bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gender and international clinician educators
Authors: Stadler Dora J , Archuleta Sophia , Ibrahim Halah , Shah Nina G , Al-Mohammed Ahmed Ali , Cofrancesco Joseph 
Published: April 2017

ABSTRACTObjectivesTo describe gender differences of international clinician educators (CEs) and leaders, and CEs’ perceptions by gender of preparation, roles, rewards and factors affecting job satisfaction and retention in emerging international competency-based residency programmes.MethodsCross-sectional surveys of CEs and leadership were conductedJune 2013–June 2014 at institutions that had adopted competency-based graduate medical education and were accredited by the Accreditation Council for Graduate Medical Education-International.Results274 (76.3%) of 359 eligible participants responded; 69 (25.2%) were female. Two (18%) of 11 chief executive officers and 1 (9%) of 11 chief medical officers were women. Female CEs were younger, more likely to be single and childless. They were less likely to hold academic appointments, despite no gender differences in length of time at current institution or in current position. A greater proportion of female CEs felt they were ‘never’ rewarded by academic promotion. Satisfaction rates were similar between the genders. Single female CEs were five times as likely to report being ‘extremely likely’ to stay in the country. Female CEs with children &lt;21 were less likely to report high likelihood of staying in academia. Marital status and children were not associated with outcomes for male CEs.ConclusionsIn the international academic medicine programmes studied, there were fewer female CEs in the pipeline and they perceived a gender gap in appointment and advancement. Stakeholders at international programmes need to develop contextualised strategies to expand entry and decrease attrition of women into CE tracks, and promote gender equity.
Comment on “the ground-state structures of Au10−, Au8Ni and Au9Ni clusters”
Authors: Zheng Ben-Xia , Die Dong , Li Qian-Qian , Dai Ming-Liang , Li Zhi-Qin , Yang Ji-Xian 
Published: April 2017

The lowest energy structures of Au[Formula: see text] and Au[Formula: see text]Ni ([Formula: see text] = 2–9) clusters have been researched using the CALYPSO structure searching method in conjunction with the density functional theory. It is found that the most stable structures of Au[Formula: see text], Au8Ni and Au9Ni clusters reported by Tang et al. [C. M. Tang, X. X. Chen and X. D. Yang, Int. J. Mod. Phys. B 28, 1450138 (2014)] are low-lying isomers. The correct ground states and vibrational spectra are given in this paper.
Anti-PD-L1 Efficacy Can Be Enhanced by Inhibition of Myeloid-Derived Suppressor Cells with a Selective Inhibitor of PI3Kδ/γ
Authors: Davis Ruth J. , Moore Ellen C. , Clavijo Paul E. , Friedman Jay , Cash Harrison , Chen Zhong , Silvin Chris , Van Waes Carter , Allen Clint 
Published: April 2017

Abstract
Checkpoint inhibitors are relatively inefficacious in head and neck cancers, despite an abundance of genetic alterations and a T-cell–inflamed phenotype. One significant barrier to efficacy may be the recruitment of myeloid-derived suppressor cells (MDSC) into the tumor microenvironment. Here we demonstrate functional inhibition of MDSC with IPI-145, an inhibitor of PI3Kδ and PI3Kγ isoforms, which enhances responses to PD-L1 blockade. Combination therapy induced CD8+ T lymphocyte–dependent primary tumor growth delay and prolonged survival only in T-cell–inflamed tumor models of head and neck cancers. However, higher doses of IPI-145 reversed the observed enhancement of anti-PD-L1 efficacy due to off-target suppression of the activity of tumor-infiltrating T lymphocytes. Together, our results offer a preclinical proof of concept for the low-dose use of isoform-specific PI3Kδ/γ inhibitors to suppress MDSC to enhance responses to immune checkpoint blockade. Cancer Res; 77(10); 2607–19. ©2017 AACR.
E3 Ligase cIAP2 Mediates Downregulation of MRE11 and Radiosensitization in Response to HDAC Inhibition in Bladder Cancer
Authors: Nicholson Judith , Jevons Sarah J. , Groselj Blaz , Ellermann Sophie , Konietzny Rebecca , Kerr Martin , Kessler Benedikt M. , Kiltie Anne E. 
Published: April 2017

Abstract
The MRE11/RAD50/NBS1 (MRN) complex mediates DNA repair pathways, including double-strand breaks induced by radiotherapy. Meiotic recombination 11 homolog (MRE11) is downregulated by histone deacetylase inhibition (HDACi), resulting in reduced levels of DNA repair in bladder cancer cells and radiosensitization. In this study, we show that the mechanism of this downregulation is posttranslational and identify a C-terminally truncated MRE11, which is formed after HDAC inhibition as full-length MRE11 is downregulated. Truncated MRE11 was stabilized by proteasome inhibition, exhibited a decreased half-life after treatment with panobinostat, and therefore represents a newly identified intermediate induced and degraded in response to HDAC inhibition. The E3 ligase cellular inhibitor of apoptosis protein 2 (cIAP2) was upregulated in response to HDAC inhibition and was validated as a new MRE11 binding partner whose upregulation had similar effects to HDAC inhibition. cIAP2 overexpression resulted in downregulation and altered ubiquitination patterns of MRE11 and mediated radiosensitization in response to HDAC inhibition. These results highlight cIAP2 as a player in the DNA damage response as a posttranscriptional regulator of MRE11 and identify cIAP2 as a potential target for biomarker discovery or chemoradiation strategies in bladder cancer. Cancer Res; 77(11); 3027–39. ©2017 AACR.
ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma
Authors: Schmitt Anna , Knittel Gero , Welcker Daniela , Yang Tsun-Po , George Julie , Nowak Michael , Leeser Uschi , Büttner Reinhard , Perner Sven , Peifer Martin , Reinhardt Hans Christian 
Published: April 2017

Abstract
Defects in maintaining genome integrity are a hallmark of cancer. The DNA damage response kinase ATM is frequently mutated in human cancer, but the significance of these events to chemotherapeutic efficacy has not been examined deeply in whole organism models. Here we demonstrate that bi-allelic Atm deletion in mouse models of Kras-mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, Atm-deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, Atm-deficient cells and tumors were sensitive to the PARP inhibitor olaparib. This actionable molecular addiction to functional PARP1 signaling was preserved in models that were proficient or deficient in p53, resembling standard or high-risk genetic constellations, respectively. Atm deficiency also markedly enhanced sensitivity to the ATR inhibitor VE-822. Taken together, our results provide a functional rationale to profile human tumors for disabling ATM mutations, particularly given their impact on PARP1 and ATR inhibitors. Cancer Res; 77(11); 3040–56. ©2017 AACR.
Behind the Scenes: Endo/Exocytosis in the Acquisition of Metastatic Traits
Authors: Lanzetti Letizia , Di Fiore Pier Paolo 
Published: April 2017

Abstract
Alterations of endo/exocytic proteins have long been associated with malignant transformation, and genes encoding membrane trafficking proteins have been identified as bona fide drivers of tumorigenesis. Focusing on the mechanisms underlying the impact of endo/exocytic proteins in cancer, a scenario emerges in which altered trafficking routes/networks appear to be preferentially involved in the acquisition of prometastatic traits. This involvement in metastasis frequently occurs through the integration of programs leading to migratory/invasive phenotypes, survival and resistance to environmental stresses, epithelial-to-mesenchymal transition, and the emergence of cancer stem cells. These findings might have important implications in the clinical setting for the development of metastasis-specific drugs and for patient stratification to optimize the use of available therapies. Cancer Res; 77(8); 1813–7. ©2017 AACR.
Multidrug Analyses in Patients Distinguish Efficacious Cancer Agents Based on Both Tumor Cell Killing and Immunomodulation
Authors: Frazier Jason P. , Bertout Jessica A. , Kerwin William S. , Moreno-Gonzalez Alicia , Casalini Joey R. , Grenley Marc O. , Beirne Emily , Watts Kori L. , Keener Andy , Thirstrup Derek J. , Tretyak Ilona , Ditzler Sally H. , Tripp Chelsea D. , Choy Kevin , Gillings Sarah , Breit Megan N. , Meleo Karri A. , Rizzo Vanessa , Herrera Chamisa L. , Perry James A. , Amaravadi Ravi K. , Olson James M. , Klinghoffer Richard A. 
Published: April 2017

Abstract
The vision of a precision medicine–guided approach to novel cancer drug development is challenged by high intratumor heterogeneity and interpatient diversity. This complexity is rarely modeled accurately during preclinical drug development, hampering predictions of clinical drug efficacy. To address this issue, we developed Comparative In Vivo Oncology (CIVO) arrayed microinjection technology to test tumor responsiveness to simultaneous microdoses of multiple drugs directly in a patient's tumor. Here, in a study of 18 canine patients with soft tissue sarcoma (STS), CIVO captured complex, patient-specific tumor responses encompassing both cancer cells and multiple immune infiltrates following localized exposure to different chemotherapy agents. CIVO also classified patient-specific tumor resistance to the most effective agent, doxorubicin, and further enabled assessment of a preclinical autophagy inhibitor, PS-1001, to reverse doxorubicin resistance. In a CIVO-identified subset of doxorubicin-resistant tumors, PS-1001 resulted in enhanced antitumor activity, increased infiltration of macrophages, and skewed this infiltrate toward M1 polarization. The ability to evaluate and cross-compare multiple drugs and drug combinations simultaneously in living tumors and across a diverse immunocompetent patient population may provide a foundation from which to make informed drug development decisions. This method also represents a viable functional approach to complement current precision oncology strategies. Cancer Res; 77(11); 2869–80. ©2017 AACR.
Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models
Authors: Suominen Mari I. , Fagerlund Katja M. , Rissanen Jukka P. , Konkol Yvonne M. , Morko Jukka P. , Peng ZhiQi , Alhoniemi Esa J. , Laine Salla K. , Corey Eva , Mumberg Dominik , Ziegelbauer Karl , Käkönen Sanna-Maria , Halleen Jussi M. , Vessella Robert L. , Scholz Arne 
Published: April 2017

AbstractPurpose: Radium-223 dichloride (radium-223, Xofigo), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models.Experimental Design: Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized into groups (n = 12–17) based on lesion grade and/or serum PSA level and administered radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals. X-rays and serum samples were obtained biweekly. Soft tissue tumors were observed macroscopically at sacrifice. Tibiae were analyzed by gamma counter, micro-CT, autoradiography and histology.Results: Radium-223 inhibited tumor-induced osteoblastic bone growth and protected normal bone architecture, leading to reduced bone volume in LNCaP and abiraterone-resistant LuCaP 58 models. Furthermore, radium-223 resulted in lower PSA values and reduced total tissue and tumor areas, indicating that treatment constrains prostate cancer growth in bone. In addition, radium-223 suppressed abnormal bone metabolic activity as evidenced by decreased number of osteoblasts and osteoclasts and reduced level of the bone formation marker PINP. Mode-of-action studies revealed that radium-223 was deposited in the intratumoral bone matrix. DNA double-strand breaks were induced in cancer cells within 24 hours after radium-223 treatment, and PSA levels were significantly lower 72 hours after treatment, providing further evidence of the antitumor effects.Conclusions: Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathologic bone formation in tumor microenvironment of osseous CRPC growth in mice. Clin Cancer Res; 23(15); 4335–46. ©2017 AACR.
A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in MetastaticBRAF-Mutant Colorectal Cancer
Authors: van Geel Robin M.J.M. , Tabernero Josep , Elez Elena , Bendell Johanna C. , Spreafico Anna , Schuler Martin , Yoshino Takayuki , Delord Jean-Pierre , Yamada Yasuhide , Lolkema Martijn P. , Faris Jason E. , Eskens Ferry A.L.M. , Sharma Sunil , Yaeger Rona , Lenz Heinz-Josef , Wainberg Zev A. , Avsar Emin , Chatterjee Arkendu , Jaeger Savina , Tan Eugene , Maharry Kati , Demuth Tim , Schellens Jan H.M. 
Published: April 2017

AbstractPreclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAFV600E colorectal cancer models. Patients with refractory BRAFV600-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (n = 28) or without (n = 26) a PI3Kα inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Dose-limiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with BRAF-mutant mCRC; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual- and triple-therapy groups, respectively.Significance: Herein, we demonstrate that dual- (encorafenib plus cetuximab) and triple- (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with BRAF-mutant mCRC. Cancer Discov; 7(6); 610–9. ©2017 AACR.See related commentary by Sundar et al., p. 558.This article is highlighted in the In This Issue feature, p. 539
Two new Neotropical species of the Dasyhelea mutabilis group (Culicomorpha: Ceratopogonidae)
Authors: Díaz Florentina , Felippe-Bauer Maria Luiza , Spinelli Gustavo Ricardo 
Published: April 2017

Two new species of Dasyhelea Kieffer, Dasyhelea jorgei Diaz, Felippe-Bauer & Spinelli sp. nov. and Dasyhelea mineira Diaz, Felippe-Bauer & Spinelli sp. nov. are described, illustrated and photographed from Peru and Brazil respectively, based on male and female adults. These species are typical members of mutabilis species group and are compared with similar species within the group.
Diet of Dendropsophus microcephalus and Scarthyla vigilans (Anura: Hylidae) at a locality in north-western Venezuela with notes on microhabitat occupation
Authors: Fonseca-Pérez Kimberlyn Andreina , Molina César , Tárano Zaida 
Published: April 2017

The coexistence of species with similar ecological requirements (food, space, time) has typically drawn attention of researchers because competition for resources is expected to be high. The diet and microhabitat occupation of two morphologically and ecologically similar species of Hylidae (Anura), Dendropsophus microcephalus and Scarthyla vigilans, were analyzed at a locality in north-western Venezuela, with the aim of addressing the potential for space and food competition between them. Diet was estimated through the analysis of stomach contents and microhabitat occupation was estimated through recordings of perch type, height and horizontal distance to water. Thirty-six prey categories (32 families, 4 orders) of arthropods were identified: 30 categories in D. microcephalus and 21 categories in S. vigilans. The most important prey (RII) in D. microcephalus were Agelenidae (11.1%), Tachinidae (9.32%) and Lepidoptera-larvae (7.96%). Gryllidae (14.13%), Cicadidae (9.1%), Cicadellidae (8.3%) and Delphacidae (8.02%) were the most important in S. vigilans. Diet overlap was relatively low (0.32). Both species have relatively generalist diets. Both species occupied the same type of perches (leaves and stems of Dicotyledons and Monocotyledons) and heights (average: S. vigilans, 24 ± 16.2 cm; D. microcephalus, 22.7 ± 9.5 cm). The potential for space competition is high if perches are limited and food competition is expected to be low.
A subadult maxilla of a Tyrannosauridae from the Two Medicine Formation, Montana, United States
Authors: Delcourt Rafael 
Published: April 2017

Daspletosaurus is a Campanian genus of Tyrannosauridae from North America. This genus occupied the same geographic area of Albertosaurus, but remains of Albertosaurus are more abundant than Daspletosaurus. Here is described a subadult maxilla (AMNH FARB 5477) of Daspletosaurus sp. from Montana (USA) and possibly from the Two Medicine Formation. The description is based on Carr (1999) that described cranial ontogenetic variations in tyrannosaurids. The maxilla belongs to the ontogenetic Stage 3 sensu Carr (1999), in which the maxilla is thick, the lateral surface of the bone well sculptured, and the maxillary fenestra is subcircular and well separated from the anterior edge of antorbital fossa. Possibly there were more than one species of Daspletosaurus and the locality of the here described subadult specimen suggests that Daspletosaurus species occurred more southern than Albertosaurus.
Genetic Analysis of Venous Thromboembolism in UK Biobank Identifies the ZFPM2 Locus and Implicates Obesity as a Causal Risk Factor
Authors: Klarin Derek , Emdin Connor A. , Natarajan Pradeep , Conrad Mark F. , Kathiresan Sekar 
Published: April 2017

Background—
UK Biobank is the world’s largest repository for phenotypic and genotypic information for individuals of European ancestry. Here, we leverage UK Biobank to understand the inherited basis for venous thromboembolism (VTE), a leading cause of cardiovascular mortality.

Methods and Results—

We identified 3290 VTE cases and 116 868 controls through billing code–based phenotyping. We performed a genome-wide association study for VTE with ≈9 000 000 imputed single-nucleotide polymorphisms. We performed a phenome-wide association study for a genetic risk score of 10 VTE-associated variants. To assess whether obesity is a causal factor for VTE, we performed Mendelian randomization analysis using a genetic risk score instrument composed of 68 body mass index–associated variants. The genome-wide association study for VTE replicated previous findings at the
F5
,
F2
,
ABO
,
F11
, and
FGG
loci. We identified 1 new locus—
ZFPM2
rs4602861—at genome-wide significance (odds ratio, 1.11; 95% confidence interval, 1.07–1.15;
P
=4.9×10
−10
) and a new independent variant at the
F2
locus (rs3136516; odds ratio, 1.10; 95% confidence interval, 1.06–1.13;
P
=7.60×10
−9
). In a phenome-wide association study, a 10 single-nucleotide polymorphism VTE genetic risk score was associated with coronary artery disease (odds ratio, 1.08; 95% confidence interval, 1.05–1.10 per unit increase in VTE odds;
P
=1.08×10
−9
). In a Mendelian randomization analysis, genetically elevated body mass index (a 1 SD increase) was associated with 57% higher risk of VTE (odds ratio, 1.57; 95% confidence interval, 1.08–1.97;
P
=0.003).

Conclusions—
For common diseases such as VTE, biobanks provide potential to perform genetic discovery, explore the phenotypic consequences for disease-associated variants, and test causal inference.
Effect of Intensive Blood Pressure Treatment on Heart Failure Events in the Systolic Blood Pressure Reduction Intervention Trial
Authors: Upadhya Bharathi , Rocco Michael , Lewis Cora E. , Oparil Suzanne , Lovato Laura C. , Cushman William C. , Bates Jeffrey T. , Bello Natalie A. , Aurigemma Gerard , Fine Lawrence J. , Johnson Karen C. , Rodriguez Carlos J. , Raj Dominic S. , Rastogi Anjay , Tamariz Leonardo , Wiggers Alan , Kitzman Dalane W. 
Published: April 2017

Background—
Acute decompensated heart failure (ADHF) was a frequent common outcome in SPRINT (Systolic Blood Pressure Intervention Trial). We examined whether there was differential reduction in ADHF events from intensive blood pressure [BP] treatment among the 6 key, prespecified subgroups in SPRINT: age ≥75 years, prior cardiovascular disease, chronic kidney disease, women, black race, and 3 levels of baseline systolic BP (≤132 versus >132 to <145 versus ≥145 mm Hg).

Methods and Results—

ADHF was defined as hospitalization for ADHF, confirmed and formally adjudicated by a blinded events committee using standardized protocols. At 3.29 years follow-up, there were 103 ADHF events (2.2%) among 4683 standard arm participants and 65 ADHF events (1.4%) among 4678 intensive arm participants (Cox proportional hazards ratio, 0.63; 95% confidence interval, 0.46–0.85;
P
value =0.003). In multivariable analyses, including treatment arm, baseline covariates that were significant predictors for ADHF included chronic kidney disease, cardiovascular disease, age≥75 years, body mass index, and higher systolic BP. The beneficial effect of the intervention on incident ADHF was consistent across all prespecified subgroups. Participants who had incident ADHF had markedly increased risk of subsequent cardiovascular events, including a 27-fold increase (
P
<0.001) in cardiovascular death.

Conclusions—
Targeting a systolic BP<120 mm Hg, compared with <140 mm Hg, significantly reduced ADHF events, and the benefit was similar across all key, prespecified subgroups. Participants who developed ADHF had markedly increased risk for subsequent cardiovascular events and death, highlighting the importance of strategies aimed at prevention of ADHF, especially intensive BP reduction.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01206062