bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analyzing the genomic and transcriptomic architecture of milk traits in Murciano-Granadina goats
Authors: Guan Dailu , Landi Vincenzo , Luigi-Sierra María Gracia , Delgado Juan Vicente , Such Xavier , Castelló Anna , Cabrera Betlem , Mármol-Sánchez Emilio , Fernández-Alvarez Javier , de la Torre Casañas José Luis Ruiz , Martínez Amparo , Jordana Jordi , Amills Marcel 
Published: March 2020

AbstractBackgroundIn this study, we aimed to investigate the molecular basis of lactation as well as to identify the genetic factors that influence milk yield and composition in goats. To achieve these two goals, we have analyzed how the mRNA profile of the mammary gland changes in seven Murciano-Granadina goats at each of three different time points, i.e. 78 d (T1, early lactation), 216 d (T2, late lactation) and 285 d (T3, dry period) after parturition. Moreover, we have performed a genome-wide association study (GWAS) for seven dairy traits recorded in the 1st lactation of 822 Murciano-Granadina goats.ResultsThe expression profiles of the mammary gland in the early (T1) and late (T2) lactation were quite similar (42 differentially expressed genes), while strong transcriptomic differences (more than one thousand differentially expressed genes) were observed between the lactating (T1/T2) and non-lactating (T3) mammary glands. A large number of differentially expressed genes were involved in pathways related with the biosynthesis of amino acids, cholesterol, triglycerides and steroids as well as with glycerophospholipid metabolism, adipocytokine signaling, lipid binding, regulation of ion transmembrane transport, calcium ion binding, metalloendopeptidase activity and complement and coagulation cascades. With regard to the second goal of the study, the performance of the GWAS allowed us to detect 24 quantitative trait loci (QTLs), including three genome-wide significant associations: QTL1 (chromosome 2, 130.72-131.01 Mb) for lactose percentage, QTL6 (chromosome 6, 78.90-93.48 Mb) for protein percentage and QTL17 (chromosome 17, 11.20 Mb) for both protein and dry matter percentages. Interestingly, QTL6 shows positional coincidence with the casein genes, which encode 80% of milk proteins.ConclusionsThe abrogation of lactation involves dramatic changes in the expression of genes participating in a broad array of physiological processes such as protein, lipid and carbohydrate metabolism, calcium homeostasis, cell death and tissue remodeling, as well as immunity. We also conclude that genetic variation at the casein genes has a major impact on the milk protein content of Murciano-Granadina goats.
Metabolomic profiling of metoprolol hypertension treatment reveals altered gut microbiota-derived urinary metabolites
Authors: Brocker Chad N. , Velenosi Thomas , Flaten Hania K. , McWilliams Glenn , McDaniel Kyle , Shelton Shelby K. , Saben Jessica , Krausz Kristopher W. , Gonzalez Frank J. , Monte Andrew A. 
Published: March 2020

Abstract
Introduction
Metoprolol succinate is a long-acting beta-blocker prescribed for the management of hypertension (HTN) and other cardiovascular diseases. Metabolomics, the study of end-stage metabolites of upstream biologic processes, yield insight into mechanisms of drug effectiveness and safety. Our aim was to determine metabolomic profiles associated with metoprolol effectiveness for the treatment of hypertension.

Methods
We performed a prospective pragmatic trial (NCT02293096) that enrolled patients between 30 and 80 years with uncontrolled HTN. Patients were started on metoprolol succinate at a dose based upon systolic blood pressure (SBP). Urine and blood pressure measurements were collected weekly. Individuals with a 10% decline in SBP or heart rate (HR) were considered responsive. Genotype for the CYP2D6 enzyme, the primary metabolic pathway for metoprolol, was evaluated for each subject. Unbiased metabolomic analyses were performed on urine samples using UPLC-QTOF mass spectrometry.

Results
Urinary metoprolol metabolite ratios are indicative of patient CYP2D6 genotypes. Patients taking metoprolol had significantly higher urinary levels of many gut microbiota-dependent metabolites including hydroxyhippuric acid, hippuric acid, and methyluric acid. Urinary metoprolol metabolite profiles of normal metabolizer (NM) patients more closely correlate to ultra-rapid metabolizer (UM) patients than NM patients. Metabolites did not predict either 10% SBP or HR decline.

Conclusion
In summary, urinary metabolites predict CYP2D6 genotype in hypertensive patients taking metoprolol. Metoprolol succinate therapy affects the microbiome-derived metabolites.
A comprehensive evaluation of ensemble learning for stock-market prediction
Authors: Nti Isaac Kofi , Adekoya Adebayo Felix , Weyori Benjamin Asubam 
Published: March 2020

AbstractStock-market prediction using machine-learning technique aims at developing effective and efficient models that can provide a better and higher rate of prediction accuracy. Numerous ensemble regressors and classifiers have been applied in stock market predictions, using different combination techniques. However, three precarious issues come in mind when constructing ensemble classifiers and regressors. The first concerns with the choice of base regressor or classifier technique adopted. The second concerns the combination techniques used to assemble multiple regressors or classifiers and the third concerns with the quantum of regressors or classifiers to be ensembled. Subsequently, the number of relevant studies scrutinising these previously mentioned concerns are limited. In this study, we performed an extensive comparative analysis of ensemble techniques such as boosting, bagging, blending and super learners (stacking). Using Decision Trees (DT), Support Vector Machine (SVM) and Neural Network (NN), we constructed twenty-five (25) different ensembled regressors and classifiers. We compared their execution times, accuracy, and error metrics over stock-data from Ghana Stock Exchange (GSE), Johannesburg Stock Exchange (JSE), Bombay Stock Exchange (BSE-SENSEX) and New York Stock Exchange (NYSE), from January 2012 to December 2018. The study outcome shows that stacking and blending ensemble techniques offer higher prediction accuracies (90–100%) and (85.7–100%) respectively, compared with that of bagging (53–97.78%) and boosting (52.7–96.32%). Furthermore, the root means square error (RMSE) recorded by stacking (0.0001–0.001) and blending (0.002–0.01) shows a better fit of ensemble classifiers and regressors based on these two techniques in market analyses compared with bagging (0.01–0.11) and boosting (0.01–0.443). Finally, the results undoubtedly suggest that an innovative study in the domain of stock market direction prediction ought to include ensemble techniques in their sets of algorithms.
Changes in extremely heavy and light snow-cover winters due to global warming over high mountainous areas in central Japan
Authors: Kawase Hiroaki , Yamazaki Takeshi , Sugimoto Shiori , Sasai Takahiro , Ito Rui , Hamada Takashi , Kuribayashi Masatoshi , Fujita Mikiko , Murata Akihiko , Nosaka Masaya , Sasaki Hidetaka 
Published: March 2020

AbstractTo investigate future changes in snow cover and snowfall over mountainous areas in central Japan, we conducted regional climate projections using a high-resolution non-hydrostatic regional climate model (NHRCM) with 5 km and 1 km grid spacings. Boundary conditions are derived from the database for Policy Decision making for Future climate change (d4PDF) 20 km regional climate projections (d4PDF20). The d4PDF20 assumes two future climates when global mean surface air temperatures are approximately 2 K and 4 K warmer than in the preindustrial period. Experiments with 5 km grid spacing are conducted by NHRCM for 372 years in d4PDF20 in each climate. Experiments with 1 km grid spacing are performed focusing on 5 years with heavy, median, and light snow cover of mountainous areas in each climate. In the years with heavy snow cover in 2 K and 4 K warming climates, snowfall is enhanced from late December to February at more than 2000 m above sea level (mASL) in the northern parts of Japan’s Northern Alps, resulting in heavy snow cover comparable to that in the present climate. Heavy daily snowfall remarkably increases due to global warming in the years with heavy snow cover. At low elevations below 500 mASL, snowfall decreases in all ranges of snowfall intensity in the 4 K warming climate, while the frequency of heavy daily snowfall increases in the 2 K warming climate. Precipitation is enhanced around the Japan-Sea Polar-airmass Convergence Zone and the mountainous area facing the Sea of Japan, resulting in strengthened heavy snowfall at high elevations where the winter mean temperature is approximately − 10 °C in the present climate. On the other hand, remarkable reductions in snow cover and snowfall are projected in years with light snow cover. Our results indicate that global warming causes heavy and light mid-winter snowfalls at high elevations of Japan’s Northern Alps that are more extreme than those in the present climate.
Graphical abstract
Epidemiological differences in levels of depressive signs among nocturnal symptoms of insomnia; results from the HUNT study
Authors: Bragantini Daniela , Sivertsen Børge , Gehrman Philip , Lydersen Stian , Güzey Ismail Cüneyt 
Published: March 2020

Abstract
Background
Insomnia is a sleep disorder characterized by multiple nocturnal symptoms (sleep onset, maintenance and terminal insomnia). However, these symptoms are assumed to have the same weight in the diagnosis and consequences of insomnia. In particular, little is known regarding whether these nocturnal symptoms are equally related to depression. In this study, we compared level of depressive signs among individuals reporting different patterns of nocturnal symptoms of insomnia.

Methods
We used data from the large population-based HUNT3 study. The final sample included 7933 individuals (4317 cases, 3616 controls). Signs of depression were measured using the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D), while the three nocturnal symptoms of insomnia were assessed using a Likert-like scale (“Never”, “Sometimes”, “Several times a week”). Individuals reporting to experience at least one symptom of insomnia “Several times a week” were grouped according to their pattern of reported symptoms and their HADS-D levels compared.

Results
Participants reporting sleep onset insomnia combined with terminal insomnia had the highest depression score (M = 5.4, SD = 3.4), but reporting maintenance insomnia in addition does not increase the HADS-D scores any further (M = 5.2, SD = 3.6). Accordingly, sleep maintenance insomnia alone had the lowest score (M = 3.4, SD = 2.9).

Conclusions
We found several differences among patterns of symptoms of insomnia but not all of them are clinically relevant. Further studies in clinical samples may help reveal relevant differences among patterns of symptoms, which may aid in refining interventions for concomitant depression and insomnia.
Statistical significance: p value, 0.05 threshold, and applications to radiomics—reasons for a conservative approach
Authors: Di Leo Giovanni , Sardanelli Francesco 
Published: March 2020

AbstractHere, we summarise the unresolved debate about p value and its dichotomisation. We present the statement of the American Statistical Association against the misuse of statistical significance as well as the proposals to abandon the use of p value and to reduce the significance threshold from 0.05 to 0.005. We highlight reasons for a conservative approach, as clinical research needs dichotomic answers to guide decision-making, in particular in the case of diagnostic imaging and interventional radiology. With a reduced p value threshold, the cost of research could increase while spontaneous research could be reduced. Secondary evidence from systematic reviews/meta-analyses, data sharing, and cost-effective analyses are better ways to mitigate the false discovery rate and lack of reproducibility associated with the use of the 0.05 threshold. Importantly, when reporting p values, authors should always provide the actual value, not only statements of “p < 0.05” or “p ≥ 0.05”, because p values give a measure of the degree of data compatibility with the null hypothesis. Notably, radiomics and big data, fuelled by the application of artificial intelligence, involve hundreds/thousands of tested features similarly to other “omics” such as genomics, where a reduction in the significance threshold, based on well-known corrections for multiple testing, has been already adopted.
A lateral well in the Shublik Formation, Alaska North Slope, with implications for unconventional resource potential
Authors: Hosford Scheirer Allegra , Bird Kenneth J. 
Published: March 2020

Analyses of a horizontal well drilled in the Shublik Formation within the southern part of the Prudhoe Bay field provide the first glimpse of the unit’s potential as an unconventional resource. Drilled in 1996, the 1450 ft (442 m) long well, PBU X-19B L1, targeted the 17 ft (5 m) thick Shublik Zone B. More than 70% of the lateral well path sampled that target, a feat of precise geosteering years before the unconventional revolution. The well operator’s drilling plan focused on the middle subzone of Zone B. The well history ascribes the focus on the middle subzone to its high silt content, open fractures, and significant hydrocarbon shows. Contrary to the drilling narrative, cuttings from 41 intervals indicate that siltstone monotonically decreases in Shublik Zone B, on average, from 50% to 40% to 30% in the three subzones from top to base. The limestone concentration inversely varies with the siltstone concentration through Zone B, steadily increasing from top to base (40%, 50%, and 60%). Hydrocarbon shows in the upper and middle subzones of Zone B range from good to fair, whereas the shows in the lower Zone B are weaker. Unfortunately, scant geochemical analyses of oil produced from the Shublik flow test combined with engineering difficulties prevent a definitive conclusion as to the source of the oil — the fractured Shublik Formation or the underlying Ivishak Sandstone. However, on the basis of favorable lithology, hydrocarbon shows, and fracture density, the upper and middle subzones of Zone B should be targeted as a potential unconventional accumulation if and when a well is drilled in the pod of active source rock downdip.
GDC-0449 in patients with advanced chondrosarcomas: A French Sarcoma Group (FSG)/French and U.S. National Cancer Institutes phase II collaborative study.
Authors: Italiano Antoine , Le Cesne Axel , Cassier Philippe A , Ray-Coquard Isabelle , Domont Julien , Piperno-Neumann Sophie , Duffaud Florence , Penel Nicolas , Takebe Naoko , Blay Jean-Yves , Bui Nguyen Binh 
Published: March 2020

10005 Background: Chondrosarcomas (CS) exhibit a strong activation of hedgehog (Hh) signaling which plays a crucial role in cartilage tumorigenesis. Preclinical data show that hedgehog blockade reduces strongly chondrosarcoma cell proliferation and tumour size. GDC-0449 is a small-molecule antagonist of the Hh pathway. Methods: This is a multicentric single-arm phase 2 clinical trial based on two-stage Simon’s design which assesses safety and efficacy of GDC-0449 in patients (pts) with advanced CS. All pts had to have documented progressive disease (PD) as per RECIST 1.1 before study entry. Pts receive GDC-0449 150mg (oral route), daily until PD or unacceptable toxicity. The primary endpoint is the 6-month non-PD rate according to RECIST. Based on the following hypotheses: 20% 6-month non-PD rate (H0), 40% acceptable 6-month non-PD rate (H1), 10% type I error rate, 90% power, a total of 37 assessable pts are necessary (17 for the first stage + 20 for the second stage). Following the inclusion of the first 17 pts, if ≥ four pts are progression-free at 6 months, the accrual will continue. In order to account for not assessable pts (+/- 10%), 41 pts will be recruited. Accrual started in February 2011 in six centers of the FSG. Results: As of January 24 2012, 40 pts (28 males, 12 females) have been included in the study. Median age is 59 years (30-86). The most frequent histological subtype is conventional CS (n=32). Twenty eight pts (70%) had grade 1 or 2 adverse events (AE) possibly related to the drug whereas 3 pts (7.5%) had grade 3 or 4 AE. The planned interim statistical analysis performed after central histological and radiological review showed that four patients out of the first 17 evaluable patients had stable disease indicating that GDC-0449 had reached the primary endpoint to justify continuing accrual after the 1st step of the study. 15 pts are still on treatment. Molecular analyses are available for 21 pts. No mutation of SMO was detected. qRT-PCR experiments and PTCH sequencing are ongoing. Conclusions: GDC-0449 is well tolerated and shows some activity in a subset of pts with advanced CS. Final clinical and molecular data will be presented at the meeting.
Phase III, placebo-controlled trial (SUCCEED) evaluating ridaforolimus as maintenance therapy in advanced sarcoma patients following clinical benefit from prior standard cytotoxic chemotherapy: Long-term (≥ 24 months) overall survival results.
Authors: Blay Jean-Yves , Chawla Sant P. , Ray-Coquard Isabelle , Cesne Axel Le , Staddon Arthur P. , Milhem Mohammed M. , Penel Nicolas , Riedel Richard F. , Bui Nguyen Binh , Cranmer Lee D. , Reichardt Peter , Bompas Emmanuelle , Alcindor Thierry , Rushing Daniel A. , Song Yang , Ebbinghaus Scot , Haluska Frank G. , Dodion Pierre F. , Demetri George D. 
Published: March 2020

10010 Background: The mammalian target of rapamycin (mTOR) regulates cell growth and proliferation and is abnormally activated in many sarcomas. Ridaforolimus, an oral mTOR inhibitor, demonstrated clinical activity in previous nonrandomized trials in advanced sarcomas following failure of prior chemotherapy. Methods: An international, multicenter, placebo-controlled, phase 3 trial was conducted to evaluate maintenance therapy with ridaforolimus in patients with metastatic soft-tissue or bone sarcomas who achieved disease control from prior chemotherapy. Patients were randomized (1:1) to receive oral ridaforolimus (40 mg) or placebo once daily for 5 days each week. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety and tolerability. For OS, patients were to be followed at 3-month intervals for at least 24 months and up to 60 months after randomization. Results: 702 of 711 randomized patients received treatment. At the time of the data cutoff for OS (386 deaths), patients in the study population had been followed for at least 15 months. Median OS was 93.3 weeks with ridaforolimus vs 83.4 weeks with placebo (hazard ratio [HR]=0.88; 95% confidence interval [CI]: 0.72, 1.08; P=0.23). Ridaforolimus significantly improved PFS vs placebo (HR=0.72; 95% CI: 0.61, 0.85; P=0.0001; median PFS: 17.7 weeks vs 14.6 weeks); PFS improved across all prespecified baseline characteristics. As expected from the class of mTOR inhibitors, the most common adverse events with ridaforolimus were stomatitis, thrombocytopenia, noninfectious pneumonitis, hypertriglyceridemia, hyperglycemia, infections, and rash. Conclusions: Oral ridaforolimus was generally well-tolerated and significantly improved PFS in metastatic sarcoma patients with benefit from prior chemotherapy, offering an effective treatment alternative to surveillance alone. Results of a long-term OS analysis (prespecified to occur at 67% mortality, 24 months minimum follow-up) in the intent-to-treat population will be available in early 2012.
18f-FDG-PET imaging as an early survival predictor in patients with high-grade soft tissue sarcomas undergoing neoadjuvant therapy.
Authors: Herrmann Ken , Benz Matthias R. , Czernin Johannes , Auerbach Martin , Tap William D. , Dry Sarah M , Schuster Tibor , Eckardt Jeff J. , Phelps Michael E. , Eilber Frederick C. 
Published: March 2020

10012 Background: Neoadjuvant therapy is associated with considerable toxicity and limited survival benefits in patients with soft tissue sarcoma (STS). We prospectively evaluated whether 18F-FDG PET/CT (PET) imaging after the initial cycle and after end of neoadjuvant therapy could predict overall survival in these patients. Methods: 76 patients (primary STS: n=57; metastatic disease: n=19) with high grade STS were included in this study. PET was performed prior to (n=76), after one cycle (n=52) and after the end of neoadjuvant therapy (n=74). Overall survival was correlated with changes of SUVpeak, RECIST, histopathological response and other parameters predictive of STS survival. Results: One-, two- and five- year survival rates were 95±3.0%, 86±4.6% and 68±6.6% for primary STS. Corresponding one- and two- year survival rates for recurrent/metastatic STS were 77±10.0% and 47±12.1%. Optimal cut-off for early decreases in SUV peak were significant predictors of survival in log-rank test (p=0.027 and p=0.043). However, late decreases in SUV peak were only predictive in primary STS (SUV peak decrease 57%; p=0.035) but not in recurrent/metastatic STS (SUV peak decrease 52%; p=0.057). In primary STS, 7/15 early PET non-responders but only 4/24 early PET responders died during follow up (p=0.068). Conclusions: 18F-FDG-PET seems feasible to predict survival after the initial cycle of neoadjuvant chemotherapy in both patients with primary STS and recurrent/metastatic STS and can potentially serve as an intermediate endpoint biomarker in clinical research and patient care.
Growth modulation index (GMI) as a metric of clinical benefit assessment among advanced soft tissue sarcoma (ASTS) patients receiving trabectedin as salvage therapy.
Authors: Penel Nicolas , Demetri George D. , Blay Jean-Yves , Cousin Sophie , Maki Robert G. , Chawla Sant P. , Judson Ian Robert , von Mehren Margaret , Schoffski Patrick , Verweij Jaap , Casali Paolo Giovanni , Rodenhuis Sjoerd , Gomez Javier , Nieto Antonio , Zintl Patrik , Pontes Valero Maria Jose , Cassar Alexia , Le Cesne Axel 
Published: March 2020

10013 Background: Von Hoff has proposed GMI >1.33 in cancer clinical trials as a sign of drug activity. GMI is the ratio between time to progression (TTP) with the nth line (TTPn) of therapy divided by the TTPn-1 with the n-1th line of therapy. With this endpoint, each patient is his/her own control. Methods: We have carried out a retrospective analysis of 279 pretreated ASTS patients treated in four consecutive phase II trials with trabectedin 1.5 mg/m², given as a 24-hour infusion every 3 weeks. Results: The study population consisted of 170 women and 109 men with a median age of 52. The two most common histologies were leiomyosarcoma (145 patients, 52%) and liposarcoma (59, 21%). 142 (51%) patients received one prior line and 137 (49%) ≥2 lines. The median TTPn was 2.8 months (range: 0.2-26.8), whereas the median TTPn-1 was 4.0 months (range: 0.3-79.5). The Spearman correlation coefficient between TTPn-1 and TTPn was 0.07 (p=0.23). The median GMI was 0.6 (range: 0.0-14.4). 177 patients (63%) had a GMI <1, 21 (8%) a GMI = 1-1.33 and 81 (29%) a GMI >1.33. The median overall survival (OS) strongly correlated with GMI groups: OS was 9.1, 13.9 and 23.8 months, respectively (p=0.0005, log-rank test). There were also a strong correlations between response rate and GMI (p<0.0001, Fisher exact test), and between GMI and progression-free survival (<0.0001, log-rank test). The logistic regression analysis retained only performance status (PS) [OR=1.76 if PS=0; p<0.04] associated with GMI>1.33. Sarcoma grade (p=0.21), histological subtype (p=0.16), and number of prior chemotherapy lines (p=0.95) were not associated with GMI>1.33. Conclusions: Overall,≈30% of patients experienced GMI>1.33 regardless of histological subtype or grade, and number of prior lines of chemotherapy. Patients with PS=0 benefit more from trabectedin. GMI>1.33 is associated with longer OS (median ≈24 months). GMI is better defined than previously described parameter such as "Tumor Growth Rate" (Lopez-Martin, Abstract 3293, ASCO 2003). GMI as an indicator of drug activity merits further exploration in this setting.