bluuebunny/crossref_metadata_2025_split huggingface dataset:
ELOVL2: a novel tumor suppressor attenuating tamoxifen resistance in breast cancer
Authors: Jeong Dawoon , Ham Juyeon , Kim Hyeon Woo , Kim Heejoo , Ji Hwee Won , Yun Sung Hwan , Park Jae Eun , Lee Keun Seok , Jo Heein , Han Jai Hong , Jung So-Youn , Lee Seeyoun , Lee Eun Sook , Kang Han-Sung , Kim Sun Jung 
Published: September 2020

Abstract
Background

To comprehensively understand the molecular mechanism of tamoxifen resistance (TamR) acquisition by epigenetically regulated genes, it is essential to identify pivotal genes by genome-wide methylation analysis and verify their function in xenograft animal model and cancer patients.
Methods

The MCF-7/TamR breast cancer cell line was developed and a genome-wide methylation array was performed. The methylation and expression of ELOVL2 was validated in cultured cells, xenografted tumor tissue, and breast cancer patients by methylation-specific PCR, qRT-PCR, Western blot analysis, and immunohistochemistry. Deregulation of ELOVL2 and THEM4 was achieved using siRNA or generating stable transfectants. Tam sensitivity, cell growth, and apoptosis were monitored by colorimetric and colony formation assay and flow cytometric analysis. Pathway analysis was performed to generate networks for the differentially methylated genes in the MCF-7/TamR cells and for the differentially expressed genes in the ELOVL2-overexpressing cells.
Results

Genome-wide methylation analysis in the MCF-7/TamR cells identified elongation of very-long chain fatty acid protein 2 (ELOVL2) to be significantly hypermethylated and downregulated, which was further verified in the tumor tissues from TamR breast cancer patients (n = 28) compared with those from Tam-sensitive (TamS) patients (n = 33) (P < 0.001). Immunohistochemical analysis of tissues from cancer patients showed lower expression of ELOVL2 in the TamR than TamS tissues. Growth of the MCF-7/TamR cells overexpressing ELOVL2 was retarded in cell culture and also in xenograft tumor tissue. Strikingly, ELOVL2 attenuated resistance to Tam up to 70% judged by the colorimetric and colony formation assay and xenograft mouse model. ELOVL2 contributed to the recovery of Tam sensitivity by regulating a group of genes in the AKT and ERα signaling pathways, e.g., THEM4, which plays crucial roles in drug resistance.
Conclusions

ELOVL2 was hypermethylated and downregulated in TamR breast cancer patients compared with TamS patients. ELOVL2 is responsible for the recovery of Tam sensitivity. AKT- and ERα-hubbed networks are pivotal in ELOVL2 signaling, where THEM4 contributes to the relaying ELOVL2 signaling. This study implies that deregulation of a gene in fatty acid metabolism can lead to drug resistance, giving insight into the development of a new therapeutic strategy for drug-resistant breast cancer.
INPP5D&nbsp;Expression is Associated with Risk for Alzheimer’s Disease and Induced by Plaque-Associated Microglia
Authors: Tsai Andy P , Lin Peter Bor-Chian , Dong Chuanpeng , Moutinho Miguel , Casali Brad , Liu Yunlong , Lamb Bruce T , Landreth Gary E , Oblak Adrian L , Nho Kwangsik 
Published: September 2020

Abstract
Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, robust microgliosis, neuroinflammation, and neuronal loss. Genome-wide association studies recently highlighted a prominent role for microglia in late-onset AD (LOAD). Specifically, inositol polyphosphate-5-phosphatase (INPP5D), also known as SHIP1, is selectively expressed in brain microglia and has been reported to be associated with LOAD. Although INPP5D is likely a crucial player in AD pathophysiology, its role in disease onset and progression remains unclear. Methods We performed differential gene expression analysis to investigate INPP5D expression in LOAD and its association with plaque density and microglial markers using transcriptomic (RNA-Seq) data from the Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) cohort. We also performed quantitative real-time PCR, immunoblotting, and immunofluorescence assays to assess INPP5D expression in the 5xFAD amyloid mouse model. Results Differential gene expression analysis found that INPP5D expression was upregulated in LOAD and positively correlated with amyloid plaque density. In addition, in 5xFAD mice, Inpp5d expression increased as the disease progressed, and selectively in plaque-associated microglia. Increased Inpp5d expression levels in 5xFAD mice were abolished entirely by depleting microglia with the colony-stimulating factor receptor-1 antagonist PLX5622. Conclusions Our findings show that INPP5D expression increases as AD progresses, predominantly in plaque-associated microglia. Importantly, we provide the first evidence that increased INPP5D expression might be a risk factor in AD, highlighting INPP5D as a potential therapeutic target. Moreover, we have shown that the 5xFAD mouse model is appropriate for studying INPP5D in AD.
Cholesterol Alters Mitophagy by Impairing Optineurin Recruitment and Lysosomal Clearance in Alzheimer’s Disease
Authors: Roca-Agujetas Vicente , Barbero-Camps Elisabet , de Dios Cristina , Podlesniy Petar , Morales Albert , Marí Montserrat , Trullàs Ramon , Riera Anna Colell 
Published: September 2020

Abstract
Background: Emerging evidence indicates that impaired mitophagy-mediated clearance of defective mitochondria is a critical event in Alzheimer’s disease (AD) pathogenesis. Amyloid-beta (A) metabolism and the microtubule-associated protein tau have been reported to regulate key components of the mitophagy machinery. However, the mechanisms that lead to mitophagy dysfunction in AD are not fully deciphered. We have previously shown that intraneuronal cholesterol accumulation can disrupt the autophagy flux, resulting in low A clearance. In this study, we examine the impact of neuronal cholesterol changes on mitochondrial removal by autophagy.Methods: Regulation of PINK1-parkin-mediated mitophagy was investigated in conditions of acute (in vitro) and chronic (in vivo) high cholesterol loading using cholesterol-enriched SH-SY5Y cells, cultured primary neurons from transgenic mice overexpressing active SREBF2 (sterol regulatory element binding factor 2), and mice of increasing age that express the amyloid precursor protein with the familial Alzheimer Swedish mutation (Mo/HuAPP695swe) and mutant presenilin 1 (PS1-dE9) together with active SREBF2.Results: In cholesterol-enriched SH-SY5Y cells and cultured primary neurons, high intracellular cholesterol levels stimulated mitochondrial PINK1 accumulation and mitophagosomes formation triggered by A while impairing lysosomal-mediated clearance. Antioxidant recovery of cholesterol-induced mitochondrial glutathione (GSH) depletion prevented mitophagosomes formation indicating mitochondrial ROS involvement. Interestingly, when brain cholesterol accumulated chronically in aged APP-PSEN1-SREBF2 mice the mitophagy flux was affected at the early steps of the pathway, with defective recruitment of the key autophagy receptor optineurin (OPTN). Sustained cholesterol-induced alterations in APP-PSEN1-SREBF2 mice promoted an age-dependent accumulation of OPTN into HDAC6-positive aggresomes, which disappeared after in vivo treatment with GSH ethyl ester (GSHee). The analyses in post-mortem brain tissues from individuals with AD confirmed these findings, showing OPTN in aggresome-like structures that correlated with high mitochondrial cholesterol levels in late AD stages. Conclusions: Our data demonstrate that accumulation of intracellular cholesterol reduces the clearance of defective mitochondria and suggest recovery of the cholesterol homeostasis and the mitochondrial scavenging of ROS as potential therapeutic targets for AD.
Building low intensity psychosocial support for Syrian refuge families in Istanbul
Authors: Weine Stevan Merrill , Arenliu Aliriza , Görmez Vahdet , Langenecker Scott , Demirtas Hakan 
Published: September 2020

Abstract
Background: The study is located in Istanbul, Turkey, where more than 750,000 Syrian refugees reside, largely in urban settings. It develops and pilot tests a novel model for helping urban refugee families in settings with limited to no access to evidence-based mental health services for refugees, by delivering a transdiagnostic family intervention for common mental disorders in health and non-health sector settings using a task-sharing approach. This case study addresses the following question: How can we address the common mental disorders of both children and parents, and support protective family resilience processes, through a low intensity trans-diagnostic family support intervention? Discussion: The rapidly growing scale of humanitarian crises requires new response capabilities geared towards addressing populations with prolonged high vulnerability to mental health consequences and limited to no access to mental health, health, and social resources. We faced multiple challenges in conducting this research including: 1) identifying local academic partners with research capacity, including in implementation science; 2) lack of culture of partnership between academics and humanitarian organizations; 3) getting local clinicians to embrace on a task-sharing model; 4) cultural competency of local and U.S. partners for refugee population; 5) getting local academics to focus on humanitarian emergency; 6) planning for a family intervention that would work with families with rigid gender role perspectives; 7) multiple social and economic problems that could not be solved, such as children working; 8) engagement challenges due to high demands on families. Through the research process, the research team learned lessons concerning: 1) building a coalition of academic and humanitarian organization partners; 2) investing in research capacity building of local partners; 3) working in a community-collaborative and multi-disciplinary approach to best understand and address socio-cultural, contextual, practical and scientific challenges needed to develop and implement the new family support model. Conclusion: Conducting research in humanitarian emergency settings calls for significant attention to building a coalition of academic and humanitarian organization partners, investing in research capacity building of local partners, and working in a community-collaborative and multi-disciplinary approach.
Clinical Outcomes of Extensive Stage Small Cell Lung Cancer Patients Treated With Thoracic Radiotherapy at Different Timing and Fractionation
Authors: Han Jinmin , Fu Chengrui , Li Baosheng 
Published: September 2020

Abstract
Objective: The purpose of this study was to assess whether combined thoracic radiotherapy (TRT) on the basis of chemotherapy (ChT) showed promising anti-tumor activity in extensive-stage small cell lung cancer (ES-SCLC), then to explore practice patterns for radiation time and dose/ fractionation and to identify prognostic factors for patients who would benefit from ChT/TRT.Methods: A total of 492 ES-SCLC patients were included from January 2010 to March 2019, of which 244 patients experienced ChT/TRT. Propensity score matching (PSM) was performed to minimize bias between the ChT/TRT and ChT-alone groups. Patients in ChT/TRT group were categorized into four groups based on the number of induction chemotherapy cycles. For effective dose fractionation calculation, we introduced the time-adjusted biological effective dose(tBED). Categorical variables were analyzed with Chi-square tests and Fisher’s exact tests. Survival rates were computed by the Kaplan-Meier method. Multivariate prognostic analysis was performed with Cox proportional hazard models. Results: Patients who received ChT/TRT were associated with improved OS (18.2 vs 10.8 months), PFS (9.0 vs 6.0 months) and LRFS (12.0 vs 6.0 months) before matching, with similar results after matching. In the ChT/TRT group, the median LRFS times for groups based on radiation time were 12.7, 12.0, 12.7, and 9.0 months, respectively. Earlier TRT had a tendency to prolong PFS (median 10.6 vs 9.8 vs 9.1 vs 7.7 months, respectively, p = 0.1095), as was not seen in OS (median 17.6 vs 19.5 vs 17.2 vs 19.1 months, respectively, p = 0.7224). To note, patients within 6 cycles had better LRFS (p = 0.0006). For radiation dose, patients in high-dose group (tBED>50Gy) had worse OS (median 25.9 vs 22.9, p = 0.0484) and PFS (median 12.1 vs 11.2, p=0.0042) in patients with complete response and partial response (CR and PR) to systemic therapy, but the above-mentioned results were not drawn when the population was confined to those receiving standard fractionation with CR and PR. Conclusion: ChT/TRT could improve survival for ES-SCLC patients. We cautiously recommend that TRT should be performed within 6 cycles and receiving hyperfractionated 45Gy in 30 fractions may be a feasible treatment scheme for ES-SCLC patients.
Health Related Quality of Life in Patients with Chronic Disease in Lebanese Community Setting
Authors: Dimassi Hani , Nasser Soumana C , Issa Aline , Adrian Sandrine Sarine , Hazimeh Bassima 
Published: September 2020

Abstract
Background: The impact of chronic diseases on patient quality of life are becoming of high priority in healthcare system. There is an increased need of such data in Middle Eastern countries. Objective: To measure health related quality of life (HRQOL) in patients with chronic disease to associate this information with demographic data, socioeconomic status, and health satisfaction.Setting: Six community pharmacies in Beirut region.Method: A prospective cross-sectional study was conducted to gather information on socioeconomic status, health condition and quality of life of participants during their visit to their local pharmacy. Main outcome measure: Health related quality of life using the EQ5D instrumentResults: Participants (n=103) gave an average of 6.8, and 7.4 over ten for their current health and for their satisfaction with their treatment, respectively. The mean utility score was 0.762 (SD 0.202). The number of prescribed medications per respondent indicated a significant impact on HRQOL (p = 0.002); with diuretic agents having a significant difference in utility scores (p<0.001). On average, participants 75 years or older, hospitalized in the past 12 months, diagnosed with hypertension, had a lower utility score of 0.15 (p<0.001), 0.111 (p=0.001), and 0.065 (p=0.035), respectively. For every unit increase in treatment satisfaction, the quality of life score increased by 0.036 unit (p= 0.001)Conclusion: HRQOL as measured by the EQ5D in this study was affected in patients with cardiac disease or diabetes. Male gender, advanced age, low socioeconomic status, frequent hospital and doctor visits were important risk factors for a poor HRQOL.
Genome-Wide Identification of Histone Acetyltransferases and Deacetylases in Epiphytic Orchid Plant Dendrobium Catenatum
Authors: Jiang Wei-Wei , Qu Dong-Hai , Tian Ji-Li , Si Jin-Ping , Chen Dong-Hong 
Published: September 2020

Abstract
Background: Dendrobium catenatum is a kind of precious Traditional Chinese Medicine, and possesses unique developmental programs and epiphytic lifestyle. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are responsible for maintenance of histone acetylation homeostasis, and they are widely involved in developmental regulation and stress responses via remodeling chromatin structure, but their biological functions in orchid plants remain largely unknown.Results: Here we identified 8 HAT genes and 14 HDAC genes from D. catenatum genome. We carried out phylogenetic construction, gene structure and domain architecture analysis of these D. catenatum HAT/HDAC (DcHAT/DcHDAC) proteins using the well-defined homologs from the model plants Arabidopsis thaliana and Oryza sativa as references. DcHAT proteins can be classified into four families: GNAT family (3 members), MYST family (2), CBP family (2), and TAFII250 family (1), and DcHDAC proteins can be grouped into three families: RPD3/HDA1 family (10), SIR2 family (2), and HD2 family (2), in accordance with previously described classification. Cis-acting element analysis indicated that the promoter regions of DcHAT/DcHDAC genes contain diverse stress-responsive elements. Subcellular localization predictions suggested that DcHAT/DcHDAC proteins might be localized in nucleus or/and cytoplasm. Spatiotemporal expression profiling showed that DcHAT/DcHDAC genes generally exhibit either universal or specific expression pattern in different tissues and organs. Finally, stress response assay suggested drought treatment significantly represses the expression of DcHAG1 and DcHDA14, cold exposure evidently influences the expression of DcHAG1 and DcHDT1, and heat shock has a broad impact on the expression of DcHAT/DcHDAC genes.Conclusions: In this study, we reveal the identification and expression profiles of DcHATs and DcHDACs in epiphytic orchid plant D. catenatum, indicating their roles in the regulation of both long-term developmental programs and short-term stress responses. This study provides a foundation for in-depth functional excavation of HATs/HDACs associated with dynamic histone acetylation levels in orchids.
Parasitic Contamination of Fresh Vegetables in Open Air Markets of Aksum, Ethiopia
Authors: Gebremariam Gebrehiwot kiros , Girmay Tsgab Gebrecherkos 
Published: September 2020

Abstract
Background: Intestinal parasitic diseases are the foremost causes of illness in humans, responsible for significant morbidity and mortality. Recently, there have been so many reports related to a foodborne illness linked to consuming fresh vegetables, especially in developing countries. The study was aimed to assess the parasitic contamination level of fresh vegetables collected from open air markets in Aksum town, Tigray region, Ethiopia.Method: A total of 384 samples belonging to six vegetable types were collected randomly from local markets in Aksum town. Samples were washed in saline solution followed by sedimentation for 24 hours.After that the supernatant was decanted leaving the sediment. The sediment was then transferred to a centrifuge tube and centrifuged at 3000 revolution per minute for 5minutes. Finally, the supernatant was decanted and the sediment was examined under light microscope for protozoan cyst, helminthes ova, and larvaeResults: The overall prevalence of parasitic contamination was 57.3%. The Cabbage was the most frequently contaminated (79.7%) vegetable succeeded by Spinach (75%), Lettuce (73.4%), Potato (46.9%), Green pepper (37.5%), and tomato (31.2%). Among the parasites detected, Taenia spp. proglottides/egg was the most frequent contaminant with 41.1% prevalence rate followed by Enetrobius vermicularis egg (20.3%), Hookworm spp.(19.5%), Fasciola spp. egg (17.2%), Giardia lamblia cyst (18.5%), Entamoeba spp. cyst(15.9%), Strongyloides stercoralis larva (12.5%),Ascarislumbricoidese gg (9.4%), and Cryptosporidium spp.Chai-square analysis showed that the type of fertilizer used, educational status of the vendors, status of wash before display, and type of vegetable they produce was statistically and significantly associated with the prevalent parasite forms detected (P < 0.001).Conclusion: This study identified a high prevalence of fresh vegetables contaminated with medically important parasites, thus effective prevention measures such as standard washing before consuming fresh vegetables, and avoiding raw manure as a fertilizer should be implemented to avoid infection from contaminated vegetables.
Correlation of Age and Bone Marrow Derived CD 34+ Cells and Leucocytes in 873 Patients.
Authors: Pabinger Christof , Dammerer Dietmar , Lothaller Harald , Gieringer Sandra , Krall Marcel , Kobinia Georg Stefan 
Published: September 2020

Abstract
Background:The use of regenerative medicine, such as autologous chondrocyte implantation (ACI), matrix associated stem cell therapy (MAST) and bone marrow derived stem cell therapy against arthritis is the gold standard for certain indications. However, the clinical improvement of patients using these novel therapies remains heterogeneous and the reasons for this are not fully understood. The impact of age is always a concern for patients and doctors and elderly patients can only be mobilized with lower total collected CD34+ cells, older age correlates with inferior results, fatty degeneration of the bone marrow, delayed fracture-healing and osteoporosis, but solid data are missing. Purpose:This is the first study to determine the average quantity of leukocytes and CD 34+ cells and their relationship in human bone marrow. Study design: Descriptive Laboratory Study Methods:We evaluated the laboratory results of 873 patients (aged 1-90 years), who underwent stem cell transplantation for non malignant diseases. Results:We found no age-related decrease regarding the number and the vitality of leukocytes and CD 34+ stem cells. The number of bone marrow derived leucocytes and CD 34+ cells showed a strong and significant correlation.Conclusion:The amount of bone marrow derived stem cells can be predicted by leukocytes. This study makes further research possible in order to link clinical outcome to the absolute number of stem cells and leukocytes.An upper age-limit for stem cell therapy can therefore not be defined from the donor-site perspective.Clinical Relevance:The number of leucocytes might be used to predict the amount of stem cells in order to select the ideal patient.