bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the Mevalonate Pathway Suppresses VHL-Deficient CC-RCC through an HIF-Dependent Mechanism
Authors: Thompson Jordan M. , Alvarez Alejandro , Singha Monika K. , Pavesic Matthew W. , Nguyen Quy H. , Nelson Luke J. , Fruman David A. , Razorenova Olga V. 
Published: May 2018

Abstract
Clear cell renal cell carcinoma (CC-RCC) is a devastating disease with limited therapeutic options available for advanced stages. The objective of this study was to investigate HMG-CoA reductase inhibitors, also known as statins, as potential therapeutics for CC-RCC. Importantly, treatment with statins was found to be synthetically lethal with the loss of the von Hippel–Lindau (VHL) tumor suppressor gene, which occurs in 90% of CC-RCC driving the disease. This effect has been confirmed in three different CC-RCC cell lines with three different lipophilic statins. Inhibition of mevalonate synthesis by statins causes a profound cytostatic effect at nanomolar concentrations and becomes cytotoxic at low micromolar concentrations in VHL-deficient CC-RCC. The synthetic lethal effect can be fully rescued by both mevalonate and geranylgeranylpyrophosphate, but not by squalene, indicating that the effect is due to disruption of small GTPase isoprenylation and not the inhibition of cholesterol synthesis. Inhibition of Rho and Rho kinase (ROCK) signaling contributes to the synthetic lethality effect, and overactivation of hypoxia-inducible factor signaling resulting from VHL loss is required. Finally, statin treatment is able to inhibit both tumor initiation and progression of subcutaneous 786-OT1-based CC-RCC tumors in mice. Thus, statins represent potential therapeutics for the treatment of VHL-deficient CC-RCC. Mol Cancer Ther; 17(8); 1781–92. ©2018 AACR.
Targeting USP22 Suppresses Tumorigenicity and Enhances Cisplatin Sensitivity Through ALDH1A3 Downregulation in Cancer-Initiating Cells from Lung Adenocarcinoma
Authors: Yun Xinwei , Zhang Keqiang , Wang Jinhui , Pangeni Rajendra P. , Yang Lu , Bonner Melissa , Wu Jun , Wang Jami , Nardi Isaac K. , Gao Ming , Raz Dan J. 
Published: May 2018

Abstract
Loss of monoubiquitination of histone H2B (H2Bub1) was found to be associated with poor-differentiation and enhanced malignancy of lung adenocarcinoma. This study investigated the association and impact of the ubiquitin-specific peptidase 22 (USP22), an H2Bub1 deubiquitinase, on stem cell-like characteristics and cisplatin resistance in cancer-initiating cells (CIC) from primary lung adenocarcinoma. CICs were isolated, enriched, and characterized from patient-derived cancer tissues using both in vitro tumorsphere formation and in vivo xenograft assays. USP22 was determined to be predominantly expressed in CICs, a subpopulation of cells with high expression of the stem cell biomarkers, CD133 and CD44. The expression of USP22 in CICs is markedly reduced upon FBS/retinoic acid-induced differentiation. Moreover, knockdown of USP22 significantly suppressed tumorsphere formation and xenograft growth in NOD-SCID gamma (NSG) mice. Notably, USP22 and aldehyde dehydrogenase (ALDH) activity were elevated in tumorsphere cells that survived cisplatin treatment, whereas knockdown of USP22 significantly sensitizes tumorsphere cells to cisplatin. Interestingly, ALDH1A3, a predominant ALDH isozyme implicated in enhancing cisplatin resistance in lung adenocarcinoma, is significantly downregulated upon knockdown of USP22 in tumorsphere cells. Furthermore, knockdown of ALDH1A3 significantly sensitizes tumorsphere cells to cisplatin. Combined, these data demonstrate that USP22, predominantly expressed in CD133+ CICs, plays a critical role in tumorigenicity and cisplatin resistance in lung adenocarcinoma.
Implications: Targeting USP22 represents a potential therapeutic approach to suppress CICs in lung adenocarcinoma partially through downregulation of ALDH1A3 expression. Mol Cancer Res; 16(7); 1161–71. ©2018 AACR.
Oncogenic Mutants of MEK1: A Trilogy Unfolds
Authors: Maust Joel D. , Whitehead Christopher E. , Sebolt-Leopold Judith S. 
Published: May 2018

Abstract
Summary: It has generally been assumed that MEK mutants function similarly to one another and respond in the same manner to targeted drugs. Gao and colleagues challenge this assumption and report that MEK1 mutants fall into three unique phenotypic classes with respect to RAF dependency. A new class of MEK1 mutants is shown here to be RAF-independent, resistant to allosteric MEK inhibitors, and yet sensitive to treatment with a new ATP-competitive MEK inhibitor. Cancer Discov; 8(5); 534–6. ©2018 AACR.
See related article by Gao et al., p. 648.
Ficções lésbicas: ponto de vista e contingências
Authors: Borysow Vitor , Arnés Laura 
Published: May 2018

Tradução do primeiro capítulo do livro Ficciones lesbianas. Literatura y afectos en la cultura argentina (Buenos Aires, Madreselva, 2016) que procura definir e conceituar a noção de ficções lésbicas na literatura argentina a partir da década de 1950.
A Mesocosm Double Feature: Insights into the Chemical Makeup of Marine Ice Nucleating Particles
Authors: McCluskey Christina S. , Hill Thomas C. J. , Sultana Camille M. , Laskina Olga , Trueblood Jonathan , Santander Mitchell V. , Beall Charlotte M. , Michaud Jennifer M. , Kreidenweis Sonia M. , Prather Kimberly A. , Grassian Vicki , DeMott Paul J. 
Published: May 2018

AbstractThe abundance of atmospheric ice nucleating particles (INPs) is a source of uncertainty for numerical representation of ice-phase transitions in mixed-phase clouds. While sea spray aerosol (SSA) exhibits less ice nucleating (IN) ability than terrestrial aerosol, marine INP emissions are linked to oceanic biological activity and are potentially an important source of INPs over remote oceans. Inadequate knowledge of marine INP identity limits the ability to parameterize this complex INP source. A previous manuscript described abundances of marine INPs in relation to several aerosol composition and ocean biology observations during two laboratory mesocosm experiments. In this study, the abundances and chemical and physical properties of INPs found during the same mesocosm experiments were directly probed in SSA, seawater, and surface microlayer samples. Two unique marine INP populations were found: 1) dissolved organic carbon INPs are suggested to be composed of IN-active molecules, and 2) particulate organic carbon INPs are attributed as intact cells or IN-active microbe fragments. Both marine INP types are likely to be emitted into SSA following decay of phytoplankton biomass when 1) the surface microlayer is significantly enriched with exudates and cellular detritus and SSA particles are preferentially coated with IN-active molecules or 2) diatom fragments and bacteria are relatively abundant in seawater and therefore more likely transferred into SSA. These findings inform future efforts for incorporating marine INP emissions into numerical models and motivate future studies to quantify specific marine molecules and isolate phytoplankton, bacteria, and other species that contribute to these marine INP types.
The Impact of SST-Forced and Unforced Teleconnections on 2015/16 El Niño Winter Precipitation over the Western United States
Authors: Lim Young-Kwon , Schubert Siegfried D. , Chang Yehui , Molod Andrea M. , Pawson Steven 
Published: May 2018

AbstractThe factors impacting western U.S. winter precipitation during the 2015/16 El Niño are investigated using the Modern-Era Retrospective Analysis for Research and Applications, version 2 (MERRA-2), data, and simulations with the Goddard Earth Observing System, version 5 (GEOS-5), atmospheric general circulation model forced with specified sea surface temperatures (SSTs). Results reveal that the simulated response to the tropical Pacific SST associated with the 2015/16 El Niño was to produce wetter than normal conditions over much of the North American west coast including California—a result at odds with the negative precipitation anomalies observed over much of the southwestern United States. It is shown that two factors acted to partly counter the canonical ENSO response in that region. First, a potentially predictable but modest response to the unusually strong and persistent warm SST in the northeastern Pacific decreased precipitation in the southwestern United States by increasing sea level pressure, driving anticyclonic circulation and atmospheric descent, and reducing moisture transport into that region. Second, large-scale unforced (by SST) components of atmospheric variability (consisting of the leading modes of unpredictable intraensemble variability) resembling the positive phase of the North Atlantic Oscillation and Arctic Oscillation are found to be an important contributor to the drying over the western United States. While a statistical reconstruction of the precipitation from our simulations that account for internal atmospheric variability does much to close the gap between the ensemble-mean and observed precipitation in the southwestern United States, some differences remain, indicating that model error is also playing a role.
On the Seasonal Cycles Observed at the Continental Slope of the Eastern Eurasian Basin of the Arctic Ocean
Authors: Baumann Till M. , Polyakov Igor V. , Pnyushkov Andrey V. , Rember Robert , Ivanov Vladimir V. , Alkire Matthew B. , Goszczko Ilona , Carmack Eddy C. 
Published: May 2018

AbstractThe Eurasian Basin (EB) of the Arctic Ocean is subject to substantial seasonality. We here use data collected between 2013 and 2015 from six moorings across the continental slope in the eastern EB and identify three domains, each with its own unique seasonal cycle: 1) The upper ocean (<100 m), with seasonal temperature and salinity differences of Δθ = 0.16°C and ΔS = 0.17, is chiefly driven by the seasonal sea ice cycle. 2) The upper-slope domain is characterized by the influence of a hydrographic front that spans the water column around the ~750-m isobath. The domain features a strong temperature and moderate salinity seasonality (Δθ = 1.4°C; ΔS = 0.06), which is traceable down to ~600-m depth. Probable cause of this signal is a combination of along-slope advection of signals by the Arctic Circumpolar Boundary Current, local wind-driven upwelling, and a cross-slope shift of the front. 3) The lower-slope domain, located offshore of the front, with seasonality in temperature and salinity mainly confined to the halocline (Δθ = 0.83°C; ΔS = 0.11; ~100–200 m). This seasonal cycle can be explained by a vertical isopycnal displacement (ΔZ ~ 36 m), arguably as a baroclinic response to sea level changes. Available long-term oceanographic records indicate a recent amplification of the seasonal cycle within the halocline layer, possibly associated with the erosion of the halocline. This reduces the halocline’s ability to isolate the ocean surface layer and sea ice from the underlying Atlantic Water heat with direct implications for the evolution of Arctic sea ice cover and climate.
Delayed Recovery in Pediatric Sudden Sensorineural Hearing Loss Predicted via Magnetic Resonance Imaging
Authors: Wu Xuan , Jiang Hongyan , Wen Lanying , Zong Ling , Chen Kaitian 
Published: May 2018

Objectives: To evaluate the potential origins via magnetic resonance imaging and the relevant hearing recovery course of pediatric sudden sensorineural hearing loss. Methods: We retrospectively analyzed data of 25 pediatric patients from our center with sudden sensorineural hearing loss from January 2011 to December 2016. All individuals were closely followed up at baseline and 1 and 6 months. Results: Magnetic resonance imaging identified presumed causes in 9 cases, 5 of which showed intralabyrinthine hyperintensity, suggesting presumptive intralabyrinthine hemorrhage. The remaining 20 patients showed no hyperintensity. Restoration of hearing and speech discrimination abilities were noted in these 25 children at 6 months versus the initial levels (74.2 ± 22.6 vs 93.5 ± 20.5 dB, p = .000, and 45.8 ± 36.0 vs. 18.3 ± 22.1%, p = .004, respectively). The prognosis of the individuals with intralabyrinthine hemorrhage were superior in terms of frequency and hearing threshold at 6 months compared with that of the no-hemorrhage participants. Word recognition scores improved in either studied group. Conclusion: The potential recovery of hearing in children raises concerns about very early surgical intervention within the first 6 months. Rational imaging and sequential audiometric evaluation to monitor the progression of recovery may be beneficial.
Contextual Contracts: On a Context-sensitive Approach to Contract Theory
Authors: Goorha Prateek 
Published: May 2018

I propose a method for introducing ‘context’ within the contractual environment based on a simple and intuitive application of control theory. The approach permits looking at several interesting practical features of contracts, be they incomplete, complete or smart, within a single framework. I define a contextual environment with the help of an interaction between three distinct spaces: a market-based contractual space framed within a formal institutional space and an even larger cultural space. Each space is characterized by a governing law built on a selection of control mechanisms that differ in their approach as well as their reliance on information generated from feedback mechanisms. I suggest how these governing laws tie the contextual spaces together and present some ideas on how they evolve through their interactions with other spaces. JEL: D20, D86, P50, Z10
Lecture-based versus problem-based learning in ethics education among nursing students
Authors: Khatiban Mahnaz , Falahan Seyede Nayereh , Amini Roya , Farahanchi Afshin , Soltanian Alireza 
Published: May 2018

Background: Moral reasoning is a vital skill in the nursing profession. Teaching moral reasoning to students is necessary toward promoting nursing ethics. Objectives: The aim of this study was to compare the effectiveness of problem-based learning and lecture-based methods in ethics education in improving (1) moral decision-making, (2) moral reasoning, (3) moral development, and (4) practical reasoning among nursing students. Research design: This is a repeated measurement quasi-experimental study. Participants and research context: The participants were nursing students in a University of Medical Sciences in west of Iran who were randomly assigned to the lecture-based (n = 33) or the problem-based learning (n = 33) groups. The subjects were provided nursing ethics education in four 2-h sessions. The educational content was similar, but the training methods were different. The subjects completed the Nursing Dilemma Test before, immediately after, and 1 month after the training. The data were analyzed and compared using the SPSS-16 software. Ethical considerations: The program was explained to the students, all of whom signed an informed consent form at the baseline. Findings: The two groups were similar in personal characteristics (p > 0.05). A significant improvement was observed in the mean scores on moral development in the problem-based learning compared with the lecture-based group (p < 0.05). Although the mean scores on moral reasoning improved in both the problem-based learning and the lecture-based groups immediately after the training and 1 month later, the change was significant only in the problem-based learning group (p < 0.05). The mean scores on moral decision-making, practical considerations, and familiarity with dilemmas were relatively similar for the two groups. Conclusion: The use of the problem-based learning method in ethics education enhances moral development among nursing students. However, further studies are needed to determine whether such method improves moral decision-making, moral reasoning, practical considerations, and familiarity with the ethical issues among nursing students.
Association of angiotensin-converting enzyme gene I/D polymorphism with chronic obstructive pulmonary disease: a meta-analysis
Authors: Xu Guodong , Fan Guohui , Sun Yingtong , Yu Lili , Wu Sinan , Niu Wenquan 
Published: May 2018

Objectives: We conducted a meta-analysis of published studies on the angiotensin-converting enzyme ( ACE) gene insertion/deletion (I/D) polymorphism associated with the risk of chronic obstructive pulmonary disease, as well as with pulmonary function and circulating angiotensin-converting enzyme changes. Methods: A literature search, quality assessment and data extraction were completed independently and in duplicate. Results: A total of 16 articles were meta-analysed, including 12 articles (2113 patients and 8786 controls) for chronic obstructive pulmonary disease risk and eight articles (11,664 subjects) for pulmonary and circulating phenotypes. In overall and subgroup analyses, no significance was noted between the I/D polymorphism and chronic obstructive pulmonary disease risk under all genetic models ( P>0.05), without heterogeneity or publication bias. Carriers of II, ID and II plus ID genotypes had significantly lower levels of circulating angiotensin-converting enzyme than those with the DD genotype (weighted mean difference −13.35, −8.13 and −10.74 U/L, respectively, P<0.001). For forced expiratory volume in one second (FEV1)/forced vital capacity, carriers of the DD genotype had marginally lower levels than those with the DD genotype (weighted mean difference –1.66, P=0.034). Furthermore in the case of FEV1 of 50% or greater of predicted FEV1, FEV1 was marginally lower in ID genotype carriers than DD genotype carriers (weighted mean difference −3.50, P=0.056). Conclusions: Our meta-analytical findings demonstrated that the ACE gene I/D polymorphism was not associated with the risk of chronic obstructive pulmonary disease.
International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia
Authors: Hrusak Ondrej , de Haas Valerie , Stancikova Jitka , Vakrmanova Barbora , Janotova Iveta , Mejstrikova Ester , Capek Vaclav , Trka Jan , Zaliova Marketa , Luks Ales , Bleckmann Kirsten , Möricke Anja , Irving Julie , Konatkowska Benigna , Alexander Thomas B. , Inaba Hiroto , Schmiegelow Kjeld , Stokley Simone , Zemanova Zuzana , Moorman Anthony V. , Rossi Jorge Gabriel , Felice Maria Sara , Dalla-Pozza Luciano , Morales Jessa , Dworzak Michael , Buldini Barbara , Basso Giuseppe , Campbell Myriam , Cabrera Maria Elena , Marinov Neda , Elitzur Sarah , Izraeli Shai , Luria Drorit , Feuerstein Tamar , Kolenova Alexandra , Svec Peter , Kreminska Olena , Rabin Karen R. , Polychronopoulou Sophia , da Costa Elaine , Marquart Hanne Vibeke , Kattamis Antonis , Ratei Richard , Reinhardt Dirk , Choi John K. , Schrappe Martin , Stary Jan 
Published: May 2018

Key Points
The largest cohort of ambiguous leukemias to date reveals a better prognosis of children who started on lymphoid-directed treatment. Myeloid-type primary treatment correlated with dismal outcomes in CD19+ leukemias.
Metabolic heterogeneity on baseline 18FDG-PET/CT scan is a predictor of outcome in primary mediastinal B-cell lymphoma
Authors: Ceriani Luca , Milan Lisa , Martelli Maurizio , Ferreri Andrés J. M. , Cascione Luciano , Zinzani Pier Luigi , Di Rocco Alice , Conconi Annarita , Stathis Anastasios , Cavalli Franco , Bellei Monica , Cozens Kelly , Porro Elena , Giovanella Luca , Johnson Peter W. , Zucca Emanuele 
Published: May 2018

Key PointsMH on 18FDG-PET/CT may be a prognostic tool for PMBCL. High TLG combined with high MH at presentation identifies patients at high risk for progression after conventional therapy.
The social biography of antibiotic use in smallholder dairy farms in India
Authors: Chauhan Abhimanyu Singh , George Mathew Sunil , Chatterjee Pranab , Lindahl Johanna , Grace Delia , Kakkar Manish 
Published: May 2018

Abstract
Background
Antimicrobial resistance (AMR) has been identified as one of the major threats to global health, food security and development today. While there has been considerable attention about the use and misuse of antibiotics amongst human populations in both research and policy environments, there is no definitive estimate of the extent of misuse of antibiotics in the veterinary sector and its contribution to AMR in humans. In this study, we explored the drivers ofirrational usage of verterinary antibiotics in the dairy farming sector in peri-urban India.

Methods and materials
The study was conducted in the peri-urban belts of Ludhiana, Guwahati and Bangalore. A total of 54 interviews (formal and non-formal) were carried out across these three sites. Theme guides were developed to explore different drivers of veterinary antimicrobial use. Data was audio recorded and transcribed. Analysis of the coded data set was carried out using AtlasTi. Version 7. Themes emerged inductively from the set of codes.

Results
Findings were presented based on concept of ‘levels of analyses’. Emergent themes were categorised as individual, health systems, and policy level drivers. Low level of knowledge related to antibiotics among farmers, active informal service providers, direct marketing of drugs to the farmers and easily available antibiotics, dispensed without appropriate prescriptions contributed to easy access to antibiotics, and were identified to be the possible drivers contributing to the non-prescribed and self-administered use of antibiotics in the dairy farms.

Conclusions
Smallholding dairy farmers operated within very small margins of profits. The paucity of formal veterinary services at the community level, coupled with easy availability of antibiotics and the need to ensure profits and minimise losses, promoted non-prescribed antibiotic consumption. It is essential that these local drivers of irrational antibiotic use are understood in order to develop interventions and policies that seek to reduce antibiotic misuse.
Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Premenopausal Patients With Early Breast Cancer: A Systematic Review and Meta-Analysis of Individual Patient–Level Data
Authors: Lambertini Matteo , Moore Halle C.F. , Leonard Robert C.F. , Loibl Sibylle , Munster Pamela , Bruzzone Marco , Boni Luca , Unger Joseph M. , Anderson Richard A. , Mehta Keyur , Minton Susan , Poggio Francesca , Albain Kathy S. , Adamson Douglas J.A. , Gerber Bernd , Cripps Amy , Bertelli Gianfilippo , Seiler Sabine , Ceppi Marcello , Partridge Ann H. , Del Mastro Lucia 
Published: May 2018

Purpose The role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal women remains controversial. This systematic review and meta-analysis using individual patient–level data was conducted to better assess the efficacy and safety of this strategy in patients with early breast cancer. Methods The trials in which premenopausal women with early breast cancer were randomly assigned to receive (neo)adjuvant chemotherapy alone or with concurrent GnRHa were eligible for inclusion. Primary end points were premature ovarian insufficiency (POI) rate and post-treatment pregnancy rate. Disease-free survival and overall survival were secondary end points. Because each study represents a cluster, statistical analyses were performed using a random effects model. Results A total of 873 patients from five trials were included. POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted odds ratio, 0.38; 95% CI, 0.26 to 0.57; P < .001). A total of 37 (10.3%) patients had at least one post-treatment pregnancy in the GnRHa group and 20 (5.5%) in the control group (incidence rate ratio, 1.83; 95% CI, 1.06 to 3.15; P = .030). No significant differences in disease-free survival (adjusted hazard ratio, 1.01; 95% CI, 0.72 to 1.42; P = .999) and overall survival (adjusted hazard ratio, 0.67; 95% CI, 0.42 to 1.06; P = .083) were observed between groups. Conclusion Our findings provide evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced POI and potentially improve future fertility in premenopausal patients with early breast cancer.