bluuebunny/crossref_metadata_2025_split huggingface dataset:
ATR‐101 inhibits cholesterol efflux and cortisol secretion by ATP‐binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells
Authors: Burns Veronica Elizabeth , Kerppola Tom Klaus 
Published: July 2017

AbstractBackground and PurposeTo further the development of new agents for the treatment of adrenocortical carcinoma (ACC), we characterized the molecular and cellular mechanisms of cytotoxicity by the adrenalytic compound ATR‐101 (PD132301‐02).Experimental ApproachWe compared the effects of ATR‐101, PD129337, and ABC transporter inhibitors on cholesterol accumulation and efflux, on cortisol secretion, on ATP levels, and on caspase activation in ACC‐derived cell lines. We examined the effects of these compounds in combination with methyl‐β‐cyclodextrin or exogenous cholesterol to determine the roles of altered cholesterol levels in the effects of these compounds.Key ResultsATR‐101 caused cholesterol accumulation, ATP depletion, and caspase activation within 30 minutes after addition to ACC‐derived cells, whereas PD129337 did not. Suppression of cholesterol accumulation by methyl‐β‐cyclodextrin or exogenous cholesterol, prevented ATP depletion and caspase activation by ATR‐101. ATR‐101 blocked cholesterol efflux and cortisol secretion, suggesting that it inhibited ABCA1, ABCG1, and MDR1 transporters. Combinations of ABCA1, ABCG1, and MDR1 inhibitors were also cytotoxic. Combinations of ATR‐101 with inhibitors of ABCG1, MDR1, or mitochondrial functions had increased cytotoxicity. Inhibitors of steroidogenesis reduced ATP depletion by ATR‐101, whereas U18666A enhanced cholesterol accumulation and ATP depletion together with ATR‐101. ATR‐101 repressed ABCA1, ABCG1, and IDOL transcription by mechanisms that were distinct from the mechanisms that caused cholesterol accumulation.Conclusions and ImplicationsInhibition of multiple ABC transporters and the consequent accumulation of cholesterol mediated the cytotoxicity of ATR‐101. Compounds that replicate these effects in tumours are likely to be useful in the treatment of ACC.
Food allergy phenotypes: The key to personalized therapy
Authors: Deschildre A. , Lejeune S. , Cap M. , Flammarion S. , Jouannic L. , Amat F. , Just J. 
Published: July 2017

SummaryFood allergies (FAs) are of increasing public health concern and are characterized by a large spectrum of diseases. Their diversity is well known for immunologic pathways (IgE, non‐IgE‐mediated FAs) and natural history. Many other factors and patient characteristics are involved including type of food, exposure route, allergic comorbidities, gender, racial and ethnic backgrounds, cofactors and health conditions. Food allergen components and sensitization profiles are also involved in FA phenotypes. A new approach to chronic disorders based on the identification of phenotypes through extensive knowledge of all the complex components is also applicable to FAs and could lead towards integrative care management. Diagnostic biomarkers for FAs are emerging which also contribute to better care modalities. The aim of this article was to highlight current knowledge regarding the phenotypic diversity of FA. This review will focus on IgE‐mediated FAs and how identifying phenotypes may help to better understand the pathophysiological complexity, improve diagnosis and lead to personalized treatment strategies.
6-Mercaptopurine modifies cerebrospinal fluid T cell abnormalities in paediatric opsoclonus–myoclonus as steroid sparer
Authors: Pranzatelli M R , Tate E D , Allison T J 
Published: July 2017

Summary
The purpose of this study was to evaluate the capacity of 6-mercaptopurine (6-MP), a known immunosuppressant, to normalize cerebrospinal fluid (CSF) lymphocyte frequencies in opsoclonus–myoclonus syndrome (OMS) and function as a steroid sparer. CSF and blood lymphocytes were immunophenotyped in 11 children with OMS (without CSF B cell expansion) using a comprehensive panel of cell surface adhesion, activation and maturation markers by flow cytometry, and referenced to 18 paediatric controls. Drug metabolites, lymphocyte counts and liver function tests were used clinically to monitoring therapeutic range and toxicity. In CSF, adjunctive oral 6-MP was associated with a 21% increase in the low percentage of CD4+ T cells in OMS, restoring the CD4/CD8 ratio. The percentage of CD4+ T cells that were interferon (IFN)-γ+ was reduced by 66%, shifting the cytokine balance away from T helper type 1 (Th1) (proinflammatory) predominance. The percentage of natural killer (NK) cells decreased significantly in CSF (–32%) and blood (–67 to −82%). Low blood absolute lymphocyte count was more predictive of improvement in CSF lymphocyte proportions (correlated with % CD4+ T cells) than the 6-thioguanine level (no correlation). 6-MP was difficult to titrate: 50% achieved the target absolute lymphocyte count (&lt; 1·5 K/mm); 20%, the ‘therapeutic’ 6-thioguanine level; and 40% the non-toxic 6-methylmercaptopurine level. Side effects and transaminase elevation were mild and reversible. Clinical steroid-sparing properties and lowered relapse frequency were demonstrated. 6-MP displayed unique pharmacodynamic properties that may be useful in OMS and other autoimmune disorders. Its steroid sparer capacity is limited to children in whom the therapeutic window can be reached without limiting pharmacokinetic factors or side effects.
Clinical features and mutation spectrum in Chinese patients with CADASIL: A multicenter retrospective study
Authors: Chen Sheng , Ni Wang , Yin Xin‐Zhen , Liu Han‐Qiu , Lu Cong , Zheng Qiao‐Juan , Zhao Gui‐Xian , Xu Yong‐Feng , Wu Lei , Zhang Liang , Wang Ning , Li Hong‐Fu , Wu Zhi‐Ying 
Published: July 2017

SummaryAimTo characterize clinical features and mutation spectrum in Chinese patients with CADASIL.MethodsWe collected 261 clinically suspected Chinese CADASIL patients from three hospitals located in different regions of China. Sanger sequencing is performed to screen the exons 2 to 24 of NOTCH3 gene. Clinical and genetic data were retrospectively studied. Haplotype analyses were performed in patients carrying p.Arg544Cys and p.Arg607Cys, respectively.ResultsA total of 214 patients were finally genetically diagnosed as CADASIL, with 45 known NOTCH3 mutations and a novel c.1817G>T mutation. We found that patients carrying p.Arg607Cys or p.Arg544Cys mutation located in exon 11 occupied nearly 35% in our mutation spectrum. In retrospectively study of clinical data, we found a higher number of patients having cognitive impairment and a lower number of patients having migraine with aura. Furthermore, we identified that patients carrying mutations in exon 11 seemed to experience a later disease onset (p=6.8×10−5). Additionally, a common haplotype was found in patients from eastern China carrying p.Arg607Cys, and the patients from Fujian carrying p.Arg544Cys shared the same haplotype with patients from Taiwan carrying p.Arg544Cys.ConclusionsThese findings broaden the mutational and clinical spectrum of CADASIL and provide additional evidences for the existence of founder effect in CADASIL patients.
Association between thyroid dysfunction and dysglycaemia: a prospective cohort study
Authors: Chang C.‐H. , Yeh Y.‐C. , Shih S.‐R. , Lin J.‐W. , Chuang L.‐M. , Caffrey J. L. , Tu Y.‐K. 
Published: July 2017

AbstractAimsTo compare the incidence of hyperglycaemia among participants with low, elevated and normal serum thyroid‐stimulating hormone concentration, as well as the incidence of abnormal thyroid function test results among participants with normal blood glucose and those with hyperglycaemia.MethodsIn a prospective study, a cohort of 72 003 participants with normal, low and elevated serum thyroid‐stimulating hormone concentration were followed from the study beginning to the first report of diabetes and prediabetes. A proportional hazards regression model was used to calculate the hazard ratios and 95% CIs for each outcome, adjusting for age, sex, education level, smoking, alcohol consumption and obesity. Analyses for the association between dysglycaemia and incident abnormal thyroid function test were also conducted.ResultsDuring a median 2.6 year follow‐up, the incident rates for dysglycaemia, particularly prediabetes, were substantially higher in participants with elevated thyroid‐stimulating hormone concentrations at baseline, while the rates for participants with normal and low thyroid‐stimulating hormone were similar. After controlling for risk factors, participants with elevated thyroid‐stimulating hormone retained a 15% increase in risk of prediabetes (adjusted hazard ratio 1.15, 95% CI 1.04–1.26), but were not at greater risk of diabetes (adjusted hazard ratio 0.96, 95% CI 0.64–1.44). By contrast, participants with normal and low thyroid‐stimulating hormone concentrations had similar dysglycaemia risks. Participants with diabetes and prediabetes were not at greater risks of developing abnormal thyroid function test results when compared with participants with euglycaemia.ConclusionsPeople with elevated serum thyroid‐stimulating hormone concentration are at greater risk of developing prediabetes. Whether this includes a greater risk of developing frank diabetes may require an extended period of follow‐up to clarify.
Fracture of the medial intercondylar eminence of the tibia in horses treated by arthroscopic fragment removal (21 horses)
Authors: Rubio‐Martínez L. M. , Redding W. R. , Bladon B. , Wilderjans H. , Payne R. J. , Tessier C. , Geffroy O. , Parker R. , Bell C. , Collingwood F. A. 
Published: July 2017

SummaryBackgroundFractures of the medial intercondylar eminence of the tibia (MICET) are scarcely reported in horses.ObjectivesTo report the clinical and diagnostic findings, surgical treatment and outcome in a series of horses presented withMICETfracture and treated with arthroscopic fragment removal.Study designMulticentre retrospective case series.MethodsCase records of horses diagnosed withMICETfractures that had undergone surgical treatment were reviewed. Follow‐up information was obtained from re‐examination visits and/or owners.ResultsTwenty‐one cases were identified at 9 equine hospitals between 2004 and 2016. A history of trauma and acute onset of lameness was reported in 12 horses. All cases underwent fracture removal via arthroscopy of the medial femorotibial joint. The cranial cruciate ligament was intact in 6 horses and damaged in 15 horses (damage was ≤25% [n = 9], 25–50% [n = 4] or ≥50% [n = 2] of the cross‐sectional area). The cranial ligament of the medial meniscus was damaged in 11 horses (≤25% [n = 8], 25–50% [n = 3]). The medial meniscus was damaged in 5 horses and articular cartilage damage was identified in 14 horses (mild [n = 8], moderate [n = 6]). Follow‐up information (median 14 months; 4 months–6 years) was available for 20 cases; 2 horses were sound but convalescing; 13 horses were sound and returned to their previous or expected use. Of the 4 horses with the most severe changes to the articular soft tissue structures, 2 remained lame and 2 were subjected to euthanasia because of persistent lameness.Main limitationsThe retrospective, multicentre nature of this study and the limited number of horses are the main limitations.ConclusionsFractures of theMICETare commonly associated with a traumatic event. Prompt diagnosis and early arthroscopic removal of the fracture are recommended.
Associations between antibody to hepatitis B core antigen positivity and outcomes in hepatocellular carcinoma patients undergoing hepatic resection
Authors: Itoh Shinji , Yoshizumi Tomoharu , Tomino Takahiro , Nagatsu Akihisa , Motomura Takashi , Harada Noboru , Harimoto Norifumi , Ikegami Toru , Soejima Yuji , Maehara Yoshihiko 
Published: July 2017

AimWe aimed to evaluate the effect of antibody to hepatitis B core antigen (HBcAb) positivity on clinical outcomes after hepatic resection in hepatocellular carcinoma (HCC) patients with negative hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (HCVAb), termed non‐B, non‐C HCC (NBNC‐HCC), or with HCV‐related HCC.MethodsTwo hundred and sixty‐three patients who underwent hepatic resection for HCC and measurements of HBsAg, HCVAb, and HBcAb were enrolled in this study.ResultsThe percentages of HBcAb positivity were 52.3% (n = 57) and 56.9% (n = 66) in patients with NBNC‐ and HCV‐related HCC, respectively. The proportion of multiple NBNC‐HCCs was significantly greater in patients with HBcAb positivity compared to HBcAb negativity (P = 0.028). There were no significant differences in the recurrence‐free and overall survival rates between NBNC‐HCC patients with HBcAb positivity versus negativity (P = 0.461 and P = 0.190, respectively). Furthermore, for HCV‐related HCC patients, there were no significant differences in the baseline factors between patients with positive versus negative HBcAb. The proportion of patients with HBcAb‐positive HCV‐related HCC who underwent anatomical resection of the liver was significantly greater than that of HBcAb‐negative patients, whereas the recurrence‐free and overall survival rates were not significantly different (P = 0.158 and P = 0.191, respectively).ConclusionIn our study, the presence of HBcAb had no impact on surgical outcomes after hepatic resection in patients with NBNB‐ and HCV‐related HCC. Occult HBV infection might be associated with hepatocarcinogenesis in patients with NBNC‐related HCC.
Prognostic significance of a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in primary myelofibrosis patients
Authors: Gianelli Umberto , Fiori Stefano , Cattaneo Daniele , Bossi Anna , Cortinovis Ivan , Bonometti Arturo , Ercoli Giulia , Bucelli Cristina , Orofino Nicola , Bulfamante Gaetano , Iurlo Alessandra 
Published: July 2017

AimsTo evaluate whether a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in bone marrow trephine biopsies (BMBs) of primary myelofibrosis (PMF) patients may have prognostic implications.Methods and resultsReticulin fibrosis, collagen deposition and osteosclerosis were graded from 0 to 3 in a series of 122 baseline BMBs. Then, we assigned to each case a comprehensive score [reticulin, collagen, osteosclerosis (RCO) score, ranging from 0 to 9] that allowed us to distinguish two groups of patients, with low‐grade (RCO score 0–4) and high‐grade (RCO score 5–9) stromal changes. Of 122 patients, 88 displayed a low‐grade and 34 a high‐grade RCO score. The latter was associated more frequently with anaemia, thrombocytopenia, peripheral blood blasts and increased lactate dehydrogenase levels. The RCO score was correlated strictly with overall mortality (P = 0.013) and International Prognostic Scoring System (IPSS) risk categories, and was able to discriminate the overall survival of both low‐ and high‐grade patients (log‐rank test: P < 0.001). Moreover, it proved to be more accurate than the European Consensus on Grading of Bone Marrow Fibrosis (ECGMF grade) in identifying high‐risk patients with poor prognosis. Finally, a combined analysis of RCO scores and IPSS risk categories in an integrated clinical–pathological evaluation was able to increase the positive predictive value (PPV) for mortality in high‐risk patients.ConclusionThe comprehensive RCO score, obtained by histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis was prognostically significant and more accurate than ECGMF grade in identifying high‐risk patients and improved PPV when applied in addition to IPSS.
Silver‐doped 58S bioactive glass as an anti‐Leishmania agent
Authors: Pires Emanuene Galdino , Bonan Roberta Ferreti , Rocha Ítalo Martins , Gonçalves Ingrid Morgana Fernandes , de Souza Joelma Rodrigues , Gonzales Laura Helena Vega , Silva Júnior José Valter Joaquim , Perez Danyel Elias da Cruz , Tavares Paula Cristina Brígido , Silva Sydnei Magno da , Alves‐Balvedi Renata Pereira , Goulart Luiz Ricardo , de Medeiros Eliton Souto , Castellano Lucio Roberto , Bonan Paulo Rogério Ferreti 
Published: July 2017

AbstractBioactive glasses (BG) incorporating antimicrobial agents can be effectively used against microorganisms. In this work, the in vitro effectiveness of silver‐doped 58S BG (BGAg) against Leishmania species was studied. BG, BGAg1, and BGAg2 belonging to the system 58SiO2∙(36‐x) CaO·6P2O5·xAg2O, where x=0, 1, and 2 mol.% Ag, were synthesized via sol‐gel, and characterized by scanning electron (SEM) and atomic force (AFM) microscopy, thermogravimetric analyses (TGA), X‐ray diffraction (XRD), Fourier‐transform infrared (FTIR), and surface‐enhanced Raman (Raman‐SERS) spectroscopy. Cytotoxicity was assessed in A549 lung adenocarcinoma cells. Leishmania amazonensis and Leishmania braziliensis cultures were exposed to all groups, and C57BL/6 macrophages were infected by over metacyclic form L. amazonensis under the exposure of BGAg particles. SEM and AFM images showed an irregular and network arranged surface. TGA, XRD, FTIR, and RAMAN‐SERS analyses confirmed silver inclusion within BG. None of the BG and BGAg presented toxicity. BGAg2 was effective in controlling promastigote forms under 150 and 300 μg/mL concentrations of both evaluated species. On macrophage invasion assay, BGAg2 presented reduction in metacyclic forms. For 72 hours, BGAg1 (150 μg/mL), BGAg1 (300 μg/mL), and BGAg2 in all concentrations were effective against intracellular infection. BGAg could be used as an alternative or complimentary agent to current chemotherapy.
Defect‐driven evolution of piezoelectric and ferroelectric properties in CuSb2O6‐doped K0.5Na0.5NbO3 lead‐free ceramics
Authors: Wang Tao , He Lihua , Deng Yunlong , Zheng Qiaoji , Xie Fengyu , Xu Chenggang , Lin Dunmin 
Published: July 2017

AbstractDefect greatly affects the microscopic structure and electrical properties of perovskite piezoelectric ceramics, but the microscopic mechanism of defect‐driven macroscopic properties in the materials is not still completely comprehended. In this work, K0.5Na0.5NbO3+x mol CuSb2O6 lead‐free piezoelectric ceramics were fabricated by a solid‐state reaction method and the defect‐driven evolution of piezoelectric and ferroelectric properties was studied. The addition of CuSb2O6 induces the formation of dimeric (DC1) and trimeric (DC2) defect dipoles. At low doping concentration of CuSb2O6 (0.5‐1.0 mol%), DC1 and DC2 coexist in the ceramics and harden the ceramics, inducing a constricted double P‐E loop and high Qm of 895 at x=0.01. However, DC2 becomes more dominant in the ceramics with high concentration of CuSb2O6 (≥1.5 mol%) and thus leads to softening behavior of piezoelectricity and ferroelectricity as compared to the ceramic with x=0.01, giving a single slanted P‐E loop and relatively low Qm of 206 at x=0.025. All ceramics exhibit relatively high d33 of 106‐126 pC/N. Our study shows that the piezoelectricity and ferroelectricity of K0.5Na0.5NbO3 ceramics can be tailored by controlling defect structure of the materials.
Quality attributes of bread fortified with staghorn sumac extract
Authors: Wang Sunan , Zhu Fan 
Published: July 2017

AbstractStaghorn sumac (Rhus typhina) is rich in polyphenols and may be used as an innovative ingredient in maintaining and enhancing food quality. In this report, aqueous extracts of sumac fruit powder were added up to 10% in wheat bread formulation. The extract concentration‐dependently delayed the mold growth (up to 5 log reduction in 7‐day storage) and the staling of bread. Adding sumac extracts dose‐dependently increased the total phenolic and anthocyanin contents of the breads. Minimal changes were observed in loaf volume, water activity, moisture content, texture (cohesiveness, springiness, and adhesive), and aroma of breads containing extracts of less than 4%. Overall, sumac addition altered several quality attributes of bread, including hardness, color, and sensory acceptance in appearance, flavor, and texture. Sumac holds potential as a natural preservative and an antistaling agent in bread formulation.Practical applicationsThe rising healthy food market demands bakery products fortified with novel functional ingredients. Staghorn sumac is an emerging healthy food ingredient that has attracted much research attention recently. This study provides a scientific basis to develop bread fortified with sumac‐derived functional ingredients. The results pointed out the feasibility of making sumac‐fortified breads with enhanced phenolic content, increased shelf life, and acceptable sensory profile.
Can quantitative hepatitis B surface antigen levels predict the severity of liver disease in genotype E Patients?
Authors: Chakrabarty Gayatri , Bruce Matthew , Horner Mary , Wang Bo , Agarwal Kosh , Carey Ivana 
Published: July 2017

SummaryThe utility of quantitative Hepatitis B surface antigen (qHBsAg) level as a marker of chronic hepatitis B (CHB)‐related liver damage is not fully delineated, but is becoming increasingly relevant. Quantitative HBsAg levels are linked with progression of liver disease in HBeAg‐negative genotype B and C patients, but it is not clear whether this is consistent across all HBV genotypes. In this single‐centre, cross‐sectional observational study, we evaluated whether qHBsAg levels can predict the severity of liver disease in genotype E patients. Demographic characteristics, viral, biochemical markers and qHBsAg levels were assessed at time of liver biopsy [all HBV DNA>2000 IU/mL and/or abnormal alanine transaminase (ALT)]. Patients were divided into three groups according to the severity of fibrosis on biopsy: mild (F0‐1), moderate (F2‐4), severe (F5‐6) liver disease and into two groups according to the NI grading, low (NI 0‐3) and high inflammation (NI ≥4). A total of 259 HBeAg‐negative CHB treatment‐naive genotype E patients were studied. The median age of this cohort was 38 years, and 61% were males. Advanced (severe) fibrosis patients had higher ALT, HBV DNA, and lower HBsAg level and qHBsAg/DNA ratio. Patients with NI ≥4 had higher ALT, HBV DNA, but lower qHBsAg/DNA ratio. There was no correlation between HBsAg and HBV DNA levels. Quantitative HBsAg levels were lower in more advanced liver fibrosis. There was no correlation between qHBsAg and HBV DNA levels. This may reflect discordance between viral replication and transcriptional activity or differential HBsAg expression in HBeAg‐negative genotype E patients with advanced liver disease.
An Arabidopsis kinase cascade influences auxin‐responsive cell expansion
Authors: Enders Tara A. , Frick Elizabeth M. , Strader Lucia C. 
Published: July 2017

SummaryMitogen‐activated protein kinase (MPK) cascades are conserved mechanisms of signal transduction across eukaryotes. Despite the importance of MPK proteins in signaling events, specific roles for many Arabidopsis MPK proteins remain unknown. Multiple studies have suggested roles for MPK signaling in a variety of auxin‐related processes. To identify MPK proteins with roles in auxin response, we screened mpk insertional alleles and identified mpk1‐1 as a mutant that displays hypersensitivity in auxin‐responsive cell expansion assays. Further, mutants defective in the upstream MAP kinase kinase MKK3 also display hypersensitivity in auxin‐responsive cell expansion assays, suggesting that this MPK cascade affects auxin‐influenced cell expansion. We found that MPK1 interacts with and phosphorylates ROP BINDING PROTEIN KINASE 1 (RBK1), a protein kinase that interacts with members of the Rho‐like GTPases from Plants (ROP) small GTPase family. Similar to mpk1‐1 and mkk3‐1 mutants, rbk1 insertional mutants display auxin hypersensitivity, consistent with a possible role for RBK1 downstream of MPK1 in influencing auxin‐responsive cell expansion. We found that RBK1 directly phosphorylates ROP4 and ROP6, supporting the possibility that RBK1 effects on auxin‐responsive cell expansion are mediated through phosphorylation‐dependent modulation of ROP activity. Our data suggest a MKK3 • MPK1 • RBK1 phosphorylation cascade that may provide a dynamic module for altering cell expansion.