver, the AUC of the thyromental distance, modified Mallampati score, and interincisor distance was 0.71, 0.67, and 0.76, respectively. Conclusions The “BURP” maneuver improves the laryngoscopic view and assists in difficult laryngoscopies. Compared with difficult laryngoscopies without the “BURP” maneuver, those with the “BURP” maneuver are more closely associated with difficult intubations and are more predictable. Trial registration: www.chictr.org.cn identifier: ChiCTR-ROC- 16009050.

Background: High cholesterol aggravates the risk development of Alzheimer's disease (AD). AD is closely related to the transport impairment of Amyloid-β (Aβ) in the blood-brain barrier. It is unclear whether high cholesterol affects the risk of cognitive impairment in AD by affecting Aβ transport. The purpose of the study is to investigate whether high cholesterol regulates Aβ transport through low-density Lipoprotein Receptor-Related Protein 1 (LRP1) and Receptor for Advanced Glycation End products (RAGE) in the risk development of AD. Methods: We established high cholesterol AD mice model. The learning and memory functions were evaluated by Morris Water Maze (MWM). Cerebral microvascular endothelial cells were isolated, cultured, and observed. The expression levels of LRP1 and RAGE of endothelial cells and their effect on Aβ transport in vivo were observed. The expression level of LRP1 and RAGE was detected in cultured microvessels after using Wnt inhibitor DKK-1 and β-catenin inhibitor XAV-939. Results: Hypercholesterolemia exacerbated spatial learning and memory impairment. Hypercholesterolemia increased serum Aβ40 level, while serum Aβ42 level did not change significantly. Hypercholesterolemia decreased LRP1 expression and increased RAGE expression in cerebral microvascular endothelial cells. Hypercholesterolemia increased brain apoptosis in AD mice. In in vitro experiment, high cholesterol decreased LRP1 expression and increased RAGE expression, increased Aβ40 expression in cerebral microvascular endothelial cells. High cholesterol regulated the expressions of LRP1 and RAGE and transcriptional activity of LRP1 and RAGE promoters by the Wnt/β-catenin signaling pathway. Conclusion : High cholesterol decreased LRP1 expression and increased RAGE expression in cerebral microvascular endothelial cells, which led to Aβ transport disorder in the blood-brain barrier. Increased Aβ deposition in the brain aggravated apoptosis in the brain, resulting to cognitive impairment of AD mice.

Major depression is a leading cause of morbidity and disease burden in modern society. Current drug treatment is only effective in a fraction of patients as underlying mechanisms of depression are not fully understood. ProBDNF, a precursor of brain-derived neurotrophic factor (BDNF), and its receptor p75NTR are highly upregulated in patients with major depression and in animal models of depression induced by chronic stress. Here, we hypothesise that proBDNF may be a pathogenic factor triggering depression. C57BL/6 mice were injected in the bilateral gluteus maximus muscle with AAV-proBDNF or AAV-EGFP. Four weeks after the injection, AAV-proBDNF injected animals developed depression-like behaviours, which were evident for 4–8 weeks and then returned to the control level after 12 weeks. In the second experiment, mice were divided into three groups; one group was treated with sheep anti-proBDNF antibody after AAV-proBDNF injection whereas the other two groups received PBS injection after the AAV-proBDNF or AAV-EGFP delivery. The group that was injected with AAV-proBDNF showed a time-dependent increase in immobility time in the tail suspension test and forced swim test, reduced sucrose consumption and decreased grooming time after sucrose spraying. Treatment with sheep anti-proBDNF antibody alleviated the depressive-like symptoms. Peripheral AAV-proBDNF delivery also resulted in a reduction of density and length of dendritic spines in the dentate gyrus and amygdala. Thus, we conclude that peripheral proBDNF is a primary pathogenic factor triggering depression-like behavioural changes in mice likely by reducing dendritic spine plasticity. Refereed/Peer-reviewed

We describe how to use several machine learning techniques organized in a learning pipeline to segment and identify subcellular structures from cryo electron tomograms. These tomograms are difficult to analyze with traditional segmentation tools. The learning pipeline in our approach starts from supervised learning via a special convolutional neural network trained with simulated data. It continues with semi-supervised reinforcement learning and/or a region merging techniques that try to piece together disconnected components that should belong to the same subcellular structure. A parametric or non-parametric fitting procedure is then used to enhance the segmentation results and quantify uncertainties in the fitting. Domain knowledge is used in generating the training data for the neural network and in guiding the fitting procedure through the use of appropriately chosen priors and constraints. We demonstrate that the approach proposed here work well for extracting membrane surfaces of protein reconstituted liposomes in a cellular environment that contains other artifacts.

Parkinson’s disease (PD) is one of the most common neurodegenerative movement disorders which is characterised neuropathologically by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (made predominately of α-synuclein) in the surviving neurons. Animal models of PD have improved our understanding of the disease and have played a critical role in the development of neuroprotective agents. Neuroinflammation has been strongly implicated in the pathogenesis of PD, and recent studies have used lipopolysaccharide (LPS), a component of gram-negative bacteria and a potent activator of microglia cells, to mimic the inflammatory events in clinical PD. Modulating the inflammatory response could ameliorate PD associated complications and thus, it is essential to understand the extent to which LPS models reflect human PD. This review will outline the routes of administration of LPS such as stereotaxic, systemic and intranasal, their ability to recapitulate neuropathological markers of PD, and mechanisms of LPS induced toxicity. We will also discuss the ability of the models to replicate motor symptoms and non-motor symptoms of PD such as gastrointestinal dysfunction, olfactory dysfunction, anxiety, depression and cognitive dysfunction., Highlights • This review describes stereotaxic, intraperitoneal and intranasal LPS animal models of PD. • The ability of the models to replicate motor symptoms and non-motor symptoms of PD are analysed. • The possible mechanisms of LPS induced toxicity and their relevance to clinical PD are discussed. • Currently most evidence exists for the stereotaxic LPS model of PD. • Further characterisation of LPS models of PD is warranted.

Ferroptosis is a form of iron-dependent regulated cell death. Evidence of its existence and the effects of its inhibitors on subarachnoid hemorrhage (SAH) is still lacking. In the present study, we found that liproxstatin-1 protected HT22 cells against hemin-induced injury by protecting mitochondrial functions and ameliorating lipid peroxidation. In in vivo experiments, we demonstrated the presence of characteristic shrunken mitochondria in ipsilateral cortical neurons after SAH. Moreover, liproxstatin-1 attenuated the neurological deficits and brain edema, reduced neuronal cell death, and restored the redox equilibrium after SAH. The inhibition of ferroptosis by liproxstatin-1 was associated with the preservation of glutathione peroxidase 4 and the downregulation of acyl-CoA synthetase long-chain family member 4 as well as cyclooxygenase 2. In addition, liproxstatin-1 decreased the activation of microglia and the release of IL-6, IL-1β, and TNF-α. These data enhance our understanding of cell death after SAH and shed light on future preclinical studies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12264-020-00620-5) contains supplementary material, which is available to authorized users.

Background The prognosis of patients with combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma (CHC) is usually poor, and effective adjuvant therapy is missing making it important to investigate whether these patients may benefit from adjuvant transarterial chemoembolization (TACE). We aimed to evaluate the efficiency of adjuvant TACE for long-term recurrence and survival after curative resection before and after propensity score matching (PSM) analysis. Methods In this retrospective study, of 230 patients who underwent resection for CHC between January 1994 and December 2014, 46 (18.0%) patients received adjuvant TACE. Univariate and multivariate regression analyses were used to identify the independent predictive factors of survival. Cox regression analyses and log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS) between patients who did or did not receive adjuvant TACE. Results A total of 230 patients (mean age 52.2 ± 11.9 years; 172 men) were enrolled, and 46 (mean age 52.7 ± 11.1 years; 38 men) patients received TACE. Before PSM, in multivariate regression analysis, γ-glutamyl transpeptidase (γ-GT), tumour nodularity, macrovascular invasion (MVI), lymphoid metastasis, and extrahepatic metastasis were associated with OS. Alanine aminotransferase (ALT), MVI, lymphoid metastasis, and preventive TACE (HR: 2.763, 95% CI: 1.769–4.314, p p = 0.720) or DFS (HR: 3.345, 95% CI: 1.686–6.638, p = 0.001). After PSM, the 5-year OS and DFS rates were comparable in the TACE group and the non-TACE group (OS: 22.7% vs 14.9%, respectively, p = 0.75; DFS: 11.2% vs 14.4%, respectively, p = 0.06). Conclusions The present study identified that adjuvant preventive TACE did not influence DFS or OS after curative resection of CHC.

Background: p75ECD-Fc is a recombinant human protein that has recently been developed as a novel therapy for Alzheimer’s disease. Current studies showed that it is able to alleviate Alzheimer’s disease pathologies in animal models of dementia. Thus, knowledge about the pharmacokinetic behavior and tissue distribution of this novel protein is crucial in order to better understand its pharmacodynamics and more importantly for its clinical development. Methods: The aim of this study is to characterize the pharmacokinetics of p75ECD-Fc after single intravenous and subcutaneous injection of 3mg/kg in Sprague Dawley rats. We calculated the bioavailability of the SC route and studied the distribution of that protein in different tissues, cerebrospinal fluid and urine using ELISA and immunofluorescence techniques. In-vitro stability of the drug was also assessed. Data obtained were analyzed with Non-compartmental pharmacokinetic method using R. Results: Results showed that the bioavailability of SC route was 66.15%. Half-life time was 7.5 ± 1.7 and 6.2 ± 2.4 days for IV and SC injection, respectively. Tissue distribution of p75ECD-Fc was modest with the ability to penetrate the blood brain barrier. It showed high in vitro stability in human plasma. Conclusion: These acceptable pharmacokinetic properties of p75ECD-Fc present it as a potential candidate for clinical development for the treatment of Alzheimer’s disease.

Background Pro‐NTs (precursor of neurotrophins) and their receptor p75 are potential targets for preventing microvascular dysfunction induced by myocardial ischemia–reperfusion injury ( IRI ). p75ECD (ectodomain of neurotrophin receptor p75) may physiologically produce neurocytoprotective effects by scavenging pro‐ NT s. We therefore hypothesized that p75 ECD may have a cardioprotective effect on IRI through microvascular mechanisms. Methods and Results Myocardial IRI was induced in Sprague‐Dawley rats by occluding the left main coronary arteries for 45 minutes before a subsequent relaxation. Compared with the ischemia–reperfusion group, an intravenous injection of p75 ECD (3 mg/kg) 5 minutes before reperfusion reduced the myocardial infarct area at 24 hours after reperfusion (by triphenyltetrazolium chloride, 44.9±3.9% versus 34.6±5.7%, P NT s expression at 24 hours and 28 days after reperfusion (by Western blotting). A simulative IRI model using rat microvascular pericytes was established in vitro by hypoxia–reoxygenation (2/6 hours) combined with pro‐ NT s treatment (3 nmol/L) at R. p75 ECD (3 μg/mL) given at R improved pericyte survival (by methyl thiazolyl tetrazolium assay) and attenuated apoptosis (by terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick‐end labeling). In the reperfused hearts and hypoxia–reoxygenation +pro‐ NT s‐injured pericytes, p75 ECD inhibited the expression of p‐JNK (phospho of c‐Jun N‐terminal kinase)/caspase‐3 (by Western blotting). SP 600125, an inhibitor of JNK , did not enhance the p75 ECD ‐induced infarct‐sparing effects and pericyte protection. Conclusions p75 ECD may attenuate myocardial IRI via pro‐ NT s reduction‐induced inhibition of p‐ JNK /caspase‐3 pathway of microvascular pericytes in rats.

Depression is a worldwide problem with a great social and economic burden in many countries. In our previous research, we found that the expression of proBDNF/p75NTR/sortilin is upregulated in patients with major depressive disorder. In addition, the treatment of proBDNF antibodies reversed both the depressive behaviors and the reduced BDNF mRNA detected in our rodent chronic stress models. Antidepressant drugs are usually only effective in a subpopulation of patients with major depression with a delayed time window of 2-4 weeks to exert their efficacy. The mechanism underlying such delayed response is not known. In this study, we hypothesize that antidepressant drugs exert their therapeutic effect by modulating proBDNF/p75NTR and mature BDNF/TrkB signaling pathways. To test the hypothesis, C57 mice were randomly divided into normal control, chronic unpredictable mild stress (CUMS), vehicle (VEH), fluoxetine (FLU), and clozapine (CLO) groups. Behavioral tests (sucrose preference, open field, and tail suspension tests) were performed before and after 4 weeks of CUMS. The gene and protein expression of proBDNF, the neurotrophin receptor (p75NTR), sortilin, and TrkB in the cortex and hippocampus were examined. At the protein level, CUMS induced a significant increase in proBDNF, p75NTR, and sortilin production while the TrkB protein level was found to be lower in the cortex and hippocampus compared with the control group. Consistently, at the mRNA level, p75NTR expression increased with reduced BDNF/TrkB mRNA in both cortex and hippocampus, while sortilin increased only in the hippocampus after CUMS. FLU and CLO treatments of CUMS mice reversed all protein and mRNA expression of the biomarkers in both cortex and hippocampus, except for sortilin mRNA in the cortex and proBDNF in the hippocampus, respectively. This study further confirms that the imbalance between proBDNF/p75NTR/sortilin and mBDNF/TrkB production is important in the pathogenesis of depression. It is likely that antidepressant FLU and antipsychotic CLO exert their antidepressant-like effect correcting the imbalance between proBDNF/p75NTR/sortilin and mBDNF/TrkB Refereed/Peer-reviewed