bluuebunny/crossref_metadata_2025_split huggingface dataset:
RETRACTED ARTICLE: The circular RNA 001971/miR-29c-3p axis modulates colorectal cancer growth, metastasis, and angiogenesis through VEGFA
Authors: Chen Chen , Huang Zhiguo , Mo Xiaoye , Song Yanmin , Li Xiangmin , Li Xiaogang , Zhang Mu 
Published: May 2020

Abstract
Background
Colorectal cancer (CRC) is one of the most common malignant tumors globally. Angiogenesis is a key event maintaining tumor cell survival and aggressiveness. The expression of vascular endothelial growth factor A (VEGFA), one of the most significant tumor cell-secreted proangiogenic factors, is frequently upregulated in CRC.

Methods
The MTT assay was used to detect the viability of CRC cells. Transwell assays were performed to detect the invasion capacity of target cells. Relative protein levels were determined by immunoblotting. Pathological characteristics of tissues were detected by H&E staining and immunohistochemical (IHC) staining. A RIP assay was conducted to validate the predicted binding between genes.

Results
We observed that circ-001971 expression was dramatically increased in CRC tissue samples and cells. Circ-001971 knockdown suppressed the capacity of CRC cells to proliferate and invade and HUVEC tube formation in vitro, as well as tumor growth in mice bearing SW620 cell-derived tumors in vivo. The expression of circ-001971 and VEGFA was dramatically increased whereas the expression of miR-29c-3p was reduced in tumor tissue samples. Circ-001971 relieved miR-29c-3p-induced inhibition of VEGFA by acting as a ceRNA, thereby aggravating the proliferation, invasion and angiogenesis of CRC. Consistent with the above findings, the expression of VEGFA was increased, whereas the expression of miR-29c-3p was decreased in tumor tissue samples. miR-29c-3p had a negative correlation with both circ-001971 and VEGFA, while circ-001971 was positively correlated with VEGFA.

Conclusions
In conclusion, the circ-001971/miR-29c-3p axis modulated CRC cell proliferation, invasion, and angiogenesis by targeting VEGFA.
Organizational changes in diabetic foot care practices for patients at low and moderate risk after implementing a comprehensive foot care program in Alberta, Canada
Authors: Chan Catherine B. , Dmytruk Kathy , Labbie Michele , O'Connell Petra 
Published: May 2020

AbstractBackgroundNeuropathy and vasculopathy can lead to costly and debilitating complications in people with diabetes. The purpose of this study was to evaluate, at an organizational level, uptake of practices included in a diabetic foot care clinical pathway and associated resources. This research focused on patients at low and moderate risk in Alberta, Canada between 2014 to 2019.MethodsSerial surveys (2014, 2019) of practices related to screening and care of the feet of people with diabetes. Surveys were administered using a combination of targeted and snowball sampling in order to assess the impact of the clinical pathway first implemented in 2015. The pathway focused on screening, assessment and referral of patients from primary care. High‐risk foot teams (HRFT) were established at six sites to provide increased access to specialty care. Comparative statistics were performed to assess differences in footcare practices between 2014 and 2019 using two‐tailed Fisher's exact test or Chi‐square test.ResultsRespondents (n = 104, 2014 and n = 75, 2019) included personnel from primary health care, home care and long‐term care, acute and emergency care, specialty clinics, diabetes‐specific programs and private contractors. The proportion of primary care and home care/long‐term care (HC/LTC) sites providing screening increased significantly (p < 0.05). A significant increase in the proportion of sites providing assessment for patients designated as moderate risk also increased from 35% (34 out of 96 sites) to 55% (36 out of 65 sites) (p < 0.05), particularly with respect to vascular assessment, and the proportion of sites reporting appropriate follow‐up intervals according to the pathway recommendation was also improved.ConclusionProvision of a clinical pathway for diabetic foot care along with education and resources led to increased screening in primary care and HC/LTC settings in Alberta, Canada. HRFT provided primary healthcare providers with an important option for referral and also provided increased expertise for procedures such as vascular assessment for patients with moderate risk of ulceration. This comprehensive model has the potential to reduce progression of foot problems and overall health services utilization. Further analyses of outcomes such as incident lower limb amputation and long‐term cost‐effectiveness of pathway implementation are underway.
Proteomics analysis of plasma protein changes in patent ductus arteriosus patients
Authors: Xu Cheng , Su Xiaoqi , Chen Yong , Xu Yang , Wang Zhiqi , Mo Xuming 
Published: May 2020

Abstract
Objective
Patent ductus arteriosus (PDA) is a congenital heart defect with an unclear etiology that occurs commonly among newborns. Adequately understanding the molecular pathogenesis of PDA can contribute to improved treatment and prevention. Plasma proteins may provide evidence to explore the molecular mechanisms of abnormal cardiac development.

Methods
Isobaric tags for relative and absolute quantitation (iTRAQ) proteomics technology was used to measure different plasma proteins in PDA patients (n = 4) and controls (n = 4). The candidate protein was validated by ELISA and Western blot (WB) assays in a larger sample. Validation of the location and expression of this protein was performed in mouse heart sections.

Results
There were three downregulated proteins and eight upregulated proteins identified in the iTRAQ proteomics data. Among these, protein disulfide-isomerase A6 (PDIA6) was further analyzed for validation. The plasma PDIA6 concentrations (3.2 ± 0.7 ng/ml) in PDA patients were significantly lower than those in normal controls (5.8 ± 1.2 ng/ml). In addition, a WB assay also supported these results. PDIA6 was widely expressed in mouse heart outflow tract on embryonic day 14.5.

Conclusion
Plasma proteomics profiles suggested novel candidate molecular markers for PDA. The findings may allow development of a new strategy to investigate the mechanism and etiology of PDA.
Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019— results from a systematic review and meta-analysis
Authors: Bauer Michael , Gerlach Herwig , Vogelmann Tobias , Preissing Franziska , Stiefel Julia , Adam Daniel 
Published: May 2020

AbstractBackgroundSepsis and septic shock remain drivers for mortality in critically ill patients. The heterogeneity of the syndrome hinders the generation of reproducible numbers on mortality risks. Consequently, mortality rates range from 15 to 56%. We aimed to update and extend the existing knowledge from meta-analyses and estimate 30- and 90-day mortality rates for sepsis and septic shock separately, stratify rates by region and study type and assess mortality rates across different sequential organ failure assessment (SOFA) scores.MethodsWe performed a systematic review of articles published in PubMed or in the Cochrane Database, between 2009 and 2019 in English language including interventional and observational studies. A meta-analysis of pooled 28/30- and 90-day mortality rated separately for sepsis and septic shock was done using a random-effects model. Time trends were assessed via Joinpoint methodology and for the assessment of mortality rate over different SOFA scores, and linear regression was applied.ResultsFour thousand five hundred records were identified. After title/abstract screening, 783 articles were assessed in full text for eligibility. Of those, 170 studies were included. Average 30-day septic shock mortality was 34.7% (95% CI 32.6–36.9%), and 90-day septic shock mortality was 38.5% (95% CI 35.4–41.5%). Average 30-day sepsis mortality was 24.4% (95% CI 21.5–27.2%), and 90-day sepsis mortality was 32.2% (95% CI 27.0–37.5%). Estimated mortality rates from RCTs were below prospective and retrospective cohort studies. Rates varied between regions, with 30-day septic shock mortality being 33.7% (95% CI 31.5–35.9) in North America, 32.5% (95% CI 31.7–33.3) in Europe and 26.4% (95% CI 18.1–34.6) in Australia. A statistically significant decrease of 30-day septic shock mortality rate was found between 2009 and 2011, but not after 2011. Per 1-point increase of the average SOFA score, average mortality increased by 1.8–3.3%.ConclusionTrends of lower sepsis and continuous septic shock mortality rates over time and regional disparities indicate a remaining unmet need for improving sepsis management. Further research is needed to investigate how trends in the burden of disease influence mortality rates in sepsis and septic shock at 30- and 90-day mortality over time.
Toxoplasma gondii in the Eurasian kestrel (Falco tinnunculus) in northern Italy
Authors: Iemmi Tiziano , Vismarra Alice , Mangia Carlo , Zanin Rolando , Genchi Marco , Lanfranchi Paolo , Kramer Laura Helen , Formenti Nicoletta , Ferrari Nicola 
Published: May 2020

AbstractBackgroundIdentifying factors that sustain parasite transmission is important for understanding their spread and emergence, including how changes in biodiversity may affect parasite prevalence and spread.Toxoplasma gondiiis a protozoan parasite infecting humans and animals. Birds can acquireT. gondiiinfection through ingestion either of oocysts from the ground or of tissue cysts present in infected prey and are therefore suitable indicators of the presence ofT. gondiiin the natural environment.MethodsThe aim of the study included the evaluation ofT. gondiiseroprevalence in clinically healthy Eurasian kestrels (Falco tinnunculus) using a modified agglutination test. Birds were captured in a small area of Parma (northern Italy) for two consecutive years (2016–2017), sex and age determined and serological study carried out. Food sources for the birds were also evaluated, in particular rodent and grasshopper population estimates in the study area. The biomass of rodents and grasshoppers per hectare was estimated in order to directly compare food availability. Statistical analyses were performed in order to evaluate factors influencing the probability of kestrels beingT. gondii-seropositive using R 3.4.4 fitting linear mixed-effect models with the ‘glmer’ function of the packagelme4, ‘lsmean’ in packagelsmeanfor pair-wise post-hoc comparisons using differences of least square means (DLSM) and the ‘betareg’ function of the packagebetaregfor beta regression.ResultsSeroprevalence forT. gondiiwas 33.3% (49/147) in 2016, while in 2017 seroprevalence decreased to 14.3% (13/91). An increase in the probability of kestrels beingT. gondii-seropositive was associated with a higher rodent biomass in the environment, suggesting a positive feedback of the biotic factors driving infection risk.ConclusionsThese results underline the need for multidisciplinary studies aimed at better understanding pathogen-host relationships and for predictions in disease ecology.
Overexpression of MIG-6 in the cartilage induces an osteoarthritis-like phenotype in mice
Authors: Bellini Melina , Pest Michael A. , Miranda-Rodrigues Manuela , Qin Ling , Jeong Jae-Wook , Beier Frank 
Published: May 2020

Abstract
Background
Osteoarthritis (OA) is the most common form of arthritis and characterized by degeneration of the articular cartilage. Mitogen-inducible gene 6 (Mig-6) has been identified as a negative regulator of the epidermal growth factor receptor (EGFR). Cartilage-specific Mig-6 knockout (KO) mice display increased EGFR signaling, an anabolic buildup of the articular cartilage, and formation of chondro-osseous nodules. Since our understanding of the EGFR/Mig-6 network in the cartilage remains incomplete, we characterized mice with cartilage-specific overexpression of Mig-6 in this study.

Methods
Utilizing knee joints from cartilage-specific Mig-6-overexpressing (Mig-6over/over) mice (at multiple time points), we evaluated the articular cartilage using histology, immunohistochemical staining, and semi-quantitative histopathological scoring (OARSI) at multiple ages. MicroCT analysis was employed to examine skeletal morphometry, body composition, and bone mineral density.

Results
Our data show that cartilage-specific Mig-6 overexpression did not cause any major developmental abnormalities in the articular cartilage, although Mig-6over/over mice have slightly shorter long bones compared to the control group. Moreover, there was no significant difference in bone mineral density and body composition in any of the groups. However, our results indicate that Mig-6over/over male mice show accelerated cartilage degeneration at 12 and 18 months of age. Immunohistochemistry for SOX9 demonstrated that the number of positively stained cells in Mig-6over/over mice was decreased relative to controls. Immunostaining for MMP13 appeared increased in areas of cartilage degeneration in Mig-6over/over mice. Moreover, staining for phospho-EGFR (Tyr-1173) and lubricin (PRG4) was decreased in the articular cartilage of Mig-6over/over mice.

Conclusion
Overexpression of Mig-6 in the articular cartilage causes no major developmental phenotype; however, these mice develop earlier OA during aging. These data demonstrate that Mig-6/EGFR pathways are critical for joint homeostasis and might present a promising therapeutic target for OA.
Endurance exercise training restores diabetes-induced alteration in circulating Glycosylphosphatidylinositol-specific phospholipase D levels in rats
Authors: Abdolmaleki Farzad , Heidarianpour Ali 
Published: May 2020

Abstract
Background
Glycosylphosphatidylinositol-specific phospholipase D (GPLD1) is responsible for cleaving membrane-associated glycosylphosphatidylinositol (GPI) molecules, which is affected by diabetes. We aimed to examine the effect of 14 weeks treadmill running on serum GPLD1 levels and its association with glycemic indexes and serum glypican-4 (GPC-4), a novel GPI-anchored adipokine, in streptozotocin-nicotinamide-induced diabetic rats.

Methods
Thirty-six male Wister rats were randomly divided into three groups of twelve animals each, involving sedentary control (SC), sedentary diabetic (SD), and trained diabetic (TD) groups. The diabetes was induced through intraperitoneal injection of 120 mg/kg nicotinamide 15 min prior to intraperitoneal injection of 65 mg/kg streptozotocin in SD and TD groups. The TD group was exercised on a treadmill for 60 min/days, 5 days/wk at 26 m/min, and zero grade for 14 weeks. Following the experiment period, blood samples were taken from all animals and analyzed for experimental indexes via sandwich ELISA.

Results
Exercise training caused a significant decrease in the elevated blood glucose levels and a significant increase in the lowered blood insulin levels in TD rats (both p < 0.001). Glucose tolerance of TD rats significantly improved following experimental protocol, as indicated by OGTT (p < 0.001). Experimental diabetes significantly increased serum GPLD1 levels (p < 0.001), while exercise training significantly decreased its levels (p < 0.001). Serum GPLD1 levels correlated directly with glycemic indexes involving FBS, 2hOGTT, and AUC of glucose (r = 0.80, r = 0.79, r = 0.79, respectively, all p < 0.001) and inversely with serum insulin levels (r = − 0.83, p < 0.001). There were no significant differences in serum GPC-4 levels among groups, and no association with GPLD1 alteration.

Conclusions
Sedentary diabetic rats have higher circulating GPLD1 compared to controls, which can be reversed by exercise training and is associated with modifying in glycemic and insulin profile.
Novel HDAC inhibitor MAKV-8 and imatinib synergistically kill chronic myeloid leukemia cells via inhibition of BCR-ABL/MYC-signaling: effect on imatinib resistance and stem cells
Authors: Lernoux Manon , Schnekenburger Michael , Losson Hélène , Vermeulen Koen , Hahn Hyunggu , Gérard Déborah , Lee Jin-Young , Mazumder Aloran , Ahamed Muneer , Christov Christo , Kim Dong-Wook , Dicato Mario , Bormans Guy , Han Byung Woo , Diederich Marc 
Published: May 2020

Abstract
Background
Chronic myeloid leukemia (CML) pathogenesis is mainly driven by the oncogenic breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) fusion protein. Since BCR-ABL displays abnormal constitutive tyrosine kinase activity, therapies using tyrosine kinase inhibitors (TKis) such as imatinib represent a major breakthrough for the outcome of CML patients. Nevertheless, the development of TKi resistance and the persistence of leukemia stem cells (LSCs) remain barriers to cure the disease, justifying the development of novel therapeutic approaches. Since the activity of histone deacetylase (HDAC) is deregulated in numerous cancers including CML, pan-HDAC inhibitors may represent promising therapeutic regimens for the treatment of CML cells in combination with TKi.

Results
We assessed the anti-leukemic activity of a novel hydroxamate-based pan-HDAC inhibitor MAKV-8, which complied with the Lipinski’s “rule of five,” in various CML cells alone or in combination with imatinib. We validated the in vitro HDAC-inhibitory potential of MAKV-8 and demonstrated efficient binding to the ligand-binding pocket of HDAC isoenzymes. In cellulo, MAKV-8 significantly induced target protein acetylation, displayed cytostatic and cytotoxic properties, and triggered concomitant ER stress/protective autophagy leading to canonical caspase-dependent apoptosis. Considering the specific upregulation of selected HDACs in LSCs from CML patients, we investigated the differential toxicity of a co-treatment with MAKV-8 and imatinib in CML versus healthy cells. We also showed that beclin-1 knockdown prevented MAKV-8-imatinib combination-induced apoptosis. Moreover, MAKV-8 and imatinib co-treatment synergistically reduced BCR-ABL-related signaling pathways involved in CML cell growth and survival. Since our results showed that LSCs from CML patients overexpressed c-MYC, importantly MAKV-8-imatinib co-treatment reduced c-MYC levels and the LSC population. In vivo, tumor growth of xenografted K-562 cells in zebrafish was completely abrogated upon combined treatment with MAKV-8 and imatinib.

Conclusions
Collectively, the present findings show that combinations HDAC inhibitor-imatinib are likely to overcome drug resistance in CML pathology.
ALICAT: a customized approach to item selection process in computerized adaptive testing
Authors: G. Jatobá Victor M. , Farias Jorge S. , Freire Valdinei , Ruela André S. , Delgado Karina V. 
Published: May 2020

AbstractComputerized adaptive testing (CAT) based on item response theory allows more accurate assessments with fewer questions than the classic paper and pencil (P&P) test. Nonetheless, the CAT construction involves some key questions that, when done properly, can further improve the accuracy and efficiency in estimating the examinees’ abilities. One of the main questions is in regard to choosing the item selection rule (ISR). The classic CAT makes exclusive use of one ISR. However, these rules have differences depending on the examinees’ ability level and on the CAT stage. Thus, the objective of this work is to reduce the dichotomous test size which is inserted in a classic CAT with no significant loss of accuracy in the estimation of the examinee’s ability level. For this purpose, we analyze the ISR performance and then build a personalized item selection process in CAT considering the use of more than one rule. The case study in Mathematics and its Technologies test of the ENEM 2012 shows that the Kullback-Leibler information with a posterior distribution (KLP) has better performance in the examinees’ ability estimation when compared with Fisher information (F), Kullback-Leibler information (KL), maximum likelihood weighted information (MLWI), and maximum posterior weighted information (MPWI) rules. Previous results in the literature show that CAT using KLP was able to reduce this test size by 46.6% from the full size of 45 items with no significant loss of accuracy in estimating the examinees’ ability level. In this work, we observe that the F and the MLWI rules performed better on early CAT stages to estimate examinees’ proficiency level with extreme negative and positive values, respectively. With this information, we were able to reduce the same test by 53.3% using the personalized item selection process, called ALICAT, which includes the best rules working together.
γ-Secretase modulators exhibit selectivity for modulation of APP cleavage but inverse γ-secretase modulators do not
Authors: Lessard Christian B. , Rodriguez Edgardo , Ladd Thomas B. , Minter Lisa M. , Osborne Barbara A. , Miele Lucio , Golde Todd E. , Ran Yong 
Published: May 2020

Abstract
Background
γ-Secretase is a multiprotein protease that cleaves amyloid protein precursor (APP) and other type I transmembrane proteins. It has two catalytic subunits, presenilins 1 and 2 (PS1 and 2). In our previous report, we observed subtle differences in PS1- and PS2-mediated cleavages of select substrates and slightly different potencies of PS1 versus PS2 inhibition for select γ-secretase inhibitors (GSIs) on various substrates. In this study, we investigated whether γ-secretase modulators (GSMs) and inverse γ-secretase modulators (iGSMs) modulate γ-secretase processivity using multiple different substrates. We next used HEK 293T cell lines in which PSEN1 or PSEN2 was selectively knocked out to investigate processivity and response to GSMs and iGSMs.

Methods
For cell-free γ-secretase cleavage assay, recombinant substrates were incubated with CHAPSO-solubilized CHO or HEK 293T cell membrane with GSMs or iGSMs in suitable buffer. For cell-based assay, cDNA encoding substrates were transfected into HEK 293T cells. Cells were then treated with GSMs or iGSMs, and conditioned media were collected. Aβ and Aβ-like peptide production from cell-free and cell-based assay were measured by ELISA and mass spectrometry.

Result
These studies demonstrated that GSMs are highly selective for effects on APP, whereas iGSMs have a more promiscuous effect on many substrates. Surprisingly, iGSMs actually appear to act as like GSIs on select substrates. The data with PSEN1 or PSEN2 knocked out HEK 293T reveal that PS1 has higher processivity and response to GSMs than PS2, but PS2 has higher response to iGSM.

Conclusion
Collectively, these data indicate that GSMs are likely to have limited target-based toxicity. In addition, they show that iGSMs may act as substrate-selective GSIs providing a potential new route to identify leads for substrate-selective inhibitors of certain γ-secretase-mediated signaling events. With growing concerns that long-term β-secretase inhibitor is limited by target-based toxicities, such data supports continued development of GSMs as AD prophylactics.