bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral cathepsin L inhibition induces fat loss in C. elegans and mice through promoting central serotonin synthesis
Authors: Lin Yan , Bao Bin , Yin Hao , Wang Xin , Feng Airong , Zhao Lin , Nie Xianqi , Yang Nan , Shi Guo-Ping , Liu Jian 
Published: November 2019

AbstractBackgroundCathepsin L and some other cathepsins have been implicated in the development of obesity in humans and mice. The functional inactivation of the proteases reduces fat accumulation during mammalian adipocyte differentiation. However, beyond degrading extracellular matrix protein fibronectin, the molecular mechanisms by which cathepsins control fat accumulation remain unclear. We now provide evidence fromCaenorhabditis elegansand mouse models to suggest a conserved regulatory circuit in which peripheral cathepsin L inhibition lowers fat accumulation through promoting central serotonin synthesis.ResultsWe established aC. elegansmodel of fat accumulation using dietary supplementation with glucose and palmitic acid. We found that nutrient supplementation elevated fat storage inC. elegans, and along with worm fat accumulation, an increase in the expression ofcpl-1was detected using real-time PCR and western blot. The functional inactivation ofcpl-1reduced fat storage inC. elegansthrough activating serotonin signaling. Further, knockdown ofcpl-1in the intestine and hypodermis promoted serotonin synthesis in worm ADF neurons and induced body fat loss inC. elegansvia central serotonin signaling. We found a similar regulatory circuit in high-fat diet-fed mice. Cathepsin L knockout promoted fat loss and central serotonin synthesis. Intraperitoneal injection of the cathepsin L inhibitor CLIK195 similarly reduced body weight gain and white adipose tissue (WAT) adipogenesis, while elevating brain serotonin level and WAT lipolysis and fatty acid β-oxidation. These effects of inhibiting cathepsin L were abolished by intracranial injection of p-chlorophenylalanine, inhibitor of a rate-limiting enzyme for serotonin synthesis.ConclusionThis study reveals a previously undescribed molecular mechanism by which peripheral CPL-1/cathepsin L inhibition induces fat loss inC. elegansand mice through promoting central serotonin signaling.
Challenges in management and prevention of ischemic heart disease in low socioeconomic status people in LLMICs
Authors: Gupta Rajeev , Yusuf Salim 
Published: November 2019

AbstractBackgroundCardiovascular diseases, principally ischemic heart disease (IHD), are the most important cause of death and disability in the majority of low- and lower-middle-income countries (LLMICs). In these countries, IHD mortality rates are significantly greater in individuals of a low socioeconomic status (SES).Main textThree important focus areas for decreasing IHD mortality among those of low SES in LLMICs are (1) acute coronary care; (2) cardiac rehabilitation and secondary prevention; and (3) primary prevention. Greater mortality in low SES patients with acute coronary syndrome is due to lack of awareness of symptoms in patients and primary care physicians, delay in reaching healthcare facilities, non-availability of thrombolysis and coronary revascularization, and the non-affordability of expensive medicines (statins, dual anti-platelets, renin-angiotensin system blockers). Facilities for rapid diagnosis and accessible and affordable long-term care at secondary and tertiary care hospitals for IHD care are needed. A strong focus on the social determinants of health (low education, poverty, working and living conditions), greater healthcare financing, and efficient primary care is required. The quality of primary prevention needs to be improved with initiatives to eliminate tobacco and trans-fats and to reduce the consumption of alcohol, refined carbohydrates, and salt along with the promotion of healthy foods and physical activity. Efficient primary care with a focus on management of blood pressure, lipids and diabetes is needed. Task sharing with community health workers, electronic decision support systems, and use of fixed-dose combinations of blood pressure-lowering drugs and statins can substantially reduce risk factors and potentially lead to large reductions in IHD. Finally, training of physicians, nurses, and health workers in IHD prevention should be strengthened.ConclusionThe management and prevention of IHD in individuals with a low SES in LLMICs are poor. Greater availability, access, and affordability for acute coronary syndrome management and secondary prevention are important. Primary prevention should focus on tackling the social determinants of health as well as policy and individual interventions for risk factor control, supported by task sharing and use of technology.
The lncRNA DLX6-AS1 promoted cell proliferation, invasion, migration and epithelial-to-mesenchymal transition in bladder cancer via modulating Wnt/β-catenin signaling pathway
Authors: Guo Jinan , Chen Zhixin , Jiang Hongtao , Yu Zhou , Peng Junming , Xie Jing , Li ZaiShang , Wu Weiqing , Cheng Zhiqiang , Xiao Kefeng 
Published: November 2019

Abstract
Background
Bladder cancer is the most common human urological malignancies with poor prognosis, and the pathophysiology of bladder cancer involves multi-linkages of regulatory networks in the bladder cancer cells. Recently, the long noncoding RNAs (lncRNAs) have been extensively studied for their role on bladder cancer progression. In this study, we evaluated the expression of DLX6 Antisense RNA 1 (DLX6-AS1) in the cancerous bladder tissues and studied the possible mechanisms of DLX6-AS1 in regulating bladder cancer progression.

Methods
Gene expression was determined by qRT-PCR; protein expression levels were evaluated by western blot assay; in vitro functional assays were used to determine cell proliferation, invasion and migration; nude mice were used to establish the tumor xenograft model.

Results
Our results showed the up-regulation of DLX6-AS1 in cancerous bladder cancer tissues and bladder cell lines, and high expression of DLX6-AS1 was correlated with advance TNM stage, lymphatic node metastasis and distant metastasis. The in vitro experimental data showed that DLX6-AS1 overexpression promoted bladder cancer cell growth, proliferation, invasion, migration and epithelial-to-mesenchymal transition (EMT); while DLX6-AS1 inhibition exerted tumor suppressive actions on bladder cancer cells. Further results showed that DLX6-AS1 overexpression increased the activity of Wnt/β-catenin signaling, and the oncogenic role of DLX6-AS1 in bladder cancer cells was abolished by the presence of XAV939. On the other hand, DLX6-AS1 knockdown suppressed the activity of Wnt/β-catenin signaling, and the tumor-suppressive effects of DLX6-AS1 knockdown partially attenuated by lithium chloride and SB-216763 pretreatment. The in vivo tumor growth study showed that DLX6-AS1 knockdown suppressed tumor growth of T24 cells and suppressed EMT and Wnt/β-catenin signaling in the tumor tissues.

Conclusion
Collectively, the present study for the first time identified the up-regulation of DLX6-AS1 in clinical bladder cancer tissues and in bladder cancer cell lines. The results from in vitro and in vivo assays implied that DLX6-AS1 exerted enhanced effects on bladder cancer cell proliferation, invasion and migration partly via modulating EMT and the activity of Wnt/β-catenin signaling pathway.
Evaluation of malaria microscopy diagnostic performance at private health facilities in Tanzania
Authors: Ngasala Billy , Bushukatale Samweli 
Published: November 2019

Abstract
Background
The World Health Organization (WHO) recommends use of parasitological diagnosis of malaria for all age groups in all malaria transmission settings. Many private health facilities rely on malaria microscopy for malaria diagnosis. However, quality of malaria microscopy is affected by number of factors including availability of skilled laboratory microscopists and lack of quality assurance systems in many malaria endemic countries. This study was carried out to assess quality of malaria microscopy in selected private health facilities in Tanzania.

Methods
A cross sectional study was conducted from August to September, 2017. A total of 40 private health laboratories in five regions were invited to participate in the study. Data were collected by distributing standardized pre-validated malaria slide-panels to each health facility. Sensitivity, specificity, and strength of agreement (with kappa score) were calculated to assess performance in detecting and quantification of Plasmodium species.

Results
Among the 40 health facilities, 31 (77.5%) returned their results to the reference centre (Muhimbili University of Health and Allied Sciences). Overall, the measures of malaria diagnostic accuracy were high, i.e. the sensitivity and specificity of malaria parasite detection by microscopy in the health facilities were 84.3% (95% CI 77–90) and 90.8% (95% CI 83.3–95.7), respectively. There was substantial agreement in parasite detection with (Kappa value: 0.74 (95% 0.65–0.83). However, only 17.8% (24 of 134) of blood slides were interpreted correctly at the health facilities in terms of parasite density counts.

Conclusion
Although there was substantial agreement between the private health microscopists and experienced microscopists in malaria parasite detection, there was poor performance in parasite counts. This calls for regular in-service training and external quality assessments at private health facilities to enhance the skills of private health facility microscopists in malaria microscopy.
A Phase I/II trial comparing autologous dendritic cell vaccine pulsed either with personalized peptides (PEP-DC) or with tumor lysate (OC-DC) in patients with advanced high-grade ovarian serous carcinoma
Authors: Sarivalasis Apostolos , Boudousquié Caroline , Balint Klara , Stevenson Brian J. , Gannon Philippe O. , Iancu Emanuela Marina , Rossier Laetitia , Martin Lluesma Silvia , Mathevet Patrice , Sempoux Christine , Coukos George , Dafni Urania , Harari Alexandre , Bassani-Sternberg Michal , Kandalaft Lana E. 
Published: November 2019

Abstract
Background
Most ovarian cancer patients are diagnosed at a late stage with 85% of them relapsing after surgery and standard chemotherapy; for this reason, new treatments are urgently needed. Ovarian cancer has become a candidate for immunotherapy by reason of their expression of shared tumor-associated antigens (TAAs) and private mutated neoantigens (NeoAgs) and the recognition of the tumor by the immune system. Additionally, the presence of intraepithelial tumor infiltrating lymphocytes (TILs) is associated with improved progression-free and overall survival of patients with ovarian cancer. The aim of active immunotherapy, including vaccination, is to generate a new anti-tumor response and amplify an existing immune response. Recently developed NeoAgs-based cancer vaccines have the advantage of being more tumor specific, reducing the potential for immunological tolerance, and inducing robust immunogenicity.

Methods
We propose a randomized phase I/II study in patients with advanced ovarian cancer to compare the immunogenicity and to assess safety and feasibility of two personalized DC vaccines. After standard of care surgery and chemotherapy, patients will receive either a novel vaccine consisting of autologous DCs pulsed with up to ten peptides (PEP-DC), selected using an agnostic, yet personalized, epitope discovery algorithm, or a sequential combination of a DC vaccine loaded with autologous oxidized tumor lysate (OC-DC) prior to an equivalent PEP-DC vaccine. All vaccines will be administered in combination with low-dose cyclophosphamide. This study is the first attempt to compare the two approaches and to use NeoAgs-based vaccines in ovarian cancer in the adjuvant setting.

Discussion
The proposed treatment takes advantage of the beneficial effects of pre-treatment with OC-DC prior to PEP-DC vaccination, prompting immune response induction against a wide range of patient-specific antigens, and amplification of pre-existing NeoAgs-specific T cell clones.
Trial registration This trial is already approved by Swissmedic (Ref.: 2019TpP1004) and will be registered at http://www.clinicaltrials.gov before enrollment opens.
Loss of alanine-glyoxylate and serine-pyruvate aminotransferase expression accelerated the progression of hepatocellular carcinoma and predicted poor prognosis
Authors: Sun Yufeng , Li Wenchao , Shen Shiqi , Yang Xuejing , Lu Bing , Zhang Xiaojing , Lu Peng , Shen Yi , Ji Juling 
Published: November 2019

AbstractBackgroundAccumulated studies reported abnormal gene expression profiles of hepatocellular carcinoma (HCC) by cDNA microarray. We tried to merge cDNA microarray data from different studies to search for stably changed genes, and to find out better diagnostic and prognostic markers for HCC.MethodsA systematic review was performed by searching publications indexed in Pubmed from March 1, 2001 to July 1, 2016. Studies that reporting cDNA microarray profiles in HCC, containing both tumor and nontumor data and published in English-language were retrieved. The differentially expressed genes from eligible studies were summarized and ranked according to the frequency. High frequency genes were subjected to survival analyses. The expression and prognostic value of alanine-glyoxylate and serine-pyruvate aminotransferase (AGXT) was further evaluated in HCC datasets in Oncomine and an independent HCC tissue array cohort. The role of AGXT in HCC progression was evaluated by proliferation and migration assays in a human HCC cell line.ResultsA total of 43 eligible studies that containing 1917 HCC patients were included, a list of 2022 non redundant abnormally expressed genes in HCC were extracted. The frequencies of reported genes were ranked. We finally obtained a list of only five genes (AGXT; ALDOB; CYP2E1; IGFBP3; TOP2A) that were differentially expressed in tumor and nontumor tissues across studies and were significantly correlated to HCC prognosis. Only AGXT had not been reported in HCC. Reduced expression of AGXT reflected poor differentiation of HCC and predicts poor survival. Knocking down of AGXT enhanced cell proliferation and migration of HCC cell line.ConclusionsThe present study supported the feasibility and necessity of systematic review on discovering new and reliable biomarkers for HCC. We also identified a list of high frequency prognostic genes and emphasized a critical role of AGXT deletion during HCC progression.
The role of Toll-like receptor 4 in apoptosis of brain tissue after induction of intracerebral hemorrhage
Authors: Fei Xiaowei , He Yeting , Chen Jia , Man Weitao , Chen Chen , Sun Kai , Ding Boyun , Wang Chongwu , Xu Ruxiang 
Published: November 2019

Abstract
Background
Inflammation and apoptosis caused by intracerebral hemorrhage (ICH) are two important factors that affect patient prognosis and survival. Toll-like receptor 4 (TLR4) triggers activation of the inflammatory pathway, causing synthesis and release of inflammatory factors. The inflammatory environment also causes neuronal apoptosis. However, no studies have reported the role of TLR4 in inflammation and apoptosis.

Methods
We performed survival curve analysis and behavioral scores on TLR4 knockout mice and wild-type mice after inducing ICH. We used TLR4 knockout mice and wild-type mice to make ICH models with type VII collagenase and explored the link between TLR4 in inflammation and apoptosis. We used Western blot to detect the expression of apoptosis-related proteins, inflammatory factors, and their receptors at different time points after ICH induction. The effects of TLR4 on apoptosis were observed by TUNEL, Hoechst, and HE staining techniques. The association with TLR4 in inflammation and apoptosis was explored using IL-1β and TNF-α antagonists. Data conforming to a normal distribution are expressed as mean ± standard deviation. Grade and quantitative data were compared with rank sum test and t test between two groups. P < 0.05 was considered statistically significant.

Results
TLR4 knockout significantly increased the survival rate of ICH mice. The scores of TLR4 knockout mice were significantly lower than those of wild-type mice. We found that TLR4 knockout mice significantly inhibited apoptosis and the expression of inflammatory factors after the induction of ICH. The apoptosis of ICH-induced mice was significantly improved after injecting IL-1β and TNF-α antagonists. Moreover, the anti-apoptotic effect of the antagonist in wild-type mice is more pronounced. A single injection of the antagonist failed to improve apoptosis in TLR4 knockout mice.

Conclusions
We conclude that TLR4-induced inflammation after ICH promotes neuronal apoptosis. IL-1β and TNF-α antagonists attenuate this apoptotic effect. Therefore, targeting TLR4 in patients with clinical ICH may attenuate inflammatory response, thereby attenuating apoptosis and improving prognosis.
Preclinical update on regulation of intracranial pressure in relation to idiopathic intracranial hypertension
Authors: Eftekhari Sajedeh , Westgate Connar Stanley James , Uldall Maria Schmidt , Jensen Rigmor Hoejland 
Published: November 2019

Abstract
Background
Elevated intracranial pressure (ICP) is observed in association with a range of brain disorders. One of these challenging disorders is idiopathic intracranial hypertension (IIH), characterized by raised ICP of unknown cause with significant morbidity and limited therapeutic options. In this review, special focus is put on the preclinical research performed in order to understand the pathophysiology behind ICP regulation and IIH. This includes cerebrospinal fluid dynamics, molecular mechanisms underlying disturbances in brain fluids leading to elevated ICP, role of obesity in IIH, development of an IIH model and ICP measurements in rodents. The review also discusses existing and new drug targets for IIH that have been evaluated in vivo.

Conclusions
ICP monitoring in rodents is challenging and different methods have been applied. Some of these methods are invasive, depend on use of anesthesia and only allow short-term monitoring. Long-term ICP recordings are needed to study IIH but existing methods are hampered by several limitations. As obesity is one of the most common risk factors for IIH, a rodent obese model has been developed that mimics some key aspects of IIH. The most commonly used drugs for IIH have been evaluated in vivo for their efficacy at lowering ICP in the existing animal models. These studies suggest these drugs, including acetazolamide, might have limited or no reducing effect on ICP. Two drug targets that can impact ICP in healthy rodents are topiramate and a glucagon-like peptide-1 receptor (GLP-1R) agonist. However, it remains to evaluate their effect in an IIH model with more precise and valid ICP monitoring system. Therefore, continued evaluation in the preclinical research with refined tools is of great importance to further understand the pathophysiology behind disorders with raised ICP and to explore new drug targets.
Chronic abdominal pain after laparoscopic hernia repair due to mesh graft migration to the cecum: a case report
Authors: AlShammari Abdullah , Alyousef Fatima , Alyousif Amal , Alsulabi Zainab , AlJishi Fatimah , Siraj Isra , Alotaibi Hissah , Aburahmah Mohammad 
Published: November 2019

Abstract
Background
Hernia repair with mesh graft is one of the most common procedures in general surgery. Mesh graft repair is the treatment of choice for umbilical and periumbilical hernias to minimize recurrence. One of the rare but serious complications is mesh graft migration to viscus. These complications can occur months to years after repair and their diagnosis can be challenging as they may present as vague abdominal pain only.

Case presentation
A 74-year-old gentleman with multiple medical comorbidities was diagnosed with a para-umbilical hernia after which he underwent a laparoscopic hernia repair at our hospital using a mesh graft with no complications. On postoperative day 10, he presented to the emergency room (ER) complaining of colicky abdominal pain in the right iliac fossa for 1 day associated with diarrhea. A Computed Tomography (CT) scan of the abdomen and pelvis showed diffuse wall thickening of the cecum and terminal ileum with small free air worrisome for perforation. The decision was made in the ER to discharge him home on antibiotics. The patient then returned back multiple times to the ER for the same complaint along with bleeding per rectum for which he underwent further investigations. Months later, the patient presented again with the same symptoms. A CT scan revealed recurrence of a periumbilical hernia and thickening of the medial wall of the cecum with mesh graft material. The patient was then taken to surgery and intra-operative findings revealed migration of almost 50% of the mesh graft size to the cecum and part of the mesh graft was eroding the distal part of ileum just proximal to the ileocecal junction. Adhesolysis and limited right hemicolectomy with ileocolic anastomosis was done. The patient had an uneventful recovery after revisions surgery without any perioperative complications. He was discharged home on postoperative readmission day 5 and followed up at 2 weeks and 3 months without any delayed complications or subjective complaints.

Conclusion
It is important to consider mesh graft migration to viscus as a cause of persistent abdominal pain and bleeding per rectum irrespective of the time of presentation post hernia repair.
Immune receptor repertoires in pediatric and adult acute myeloid leukemia
Authors: Zhang Jian , Hu Xihao , Wang Jin , Sahu Avinash Das , Cohen David , Song Li , Ouyang Zhangyi , Fan Jingyu , Wang Binbin , Fu Jingxin , Gu Shengqing , Sade-Feldman Moshe , Hacohen Nir , Li Wuju , Ying Xiaomin , Li Bo , Liu X. Shirley 
Published: November 2019

Abstract
Background
Acute myeloid leukemia (AML), caused by the abnormal proliferation of immature myeloid cells in the blood or bone marrow, is one of the most common hematologic malignancies. Currently, the interactions between malignant myeloid cells and the immune microenvironment, especially T cells and B cells, remain poorly characterized.

Methods
In this study, we systematically analyzed the T cell receptor and B cell receptor (TCR and BCR) repertoires from the RNA-seq data of 145 pediatric and 151 adult AML samples as well as 73 non-tumor peripheral blood samples.

Results
We inferred over 225,000 complementarity-determining region 3 (CDR3) sequences in TCR α, β, γ, and δ chains and 1,210,000 CDR3 sequences in B cell immunoglobulin (Ig) heavy and light chains. We found higher clonal expansion of both T cells and B cells in the AML microenvironment and observed many differences between pediatric and adult AML. Most notably, adult AML samples have significantly higher level of B cell activation and more secondary Ig class switch events than pediatric AML or non-tumor samples. Furthermore, adult AML with highly expanded IgA2 B cells, which might represent an immunosuppressive microenvironment, are associated with regulatory T cells and worse overall survival.

Conclusions
Our comprehensive characterization of the AML immune receptor repertoires improved our understanding of T cell and B cell immunity in AML, which may provide insights into immunotherapies in hematological malignancies.