bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of carboplatin and bevacizumab in patients with breast cancer brain metastases
Authors: Leone Jose Pablo , Emblem Kyrre E. , Weitz Michelle , Gelman Rebecca S. , Schneider Bryan P. , Freedman Rachel A. , Younger Jerry , Pinho Marco C. , Sorensen A. Gregory , Gerstner Elizabeth R. , Harris Gordon , Krop Ian E. , Morganstern Daniel , Sohl Jessica , Hu Jiani , Kasparian Elizabeth , Winer Eric P. , Lin Nancy U. 
Published: November 2020

Abstract
Background
We aimed to examine the safety and efficacy of bevacizumab and carboplatin in patients with breast cancer brain metastases.

Methods
We enrolled patients with breast cancer and > 1 measurable new or progressive brain metastasis. Patients received bevacizumab 15 mg/kg intravenously (IV) on cycle 1 day 1 and carboplatin IV AUC = 5 on cycle 1 day 8. Patients with HER2-positive disease also received trastuzumab. In subsequent cycles, all drugs were administered on day 1 of each cycle. Contrast-enhanced brain MRI was performed at baseline, 24–96 h after the first bevacizumab dose (day + 1), and every 2 cycles. The primary endpoint was objective response rate in the central nervous system (CNS ORR) by composite criteria. Associations between germline VEGF single nucleotide polymorphisms (rs699947, rs2019063, rs1570360, rs833061) and progression-free survival (PFS) and overall survival (OS) were explored, as were associations between early (day + 1) MRI changes and outcomes.

Results
Thirty-eight patients were enrolled (29 HER2-positive, 9 HER2-negative); all were evaluable for response. The CNS ORR was 63% (95% CI, 46–78). Median PFS was 5.62 months and median OS was 14.10 months. As compared with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, patients with ECOG PS 1–2 had significantly worse PFS and OS (all P < 0.01). No significant associations between VEGF genotypes or early MRI changes and clinical outcomes were observed.

Conclusions
The combination of bevacizumab and carboplatin results in a high rate of durable objective response in patients with brain metastases from breast cancer. This regimen warrants further investigation.

Trial registration
NCT01004172. Registered 28 October 2009.
Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-negative breast cancer
Authors: Zoeller Jason J. , Vagodny Aleksandr , Daniels Veerle W. , Taneja Krishan , Tan Benjamin Y. , DeRose Yoko S. , Fujita Maihi , Welm Alana L. , Letai Anthony , Leverson Joel D. , Blot Vincent , Bronson Roderick T. , Dillon Deborah A. , Brugge Joan S. 
Published: November 2020

Abstract
Background
Targeted therapies for triple-negative breast cancer (TNBC) are limited; however, the epidermal growth factor receptor (EGFR) represents a potential target, as the majority of TNBC express EGFR. The purpose of these studies was to evaluate the effectiveness of two EGFR-targeted antibody-drug conjugates (ADC: ABT-414; ABBV-321) in combination with navitoclax, an antagonist of the anti-apoptotic BCL-2 and BCL-XL proteins, in order to assess the translational relevance of these combinations for TNBC.

Methods
The pre-clinical efficacy of combined treatments was evaluated in multiple patient-derived xenograft (PDX) models of TNBC. Microscopy-based dynamic BH3 profiling (DBP) was used to assess mitochondrial apoptotic signaling induced by navitoclax and/or ADC treatments, and the expression of EGFR and BCL-2/XL was analyzed in 46 triple-negative patient tumors.

Results
Treatment with navitoclax plus ABT-414 caused a significant reduction in tumor growth in five of seven PDXs and significant tumor regression in the highest EGFR-expressing PDX. Navitoclax plus ABBV-321, an EGFR-targeted ADC that displays more effective wild-type EGFR-targeting, elicited more significant tumor growth inhibition and regressions in the two highest EGFR-expressing models evaluated. The level of mitochondrial apoptotic signaling induced by single or combined drug treatments, as measured by DBP, correlated with the treatment responses observed in vivo. Lastly, the majority of triple-negative patient tumors were found to express EGFR and co-express BCL-XL and/or BCL-2.

Conclusions
The dramatic tumor regressions achieved using combined agents in pre-clinical TNBC models underscore the abilities of BCL-2/XL antagonists to enhance the effectiveness of EGFR-targeted ADCs and highlight the clinical potential for usage of such targeted ADCs to alleviate toxicities associated with combinations of BCL-2/XL inhibitors and systemic chemotherapies.
Human A-to-I RNA editing SNP loci are enriched in GWAS signals for autoimmune diseases and under balancing selection
Authors: Zhang Hui , Fu Qiang , Shi Xinrui , Pan Ziqing , Yang Wenbing , Huang Zichao , Tang Tian , He Xionglei , Zhang Rui 
Published: November 2020

AbstractBackgroundAdenosine-to-inosine (A-to-I) RNA editing plays important roles in diversifying the transcriptome and preventing MDA5 sensing of endogenous dsRNA as nonself. To date, few studies have investigated the population genomic signatures of A-to-I editing due to the lack of editing sites overlapping with SNPs.ResultsIn this study, we applied a pipeline to robustly identify SNP editing sites from population transcriptomic data and combined functional genomics, GWAS, and population genomics approaches to study the function and evolution of A-to-I editing. We find that the G allele, which is equivalent to edited I, is overrepresented in editing SNPs. Functionally, A/G editing SNPs are highly enriched in GWAS signals of autoimmune and immune-related diseases. Evolutionarily, derived allele frequency distributions of A/G editing SNPs for both A and G alleles as the ancestral alleles are skewed toward intermediate frequency alleles relative to neutral SNPs, a hallmark of balancing selection, suggesting that both A and G alleles are functionally important. The signal of balancing selection is confirmed by a number of additional population genomic analyses.ConclusionsWe uncovered a hidden layer of A-to-I RNA editing SNP loci as a common target of balancing selection, and we propose that the maintenance of such editing SNP variations may be at least partially due to constraints on the resolution of the balance between immune activity and self-tolerance.
Comparison of GlideScope™ visualization and neck flexion with lateral neck pressure nasogastric tube insertion techniques in anesthetized patients: a randomized clinical study
Authors: Purngpipattrakul Pitchaporn , Petsakul Suttasinee , Chatmonkolchart Sunisa , Nuanjun Kanjana , Boonchuduang Somrutai 
Published: November 2020

Abstract
Objective
Nasogastric tube (NGT) insertion in anesthetized and intubated patients can be challenging, even for experienced anesthesiologists. Various techniques have been proposed to facilitate NGT insertion in these patients. This study aimed to compare the success rate and time required for NGT insertion between GlideScope™ visualization and neck flexion, with lateral neck pressure techniques.

Material and methods
This randomized clinical trial was performed at a teaching hospital on 86 adult patients undergoing abdominal surgery, under relaxant general anesthesia, who required intraoperative NGT insertion. The patients were randomized into two groups, the GlideScope™ group (group G) and the neck flexion with lateral neck pressure group (group F). The success rate of the first and second attempts, duration of insertion, and complications were recorded.

Results
The total success rate was 79.1% in group G, compared with 76.7% in group F (P = 1). The median time required for NGT insertion was significantly longer in group G, for both first and second attempts (97 vs 42 s P < 0.001) and (70 vs 48.5 s P = 0.015), respectively. Complications were reported in 23 patients (53.5%) in group G and 13 patients (30.2%) in group F. Bleeding and kinking were the most common complications for both techniques.

Conclusion
Using GlideScope™ visualization to facilitate NGT insertion was comparable to neck flexion with lateral neck pressure technique, in the degree of success rates of insertion. Although complications were not statistically significant between groups, neck flexion with lateral neck pressure technique was significantly less time-consuming for both first and second attempts.

Trial registration
Retrospectively registered: Thai Clinical Trial Registry (TCTR)20171229003. Registered on 19 December 2017
Evaluation of the effect of curcumin and zinc co-supplementation on glycemic measurements, lipid profiles, and inflammatory and antioxidant biomarkers in overweight or obese prediabetic patients: a study protocol for a randomized double-blind placebo-controlled phase 2 clinical trial
Authors: Karandish Majid , Mozaffari-khosravi Hassan , Mohammadi Seyed Mohammad , Azhdari Maryam , Cheraghian Bahman 
Published: November 2020

Abstract
Background
The prevalence of prediabetes is increasing worldwide. Unfortunately, prediabetes is related to non-communicable diseases. A high risk of developing type 2 diabetes mellitus (T2DM) is reported in people with prediabetes. Curcumin, a polyphenol, might lead to its therapeutic role in obesity and some obesity-related metabolic diseases. Zinc is a trace element that plays a key role in the synthesis and action of insulin, carbohydrate metabolism, and decreasing inflammation. There has been no clinical trial of zinc and curcumin co-supplementation in patients with prediabetes. In previous studies, the single administration of zinc or curcumin has not been conducted on many of the studied markers in prediabetic patients.

Methods
The purpose of this randomized double-blind placebo-controlled clinical trial is to investigate the effect of curcumin and zinc co-supplementation on glycemic measurements, lipid profiles, and inflammatory and antioxidant biomarkers among 84 prediabetic patients with body mass index (BMI) between 25 and 35. Also, liver enzyme, serum zinc, urine zinc, blood pressure, anthropometric parameters, quality of life, adherence to co-supplementation, the side effects of co-supplementation, physical activity, and dietary intake will be assessed. Women or men (18–50 years old for men and 18 years to before menopause for women) will be followed for 3 months (90 days). This study will be conducted at Yazd Diabetes Research Clinic, Shahid Sadoughi University of Medical Sciences.

Discussion
A diet rich in antioxidants, polyphenols, and phytochemicals has been shown to have a beneficial role in prediabetes. According to the beneficial properties of curcumin or zinc and inadequate evidence, RCTs are needed to assess the effect of curcumin and zinc co-supplementation in native prediabetes patients. We hope the results of the present trial, negative or positive, fill this gap in the literature and facilitate the approach for a much larger, multi-center clinical trial. In conclusion, a synergic effect of co-supplementation along with a weight-loss diet may delay the progression to type 2 diabetes mellitus.

Trial registration
Iranian Registry of Clinical Trials (IRCT) IRCT20190902044671N1. Registered on 11 October 2019
A thermostable bacterial lytic polysaccharide monooxygenase with high operational stability in a wide temperature range
Authors: Tuveng Tina Rise , Jensen Marianne Slang , Fredriksen Lasse , Vaaje-Kolstad Gustav , Eijsink Vincent G. H. , Forsberg Zarah 
Published: November 2020

Abstract
Background
Lytic polysaccharide monooxygenases (LPMOs) are oxidative, copper-dependent enzymes that function as powerful tools in the turnover of various biomasses, including lignocellulosic plant biomass. While LPMOs are considered to be of great importance for biorefineries, little is known about industrial relevant properties such as the ability to operate at high temperatures. Here, we describe a thermostable, cellulose-active LPMO from a high-temperature compost metagenome (called mgLPMO10).

Results
MgLPMO10 was found to have the highest apparent melting temperature (83 °C) reported for an LPMO to date, and is catalytically active up to temperatures of at least 80 °C. Generally, mgLPMO10 showed good activity and operational stability over a wide temperature range. The LPMO boosted cellulose saccharification by recombinantly produced GH48 and GH6 cellobiohydrolases derived from the same metagenome, albeit to a minor extent. Cellulose saccharification studies with a commercial cellulase cocktail (Celluclast®) showed that the performance of this thermostable bacterial LPMO is comparable with that of a frequently utilized fungal LPMO from Thermoascus aurantiacus (TaLPMO9A).

Conclusions
The high activity and operational stability of mgLPMO10 are of both fundamental and applied interest. The ability of mgLPMO10 to perform oxidative cleavage of cellulose at 80 °C and the clear synergy with Celluclast® make this enzyme an interesting candidate in the development of thermostable enzyme cocktails for use in lignocellulosic biorefineries.
Whole blood DNA methylation aging markers predict colorectal cancer survival: a prospective cohort study
Authors: Gào Xīn , Zhang Yan , Boakye Daniel , Li Xiangwei , Chang-Claude Jenny , Hoffmeister Michael , Brenner Hermann 
Published: November 2020

Abstract
Background
Blood DNA methylation-based aging algorithms predict mortality in the general population. We investigated the prognostic value of five established DNA methylation aging algorithms for patients with colorectal cancer (CRC).

Methods
AgeAccelHorvath, AgeAccelHannum, DNAmMRscore, AgeAccelPheno and AgeAccelGrim were constructed using whole blood epi-genomic data from 2206 CRC patients. After a median follow-up of 6.2 years, 1079 deaths were documented, including 596 from CRC. Associations of the aging algorithms with survival outcomes were evaluated using the Cox regression and survival curves. Harrell’s C-statistics were computed to investigate predictive performance.

Results
Adjusted hazard ratios (95% confidence intervals) of all-cause mortality for patients in the third compared to the first tertile were 1.66 (1.32, 2.09) for the DNAmMRscore, 1.35 (1.14, 1.59) for AgeAccelPheno and 1.65 (1.37, 2.00) for AgeAccelGrim, even after adjustment for age, sex and stage. AgeAccelHorvath and AgeAccelHannum were not associated with all-cause or CRC-specific mortality. In stage-specific analyses, associations were much stronger for patients with early or intermediate stage cancers (stages I, II and III) than for patients with metastatic (stage IV) cancers. Associations were weaker and less often statistically significant for CRC-specific mortality. Adding DNAmMRscore, AgeAccelPheno or AgeAccelGrim to models including age, sex and tumor stage improved predictive performance moderately.

Conclusions
DNAmMRscore, AgeAccelPheno and AgeAccelGrim could serve as non-invasive CRC prognostic biomarkers independent of other commonly used markers. Further research should aim for tailoring and refining such algorithms for CRC patients and to explore their value for enhanced prediction of treatment success and treatment decisions.
Developmental programming in human umbilical cord vein endothelial cells following fetal growth restriction
Authors: Terstappen Fieke , Calis Jorg J. A. , Paauw Nina D. , Joles Jaap A. , van Rijn Bas B. , Mokry Michal , Plösch Torsten , Lely A. Titia 
Published: November 2020

AbstractBackgroundFetal growth restriction (FGR) is associated with an increased susceptibility for various noncommunicable diseases in adulthood, including cardiovascular and renal disease. During FGR, reduced uteroplacental blood flow, oxygen and nutrient supply to the fetus are hypothesized to detrimentally influence cardiovascular and renal programming. This study examined whether developmental programming profiles, especially related to the cardiovascular and renal system, differ in human umbilical vein endothelial cells (HUVECs) collected from pregnancies complicated by placental insufficiency-induced FGR compared to normal growth pregnancies. Our approach, involving transcriptomic profiling by RNA-sequencing and gene set enrichment analysis focused on cardiovascular and renal gene sets and targeted DNA methylation assays, contributes to the identification of targets underlying long-term cardiovascular and renal diseases.ResultsGene set enrichment analysis showed several downregulated gene sets, most of them involved in immune or inflammatory pathways or cell cycle pathways. seven of the 22 significantly upregulated gene sets related to kidney development and four gene sets involved with cardiovascular health and function were downregulated in FGR (n = 11) versus control (n = 8). Transcriptomic profiling by RNA-sequencing revealed downregulated expression ofLGALS1,FPR3andNRMand upregulation of lincRNARP5-855F14.1in FGR compared to controls. DNA methylation was similar forLGALS1between study groups, but relative hypomethylation ofFPR3and hypermethylation ofNRMwere present in FGR, especially in male offspring. Absolute differences in methylation were, however, small.ConclusionThis study showed upregulation of gene sets related to renal development in HUVECs collected from pregnancies complicated by FGR compared to control donors. The differentially expressed gene sets related to cardiovascular function and health might be in line with the downregulated expression ofNRMand upregulated expression of lincRNARP5-855F14.1in FGR samples; NRM is involved in cardiac remodeling, and lincRNAs are correlated with cardiovascular diseases. Future studies should elucidate whether the downregulatedLGALS1andFPR3expressions in FGR are angiogenesis-modulating regulators leading to placental insufficiency-induced FGR or whether the expression of these genes can be used as a biomarker for increased cardiovascular risk. Altered DNA methylation might partly underlieFPR3andNRMdifferential gene expression differences in a sex-dependent manner.
Epigenetic regulation of inflammation in periodontitis: cellular mechanisms and therapeutic potential
Authors: Jurdziński Krzysztof T. , Potempa Jan , Grabiec Aleksander M. 
Published: November 2020

AbstractEpigenetic mechanisms, namely DNA and histone modifications, are critical regulators of immunity and inflammation which have emerged as potential targets for immunomodulating therapies. The prevalence and significant morbidity of periodontitis, in combination with accumulating evidence that genetic, environmental and lifestyle factors cannot fully explain the susceptibility of individuals to disease development, have driven interest in epigenetic regulation as an important factor in periodontitis pathogenesis. Aberrant promoter methylation profiles of genes involved in inflammatory activation, includingTLR2,PTGS2,IFNG,IL6,IL8,andTNF, have been observed in the gingival tissue, peripheral blood or buccal mucosa from patients with periodontitis, correlating with changes in expression and disease severity. The expression of enzymes that regulate histone acetylation, in particular histone deacetylases (HDACs), is also dysregulated in periodontitis-affected gingival tissue. Infection of gingival epithelial cells, gingival fibroblasts and periodontal ligament cells with the oral pathogensPorphyromonas gingivalisorTreponema denticolainduces alterations in expression and activity of chromatin-modifying enzymes, as well as site-specific and global changes in DNA methylation profiles and in histone acetylation and methylation marks. These epigenetic changes are associated with excessive production of inflammatory cytokines, chemokines, and matrix-degrading enzymes that can be suppressed by small molecule inhibitors of HDACs (HDACi) or DNA methyltransferases. HDACi and inhibitors of bromodomain-containing BET proteins ameliorate inflammation, osteoclastogenesis, and alveolar bone resorption in animal models of periodontitis, suggesting their clinical potential as host modulation therapeutic agents. However, broader application of epigenomic methods will be required to create a comprehensive map of epigenetic changes in periodontitis. The integration of functional studies with global analyses of the epigenetic landscape will provide critical information on the therapeutic and diagnostic potential of epigenetics in periodontal disease.
Interventional radiology and artificial intelligence in radiology: Is it time to enhance the vision of our medical students?
Authors: Auloge Pierre , Garnon Julien , Robinson Joey Marie , Dbouk Sarah , Sibilia Jean , Braun Marc , Vanpee Dominique , Koch Guillaume , Cazzato Roberto Luigi , Gangi Afshin 
Published: November 2020

Abstract
Objectives
To assess awareness and knowledge of Interventional Radiology (IR) in a large population of medical students in 2019.

Methods
An anonymous survey was distributed electronically to 9546 medical students from first to sixth year at three European medical schools. The survey contained 14 questions, including two general questions on diagnostic radiology (DR) and artificial intelligence (AI), and 11 on IR. Responses were analyzed for all students and compared between preclinical (PCs) (first to third year) and clinical phase (Cs) (fourth to sixth year) of medical school. Of 9546 students, 1459 students (15.3%) answered the survey.

Results
On DR questions, 34.8% answered that AI is a threat for radiologists (PCs: 246/725 (33.9%); Cs: 248/734 (36%)) and 91.1% thought that radiology has a future (PCs: 668/725 (92.1%); Cs: 657/734 (89.5%)). On IR questions, 80.8% (1179/1459) students had already heard of IR; 75.7% (1104/1459) stated that their knowledge of IR wasn’t as good as the other specialties and 80% would like more lectures on IR. Finally, 24.2% (353/1459) indicated an interest in a career in IR with a majority of women in preclinical phase, but this trend reverses in clinical phase.

Conclusions
Development of new technology supporting advances in artificial intelligence will likely continue to change the landscape of radiology; however, medical students remain confident in the need for specialty-trained human physicians in the future of radiology as a clinical practice. A large majority of medical students would like more information about IR in their medical curriculum; almost a quarter of students would be interested in a career in IR.