bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Alternative Splicing Factor, MBNL1, Inhibits Glioblastoma Tumor Initiation and Progression by Reducing Hypoxia-Induced Stemness
Authors: Voss Dillon M. , Sloan Anthony , Spina Raffaella , Ames Heather M. , Bar Eli E. 
Published: September 2020

Abstract

Muscleblind-like proteins (MBNL) belong to a family of tissue-specific regulators of RNA metabolism that control premessenger RNA splicing. Inactivation of MBNL causes an adult-to-fetal alternative splicing transition, resulting in the development of myotonic dystrophy. We have previously shown that the aggressive brain cancer, glioblastoma (GBM), maintains stem-like features (glioma stem cell, GSC) through hypoxia-induced responses. Accordingly, we hypothesize here that hypoxia-induced responses in GBM might also include MBNL-based alternative splicing to promote tumor progression. When cultured in hypoxia condition, GSCs rapidly exported muscleblind-like-1 (MBNL1) out of the nucleus, resulting in significant inhibition of MBNL1 activity. Notably, hypoxia-regulated inhibition of MBNL1 also resulted in evidence of adult-to-fetal alternative splicing transitions. Forced expression of a constitutively active isoform of MBNL1 inhibited GSC self-renewal and tumor initiation in orthotopic transplantation models. Induced expression of MBNL1 in established orthotopic tumors dramatically inhibited tumor progression, resulting in significantly prolonged survival. This study reveals that MBNL1 plays an essential role in GBM stemness and tumor progression, where hypoxic responses within the tumor inhibit MBNL1 activity, promoting stem-like phenotypes and tumor growth. Reversing these effects on MBNL1 may therefore, yield potent tumor suppressor activities, uncovering new therapeutic opportunities to counter this disease.

Significance:
This study describes an unexpected mechanism by which RNA-binding protein, MBNL1, activity is inhibited in hypoxia by a simple isoform switch to regulate glioma stem cell self-renewal, tumorigenicity, and progression.
Iron Induces Cell Death and Strengthens the Efficacy of Antiandrogen Therapy in Prostate Cancer Models
Authors: Bordini Jessica , Morisi Federica , Elia Angela Rita , Santambrogio Paolo , Pagani Alessia , Cucchiara Vito , Ghia Paolo , Bellone Matteo , Briganti Alberto , Camaschella Clara , Campanella Alessandro 
Published: September 2020

Abstract

Purpose:
In search of novel strategies to improve the outcome of advanced prostate cancer, we considered that prostate cancer cells rearrange iron homeostasis, favoring iron uptake and proliferation. We exploited this adaptation by exposing prostate cancer preclinical models to high-dose iron to induce toxicity and disrupt adaptation to androgen starvation.

Experimental Design:
We analyzed markers of cell viability and mechanisms underlying iron toxicity in androgen receptor–positive VCaP and LNCaP, castration-resistant DU-145 and PC-3, and murine TRAMP-C2 cells treated with iron and/or the antiandrogen bicalutamide. We validated the results in vivo in VCaP and PC-3 xenografts and in TRAMP-C2 injected mice treated with iron and/or bicalutamide.

Results:
Iron was toxic for all prostate cancer cells. In particular, VCaP, LNCaP, and TRAMP-C2 were highly iron sensitive. Toxicity was mediated by oxidative stress, which primarily affected lipids, promoting ferroptosis. In highly sensitive cells, iron additionally caused protein damage. High-basal iron content and oxidative status defined high iron sensitivity. Bicalutamide–iron combination exacerbated oxidative damage and cell death, triggering protein oxidation also in poorly iron-sensitive DU-145 and PC-3 cells.
In vivo, iron reduced tumor growth in TRAMP-C2 and VCaP mice. In PC-3 xenografts, bicalutamide–iron combination caused protein oxidation and successfully impaired tumor expansion while single compounds were ineffective. Macrophages influenced body iron distribution but did not limit the iron effect on tumor expansion.

Conclusions:
Our models allow us to dissect the direct iron effect on cancer cells. We demonstrate the proof of principle that iron toxicity inhibits prostate cancer cell proliferation, proposing a novel tool to strengthen antiandrogen treatment efficacy.
Contemporary Incidence and Prevalence of Rheumatic Fever and Rheumatic Heart Disease in Australia Using Linked Data: The Case for Policy Change
Authors: Katzenellenbogen Judith M. , Bond‐Smith Daniela , Seth Rebecca J. , Dempsey Karen , Cannon Jeffrey , Stacey Ingrid , Wade Vicki , de Klerk Nicholas , Greenland Melanie , Sanfilippo Frank M. , Brown Alex , Carapetis Jonathan R. , Wyber Rosemary , Nedkoff Lee , Hung Joe , Bessarab Dawn , Ralph Anna P. 
Published: September 2020

Background
In 2018, the World Health Organization prioritized control of acute rheumatic fever (ARF) and rheumatic heart disease (RHD), including disease surveillance. We developed strategies for estimating contemporary ARF/RHD incidence and prevalence in Australia (2015–2017) by age group, sex, and region for Indigenous and non‐Indigenous Australians based on innovative, direct methods.

Methods and Results
This population‐based study used linked administrative data from 5 Australian jurisdictions. A cohort of ARF (age <45 years) and RHD cases (<55 years) were sourced from jurisdictional ARF/RHD registers, surgical registries, and inpatient data. We developed robust methods for epidemiologic case ascertainment for ARF/RHD. We calculated age‐specific and age‐standardized incidence and prevalence. Age‐standardized rate and prevalence ratios compared disease burden between demographic subgroups. Of 1425 ARF episodes, 72.1% were first‐ever, 88.8% in Indigenous people and 78.6% were aged <25 years. The age‐standardized ARF first‐ever rates were 71.9 and 0.60/100 000 for Indigenous and non‐Indigenous populations, respectively (age‐standardized rate ratio=124.1; 95% CI, 105.2–146.3). The 2017 Global Burden of Disease RHD prevalent counts for Australia (<55 years) underestimate the burden (1518 versus 6156 Australia‐wide extrapolated from our study). The Indigenous age‐standardized RHD prevalence (666.3/100 000) was 61.4 times higher (95% CI, 59.3–63.5) than non‐Indigenous (10.9/100 000). Female RHD prevalence was double that in males. Regions in northern Australia had the highest rates.

Conclusions
This study provides the most accurate estimates to date of Australian ARF and RHD rates. The high Indigenous burden necessitates urgent government action. Findings suggest RHD may be underestimated in many high‐resource settings. The linked data methods outlined here have potential for global applicability.
Mortality in Patients With Right Bundle‐Branch Block in the Absence of Cardiovascular Disease
Authors: Gaba Prakriti , Pedrotty Dawn , DeSimone Christopher V. , Bonikowske Amanda R. , Allison Thomas G. , Kapa Suraj 
Published: September 2020

Background
Right bundle‐branch block (RBBB) occurs in 0.2% to 1.3% of people and is considered a benign finding. However, some studies have suggested increased risk of cardiovascular morbidity and mortality. We sought to evaluate risk attributable to incidental RBBB in patients without prior diagnosis of cardiovascular disease (CVD).

Methods and Results

We reviewed the Mayo Clinic Integrated Stress Center database for exercise stress tests performed from 1993 to 2010. Patients with no known CVD—defined as absence of coronary disease, structural heart disease, heart failure, or cerebrovascular disease—were selected. Only Minnesota residents were included, all of whom had full mortality and outcomes data. There were 22 806 patients without CVD identified; 220 of whom (0.96%) had RBBB, followed for 6 to 23 years (mean 12.4±5.1). There were 8256 women (36.2%), mean age was 52±11 years; and 1837 deaths (8.05%), including 645 cardiovascular‐related deaths (2.83%), occurred over follow‐up. RBBB was predictive of all‐cause (hazard ratio [HR], 1.5; 95% CI, 1.1–2.0;
P
=0.0058) and cardiovascular‐related mortality (HR,1.7; 95% CI, 1.1–2.8;
P
=0.0178) after adjusting for age, sex, diabetes mellitus, hypertension, obesity, current and past history of smoking, and use of a heart rate‐lowering drug. Patients with RBBB exhibited more hypertension (34.1% versus 23.7%,
P
<0.0003), decreased functional aerobic capacity (82±25% versus 90±24%;
P
<0.0001), slower heart rate recovery (13.5±11.5 versus 17.1±9.4 bpm;
P
<0.0001), and more dyspnea (28.2% versus 22.4%;
P
<0.0399) on exercise testing.

Conclusions
Patients with RBBB without CVD have increased risk of all‐cause mortality, cardiovascular‐related mortality, and lower exercise tolerance. These data suggest RBBB may be a marker of early CVD and merit further prospective evaluation.
High Dietary Inflammatory Index Is Associated With Increased Plaque Vulnerability of Carotid in Patients With Ischemic Stroke
Authors: Peng Min , Wang Ling , Xia Yaqian , Tao Lei , Liu Yujing , Huang Feihong , Li Shun , Gong Xiuqun , Liu Xinfeng , Xu Gelin 
Published: September 2020

Background and Purpose:
Long-term dietary patterns can influence the intensity of systemic inflammation and, therefore, the development of atherosclerosis. This study aimed to evaluate the association between dietary inflammatory index (DII) and vulnerability characteristics of carotid atherosclerotic plaques in patients with ischemic stroke.

Methods:
Patients with ischemic stroke within 7 days of onset were enrolled. DII was calculated from 32 food components with the help of a food frequency questionnaire. Vulnerable plaque was defined as presence of artery positive remodeling (remodeling index >1.1) and low CT attenuation plaques (<35 HU) on carotid arteries by computed tomography angiography.

Results:

Of the 398 enrolled patients, 144 (36.2%) were detected with vulnerable plaque. Their DII ranged from −4.58 to 4.18. Patients with vulnerable plaques consumed less nutrients with anti-inflammatory properties, less fruits and vegetables (85.6±64.3 versus 94.6±74.4 g/d,
P
=0.027), and less nuts (5.66±7.14 versus 8.84±15.9 g/d,
P
=0.024) than patients without vulnerable plaques. Patients with vulnerable plaque had higher DII than patients without vulnerable plaque (−0.26±1.54 versus −0.64±1.53,
P
=0.018). Logistic regression analysis revealed that DII was associated with vulnerable plaques after adjusted for major confounding factors (odds ratio=1.307; 95% CI, 1.113–1.533).

Conclusions:
DII is associated with the vulnerability of carotid plaques in patients with ischemic stroke. Considering a possible causal relationship, the mechanisms underlying the association between diet and atherosclerosis warrant further study.
Automated Activity Estimation of the Cold-Water Coral Lophelia pertusa by Multispectral Imaging and Computational Pixel Classification
Authors: Liu Hongbo , Büscher Janina V. , Köser Kevin , Greinert Jens , Song Hong , Chen Ying , Schoening Timm 
Published: September 2020

AbstractThe cold-water coral Lophelia pertusa builds up bioherms that sustain high biodiversity in the deep ocean worldwide. Photographic monitoring of the polyp activity represents a helpful tool to characterize the health status of the corals and to assess anthropogenic impacts on the microhabitat. Discriminating active polyps from skeletons of white Lophelia pertusa is usually time consuming and error prone due to their similarity in color in common red–green–blue (RGB) camera footage. Acquisition of finer-resolved spectral information might increase the contrast between the segments of polyps and skeletons, and therefore could support automated classification and accurate activity estimation of polyps. For recording the needed footage, underwater multispectral imaging systems can be used, but they are often expensive and bulky. Here we present results of a new, lightweight, compact, and low-cost deep-sea tunable LED-based underwater multispectral imaging system (TuLUMIS) with eight spectral channels. A branch of healthy white Lophelia pertusa was observed under controlled conditions in a laboratory tank. Spectral reflectance signatures were extracted from pixels of polyps and skeletons of the observed coral. Results showed that the polyps can be better distinguished from the skeleton by analysis of the eight-dimensional spectral reflectance signatures compared to three-channel RGB data. During a 72-h monitoring of the coral with a half-hour temporal resolution in the laboratory, the polyp activity was estimated based on the results of the multispectral pixel classification using a support vector machine (SVM) approach. The computational estimated polyp activity was consistent with that of the manual annotation, which yielded a correlation coefficient of 0.957.
Local therapies for liver metastases of rare head and neck cancers: a monoinstitutional case series
Authors: Bergamini Cristiana , Cavalieri Stefano , Cascella Tommaso , Lanocita Rodolfo , Alfieri Salvatore , Resteghini Carlo , Platini Francesca , Orlandi Ester , Locati Laura Deborah , Marchianò Alfonso , Licitra Lisa 
Published: September 2020

Introduction: Transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) are established procedures for treating hepatocellular cancer and selected malignancies with liver metastasis. The aim of this study is to describe a monoinstitutional case series of local approaches in patients with liver metastases from rare head and neck cancers (HNCs). Methods: This is a retrospective series of adult patients with HNC treated with liver locoregional approaches (TACE or RFA) at our institution from 2007 to 2018. In case of chemoembolization, the preferred chemotherapeutic drug was doxorubicin. Response according to RECIST (Response Evaluation Criteria in Solid Tumors) was assessed with contrast-enhanced computed tomography scans. Results: Thirty-four patients were treated (20 men, median age 58 years) with TACE (27), transarterial embolization (2), or RFA (7). Primary tumours were salivary gland (21), thyroid (6), nasopharyngeal (5), and sinonasal cancers (2). Seventeen patients (50%) had a single metastatic liver nodule; 70% of the remaining 17 patients had at least three liver metastases. The median diameter of the metastatic liver mass undergoing treatment was 39 mm (range 11–100 mm). Median follow-up was 27.6 months. Response rate was 35% (3% complete, 32% partial response). Median progression-free survival and overall survival were 6.9 and 19.6 months, respectively. Treatment-related adverse events occurred in 59% of patients (21% grade ⩾ 3; no grade 5). Discussion: This retrospective case series demonstrates that locoregional radiologic approaches for rare HNCs with liver metastases are feasible. These procedures deserve further prospective studies before being considered safe and active in these malignancies where the availability of effective systemic treatments is lacking.
Feeding and Growth in Infants With Cleft Lip and/or Palate: Relationships With Maternal Distress
Authors: Madhoun Lauren L. , Crerand Canice E. , O’Brien Meghan , Baylis Adriane L. 
Published: September 2020

Objective: To examine relationships between early feeding and growth and maternal distress in infants with and without cleft lip and/or palate (CL/P). Design: Cross-sectional. Setting: Pediatric academic medical center in the Midwestern United States. Participants: Mothers of infants 1 to 12 weeks old with CL/P (n = 30) and without CL/P (control group, n = 30) were recruited at craniofacial clinic or pediatrician appointments. Main Outcome Measure(s): Maternal responses on the Feeding/Swallowing Impact Survey (FS-IS), Parenting Stress Index, Fourth Edition, Short Form (PSI-4-SF), and Edinburgh Postnatal Depression Scale. Infant feeding history and growth measurements were obtained. Results: Having an infant with CL/P revealed greater impact on maternal health-related quality of life due to feeding problems ( F = 4.83, P = .03). Mothers of infants with CL/P reported average range Total Stress scores on the PSI-4-SF, which were higher than controls ( F = 4.12, P = .05). Edinburgh Postnatal Depression Scale scores did not differ between groups. Compared to controls, infants with cleft palate had lower percentiles for weight ( t = 4.13, P = .04) and length ( t = 2.93, P = .01). Higher FS-IS scores were associated with longer feeding duration ( r = 0.32, P = .01) and lower weight ( r = −0.31, P = .02) and length ( r = −0.32, P = .02). Conclusions: Despite receiving early team care and feeding interventions, mothers of infants with CL/P reported higher stress and more challenges with feeding and growth. Future studies should examine targeted psychosocial interventions to improve feeding and growth outcomes in infants with CL/P.
MRI correlates of clinical disability and hand-motor performance in multiple sclerosis phenotypes
Authors: Cordani Claudio , Hidalgo de la Cruz Milagros , Meani Alessandro , Valsasina Paola , Esposito Federica , Pagani Elisabetta , Filippi Massimo , Rocca Maria A 
Published: September 2020

Background: Hand-motor impairment affects a large proportion of multiple sclerosis (MS) patients; however, its substrates are still poorly understood. Objectives: To investigate the association between global disability, hand-motor impairment, and alterations in motor-relevant structural and functional magnetic resonance imaging (MRI) networks in MS patients with different clinical phenotypes. Methods: One hundred thirty-four healthy controls (HC) and 364 MS patients (250 relapsing-remitting MS (RRMS) and 114 progressive MS (PMS)) underwent Expanded Disability Status Scale (EDSS) rating, nine-hole peg test (9HPT), and electronic finger tapping rate (EFTR). Structural and resting state (RS) functional MRI scans were used to perform a source-based morphometry on gray matter (GM) components, to analyze white matter (WM) tract diffusivity indices and to perform a RS seed-based approach from the primary motor cortex involved in hand movement (hand-motor cortex). Random forest analyses identified the predictors of clinical impairment. Result: In RRMS, global measures of atrophy and lesions together with measures of structural damage of motor-related regions predicted EDSS (out-of-bag (OOB)- R2 = 0.19, p-range = <0.001–0.04), z9HPT (right: OOB- R2 = 0.14; left: OOB- R2 = 0.24, p-range = <0.001–0.03). No RS functional connectivity (FC) abnormalities were identified in RRMS models. In PMS, cerebellar and sensorimotor regions atrophy, cerebellar peduncles integrity and increased RS FC between left hand-motor cortex and right inferior frontal gyrus predicted EDSS (OBB- R2 = 0.16, p-range = 0.02–0.04). Conclusion: In RRMS, only measures of structural damage contribute to explain motor impairment, whereas both structural and functional MRI measures predict clinical disability in PMS. A multiparametric MRI approach could be relevant to investigate hand-motor impairment in different MS phenotypes.
Comparison Between Nailing and Plating in the Treatment of Distal Tibial Fractures: A Meta-Analysis
Authors: Ekman E. , Lehtimäki K. , Syvänen J. , Saltychev M. 
Published: September 2020

Background and Aims: To evaluate evidence on the superiority of plate fixation over intramedullary nail fixation in the treatment of distal tibial fractures regarding functional outcomes and complication rates. Material and Methods: Cochrane Controlled Trials Register, Medline, Embase, CINAHL, Scopus, and Web of Science databases were searched in December 2019. The risk of systematic bias was assessed according to the Cochrane Collaboration’s domain-based evaluation framework. Results: The search resulted in 514 records, the final sample included 10 randomized controlled trials (782 patients). There were statistically significant differences in operating time (−11.2, 95% confidence interval: −16.3 to −6.1 min), time to partial weight bearing (−0.96, 95% confidence interval: −1.8 to −0.1 weeks), time to full weight bearing (−2.2, 95% confidence interval: −4.32 to −0.01 weeks), the rates of deep infections (risk ratio = 0.37, 95% confidence interval: 0.19 to 0.69), and the rates of soft-tissue complications (risk ratio = 0.52, 95% confidence interval: 0.33 to 0.82) favoring intramedullary nail. Intraoperative blood loss (127.2, 95% confidence interval: 34.7 to 219.7 mL) and postoperative knee pain and stiffness (relative risk = 5.6, 95% confidence interval: 1.4–22.6) showed significant differences favoring plate fixation. When combining all complication rates, the difference was risk ratio = 0.77 (95% confidence interval: 0.63 to 0.95) favoring intramedullary nail. No significant differences in radiation time, length of incision, length of hospital stay, time to return to work, time to union, the rates of healing complications or secondary procedures, ankle pain or stiffness, or functional scores were found. Conclusion: This meta-analysis suggests that intramedullary nail might be slightly superior in reducing postoperative complications and result in slightly faster healing when compared to plate fixation.
MiR-331-3p Links to Drug Resistance of Pancreatic Cancer Cells by Activating WNT/β-Catenin Signal via ST7L
Authors: Zhan Ting , Chen Xiaoli , Tian Xia , Han Zheng , Liu Meng , Zou Yanli , Huang Shasha , Chen Aifang , Cheng Xueting , Deng Junsheng , Tan Jie , Huang Xiaodong 
Published: September 2020

Background: Pancreatic cancer is an aggressive type of cancer with poor prognosis, short survival rate, and high mortality. Drug resistance is a major cause of treatment failure in the disease. MiR-331-3p has been reported to play an important role in several cancers. We previously showed that miR-331-3p is upregulated in pancreatic cancer and promotes pancreatic cancer cell proliferation and epithelial-to-mesenchymal transition–mediated metastasis by targeting ST7L. However, it is uncertain whether miR-331-3p is involved in drug resistance. Methods: We investigated the relationship between miR-331-3p and pancreatic cancer drug resistance. As part of this, microRNA mimics or inhibitors were transfected into pancreatic cancer cells. Quantitative polymerase chain reaction was used to detect miR-331-3p expression, and flow cytometry was used to detect cell apoptosis. The Cell Counting Kit-8 assay was used to measure the IC50 values of gemcitabine in pancreatic cancer cells. The expression of multidrug resistance protein 1, multidrug resistance-related protein 1, breast cancer resistance protein, β-Catenin, c-Myc, Cyclin D1, Bcl-2, and Caspase-3 was evaluated by Western blotting. Results: We confirmed that miR-331-3p is upregulated in gemcitabine-treated pancreatic cancer cells and plasma from chemotherapy patients. We also confirmed that miR-331-3p inhibition decreased drug resistance by regulating cell apoptosis and multidrug resistance protein 1, multidrug resistance-related protein 1, and breast cancer resistance protein expression in pancreatic cancer cells, whereas miR-331-3p overexpression had the opposite effect. We further demonstrated that miR-331-3p effects in drug resistance were partially reversed by ST7L overexpression. In addition, overexpression of miR-331-3p activated Wnt/β-catenin signaling in pancreatic cancer cells, and ST7L overexpression restored activation of Wnt/β-catenin signaling. Conclusions: Taken together, our data demonstrate that miR-331-3p contributes to drug resistance by activating Wnt/β-catenin signaling via ST7L in pancreatic cancer cells. These data provide a theoretical basis for new targeted therapies in the future.