bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence Trend of Breast Cancer in Women of Eastern Mediterranean Region countries from 1998 to 2019: A Systematic Review and Meta-Analysis
Authors: Zahedi Razieh , Vardanjani Hossein Molavi , Baneshi Mohammad Reza , Haghdoost Ali Akbar , Afshar Reza Malekpour , Sarabi Roghayeh Ershad , Tavakoli Fatemeh , zolala farzaneh
Published: February 2020

Background
This study was conducted to provide evidence on the current status of breast cancer and its incidence trend in Eastern Mediterranean Region during 1998-2019. Also, this study aimed to investigate the association between the incidence of breast cancer and Human Development Index and some factors related to this index, including total fertility rate, and obesity, using a meta-analysis.
Method
Data on incidence of breast cancer were collected from various sources, including PubMed, Embase, Web of Science, and WHO, from 1998 to 2019 using systematic review and meta-analysis. Pooled age standardized rate was calculated based on study duration and quality of data using a subgroup analysis and random effect meta-analysis.
Results
A total of 80 studies (545 data points) were analyzed. Pooled age standardized rate of breast cancer for Eastern Mediterranean Region was 37.1 per 100 000 person-year (95% confidence interval [CI], 34.5, 39.8) during 2011-2019. age standardized rate of breast cancer had an upward trend in Eastern Mediterranean Region from 2005 to 2019. However, the increasing trend was found to be slightly different in various regions based on quality of data. Moreover, pooled age standardized rate had a significant association with Human Development Index [-89.2 (95% CI, -119.8, -58.7)] and obesity [1.2 (95% CI, 0.9, 1.5)].
Conclusion
Pooled age standardized rate of breast cancer in Eastern Mediterranean Region was lower than the global average. Also, the age standardized rate value and its incremental trend have been higher in countries with high-quality data than in other countries of this region in recent years. Data quality or physiological factors, such as increase in obesity rates, could be the reasons for this incremental trend.
Key words
Breast cancer, meta-analysis, Eastern Mediterranean region, Incidence
Setting up a nurse-led model of care for management of Hypertension and Diabetes Mellitus in a high HIV prevalence context in rural Zimbabwe: a descriptive study
Authors: Frieden Marthe Marie , Zamba Blessing , Mukumbi Nisbert , Mafaune Patron Titsha , Makumbe Brian , Irungu Elizabeth , Moneti Virginia , Isaakidis Petros , Garone Daniela , Prasai Madhu Janina
Published: February 2020

Background

In the light of the increasing burden of non-communicable diseases on health systems in low- and middle-income countries, particularly in Sub-Saharan Africa, context-adapted, cost-effective service delivery models are required urgently. Multiple models have been trialled across Africa with varying degrees of success. Zimbabwe is a low-income country with unique socio-economic challenges and a dual disease burden of infectious chronic diseases such as HIV and non-communicable diseases. We describe the experience of setting up and organising a nurse-led Diabetes Mellitus (DM) and Hypertension (HTN) model of care in rural Zimbabwe from July 2016 to June 2019.

Programme design and implementation

We used a conceptual framework successfully applied in the roll-out of antiretroviral therapy in Zimbabwe. Mirroring the HIV experience, we describe key enablers in the design and implementation of the model: decentralization of services, integration of care, simplification of guidelines, mentoring and task-sharing, provision of affordable medicines, quality assured laboratory support, patient empowerment, a dedicated monitoring and evaluation system, and a robust referral system. DM and HTN services were set up in 9 primary health care (PHC) facilities and two hospitals in Chipinge district, and integrated into the general out-patient department or pre-existing HIV clinics. In one hospital, an integrated chronic care clinic (ICCC) emerged. We provided mentoring for staff using simplified protocols, and patient education. Free medication and monitoring with point of care (POC) glycosylated haemoglobin (HbA1c) were provided. Nurses in 7 PHC facilities and one hospital developed sufficient knowledge and skills to diagnose and manage DM and HTN patients, and 3094 patients were registered. Major lessons learned include: the value of POC devices in the management of diabetes; the pressure on services due to added caseload, exacerbated by the availability of free medications; and the importance of leadership in successful programme implementation.

Conclusion

Our experience demonstrates a model for nurse-led decentralized integrated DM and HTN care in a high HIV prevalence rural, low-income context. Developing a context-adapted model of care is a dynamic process. We present our lessons learned with the intention of sharing experience which may be of value to other public health programme managers.
Exploring and analysing single cell multi-omics data with VDJView
Authors: Samir Jerome , Rizzetto Simone , Gupta Money , Luciani Fabio
Published: February 2020

Background Single cell RNA sequencing provides unprecedented opportunity to simultaneously explore the transcriptomic and immune receptor diversity of T and B cells. However, there are limited tools available that simultaneously analyse large multi-omics datasets integrated with metadata such as patient and clinical information.Results We developed VDJView, which permits the simultaneous or independent analysis and visualisation of gene expression, immune receptors, and clinical metadata of both T and B cells. This tool is implemented as an easy-to-use R shiny web-application, which integrates numerous gene expression and TCR analysis tools, and accepts data from plate-based sorted or high-throughput single cell platforms. We utilised VDJView to analyse several 10X scRNA-seq datasets, including a recent dataset of 150,000 CD8+ T cells with available gene expression, TCR sequences, quantification of 15 surface proteins, and 44 antigen specificities (across viruses, cancer, and self-antigens). We performed quality control, filtering of tetramer non-specific cells, clustering, random sampling and hypothesis testing to discover antigen specific gene signatures which were associated with immune cell differentiation states and clonal expansion across the pathogen specific T cells. We also analysed 563 single cells (plate-based sorted) obtained from 11 subjects, revealing clonally expanded T and B cells across primary cancer tissues and metastatic lymph-node. These immune cells clustered with distinct gene signatures according to the breast cancer molecular subtype. VDJView has been tested in lab meetings and peer-to-peer discussions, showing effective data generation and discussion without the need to consult bioinformaticians.Conclusions VDJView enables researchers without profound bioinformatics skills to analyse immune scRNA-seq data, integrating and visualising this with clonality and metadata profiles, thus accelerating the process of hypothesis testing, data interpretation and discovery of cellular heterogeneity. VDJView is freely available at https://bitbucket.org/kirbyvisp/vdjview .
Positive deviance for dual-method promotion among women in Uganda: Study protocol for a cluster randomized controlled trial
Authors: Kosugi Hodaka , Shibanuma Akira , Kiriya Junko , Ong Ken Ing Cherng , Mucunguzi Stephen , Muzoora Conrad , Jimba Masamine
Published: February 2020

Background Dual-method use is known as the most reliable protection against unintended pregnancies and sexually transmitted infections, including HIV. However, it is not commonly used in sub-Sharan Africa, especially among women using highly effective contraceptives. This article describes a protocol to evaluate the effect of an intervention formulated under the positive deviance approach for promoting dual-method use in Uganda. Methods One hundred women will be interviewed using a structured questionnaire to find those practicing dual-method use. Then, in-depth interviews will be conducted with all women using dual-method and ten women using only highly effective contraceptives to identify their unique practice. Then, a cluster randomized controlled trial will be conducted to examine the effect of an intervention formulated under the positive deviance approach on dual-method uptake and adherence. Twenty health facilities will be randomized to an intervention or control arm, and 480 women will be enrolled in each group. The participants will be followed up for eight months. Discussion This trial focuses on women who already adapted dual-method use and identifies their unique solutions to promote dual-method use. This trial could tackle barriers for dual-method use, which expert outsiders may fail to recognize, by analyzing and promulgating their unique behaviors. This study could provide evidence that the positive deviance approach can address unintended pregnancies and sexually transmitted infections as well as other health problems which usual approaches have failed to address.
Lapatinib in combination with capecitabine versus continued use of trastuzumab in breast cancer patients with trastuzumab-resistance: a retrospective study of a Chinese population.
Authors: Yang fan , Huang Xiang , Sun Chunxiao , Li Jianbin , Wang Biyun , Yan Min , Jin Feng , Wang Haibo , Zhang Jin , Fu Peifen , Zeng Tianyu , Wang Jian , Li Wei , Li Yongfei , Yang Mengzhu , Li Jun , Wu Hao , Fu Ziyi , Yin Yongmei , jiang zefei
Published: February 2020

Background: The efficacy and safety of lapatinib plus capecitabine (LC or LX) versus trastuzumab plus chemotherapy in patients with HER-positive metastatic breast cancer who are resistant to trastuzumab is unknown.
Methods: We retrospectively analyzed data from breast cancer patients who began treatment with regimens of lapatinib plus capecitabine (LC or LX) or trastuzumab beyond progression (TBP) at eight hospitals between May 2010 and October 2017.
Results: Among 554 patients who had developed resistance to trastuzumab, the median PFS (progression free survival) was 6.77 months in the LX group compared with 5.6 months in the TBP group (hazard ratio 0.804; 95% CI, 0.67 to 0.96; P=0.019). The central nervous system progression rate during treatment was 5.9% in the LX group and 12.5% in the TBP group (P=0.018).
Conclusion: The combination of lapatinib and capecitabine showed a prolonged PFS relative to TBP in patients who had progressed on trastuzumab.
The construction of a conceptual framework explaining the relation between barriers to change of management of neuropsychiatric symptoms in nursing homes: a qualitative study using focus groups
Authors: Teunenbroek Charlotte Frederike van , Verhagen Kim , Smalbrugge Martin , Persoon Anke , Zuidema Sytse U. , Gerritsen Debby L.
Published: February 2020

Background. Several efforts have been made to change management of neuropsychiatric symptoms (NPS) in nursing homes, however only few were successful. Numerous barriers to change in healthcare were identified, yet only one conceptual model is known to study their interrelationships . Unfortunately, this model does not discuss specific barriers encountered in nursing home practice. The aim of this study is to explore perceived barriers to change in the management of NPS in nursing homes and to construct a conceptual framework providing insight into the relative importance and interrelationships of these barriers when improving quality of care.
Methods. Four focus groups were conducted in different dementia special care units of one Dutch nursing home. Participants were either nursing staff, treatment staff or relatives of residents. Qualitative thematic analysis was conducted according to the five phases defined by Braun & Clarke. Finally, a conceptual framework showing the interrelations of barrier-themes was constructed using text fragments of the focus groups.
Results. We constructed a conceptual framework consisting of eight themes of barriers explaining the extent to which change in NPS-management can be achieved: 'organizational barriers', 'personal barriers', 'deficiency of staff knowledge', 'suboptimal communication', 'inadequate (multidisciplinary) collaboration', 'disorganization of processes', 'reactive coping' and 'differences in perception'. Addressing 'organizational barriers' and 'deficiency of staff knowledge' is a precondition for change. 'Suboptimal communication' and 'inadequate (multidisciplinary) collaboration' play a key role in the extent of change achieved via the themes 'differences in perception' and 'disorganization of processes'. Furthermore, 'personal barriers' influence all themes - except 'organizational barriers' - and may cause 'reactive coping', which in turn may lead to 'difficulties to structure processes'.
Conclusions. A conceptual framework was created explaining the relationships between barriers towards achieving change focused on improving management of NPS in nursing homes. After this framework has been confirmed and refined in additional research, it can be used to study the interrelatedness of barriers to change, and to determine the importance of addressing them for achieving change in the provided care.
Oral rinses in growth inhibition and treatment of Helicobacter pylori infection
Authors: Kashyap Dharmendra , Baral Budhadev , Verma Tarun Prakash , Sonkar Charu , Chatterji Debi , Jain Ajay Kumar , Jha Hem Chandra
Published: February 2020

Background Helicobacter pylori ( H. pylori ) is well-known for its role in chronic gastritis and gastric cancer. Eradication of these carcinogenic bacteria from the gut is one of the challenges for clinicians. The complexity of treatment mainly owes to antibiotic resistance and relapse due to an additional reservoir in the oral cavity. Our study emphases the isolation of H. pylori from distinct habitats of the gut microenvironment (gastric biopsy and gastric juice) and its subsequent characterization. We have also evaluated the effect of various oral rinses on isolated H. pylori from different anatomical locations of included subjects. Results The possible strains isolated from two different habitats of the same subject shows a striking difference in their growth pattern. Promisingly, some of the included oral rinses are efficient in growth inhibition as per recommended 30 sec treatment. The subsequent evaluation shows that oral rinse B (among A-E) is most effective and down-regulates the expression of one of the potent H. pylori gene, CagA, in the infected gastric adenocarcinoma (AGS) cells. Conclusion Our study, for the first time, revealed that H. pylori, isolated from the different habitat of the same subject, show a different growth pattern. The expression of H. pylori pathogenic gene (CagA) was down-regulated by the use of oral rinses. Hence, oral rinses will reduce the H. pylori in the oral cavity and help to control its migration from oral to the gastric compartment and may be used as an adjuvant treatment option for its re-infection.
Dimensions of leisure-time physical activity and risk of depression in the “SEGUIMIENTO UNIVERSIDAD DE NAVARRA” (SUN) prospective cohort.
Authors: Montero Alejandro Fernández , Moreno-Galarraga Laura , Sánchez-Villegas Almudena , Lahortiga-Ramos Francisca , Ruiz-Canela Miguel , Martínez-González Miguel Ángel , Molero Patricio
Published: February 2020

Background: An inverse association between total leisure-time physical activity (LTPA) and depression has been previously documented in the scientific literature. Our objective was to prospectively assess the association of LTPA with the risk of depression, focusing on several dimensions of LTPA (intensity, duration and type).Methods: The SUN (Seguimiento Universidad de Navarra) project is a prospective cohort study formed by Spanish university graduates. A total of 15,488 adults (40.2% men, mean age 37±12 years) initially free of depression were assessed. A report of a validated medical diagnosis of depression or the habitual use of antidepressants (any of both) were considered as incident cases of depression. LTPA was estimated through previously validated self-reported questionnaires. Participants were classified following Physical Activity recommendations from the World Health Organization, and according to the intensity, duration and type of LTPA. Cox proportional hazards regression models were run, adjusted for demographic, lifestyle, and dietary factors, to estimate adjusted hazard ratios (HR) of depression and 95% confidence intervals (CI). Results: During 163,059 person-years of follow-up we registered 870 incident cases of depression. Participants with higher total LTPA (METs-h/wk) and higher duration of LTPA (hours/wk) exhibited a lower risk of depression HR=0.84 (95% CI: 0.72-0.99) and HR=0.83 (0.70-0.99) respectively, whereas intensity of LTPA (MET) did not show any association with depression. Conclusion: Participants with higher LTPA had a lower risk of depression. The inverse association was stronger for total LPTA time than for its intensity. Higher duration of LTPA should be encouraged to prevent depression.
Reduced methane oxidizing activity by sediment methanotrophs in shallow coastal zones with high methane emissions
Authors: Broman Elias , Sun Xiaole , Stranne Christian , Salgado Marco G , Bonaglia Stefano , Geibel Marc , Norkko Alf , Humborg Christoph , Nascimento Francisco J.A
Published: February 2020

Background Coastal zones are transitional areas between land and sea where large amounts of organic and inorganic carbon compounds are recycled by microbes. Especially shallow zones near land have been shown to be the main source for oceanic methane (CH4) emissions. Water depth has been predicted as the best explanatory variable, which is related to CH4 ebullition, but exactly how sediment methanotrophic bacteria mediates these emissions along water depth is unknown. Here, we investigated the activity of methanotrophs in the sediment of shallow coastal zones with high CH4 emissions within a depth gradient from 10–45 m. Field sampling consisted of collecting sediment slices from eight stations along a coastal gradient (0–4 km from land) in the coastal Baltic Sea. We combined real-time measurements of surface water CH4 concentrations, acoustic detection of CH4 seeps in the bottom water, and sediment DNA plus RNA sequencing.Results The relative abundance and CH4 oxidizing activity (pMMO; particulate methane monooxygenase) of the dominant methanotroph Methylococcales was significantly higher in deeper costal offshore areas (36–45 m water depth) compared to adjacent shallow zones (10–28 m). This was in accordance with the shallow zones having CH4 concentrations in the surface water, as well as more CH4 seeps from the sediment. Furthermore, our findings indicate that the low prevalence of Methylococcales and their activity was restrained to the euphotic zone (indicated by PAR data, photosynthesis proteins, and 18S rRNA data of benthic diatoms). This was also indicated by a positive relationship between water depth and the relative abundance of Methylococcales and pMMO.Conclusions We detected a low relative abundance of methanotrophs and CH4 oxidizing activity in shallow coastal areas, this can partly explain the difference in CH4 emissions between shallow and deep coastal areas (and the relationship between CH4 emission and water depth). Potentially a reduced activity of methanotrophs also facilities the build-up of CH4 bubbles in the sediment. CH4 emissions from the study area has previously been calculated to be comparable to that of subarctic lakes, and it is suggested that shallow coastal waters, similarly to inland waters, are hotspots for CH4 emissions.
Multiple m6A RNA methylation modulators promote the malignant progression of hepatocellular carcinoma and affect its clinical prognosis
Authors: Qu Nanfang , Qin Sanyu , Zhang Xuemei , Bo Xiaotong , Liu Zhengchun , Tan Chao , Wen Guiqiong , Jiang Haixing
Published: February 2020

Background: Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in the world. N 6 -methyladenosine (m 6 A) RNA methylation is dynamically regulated by m 6 A RNA methylation modulators (“writer,” “eraser,” and “reader” proteins), which are associated with cancer occurrence and development. The purpose of this study was to explore the relationships between m 6 A RNA methylation modulators and HCC.
Methods: First, using data from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases, we compared the expression levels of 13 major m6A RNA methylation modulators between HCC and normal tissues. Second, we applied consensus clustering to the expression data on the m 6 A RNA methylation modulators to divide the HCC tissues into two subgroups (clusters 1 and 2), and we compared the clusters in terms of overall survival (OS), World Health Organization (WHO) stage, and pathological grade. Third, using least absolute shrinkage and selection operator (LASSO) regression, we constructed a risk signature involving the m 6 A RNA methylation modulators that affected OS in TCGA and ICGC analyses.
Results: We found that the expression levels of 12 major m6A RNA methylation modulators were significantly different between HCC and normal tissues. After dividing the HCC tissues into clusters 1 and 2, we found that cluster 2 had poorer OS, higher WHO stage, and higher pathological grade. Four m 6 A RNA methylation modulators (YTHDF1, YTHDF2, METTL3, and KIAA1429) affecting OS in the TCGA and ICGC analyses were selected to construct a risk signature, which was significantly associated with WHO stage and was also an independent prognostic marker of OS.
Conclusions: In summary, m 6 A RNA methylation modulators are key participants in the malignant progression of HCC and have potential value in prognostication and treatment decisions.
CA724 predicts overall survival in locally advanced gastric cancer patients with neoadjuvant chemotherapy
Authors: Tong Yilin , Zhao Yan , Shan Zexing , Zhang Jianjun
Published: February 2020

Background: Serum tumor markers are of great importance in diagnosis, prognostic predicting and recurrence monitoring in gastrointestinal malignancy, including AFU, AFP, CEA, CA199, CA125 and CA724. However, their significances in gastric cancer (GC) patients with neoadjuvant therapy (NCT) are still uncertain. The aim of this study is to evaluate the predictive value of these six tumor markers in locally advanced GC patients with NCT and curative surgery.
Methods: 290 locally advanced GC patients with NCT and D2 radical gastrectomy were retrospectively analyzed. Their tumor markers before (pre-) and after (post-) NCT and pathological characters were exacted from the database in our hospital. The optimal cutoff values of six tumor markers were calculated by ROC and Youden index. Their predictive significances were analyzed and survival curves on overall survival (OS) were obtained by Kaplan-Meier method. Associations between categorical variables were explored by Chi-square test or Fisher's exact method. Multivariate analyses were performed by Cox regression model.
Results: Not only the pre- and post- CA199, CA125 and CA724 could predict the OS respectively, but also the changes (diff-) between post- and pre- groups were related to the prognosis (P < 0.05). In multivariable analysis, only pre- (P = 0.016) and post-CA724 (P = 0.033) remained significant, and the significance of diff-CA724 was on borderline (P = 0.085). Besides, pre- and post-CA199, CA125 and CA724 were associated with the metastasis of lymph node (N- vs N+) and pathological stage (Ⅰ-Ⅱ vs Ⅲ) (P < 0.05). Post-CA724 was related to the invasion of vascular or lymphatic vessels (P = 0.019), and pre-CA724 was nearly remarkable (P = 0.082). However, AFU, AFP and CEA showed no association with survival (P > 0.05).
Conclusions: CA724 is an independent factor to prognosis, and could be used to predict the ypN and ypTNM stage in locally advanced GC patients undergone NCT and curative resection.
PNO1 promotes cell proliferation in prostate cancer
Authors: Hu Jianpeng , Cui Feilun , Xv Zhipeng , Tan Jian , Wang Zhengyu
Published: February 2020

BackgroundProstate cancer (PCa) is one of the most commonly diagnosed cancers. The functions of PNO1 in yeasts were involved in regulating ribosome and proteasome biogenesis. Human PNO1 is crucial to the site 3 cleavage at the 3ʹ-end of 18S pre-rRNA. Previous studies indicated that PNO1 may be related to the progression of cancers. However, the functions of PNO1 in PCa remained unclear. MethodsThe present study evaluated the expression levels of PNO1 in PCa by using GSE45016, GSE55945 and GSE17951 datasets. Then, in vivo and in vitro assays were conducted to detect the biological functions of PNO1 in PCa. Microarray and bioinformatic analysis were carried out to detect the downstream targets and pathways regulated by PNO1.ResultsThe present study for the first time demonstrated PNO1 was up-regulated in PCa samples compared to normal tissues. ShRNA mediated knockdown of PNO1 significantly suppressed PCa proliferation and clone formation, however, induced PCa apoptosis. Microarray analysis and bioinformatics analysis revealed PNO1 was involved in regulating multiple cancer related biological processes, such as regulation of DNA repair, single organismal cell-cell adhesion, translational initiation, RNA splicing, transcription, and positive regulation of mRNA catabolic process. OF note, in vivo results showed PNO1 knockdown remarkably reduced the PCa growth rate. ConclusionsDespite more in-depth research is still required, this study showed PNO1 could serve as a potential biomarker for PCa.
The role of residents in medical students’ neurology education: current status and future perspectives
Authors: Keser Zafer , Rodriguez Yvo A , Tremont Jennifer , Hsieh Peggy H , McCullough Louise D. , Sandrone Stefano , Stimming Erin F
Published: February 2020

Background: Neurophobia, a well-described fear of neurology affects medical students worldwide and may be one of the factors contributing to a shortage of neurologists in the United States. Residents spend a considerable amount of time with medical students, therefore, we sought to better understand the impact neurology residents have on the medical students experience during their neurology clerkship and their subsequent interest in neurology. We aimed to identify and implement strategies to decrease neurophobia and increase the number of students pursuing neurology as a career. Methods: Third-year medical students (n=234) of UTHealth’s McGovern Medical School rotating through their neurology core clerkship completed two surveys regarding their rotation experiences. Surveys were completed anonymously before and after the clerkship to measure their interest and confidence in neurology and the impact of their interactions with the neurology residents during the clerkship. In parallel, residents participated in a teaching workshop focused on small group teaching to improve their teaching effectiveness. Non-parametrical comparison and ordinal regression analyses were utilized for data analyses. Results: Medical students reported a statistically significant increase in their confidence in managing neurological conditions and interest in pursuing a neurology residency after their clerkship. There was a significant association between the medical students’ overall rotation experience and the residents’ teaching effectiveness. Their overall clerkship experience correlated with their interest and confidence in neurology. There was a trend towards an increase in residents’ teaching effectiveness and students’ rotation experience after the resident workshop. Additionally, students who rotated in both and outpatient and inpatient site reported an increased interest in neurology. Conclusion: Our study supports that resident-led teaching efforts are important in improving medical students’ neurologic education and their interest in neurology . We examined future strategies to implement “near-peer” teaching activities to enhance the medical students' neurologic educational experience. These strategies could potentially mitigate neurophobia and ultimately lead to a much-needed increase in future neurologists.
Modulation of Actin network and Tau phosphorylation by HDAC6 ZnF UBP domain
Authors: Balmik Abhishek Ankur , Sonawane Shweta Kishor , Chinnathambi Subashchandrabose
Published: February 2020

Background: Microtubule-associated protein Tau undergoes aggregation in Alzheimer`s disease and a group of other related diseases collectively known as Tauopathies. In AD, Tau forms aggregates, which are deposited intracellularly as neurofibrillary tangles. HDAC6 plays an important role in aggresome formation where it recruits poly-ubiquitinated aggregates to the motor protein dynein.
Methods: Here, we have studied the effect of HDAC6 ZnF UBP on Tau phosphorylation, ApoE localization, GSK-3β regulation and cytoskeletal organization in neuronal cells by immunofluorescence analysis using fluorescently tagged molecules or antibodies. We have assessed neuronal cell viability and membrane integrity under different treatment conditions by employing MTT and LDH assay respectively.
Results: Immunocytochemistry reveals that HDAC6 ZnF UBP can modulate Tau phosphorylation and actin cytoskeleton organization when the cells are exposed to the domain. HDAC6 ZnF UBP treatment to cells does not affect their viability and resulted in enhanced neurite extension and formation of structures similar to podosomes, lamellipodia and podonuts suggesting its role in actin re-organization. Also, HDAC6 treatment showed increased nuclear localization of ApoE and tubulin localization in microtubule organizing centre.
Conclusions: Altogether, our studies suggest the regulatory role of this domain in different aspects related to neurodegenerative diseases.
The effect of antiretroviral therapy initiation time and baseline CD4+ cell counts on AIDS-related mortality among former plasma donors in China: a 20-Year retrospective cohort study
Authors: Zhang Xuening , Yang Yongli , Zhang Weiping , Jia Xiaocan , Shi Nian , Gondwe Theodore , Shi Xuezhong
Published: February 2020

Background: To estimate the influence of antiretroviral therapy (ART) initiation time， baseline CD4+ cell counts and other prognostic factors on AIDS-related death among former plasma donors patients (FPD). Methods: A retrospective cohort study was conducted involving 11,905 HIV/AIDS patients in a high-risk area of illicit blood donation of Henan province in China between 1995 and 2016. Demographic and clinical characteristics information was collected. Hazard Ratios (HRs) for AIDS-related mortality by categories of baseline CD4+ cell counts and ART initiation time, were determined using competing risk model. Competing risk model also was used to evaluate the prognostic factors of AIDS-related mortality. The model performance was assessed by time-dependent receiver operating characteristic curve. Results: Patients who initiated ART within 90 days of HIV/AIDS diagnosis (sHR: 0.24, 95% CI: 0.22-0.27) and baseline CD4+ cell counts of ≥500 cells/μL (sHR: 0.23, 95% CI: 0.19-0.28) were associated with lower AIDS-related mortality risk. ART initiation time >1 year and CD4+ counts >350 (sHR: 4.42, 95% CI: 3.30-5.91) had a higher AIDS-related mortality risk than ART initiation time >90 days and CD4+ counts ≤350 (sHR: 4.33, 95% CI: 3.58-5.23). Male (sHR: 1.32, 95% CI: 1.22-1.43), older age (sHR: 1.97, 95% CI: 1.59-2.46), and infection by blood transmission (sHR: 1.57, 95% CI: 1.37-1.80) were risk factors.Conclusions: Early ART should be promoted to improve the survival of HIV/AIDS patients regardless of baseline CD4+ cell counts, especially elders, males, and infected through blood transmission. Key words: HIV/AIDS; antiretroviral therapy; treatment initiation; CD4+ cell counts; AIDS-related mortality; competing risk model
Effect of Residual Extractable Lignin on Acetone-Butanol-Ethanol Production in SHF and SSF Processes
Authors: Li Jing , Zhang Yu , Shi Suan , Tu Maobing
Published: February 2020

Background Lignin played an important role in biochemical conversion of biomass to biofuels. A significant amount of lignin is precipitated on the surface of pretreated substrates after organosolv pretreatment. The effect of this residual lignin on enzymatic hydrolysis has been well understood, however, their effect on subsequent ABE fermentation is still unknown. Results To determine the effect of residual extractable lignin on Acetone-Butanol-Ethanol (ABE) fermentation in separate hydrolysis and fermentation (SHF) and simultaneous saccharification and fermentation (SSF) processes, we compared ABE production from ethanol washed and unwashed substrates. The ethanol organosolv pretreated loblolly pine (OPLP) was used as the substrates. It was observed that butanol production from OPLP-UW (unwashed) and OPLP-W(washed) reached 8.16 and 1.69 g/L, respectively in SHF. The results showed that ABE production in SHF from OPLP-UW prevents an “acid crash” as comparing the OPLP-W. In SSF process, the “acid crash” occurred for both OPLP-W and OPLP-UW. The inhibitory extractable lignin intensified the “acid crash” for OPLP-UW and resulted in less ABE production than OPLP-W. The addition of detoxified prehydrolysates in SSF processes shortened the fermentation time and could potentially prevent the “acid crash”. Conclusions The results suggested that residual extractable lignin in high sugar concentration could help ABE production by slowing the metabolic rate and preventing “acid crash”. However, it became unfavorable in SSF due to its inhibition of both enzymatic hydrolysis and ABE fermentation with low initial sugar concentration. It is essential to remove extractable lignin of substrates for ABE production in SSF processes. And a higher initial sugar concentration is needed to prevent the “acid crash” in SSF processes.
The Distance and Median Problems in the Single-Cut-or-Join model with Single-Gene Duplications
Authors: Mane Aniket , Lafond Manuel , Feijao Pedro , Chauve Cedric
Published: February 2020

Background: In the field of genome rearrangement algorithms, models accounting for gene duplication lead often to hard problems. For example, while computing the pairwise distance is tractable in most duplication-free models, it is NP-complete for most extensions of these models accounting for duplicated genes. Moreover, problems involving more than two genomes, such as the genome median and the Small Parsimony problem, are intractable for most duplication-free models, with some exceptions, for example the Single-Cut-or-Join (SCJ) model. Result: We introduce a variant of the SCJ distance that accounts for duplicated genes, in the context of directed evolution from an ancestral genome to a descendant genome where orthology relations between ancestral genes and their descendant are known. Our model includes two duplication mechanisms: single-gene tandem duplication and the creation of single-gene circular chromosomes. We prove that in this model, computing the directed distance and a parsimonious evolutionary scenario in terms of SCJ and single-gene duplication events can be done in linear time. We also show that the directed median problem is tractable for this distance, while the rooted median problem, where we assume that one of the given genomes is ancestral to the median, is NP-complete. We also describe an Integer Linear Program for solving this problem. We evaluate the directed distance and rooted median algorithms on simulated data. Conclusion: Our results provide a simple genome rearrangement model, extending the SCJ model to account for single-gene duplications, for which we prove a mix of tractability and hardness results. For the NP-complete rooted median problem, we design a simple Integer Linear Program. Our publicly available implementation of these algorithms for the directed distance and median problems allow to solve efficiently these problems on large instances. Availability: https://github.com/cchauve/SCJ-with-SGD
Effect of aspirin and statins on pulmonary function and inflammation in patients with AECOPD
Authors: Duan Guangqing , Li Xiaoshuang , Lyu Juncheng , Tian Na , Lv Kaixuan , Liu Qi , Wang Mengjie , Sun Shiyu , Yu Jielun , Guo Guifang , Tan Wei , Yang Nana
Published: February 2020

Background: The influence of coronary atherosclerosis and related treatment drugs on acute exacerbation of chronic obstructive pulmonary disease (AECOPD) development requires in-depth study. The study investigated the effect of coronary artery calcification (CAC) and drugs for the treatment of CAC on the development of AECOPD. Methods : This retrospective clinical study recruited subjects with AECOPD from Weifang People’s Hospital from May 2017 to May 2019. All subjects were performed spirometry and coronary computed tomography (CT), and were divided into two groups according to whether coronary CT revealed coronary artery calcification: AECOPD group and AECOPD+CAC group. Then the AECOPD+CAC subjects were subdivided into two groups according to whether they had received oral aspirin and statins: AECOPD + CAC non-medication and AECOPD + CAC medication. T he t -test and nonparametric test were used for analyzed the lung function, arterial blood gas, routine blood and blood lipid between groups. Results : AECOPD subjects with CAC had significant increases in FEV 1 %pred, PaO 2 and Lym% ( P <0.05), but WBC, Neu, and Neu% were lower ( P <0.05) compared with the AECOPD group. There were no statistically significant differences in blood lipid levels between the two groups. Compared to the AECOPD group, the AECOPD+CAC medication group also had significantly higher PaO 2 and Lym% ( P <0.05), and WBC, Neu, and Neu% in the AECOPD+CAC medication group were significantly lower ( P <0.05) than in the AECOPD group. Conclusions : Aspirin and statins for the treatment of cardiovascular diseases can improve lung function, normalize blood gas levels, and reduce inflammation in patients with AECOPD and CAC.
Sources of Variation in Cell-Type RNA-Seq Profiles
Authors: Gustafsson Johan , Held Felix , Robinson Jonathan , Björnson Elias , Jörnsten Rebecka , Nielsen Jens
Published: February 2020

Background Cell-type specific gene expression profiles are needed for many computational methods operating on bulk RNA-Seq samples, such as deconvolution of cell-type fractions and digital cytometry. However, the gene expression profile of a cell type can vary substantially due to both technical factors and biological differences in cell state and surroundings, reducing the efficacy of such methods. Here, we investigated which factors contribute most to this variation. Results We evaluated different normalization methods, quantified the magnitude of variation introduced by different sources, and examined the differences between UMI-based single-cell RNA-Seq and bulk RNA-Seq. We applied methods such as random forest regression to a collection of publicly available bulk and single-cell RNA-Seq datasets containing B and T cells, and found that the technical variation across laboratories is of the same magnitude as the biological variation across cell types. Tissue of origin and cell subtype are less important but still substantial factors, while the difference between individuals is relatively small. We also show that much of the differences between UMI-based single-cell and bulk RNA-Seq methods can be explained by the number of read duplicates per mRNA molecule in the single-cell sample.Conclusions Our work shows the importance of either matching or correcting for technical factors when creating cell-type specific gene expression profiles that are to be used together with bulk samples.
Deconvolution of bulk blood eQTL effects into immune cell subpopulations
Authors: Aguirre-Gamboa Raul , de Klein Niek , Tommaso Jennifer di , Claringbould Annique , Wijst Monique van der , de Vries Dylan , Brugge Harm , Oelen Roy , Võsa Urmo , Zorro Maria , Chu Xiaojin , Bakker Olivier B , Borek Zuzanna , Ricaño-Ponce Isis , Deelen Patrick , Xu Cheng-Jian , Swertz Morris , Jonkers Iris , Withoff Sebo , Joosten Irma , Sanna Serena , Kumar Vinod , Koenen Hans , Joosten Leo A.B. , Netea Mihai , Wijmenga Cisca , Franke Lude , Li Yang
Published: February 2020

Background Expression quantitative trait loci (eQTL) studies are used to interpret the function of disease-associated genetic risk factors. To date, most eQTL analyses have been conducted in bulk tissues, such as whole blood and tissue biopsies, which are likely to mask the cell type context of the eQTL regulatory effects. Although this context can be investigated by generating transcriptional profiles from purified cell subpopulations, the current methods are labor-intensive and expensive. Here we introduce a new method, Decon2, a framework for estimating cell proportions using expression profiles from bulk blood samples (Decon-cell) followed by deconvolution of cell type eQTLs (Decon-eQTL).Results The estimated cell proportions from Decon-cell agree with experimental measurements across cohorts (R ≥ 0.77). Using Decon-cell we can predict the proportions of 34 circulating cell types for 3,194 samples from a population-based cohort. Next we identified 16,362 whole blood eQTLs and deconvoluted cell type interaction (CTi) eQTLs using the predicted cell proportions from Decon-cell. CTi eQTLs show excellent allelic directional concordance with those of eQTL(≥ 96%-100%) and chromatin mark QTL (≥87%-92%) studies that used either purified cell subpopulations or single-cell RNA-seq, outperforming the conventional interaction effect.Conclusions Decon2 provides a method to detect cell type interaction effects from bulk blood eQTLs, which is useful in pinpointing the most relevant cell type for a certain complex disease. Decon2 is available as an R package and Java application. (https://github.com/molgenis/systemsgenetics/tree/master/Decon2), and as a web tool (www.molgenis.org/deconvolution).
Anti-Tyro3 IgG associates with disease activity and reduces efferocytosis of macrophages in new-onset systemic lupus erythematosus
Authors: Zhou Zhuochao , Xu Aining , Teng Jialin , Wang Fan , Tan Yun , Liu Honglei , Cheng Xiaobing , Su Yutong , Shi Hui , Hu Qiongyi , Chi Huihui , Li Jian , Hou Jiaqi , Sun Yue , Yang Chengde , Ye Junna
Published: February 2020

Backgroud: To investigate the role of Tyro3 receptor in macrophages’ efferocytosis of apoptotic cells in systemic lupus erythematosus (SLE), we aimed to reveal the clinical relevance and impact of anti-Tyro3 antibody on SLE. Methods : The serum levels of IgG-type autoantibody against Tyro3 receptor were detected in new-onset, treatment-naïve SLE patients (n =70) and healthy controls (HCs) (n =70) using enzyme-linked immunosorbent assay (ELISA). The correlation of the levels of autoantibodies against Tyro3 receptor with clinical and laboratory characteristics were analyzed by Spearman correlation analysis. Receiver operating characteristic (ROC) curve was used to assess the sensitivity and specificity of anti-Tyro3 IgG for the diagnosis of SLE. The effects of purified Tyro3 autoantibody from SLE patients on the efferocytosis of human monocyte-derived macrophages were measured by flow cytometry and immunofluorescence. Results : The serum levels of IgG-type autoantibody against Tyro3 receptor were significantly elevated in patients with SLE compared to HCs ( p < 0.0001). The levels of anti-Tyro3 IgG were negatively associated with haemoglobin (Hb) ( r =-0.294, p = 0.014), and positively correlated with the presence of oral ulcers ( r = 0.254, p = 0.034), SLE disease activity index (SLEDAI) score ( r = 0.254, p = 0.034), erythrocyte sedimentation rate (ESR) ( r = 0.430, p = 0.000), C-reactive protein (CRP) ( r = 0.246, p = 0.049) and immunoglobulin G (IgG) ( r = 0.408, p = 0.001). Higher levels of anti-Tyro3 antibody were observed in patients with oral ulcers than paitents without oral ulcers ( p = 0.035). Further flow cytometry demonstrated that purified anti-Tyro3 IgG inhibited the efferocytosis of macrophages ( p = 0.004). Immunofluorescence assay also showed a decreased engulfment of apoptotic cells in the macrophages incubated with purified anti-Tyro3 IgG ( p = 0.044) compared with control IgG. Conclusions: These observations indicated that autoantibody against Tyro3 was associated with disease activity and impaired efferocytosis of macrophages, which might be involved in the pathogenesis of SLE.
The Combination of an Inflammatory Peripheral Blood Transcriptome and Imaging Biomarkers Enhance Prediction of Radiographic Progression in Knee Osteoarthritis.
Authors: Attur Mukundan , Krasnokutsky Svetlana , Zhou Hua , Samuels Jonathan , Chang Gregory , Bencardino Jenny T. , Rosenthal Pamela , Rybak Leon , Huebner Janet L. , Kraus Virginia B. , Abramson Steven B.
Published: February 2020

Objective Predictive biomarkers of progression in knee osteoarthritis are sought to enable clinical trials of structure modifying drugs. A peripheral blood leukocyte (PBL) inflammatory gene signature, MRI-based bone marrow lesions (BML) and meniscus extrusion scores), meniscal lesions, and osteophytes on x-ray each have been shown separately to predict radiographic joint space narrowing (JSN) in subjects with symptomatic knee osteoarthritis (SKOA). In these studies, we determined whether the combination of the PBL transcriptome and these imaging findings at baseline enhanced the prognostic value of either alone. Methods An inflammatory PBL transcriptome (increased mRNA for IL-1β, TNFα, and COX-2), routine radiographs, and 3T knee MRI were assessed in two independent populations with SKOA: an NYU cohort, and the Osteoarthritis Initiative (OAI). At baseline and 24 months, subjects underwent standardized fixed-flexion knee radiographs and knee MRI. Medial JSN (mJSN) was determined as the change in medial JSW. Progressors were defined by a mJSN cut-point (≥0.5 mm/24 months). Models were evaluated by odds ratios (OR) and area under the receiver operating characteristic curve (AUC). Results We validated our prior finding in these two independent (NYU and OAI) cohorts, individually and combined, that an inflammatory PBL transcriptome predicted radiographic progression of SKOA after adjustment for age, gender, and BMI. Similarly, the presence of baseline BML and meniscal lesions by MRI or semi-quantitative osteophyte score on x-ray each predicted radiographic medial JSN at 24 months. The combination of the PBL transcriptome and medial BML increased the AUC from 0.66 (p=0.004) to 0.75 (p<0.0001) and the odds ratio from 6.31 to 19.10 (p<0.0001) in the combined cohort of 473 subjects. The addition of osteophyte score to BML and PBL transcriptome further increased the predictive value of any single biomarker. A causal analysis demonstrated that the PBL transcriptome and BML independently influenced mJSN. Conclusion The use of the PBL transcriptome together with imaging biomarkers as combinatorial predictive biomarkers, markedly enhances the identification of radiographic progressors. The identification of the SKOA population at risk for progression will help in the future design of disease-modifying OA drug trials and personalized medicine strategies.