bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role for autophagy-related markers Beclin-1 and LC3 in endometriosis
Authors: Kong Zhiwei , Yao Tingting 
Published: June 2022

Abstract
Background
Endometriosis is a common and challenging disease in women of childbearing age with high personal and social costs. Many molecular differences between ectopic and eutopic endometrium present difficulties in the development of new drug therapies and therapies. Autophagy is a response to stress and has recently been studied in human cancers. Two important autophagy genes, Beclin-1 and LC3, have been reported in several human cancers. However, the reports of Beclin-1 and LC3 in endometriosis are limited and controversial.

Methods
In this study, we investigated the expression of Beclin-1 and LC3 by Immunohistochemistry.

Results
We found their downregulation in endometriosis. We also found these two autophagy gene expression are negatively correlated with the stage of endometriosis.

Conclusions
Decreased expression of Beclin-1 and LC3 may be related to the occurrence and development of endometriosis.
Effects of obesity on CC16 and their potential role in overweight/obese asthma
Authors: Goudarzi Houman , Kimura Hirokazu , Kimura Hiroki , Makita Hironi , Matsumoto Munehiro , Takei Nozomu , Shimizu Kaoruko , Suzuki Masaru , Watanabe Taku , Kikuchi Eiki , Ohira Hiroshi , Tsujino Ichizo , Sakakibara-Konishi Jun , Shinagawa Naofumi , Shijubo Noriharu , Sato Hirokazu , Shigehara Katsunori , Kaga Kichizo , Hida Yasuhiro , Murakami Soichi , Ebihara Yuma , Nakamura Akinobu , Miyoshi Hideaki , Hirano Satoshi , Hizawa Nobuyuki , Atsumi Tatsuya , Huang Shau-ku , Ito Yoichi M. , Nishimura Masaharu , Konno Satoshi 
Published: June 2022

Abstract
Introduction
Club cell secretory protein-16 (CC16) is a major anti-inflammatory protein expressed in the airway; however, the potential role of CC16 on overweight/obese asthma has not been assessed. In this study, we examined whether obesity reduces airway/circulatory CC16 levels using experimental and epidemiological studies. Then, we explored the mediatory role of CC16 in the relationship of overweight/obesity with clinical asthma measures.

Methods
Circulating CC16 levels were assessed by ELISA in three independent human populations, including two groups of healthy and general populations and asthma patients. The percentage of cells expressing club markers in obese vs. non-obese mice and human airways was determined by immunohistochemistry. A causal mediation analysis was conducted to determine whether circulatory CC16 acted as a mediator between overweight/obesity and clinical asthma measures.

Results
BMI was significantly and monotonously associated with reduced circulating CC16 levels in all populations. The percentage of CC16-expressing cells was reduced in the small airways of both mice and humans with obesity. Finally, mediation analysis revealed significant contributions of circulatory CC16 in the association between BMI and clinical asthma measures; 21.8% of its total effect in BMI’s association with airway hyperresponsiveness of healthy subjects (p = 0.09), 26.4% with asthma severity (p = 0.030), and 23% with the required dose of inhaled corticosteroid (p = 0.042). In logistic regression analysis, 1-SD decrease in serum CC16 levels of asthma patients was associated with 87% increased odds for high dose ICS requirement (p < 0.001).

Conclusions
We demonstrate that airway/circulating CC16, which is inversely associated with BMI, may mediate development and severity in overweight/obese asthma.
circFBXO7/miR-96-5p/MTSS1 axis is an important regulator in the Wnt signaling pathway in ovarian cancer
Authors: Wu Mengting , Qiu Qiongzi , Zhou Qing , Li Jia , Yang Juze , Zheng Chengcai , Luo Aoran , Li Xufan , Zhang Honghe , Cheng Xiaodong , Lu Weiguo , Liu Pengyuan , Lu Bingjian , Lu Yan 
Published: June 2022

Abstract
Background
CircRNAs are a novel class of evolutionarily conserved noncoding RNA molecules that form covalently closed continuous loop structures without 5′ caps and 3′ poly(A) tails. Accumulating evidence suggests that circRNAs play important regulatory roles in cancer and are promising biomarkers for cancer diagnosis and prognosis, as well as targets for cancer therapy. In this study, we identify and explore the role of a novel circRNA, circFBXO7, in ovarian cancer.

Methods
rRNA-depleted RNA-sequencing was performed to identify differentially expressed circRNAs between ovarian cancerous and normal tissues. qRT-PCR and single-molecule RNA in-situ hybridization was used to quantify circFBXO7 expression in tumor tissues. The association of circFBXO7 expression with patient prognosis was evaluated by Kaplan–Meier survival analysis. The biological function of circFBXO7 was also investigated using loss-of-function and gain-of-function assays in vivo and in vitro. Luciferase reporter and TOP/FOP-Flash reporter assays were then conducted together with RNA immunoprecipitation and western blot to assess the circFBXO7/miR-96-5p/MTSS1/Wnt/β-catenin axis.

Results
circFBXO7 was downregulated in ovarian cancer which was associated with poor prognosis. Biologically, circFBXO7 overexpression significantly suppressed ovarian cancer cell proliferation, migration, and invasion in vitro, and inhibited tumor growth and metastasis in vivo, whereas its knockdown exerted an opposite role. Mechanistically, circFBXO7 functioned as a competing endogenous RNA for miR-96-5p to regulate the expression of MTSS1. Consequently, downregulation of MTSS1 led to excessive accumulation of β-catenin and increased phosphorylation of GSK3β, leading to the translocation of β-catenin to the nucleus, thereby activating the Wnt/β-catenin signaling pathway and ultimately promoting ovarian cancer progression.

Conclusions
Our findings indicate that circFBXO7 acts as a bone fide tumor suppressor in ovarian cancer and that the circFBXO7/miR-96-5p/MTSS1 axis is an important regulator in the Wnt/β-catenin signaling pathway which may provide a promising target for ovarian cancer therapy.
Pathways to improve health information systems in Ethiopia: current maturity status and implications
Authors: Biru Amanuel , Birhan Dawit , Melkamu Gemechis , Gebeyehu Abebaw , Omer Afrah Mohammedsanni 
Published: June 2022

Abstract
Background
To achieve national and international strategic goals, countries are advised to assess the maturity status of their health information systems (HIS), including business continuity and interoperability. This work aims to determine the existing maturity status of the Ethiopian HIS, set HIS improvement goals, and inform a path towards an improved national HIS by the end of 2024.

Methods
This assessment was a collaborative and transparent process that was carried out with the engagement of all key stakeholders through consultation. We used the Stages of Continuous Improvement (SOCI) tool to guide the assessment to measure the maturity level of the Ethiopian HIS in five core domains, 13 components and 39 subcomponents and to guide future plans.

Results
The overall average score of the national HIS maturity was 2.68/5, which is categorized between repeatable (stage 2) and defined (stage 3) maturity levels. The assessment findings revealed that three out of the five HIS maturity domains were at a repeatable stage. Only the leadership and governance and the data quality and use domains were at the defined maturity level. A majority (7/13) of the subcomponents were at the repeatable level of maturity, while four were at the defined level. Policy, legal and regulatory framework and compliance from the leadership and governance domain and interoperability from the data quality and use domain were categorized as having an emerging status. Considering the current HIS maturity status, gaps and strengths identified, ongoing HIS initiatives, existing platforms, and the interest and level of engagement of senior government leadership, this assessment put forward an improvement roadmap for achieving the desired managed stage (4.37) of maturity by the end of 2024.

Conclusions
The findings show that the overall maturity level of the Ethiopian HIS is 2.68, which is between the repeatable and defined maturity stages. Enforcement of policies and legislation, data exchange among systems, and information and communication technology infrastructure business continuity planning are the main challenges of Ethiopian HIS requiring further investment. Strengthened and collaborative effort is critical to reaching the desired goal of “managed” HIS (stage 4) in the country by 2024.
Cardiac involvement in MPS patients: incidence and response to therapy in an Italian multicentre study
Authors: Sestito Simona , Rinninella Giada , Rampazzo Angelica , D’Avanzo Francesca , Zampini Lucia , Santoro Lucia , Gabrielli Orazio , Fiumara Agata , Barone Rita , Volpi Nicola , Scarpa Maurizio , Tomanin Rosella , Concolino Daniela 
Published: June 2022

Abstract
Background
Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders caused by the deficit of lysosomal hydrolases involved in the degradation of glycosaminoglycans (GAGs). The course is chronic and progressive, with multisystemic involvement that often leads to cardiovascular disease. We describe the overall incidence and type of cardiac damage in a cohort of Italian MPS patients, and their progression over time, also with reference to treatment efficacy in patients under Enzyme Replacement Therapy (ERT). Moreover, we report a possible association between genetic variants and cardiac phenotype in homozygous and hemizygous patients to understand whether a more aggressive clinical phenotype would predict a greater cardiac damage.

Results
Our findings confirm that cardiac involvement is very common, already at diagnosis, in MPS VI (85.7% of our cohort), and in MPS II (68% of our cohort) followed by MPS I subjects (55% of our cohort). The most frequent heart defect observed in each MPS and at any time-point of evaluation was mitral insufficiency; 37% of our patients had mitral insufficiency already at diagnosis, and 60% at post-ERT follow-up. After at least six years of treatment, we observed in some cases (including 6 MPS II, 2 MPS IV and 2 MPS VI) a total regression or improvement of some signs of the cardiac pathology, including some valve defects, though excluding aortic insufficiency, the only valvulopathy for which no regression was found despite ERT. The general clinical phenotype proved not to be strictly correlated with the cardiac one, in fact in some cases patients with an attenuated phenotype developed more severe heart damage than patients with severe phenotype.

Conclusions
In conclusion, our analysis confirms the wide presence of cardiopathies, at different extent, in the MPS population. Since cardiac pathology is the main cause of death in many MPS subtypes, it is necessary to raise awareness among cardiologists about early cardiac morpho-structural abnormalities. The encouraging data regarding the long-term effects of ERT, also on heart damage, underlines the importance of an early diagnosis and timely start of ERT.
Synaptotagmin 11 scaffolds MKK7–JNK signaling process to promote stem-like molecular subtype gastric cancer oncogenesis
Authors: Kim Bo-Kyung , Kim Da-Mi , Park Hyunkyung , Kim Seon-Kyu , Hwang Mi-Aie , Lee Jungwoon , Kang Mi-Jung , Byun Jae-Eun , Im Joo-Young , Kang Minho , Park Kyung Chan , Yeom Young Il , Kim Seon-Young , Jung Haiyoung , Kweon Dae-Hyuk , Cheong Jae-Ho , Won Misun 
Published: June 2022

Abstract
Background
Identifying biomarkers related to the diagnosis and treatment of gastric cancer (GC) has not made significant progress due to the heterogeneity of tumors. Genes involved in histological classification and genetic correlation studies are essential to develop an appropriate treatment for GC.

Methods
In vitro and in vivo lentiviral shRNA library screening was performed. The expression of Synaptotagmin (SYT11) in the tumor tissues of patients with GC was confirmed by performing Immunohistochemistry, and the correlation between the expression level and the patient’s survival rate was analyzed. Phospho-kinase array was performed to detect Jun N-terminal kinase (JNK) phosphorylation. SYT11, JNK, and MKK7 complex formation was confirmed by western blot and immunoprecipitation assays. We studied the effects of SYT11 on GC proliferation and metastasis, real-time cell image analysis, adhesion assay, invasion assay, spheroid formation, mouse xenograft assay, and liver metastasis.

Results
SYT11 is highly expressed in the stem-like molecular subtype of GC in transcriptome analysis of 527 patients with GC. Moreover, SYT11 is a potential prognostic biomarker for histologically classified diffuse-type GC. SYT11 functions as a scaffold protein, binding both MKK7 and JNK1 signaling molecules that play a role in JNK1 phosphorylation. In turn, JNK activation leads to a signaling cascade resulting in cJun activation and expression of downstream genes angiopoietin-like 2 (ANGPTL2), thrombospondin 4 (THBS4), Vimentin, and junctional adhesion molecule 3 (JAM3), which play a role in epithelial-mesenchymal transition (EMT). SNU484 cells infected with SYT11 shRNA (shSYT11) exhibited reduced spheroid formation, mouse tumor formation, and liver metastasis, suggesting a pro-oncogenic role of SYT11. Furthermore, SYT11-antisense oligonucleotide (ASO) displayed antitumor activity in our mouse xenograft model and was conferred an anti-proliferative effect in SNU484 and MKN1 cells.

Conclusion
SYT11 could be a potential therapeutic target as well as a prognostic biomarker in patients with diffuse-type GC, and SYT11-ASO could be used in therapeutic agent development for stem-like molecular subtype diffuse GC.
Deep oncopanel sequencing reveals within block position-dependent quality degradation in FFPE processed samples
Authors: Zhang Yifan , Blomquist Thomas M. , Kusko Rebecca , Stetson Daniel , Zhang Zhihong , Yin Lihui , Sebra Robert , Gong Binsheng , Lococo Jennifer S. , Mittal Vinay K. , Novoradovskaya Natalia , Yeo Ji-Youn , Dominiak Nicole , Hipp Jennifer , Raymond Amelia , Qiu Fujun , Arib Hanane , Smith Melissa L. , Brock Jay E. , Farkas Daniel H. , Craig Daniel J. , Crawford Erin L. , Li Dan , Morrison Tom , Tom Nikola , Xiao Wenzhong , Yang Mary , Mason Christopher E. , Richmond Todd A. , Jones Wendell , Johann Donald J. , Shi Leming , Tong Weida , Willey James C. , Xu Joshua 
Published: June 2022

Abstract
Background
Clinical laboratories routinely use formalin-fixed paraffin-embedded (FFPE) tissue or cell block cytology samples in oncology panel sequencing to identify mutations that can predict patient response to targeted therapy. To understand the technical error due to FFPE processing, a robustly characterized diploid cell line was used to create FFPE samples with four different pre-tissue processing formalin fixation times. A total of 96 FFPE sections were then distributed to different laboratories for targeted sequencing analysis by four oncopanels, and variants resulting from technical error were identified.

Results
Tissue sections that fail more frequently show low cellularity, lower than recommended library preparation DNA input, or target sequencing depth. Importantly, sections from block surfaces are more likely to show FFPE-specific errors, akin to “edge effects” seen in histology, while the inner samples display no quality degradation related to fixation time.

Conclusions
To assure reliable results, we recommend avoiding the block surface portion and restricting mutation detection to genomic regions of high confidence.
Imipramine and olanzapine block apoE4-catalyzed polymerization of Aβ and show evidence of improving Alzheimer’s disease cognition
Authors: Johnson Noah R. , Wang Athena C.-J. , Coughlan Christina , Sillau Stefan , Lucero Esteban , Viltz Lisa , Markham Neil , Allen Cody , Dhanasekaran A. Ranjitha , Chial Heidi J. , Potter Huntington 
Published: June 2022

Abstract
Background
The apolipoprotein E (APOE) ε4 allele confers the strongest risk for late-onset Alzheimer’s disease (AD) besides age itself, but the mechanisms underlying this risk are debated. One hypothesis supported by evidence from multiple labs is that apoE4 binds to the amyloid-β (Aβ) peptide and catalyzes its polymerization into neurotoxic oligomers and fibrils. Inhibiting this early step in the amyloid cascade may thereby reduce or prevent neurodegeneration and AD.

Methods
Using a design of experiments (DOE) approach, we developed a high-throughput assay to identify inhibitors of apoE4-catalyzed polymerization of Aβ into oligomers and fibrils. We used it to screen the NIH Clinical Collection of small molecule drugs tested previously in human clinical trials. We then evaluated the efficacy and cytotoxicity of the hit compounds in primary neuron models of apoE4-induced Aβ and phosphorylated tau aggregation. Finally, we performed retrospective analyses of the National Alzheimer’s Coordinating Center (NACC) clinical dataset, using Cox regression and Cox proportional hazards models to determine if the use of two FDA-approved hit compounds was associated with better cognitive scores (Mini-Mental State Exam), or improved AD clinical diagnosis, when compared with other medications of the same clinical indication.

Results
Our high-throughput screen identified eight blood-brain barrier (BBB)-permeable hit compounds that reduced apoE4-catalyzed Aβ oligomer and fibril formation in a dose-dependent manner. Five hit compounds were non-toxic toward cultured neurons and also reduced apoE4-promoted Aβ and tau neuropathology in a dose-dependent manner. Three of the five compounds were determined to be specific inhibitors of apoE4, whereas the other two compounds were Aβ or tau aggregation inhibitors. When prescribed to AD patients for their normal clinical indications, two of the apoE4 inhibitors, imipramine and olanzapine, but not other (non-hit) antipsychotic or antidepressant medications, were associated with improvements in cognition and clinical diagnosis, especially among APOE4 carriers.

Conclusions
The critical test of any proposed AD mechanism is whether it leads to effective treatments. Our high-throughput screen identified two promising FDA-approved drugs, imipramine and olanzapine, which have no structural, functional, or clinical similarities other than their shared ability to inhibit apoE4-catalyzed Aβ polymerization, thus identifying this mechanism as an essential contribution of apoE4 to AD.
White matter hyperintensities are a prominent feature of autosomal dominant Alzheimer’s disease that emerge prior to dementia
Authors: Schoemaker Dorothee , Zanon Zotin Maria Clara , Chen Kewei , Igwe Kay C. , Vila-Castelar Clara , Martinez Jairo , Baena Ana , Fox-Fuller Joshua T. , Lopera Francisco , Reiman Eric M. , Brickman Adam M. , Quiroz Yakeel T. 
Published: June 2022

Abstract

Background
To promote the development of effective therapies, there is an important need to characterize the full spectrum of neuropathological changes associated with Alzheimer’s disease. In line with this need, this study examined white matter abnormalities in individuals with early-onset autosomal dominant Alzheimer’s disease, in relation to age and symptom severity.

Methods
This is a cross-sectional analysis of data collected in members of a large kindred with a PSEN1 E280A mutation. Participants were recruited between September 2011 and July 2012 from the Colombian Alzheimer’s Prevention Initiative registry. The studied cohort comprised 50 participants aged between 20 and 55 years, including 20 cognitively unimpaired mutation carriers, 9 cognitively impaired mutation carriers, and 21 non-carriers. Participants completed an MRI, a lumbar puncture for cerebrospinal fluid collection, a florbetapir PET scan, and neurological and neuropsychological examinations. The volume of white matter hyperintensities (WMH) was compared between cognitively unimpaired carriers, cognitively impaired carriers, and non-carriers. Relationships between WMH, age, and cognitive performance were further examined in mutation carriers.

Results
The mean (SD) age of participants was 35.8 (9.6) years and 64% were women. Cardiovascular risk factors were uncommon and did not differ across groups. Cognitively impaired carriers [median, 6.37; interquartile range (IQR), 9.15] had an increased volume of WMH compared to both cognitively unimpaired carriers [median, 0.85; IQR, 0.79] and non-carriers [median, 1.07; IQR, 0.71]. In mutation carriers, the volume of WMH strongly correlated with cognition and age, with evidence for an accelerated rate of changes after the age of 43 years, 1 year earlier than the estimated median age of symptom onset. In multivariable regression models including cortical amyloid retention, superior parietal lobe cortical thickness, and cerebrospinal fluid phospho-tau, the volume of WMH was the only biomarker independently and significantly contributing to the total explained variance in cognitive performance.

Conclusions
The volume of WMH is increased among individuals with symptomatic autosomal-dominant Alzheimer’s disease, begins to increase prior to clinical symptom onset, and is an independent determinant of cognitive performance in this group. These findings suggest that WMH are a key component of autosomal-dominant Alzheimer’s disease that is closely related to the progression of clinical symptoms.
Dietary patterns and survival to 100 + years: an empty systematic review of cohort and case–control studies
Authors: Poulsen Winnie , Christensen Kaare , Dalgård Christine 
Published: June 2022

AbstractBackgroundCentenarians are used as a model of healthy ageing and longevity. Diet is a factor known to affect mortality in middle aged adults and elderly. However, it is unknown whether diet has an impact on survival to 100 + years. The aims of this systematic review were to summarize the evidence on (i) the association between dietary patterns in late adult life and survival to 100 + years and (ii) the common characteristics across dietary patterns that are shown to be positively associated with survival to 100 + years.MethodsWe performed a systematic literature search in MEDLINE and EMBASE, and a hand search at four longevity projects homepages up to 4 June 2021. We searched for cohort and case–control studies investigating the association between dietary patterns and all-cause mortality among individuals aged ≥ 65 years at enrolment regardless of their health status and residence. Studies were excluded if follow-up was performed too soon to allow the population or a subgroup of it to have become 100 + years of age.ResultsOf 3,685 identified records 108 reports were retrieved and full text screened. No studies met our inclusion criteria, thus the review process resulted in no eligible studies found. Hence, no risk of bias assessment and no synthesis of data was performed.ConclusionsNo studies have investigated dietary patterns in late adult life in relation to survival to 100 + years of age. We have observed that as of June 2021 published cohort studies exist investigating all-cause mortality risk from different dietary patterns among the oldest old, but follow-up has been performed before the cohort could have reached 100 years of age. However, cohorts do exist where data on dietary habits in adult life has been collected decades ago and where follow-up in 2022 will allow the participants to have become 100 + years old.RegistrationThe review protocol is published at University of Southern Denmark’s Research Portal (Poulsen et al. Dietary Patterns and Survival to 100 + Years: Protocol for a Systematic Review of cohort and case–control studies University of Southern Denmark's Research Portal: University of Southern Denmark, 2021) available at https://portal.findresearcher.sdu.dk/en/publications/kostm%C3%B8nstre-og-overlevelse-til-100-%C3%A5r-protokol-for-en-systematisk. We have specified aim (i) of our research question in this report compared to the protocol, by adding “late” to “adult life”.