bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vitamin D levels were significantly higher during and after lifestyle intervention in pregnancy: A randomized controlled trial
Authors: Tanvig Mette H. , Jensen Dorte M. , Andersen Marianne S. , Ovesen Per G. , Jørgensen Jan S. , Vinter Christina A. 
Published: August 2019

AbstractIntroductionVitamin D deficiency is common in pregnancy, especially in obese women. Lifestyle intervention could potentially result in higher levels of vitamin D. We therefore aimed to study the effect of lifestyle intervention during pregnancy on serum levels of 25‐hydroxyvitamin D (25(OH)D).Material and methodsA total of 360 obese women were randomized before gestational age 14 weeks to lifestyle intervention (diet and exercise) or routine clinical follow up (controls). Clinical outcomes and levels of 25(OH)D were determined three times: At gestational age 12‐15 weeks (baseline), gestational age 28‐30 weeks and 6 months postpartum.ResultsA total of 304 (84%) women completed the intervention study and 238 (66%) attended postpartum follow up. Vitamin D levels were similar in the two groups at baseline. At gestational age 28‐30 weeks and 6 months postpartum, 25(OH)D levels were significantly higher in the intervention group than in controls (75.6 vs 66.8 nmol/L, P = 0.009) and (54.8 vs 43.1 nmol/L, P = 0.013), respectively. Concurrently, vitamin D deficiency (25‐hydroxyvitamin D <50 nmol/L) was less frequent in the intervention group than in controls: 15 vs 25% (P = 0.038) at gestational age 28‐30 and 45 vs 63% (P = 0.011) 6 months postpartum, respectively.ConclusionsLifestyle intervention during pregnancy was associated with significantly increased vitamin D levels in late pregnancy and postpartum compared with controls.
Impact of restricting feed and probiotic supplementation on growth performance, mortality and carcass traits of meat‐type quails
Authors: Soomro Rab N. , Abd El‐Hack Mohamed E. , Shah Syed S. , Taha Ayman E. , Alagawany Mahmoud , Swelum Ayman A. , Hussein Elsayed O.S. , Ba‐Aawdh Hani A. , Saadeldin Islam , El‐Edel Mohamed A. , Tufarelli Vincenzo 
Published: August 2019

AbstractThe objective of this study was to evaluate the effects of quantitative feed restriction, along with dietary supplementation with a probiotic blend (Protexin) as a natural growth promoter, on the performance, water consumption, mortality rate and carcass traits of meat‐type quails. A total of 250 1‐day unsexed quails were randomly allocated to five equal groups in a completely randomized design. The first group (A) fed a basal diet without any restriction (24 hr/day); the second group (B1) fed the basal diet for 20 hr/day; the third group (B2) fed the basal diet enriched with probiotic (0.1 g/kg diet) for 20 hr/day; the fourth group (C1) fed the basal diet for 16 hr/day; and the fifth group (C2) fed the basal diet enriched with probiotic (0.1 g/kg diet) for 16 hr/day. Birds were fed ad‐libitum from 0–14 days of age, and then the feed restriction regimes started from 14 till 28 days of age. Results showed that quails in the control‐group consumed more feed and water than the other treatment groups (p < .01), however their body weights did not differ (p > .05) compared with the other treated groups. The best feed conversion values were achieved in quails supplemented with probiotic blend (B2 and C2) in comparison with the other groups (p < .01). Feeding probiotic had a positive effect on bird health which reduced the mortality rate. Further, mortality rate was significantly reduced (p < .05) by feed restriction, with or without probiotic supplementation. No carcass parameters were significantly affected (p > .05) by treatments. Our results show that quail could be reared under a feed restriction system, for 4–8 hr daily, along with dietary supplementation of probiotic as growth promoter for better growth performance.
An examination of the quality and performance of the Alda scale for classifying lithium response phenotypes
Authors: Scott Jan , Etain Bruno , Manchia Mirko , Brichant‐Petitjean Clara , Geoffroy Pierre A. , Schulze Thomas , Alda Martin , Bellivier Frank ,   ConLiGen collaborators
Published: August 2019

AbstractObjectivesThe Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale) is the most widely used clinical measure of lithium response phenotypes. We assess its performance against recommended psychometric and clinimetric standards.MethodsWe used data from the Consortium for Lithium Genetics and a French study of lithium response phenotypes (combined sample >2500) to assess reproducibility, responsiveness, validity, and interpretability of the A scale (assessing change in illness activity), the B scale, and its items (assessing confounders of response) and the previously established response categories derived from the Total Score for the Alda scale.ResultsThe key findings are that the B scale is vulnerable to error measurement. For example, some items contribute little to overall performance of the Alda scale (eg, B2) and that the B scale does not reliably assess a single construct (uncertainty in response). Machine learning models indicate that it may be more useful to employ an algorithm for combining the ratings of individual B items in a sequence that clarifies the noise to signal ratio instead of using a composite score.ConclusionsThis study highlights three important topics. First, empirical approaches can help determine which aspects of the performance of any scale can be improved. Second, the B scale of the Alda is best applied as a multidimensional index (identifying several independent confounders of the assessment of response). Third, an integrated science approach to precision psychiatry is vital, otherwise phenotypic misclassifications will undermine the reliability and validity of findings from genetics and biomarker studies.
Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease
Authors: Ohm Daniel T. , Fought Angela J. , Rademaker Alfred , Kim Garam , Sridhar Jaiashre , Coventry Christina , Gefen Tamar , Weintraub Sandra , Bigio Eileen , Mesulam Marek Marsel , Rogalski Emily , Geula Changiz 
Published: August 2019

AbstractThe neuropathologic basis of in vivo cortical atrophy in clinical dementia syndromes remains poorly understood. This includes primary progressive aphasia (PPA), a language‐based dementia syndrome characterized by asymmetric cortical atrophy. The neurofibrillary tangles (NFTs) and amyloid‐ß plaques (APs) of Alzheimer's disease (AD) can cause PPA, but a quantitative investigation of the relationships between NFTs, APs and in vivo cortical atrophy in PPA‐AD is lacking. The present study measured cortical atrophy from corresponding bilateral regions in five PPA‐AD participants with in vivo magnetic resonance imaging scans 7–30 months before death and acquired stereologic estimates of NFTs and dense‐core APs visualized with the Thioflavin‐S stain. Linear mixed models accounting for repeated measures and stratified by hemisphere and region (language vs. non‐language) were used to determine the relationships between cortical atrophy and AD neuropathology and their regional selectivity. Consistent with the aphasic profile of PPA, left language regions displayed more cortical atrophy (P = 0.01) and NFT densities (P = 0.02) compared to right language homologues. Left language regions also showed more cortical atrophy (P < 0.01) and NFT densities (P = 0.02) than left non‐language regions. A subset of data was analyzed to determine the predilection of AD neuropathology for neocortical regions compared to entorhinal cortex in the left hemisphere, which showed that the three most atrophied language regions had greater NFT (P = 0.04) and AP densities (P < 0.01) than the entorhinal cortex. These results provide quantitative evidence that NFT accumulation in PPA selectively targets the language network and may not follow the Braak staging of neurofibrillary degeneration characteristic of amnestic AD. Only NFT densities, not AP densities, were positively associated with cortical atrophy within left language regions (P < 0.01) and right language homologues (P < 0.01). Given previous findings from amnestic AD, the current study of PPA‐AD provides converging evidence that NFTs are the principal determinants of atrophy and clinical phenotypes associated with AD.
Connexin32 ameliorates renal fibrosis in diabetic mice by promoting K48‐linked NADPH oxidase 4 polyubiquitination and degradation
Authors: Chen Zhiquan , Sun Xiaohong , Chen Qiuhong , Lan Tian , Huang Kaipeng , Xiao Haiming , Lin Zeyuan , Yang Yan , Liu Peiqing , Huang Heqing 
Published: August 2019

Background and PurposeNox4 is the major isoform of NADPH oxidase found in the kidney and contributes to the pathogenesis of diabetic nephropathy. However, the molecular mechanisms of increased Nox4 expression induced by hyperglycaemia remain to be elucidated. Here, the role of the connexin32–Nox4 signalling axis in diabetic nephropathy and its related mechanisms were investigated.Experimental ApproachDiabetes was induced in mice by low‐dose streptozotocin (STZ) combined with a high‐fat diet. Effects of connexin32 on Nox4 expression and on renal function and fibrosis in STZ‐induced diabetic mice were investigated using adenovirus‐overexpressing connexin32 and connexin32‐deficient mice. Interactions between connexin32 and Nox4 were analysed by co‐immunoprecipitation and immunofluorescence assays.Key ResultsConnexin32 was down‐regulated in the kidneys of STZ‐induced diabetic mice. Overexpression of connexin32 reduced expression of Nox4 and improved renal function and fibrosis in diabetic mice, whereas connexin32 deficiency had opposite effects. Down‐regulation of fibronectin expression by connexin32 was not dependent on gap junctional intercellular communication involving connexin32. Connexin32 interacted with Nox4 and reduced the generation of hydrogen peroxide, leading to the down‐regulation of fibronectin expression. Mechanistically, connexin32 decreased Nox4 expression by promoting its K48‐linked polyubiquitination. Interestingly, Smurf1 overexpression inhibited K48‐linked polyubiquitination of Nox4. Furthermore, connexin32 interacted with Smurf1 and inhibited its expression.Conclusion and ImplicationsConnexin32 ameliorated renal fibrosis in diabetic mice by promoting K48‐linked Nox4 polyubiquitination and degradation via inhibition of Smurf1 expression. Targeting the connexin32–Nox4 signalling axis may contribute to the development of novel treatments for diabetic nephropathy.
SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met) antibody‐drug conjugate, overcomes AZD9291 resistance in non‐small cell lung cancer cells overexpressing c‐Met
Authors: Tong Mengya , Gao Mingzhao , Xu Yongping , Fu Li , Li Yun , Bao Xubin , Fu Haoyu , Quan Haitian , Lou Liguang 
Published: August 2019

AbstractEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been used as the first‐line treatment of non‐small cell lung cancers (NSCLC) harboring EGFR‐activating mutations, but acquired resistance is ubiquitous and needs to be solved urgently. Here, we introduce an effective approach for overcoming resistance to the EGFR‐TKI, AZD9291, in NSCLC cells using SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met)‐targeting antibody‐drug conjugate (ADC) consisting of an anti‐c‐Met monoclonal antibody (c‐Met mAb) conjugated to a microtubule inhibitor. Resistant cells were established by exposing HCC827 to increasing concentrations of EGFR‐TKI. c‐Met was found to be overexpressed in most resistant cells. AZD9291 resistance was partially restored by combination of AZD9291 and crizotinib only in resistant cells overexpressing phospho‐c‐Met, which synergistically inhibited c‐Met‐mediated phosphorylation of the downstream targets ERK1/2 and AKT. In resistant cells overexpressing c‐Met, neither crizotinib nor c‐Met mAb was able to overcome AZD9291 resistance. In contrast, SHR‐A1403 strongly inhibited proliferation of AZD9291‐resistant HCC827 overexpressing c‐Met, regardless of the levels of c‐Met phosphorylation. SHR‐A1403 bound to resistant cells overexpressing c‐Met was internalized into cells and released associated microtubule inhibitor, resulting in cell‐killing activity that was dependent on c‐Met expression levels only, irrespective of the involvement of c‐Met or EGFR signaling in AZD9291 resistance. Consistent with its activity in vitro, SHR‐A1403 significantly inhibited the growth of AZD9291‐resistant HCC827 tumors and caused tumor regression in vivo. Thus, our findings show that SHR‐A1403 efficiently overcomes AZD9291 resistance in cells overexpressing c‐Met, and further indicate that c‐Met expression level is a biomarker predictive of SHR‐A1403 efficacy.
Targeted exosome‐encapsulated erastin induced ferroptosis in triple negative breast cancer cells
Authors: Yu Mengyu , Gai Chengcheng , Li Zihaoran , Ding Dejun , Zheng Jie , Zhang Weifen , Lv Shijun , Li Wentong 
Published: August 2019

AbstractFerroptosis is an iron‐dependent, lipid peroxide‐driven cell death caused by inhibition of the cystine/glutamate transporter, which is of importance for the survival of triple‐negative breast cancer (TNBC) cells. Erastin is a low molecular weight chemotherapy drug that induces ferroptosis; however, poor water solubility and renal toxicity have limited its application. Exosomes, as drug delivery vehicles with low immunogenicity, high biocompatibility and high efficiency, have attracted increasing attention in recent years. Herein, we developed a formulation of erastin‐loaded exosomes labeled with folate (FA) to form FA‐vectorized exosomes loaded with erastin (erastin@FA‐exo) to target TNBC cells with overexpression of FA receptors. The characterization, drug release, internalization and anti–tumor effect in vitro of erastin@FA‐exo were determined. Erastin@FA‐exo could increase the uptake efficiency of erastin into MDA‐MB‐231 cells; compared with erastin@exo and free erastin, erastin@FA‐exo has a better inhibitory effect on the proliferation and migration of MDA‐MB‐231 cells. Furthermore, erastin@FA‐exo promoted ferroptosis with intracellular depletion of glutathione and reactive oxygen species overgeneration. Western blot analyses revealed that erastin@FA‐exo suppressed expression of glutathione peroxidase 4 (GPX4) and upregulated expression of cysteine dioxygenase (CDO1). We conclude that targeting and biocompatibility of exosome‐based erastin preparations provide an innovative and powerful delivery platform for anti–cancer therapy.
Use of mycophenolate mofetil and azathioprine for the treatment of chronic hypersensitivity pneumonitis—A single‐centre experience
Authors: Fiddler Christine A. , Simler Nicky , Thillai Muhunthan , Parfrey Helen 
Published: August 2019

AbstractIntroductionThe optimal pharmacological management of chronic hypersensitivity pneumonitis (cHP) is unknown. Corticosteroids are often used as first line therapy but can be associated with side effects. There is a paucity of data examining the role of steroid‐sparing agents in cHP. We aimed to determine the effect of mycophenolate mofetil (MMF) and azathioprine (AZA) on lung function and prednisolone dose in cHP patients.MethodsRetrospective analysis of patients initiated on either MMF or AZA following a multidisciplinary team diagnosis of cHP. Changes in lung function and prednisolone dose up to 12 months before and after MMF/AZA initiation were analysed.ResultsTwenty two out of 30 patients remained on treatment at 12 months (18 MMF, 4 AZA). Steroid‐sparing therapy resulted in a significant reduction in prednisolone dose from 16.2 ± 9.7 to 8.2 ± 4.2 mg daily (P = 0.002). Treatment with MMF or AZA for 12 months was associated with a significant improvement in carbon monoxide diffusing capacity (TLCO) (−0.55 ± 0.96 vs. +0.31 ± 0.58 mmol/kPa/min, P = 0.02). Although treatment reduced the rate of forced vital capacity decline (−111 ± 295 vs. +2.3 ± 319 mL), it was not significant (P = 0.22).ConclusionMMF or AZA therapy in cHP is associated with an improvement in TLCO and reduction in prednisolone dose. There is a need for prospective trials.
GDF‐15 in solid vs non‐solid treatment‐naïve malignancies
Authors: Arfsten Henrike , Cho Anna , Freitag Claudia , Raderer Markus , Goliasch Georg , Bartko Philipp E. , Wurm Raphael , Strunk Guido , Gisslinger Heinz , Marosi Christine , Kornek Gabriela , Zielinski Christoph , Hülsmann Martin , Pavo Noemi 
Published: August 2019

AbstractAimGDF‐15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF‐15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF‐15 to other cardiac biomarkers and the general association of GDF‐15 on prognosis in an unselected cohort of treatment‐naïve cancer patients.MethodsWe prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF‐15 concentrations were determined alongside other cardiac and routine laboratory markers. All‐cause mortality was defined as primary endpoint.ResultsGDF‐15 levels were 338 ng/L (IQR:205‐534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF‐15 [435 ng/L (IQR:279‐614) vs 266 ng/L (IQR:175‐427), P < .001]. GDF‐15 correlated positively with inflammatory status reflected by CRP, SAA and IL‐6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NT‐proBNP, hsTnT, MR‐proADM and CT‐proET‐1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF‐15 was significantly associated with all‐cause mortality after multivariate adjustment [adj.HR for ln(GDF‐15) 1.78, 95%CI:1.47‐2.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF‐15 with outcome in myelodysplastic and myeloproliferative disease.ConclusionsElevated plasma GDF‐15 is associated with progressing disease severity and poor prognosis in solid tumours of treatment‐naïve cancer patients. GDF‐15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF‐15 represents a promising target for our pathophysiologic understanding in cardio‐oncology linking conditions of both cardiac and neoplastic disease.
Allogeneic stem cell transplantation in patients with myelofibrosis harboring the MPL mutation
Authors: Mannina Daniele , Gagelmann Nico , Badbaran Anita , Ditschkowski Markus , Bogdanov Rashit , Robin Marie , Cassinat Bruno , Heuser Michael , Shahswar Rabia , Thol Felicitas , Beelen Dietrich , Kröger Nicolaus 
Published: August 2019

AbstractIntroductionPrimary and post‐ET/PV myelofibrosis are myeloproliferative neoplasms harboring in most cases driving mutations in JAK2, CALR or MPL, and a variable number of additional mutations in other genes. Molecular analysis represents a powerful tool to guide prognosis and clinical management. Only about 10% of patients with myelofibrosis harbor alterations in MPL gene. No data are available about the transplantation outcome in the specific MPL‐mutated group.PatientsWe collected the data of 18 myelofibrosis patients(primary: 14; post‐ET: 4) transplanted in 4 EBMT centers (Hamburg, Paris, Essen, and Hannover) between 2005 and 2016.ResultsBefore the transplant, we explored the molecular profile by NGS and reported the frequency of mutations occurring in a panel of genes including JAK2, MPL, CALR, U2AF1, SRSF2, SF3B1, ASXL1, IDH1, IDH2, CBL, DNMT3A, TET2, EZH2, TP53, IKZF1, NRAS, KRAS, FLT3, SH2B3, and RUNX1. The 1‐year transplant‐related mortality was 16.5%, 5‐years overall survival and 5‐y relapse‐free survival 83.5%. The only relapse occurred in a patient who harbored mutations in both ASXL1 and EZH2 genes.ConclusionThese retrospective data suggest that MPL‐mutated myelofibrosis patients have a favorable outcome after allogeneic transplantation with very low rate of disease relapse (5.5%) in comparison with the available historical controls regarding myelofibrosis in all.
Gender difference in the effect of uric acid on striatal dopamine in early Parkinson's disease
Authors: Oh Y. ‐S. , Kim J. ‐S. , Yoo S. ‐W. , Hwang E. ‐J. , Lyoo C. H. , Lee K. ‐S. 
Published: August 2019

Background and purposeHigh uric acid (UA) levels have been shown to exert a neuroprotective effect in Parkinson's disease (PD) by inhibiting oxidative stress in the nigrostriatal pathway. However, the association between striatal dopamine activity and UA level has not been clarified.MethodsA total of 213 patients with early PD were enrolled. All patients underwent positron emission tomography using 18F‐N‐(3‐fluoropropyl)‐2beta‐carbon ethoxy‐3beta‐(4‐iodophenyl) nortropane and a venous blood test for quantification of serum UA. All patients were stratified into either the lower UA group or the higher UA group using the median UA level. After normalizing the positron emission tomography images, differences in the regional standardized uptake value ratios (SUVRs) were analyzed with a volume‐of‐interest template. All tested SUVRs were also compared after categorizing patients by gender.ResultsThe UA affected dopamine transporter SUVRs in different ways by gender. In female patients, the higher UA level group showed a smaller reduction in dopamine transporter uptake in the posterior putamen, whereas there was no such association observed in male patients.ConclusionsHigher UA levels were correlated with higher dopamine transporter uptake in the putamen in female patients with early PD. This finding suggests that UA has a neuroprotective effect, as demonstrated by the relatively preserved striatal dopamine activity in women.
Novel signals of adaptive genetic variation in northwestern Atlantic cod revealed by whole‐genome sequencing
Authors: Clucas Gemma V. , Lou R. Nicolas , Therkildsen Nina O. , Kovach Adrienne I. 
Published: August 2019

AbstractSelection can create complex patterns of adaptive differentiation among populations in the wild that may be relevant to management. Atlantic cod in the Northwest Atlantic are at a fraction of their historical abundance and a lack of recovery within the Gulf of Maine has created concern regarding the misalignment of fisheries management structures with biological population structure. To address this and investigate genome‐wide patterns of variation, we used low‐coverage sequencing to perform a region‐wide, whole‐genome analysis of fine‐scale population structure. We sequenced 306 individuals from 20 sampling locations in U.S. and Canadian waters, including the major spawning aggregations in the Gulf of Maine in addition to spawning aggregations from Georges Bank, southern New England, the eastern Scotian Shelf, and St. Pierre Bank. With genotype likelihoods estimated at almost 11 million loci, we found large differences in haplotype frequencies of previously described chromosomal inversions between Canadian and U.S. sampling locations and also among U.S. sampling locations. Our whole‐genome resolution also revealed novel outlier peaks, some of which showed significant genetic differentiation among sampling locations. Comparisons between allochronic winter‐ and spring‐spawning populations revealed highly elevated relative (FST) and absolute (dxy) genetic differentiation near genes involved in reproduction, particularly genes associated with the brain‐pituitary‐gonadal axis, which likely control timing of spawning, contributing to prezygotic isolation. We also found genetic differentiation associated with heat shock proteins and other genes of functional relevance, with complex patterns that may point to multifaceted selection pressures and local adaptation among spawning populations. We provide a high‐resolution picture of U.S. Atlantic cod population structure, revealing greater complexity than is currently recognized in management. Our genome‐scan approach likely underestimates the full suite of adaptive differentiation among sampling locations. Nevertheless, it should inform the revision of stock boundaries to preserve adaptive genetic diversity and evolutionary potential of cod populations.