bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I/II Trial of Belinostat in Combination with Cisplatin, Doxorubicin, and Cyclophosphamide in Thymic Epithelial Tumors: A Clinical and Translational Study
Authors: Thomas Anish , Rajan Arun , Szabo Eva , Tomita Yusuke , Carter Corey A. , Scepura Barbara , Lopez-Chavez Ariel , Lee Min-Jung , Redon Christophe E. , Frosch Ari , Peer Cody J. , Chen Yuanbin , Piekarz Richard , Steinberg Seth M. , Trepel Jane B. , Figg William D. , Schrump David S. , Giaccone Giuseppe 
Published: September 2014

Abstract
Purpose: This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor (HDAC) administered before and in combination with cisplatin (P), doxorubicin (A), and cyclophosphamide (C) in thymic epithelial tumors (TET). Antitumor activity, pharmacokinetics, and biomarkers of response were also assessed.
Experimental Design: Patients with advanced, unresectable TET received increasing doses of belinostat as a continuous intravenous infusion over 48 hours with chemotherapy in 3-week cycles. In phase II, belinostat at the MTD was used.
Results: Twenty-six patients were enrolled (thymoma, 12; thymic carcinoma, 14). Dose-limiting toxicities at 2,000 mg/m2 belinostat were grade 3 nausea and diarrhea and grade 4 neutropenia and thrombocytopenia, respectively, in two patients. Twenty-four patients were treated at the MTD of 1,000 mg/m2 with chemotherapy (P, 50 mg/m2 on day 2; A, 25 mg/m2 on days 2 and 3; C, 500 mg/m2 on day 3). Objective response rates in thymoma and thymic carcinoma were 64% (95% confidence interval, 30.8%-89.1%) and 21% (4.7%–50.8%), respectively. Modulation of pharmacodynamic markers of HDAC inhibition and declines in regulatory T cell (Treg) and exhausted CD8+ T-cell populations were observed. Decline in Tregs was associated with response (P = 0.0041) and progression-free survival (P = 0.021). Declines in TIM3+ CD8+ T cells were larger in responders than nonresponders (P = 0.049).
Conclusion: This study identified the MTD of belinostat in combination with PAC and indicates that the combination is active and feasible in TETs. Immunomodulatory effects on Tregs and TIM3+ CD8+ T cells warrant further study. Clin Cancer Res; 20(21); 5392–402. ©2014 AACR.
Galectin-1 Mediates Radiation-Related Lymphopenia and Attenuates NSCLC Radiation Response
Authors: Kuo Peiwen , Bratman Scott V. , Shultz David B. , von Eyben Rie , Chan Cato , Wang Ziwei , Say Carmen , Gupta Aparna , Loo Bill W. , Giaccia Amato J. , Koong Albert C. , Diehn Maximilian , Le Quynh-Thu 
Published: September 2014

Abstract
Purpose: Radiotherapy can result in lymphopenia, which has been linked to poorer survival. Here, we test the hypothesis that radiotherapy-induced lymphopenia is mediated by a tumor-secreted factor, Galectin-1 (Gal-1), which possesses T-cell proapoptotic activities.
Experimental Design: Matched Gal-1 wild-type (WT) or null mice were implanted with Lewis lung carcinoma (LLC-1) that either expressed Gal-1 or had Gal-1 stably downregulated. Tumors were irradiated locally and circulating Gal-1 and T cells were measured. Tumor growth, lung metastasis, intratumoral T-cell apoptosis, and microvessel density count were quantified. Thiodigalactoside (TDG), a Gal-1 inhibitor, was used to inhibit Gal-1 function in another group of mice to validate the observations noted with Gal-1 downregulation. Lymphocyte counts, survival, and plasma Gal-1 were analyzed in cohorts of radiotherapy-treated lung [non–small cell lung cancer (NSCLC)] and head and neck cancer patients.
Results: LLC irradiation increased Gal-1 secretion and decreased circulating T cells in mice, regardless of host Gal-1 expression. Inhibition of tumor Gal-1 with either shRNA or thiodigalactoside ablated radiotherapy-induced lymphopenia. Irradiated shGal-1 tumors showed significantly less intratumoral CD8+ T-cell apoptosis and microvessel density, which led to marked tumor growth delay and reduced lung metastasis compared with controls. Similar observations were made after thiodigalactoside treatment. Radiotherapy-induced lymphopenia was associated with poorer overall survival in patients with NSCLC treated with hypofractionated radiotherapy. Plasma Gal-1 increased whereas T-cell decreased after radiation in another group of patients.
Conclusions: Radiotherapy-related systemic lymphopenia appeared to be mediated by radiotherapy-induced tumor Gal-1 secretion that could lead to tumor progression through intratumoral immune suppression and enhanced angiogenesis. Clin Cancer Res; 20(21); 5558–69. ©2014 AACR.
Preclinical Profile of the HER2-Targeting ADC SYD983/SYD985: Introduction of a New Duocarmycin-Based Linker-Drug Platform
Authors: Dokter Wim , Ubink Ruud , van der Lee Miranda , van der Vleuten Monique , van Achterberg Tanja , Jacobs Danielle , Loosveld Eline , van den Dobbelsteen Diels , Egging David , Mattaar Ellen , Groothuis Patrick , Beusker Patrick , Coumans Ruud , Elgersma Ronald , Menge Wiro , Joosten John , Spijker Henri , Huijbregts Tijl , de Groot Vincent , Eppink Michel , de Roo Guy , Verheijden Gijs , Timmers Marco 
Published: September 2014

AbstractA linker-drug platform was built on the basis of a cleavable linker-duocarmycin payload for the development of new-generation antibody–drug conjugates (ADC). A leading ADC originating from that platform is SYD983, a HER2-targeting ADC based on trastuzumab. HER2-binding, antibody-dependent cell-mediated cytotoxicity and HER2-mediated internalization are similar for SYD983 as compared with trastuzumab. HER2-expressing cells in vitro are very potently killed by SYD983, but SYD983 is inactive in cells that do not express HER2. SYD983 dose dependently reduces tumor growth in a BT-474 mouse xenograft in vivo. The ADC is stable in human and cynomolgus monkey plasma in vitro but shows relatively poor stability in mouse plasma due to mouse-specific carboxylesterase. SYD983 could be dosed up to 30 mg/kg in cynomolgus monkeys with high exposure, excellent stability in blood, and without severe toxic effects. The monkey safety study showed no SYD983-induced thrombocytopenia and no induction of peripheral sensory neuropathy, both commonly observed in trials and studies with ADCs based on tubulin inhibitors. Finally, to improve homogeneity, SYD983 was further purified by hydrophobic interaction chromatography resulting in an ADC (designated SYD985) predominantly containing DAR2 and DAR4 species. SYD985 showed high antitumor activity in two patient-derived xenograft models of HER2-positive metastatic breast cancers. In conclusion, the data obtained indicate great potential for this new HER2-targeting ADC to become an effective drug for patients with HER2-positive cancers with a favorable safety profile. More generally, this new-generation duocarmycin-based linker-drug technology could be used with other mAbs to serve more indications in oncology. Mol Cancer Ther; 13(11); 2618–29. ©2014 AACR.
Identification of Kinase Inhibitor Targets in the Lung Cancer Microenvironment by Chemical and Phosphoproteomics
Authors: Gridling Manuela , Ficarro Scott B. , Breitwieser Florian P. , Song Lanxi , Parapatics Katja , Colinge Jacques , Haura Eric B. , Marto Jarrod A. , Superti-Furga Giulio , Bennett Keiryn L. , Rix Uwe 
Published: September 2014

Abstract
A growing number of gene mutations, which are recognized as cancer drivers, can be successfully targeted with drugs. The redundant and dynamic nature of oncogenic signaling networks and complex interactions between cancer cells and the microenvironment, however, can cause drug resistance. While these challenges can be addressed by developing drug combinations or polypharmacology drugs, this benefits greatly from a detailed understanding of the proteome-wide target profiles. Using mass spectrometry-based chemical proteomics, we report the comprehensive characterization of the drug–protein interaction networks for the multikinase inhibitors dasatinib and sunitinib in primary lung cancer tissue specimens derived from patients. We observed in excess of 100 protein kinase targets plus various protein complexes involving, for instance, AMPK, TBK1 (sunitinib), and ILK (dasatinib). Importantly, comparison with lung cancer cell lines and mouse xenografts thereof showed that most targets were shared between cell lines and tissues. Several targets, however, were only present in tumor tissues. In xenografts, most of these proteins were of mouse origin suggesting that they originate from the tumor microenvironment. Furthermore, intersection with subsequent global phosphoproteomic analysis identified several activated signaling pathways. These included MAPK, immune, and integrin signaling, which were affected by these drugs in both cancer cells and the microenvironment. Thus, the combination of chemical and phosphoproteomics can generate a systems view of proteins, complexes, and signaling pathways that are simultaneously engaged by multitargeted drugs in cancer cells and the tumor microenvironment. This may allow for the design of novel anticancer therapies that concurrently target multiple tumor compartments. Mol Cancer Ther; 13(11); 2751–62. ©2014 AACR.
As redes sociais na perspectiva de pessoas com o diagnóstico de esquizofrenia em tratamento em um CAPS de Campinas e as implicações no recovery
Authors: Montanher Monica Krieck , Leal Erotildes Maria 
Published: September 2014

O modelo de assistência preconizado pela Reforma Psiquiátrica introduz um cuidado em saúde mental baseado em estratégias de reabilitação psicossocial das pessoas com transtornos mentais. Nesse sentido, as redes sociais podem ajudar os sujeitos a lidarem com a doença. Assim, a análise das redes sociais, a partir da experiência dos sujeitos, pode indicar de que forma essas redes contribuem (ou não) para o processo de recovery. Este artigo apresenta os resultados de uma pesquisa qualitativa informada pelo referencial da Análise Fenomenológica Interpretativa. Teve como objetivo conhecer como as pessoas com diagnóstico de esquizofrenia em tratamento em um CAPS da cidade de Campinas compõem e experimentam as suas redes sociais e que implicações as redes sociais tem no seu processo de recovery. Resultou-se da análise a identificação de categorias temáticas referentes aos vínculos e tipos de interação estabelecidos pelos participantes. Concluiu-se a partir das narrativas que as redes são positivas para a experiência de recovery, se vivenciadas com alguma capacidade de proporcionar esperança, incentivo e suporte. Uma relação será experiência da positivamente se for capaz de minimizar ou ressignificar uma relação ruim ou a própria relação garantindo-lhe plasticidade.
AVALIAÇÃO DAS ATIVIDADES DE VIDA DIÁRIA EM CONTEXTOS INFANTIS: UMA REVISÃO DA LITERATURA
Authors: Vasconcelos Thamires Bezerra de , Cavalcante Lília Iêda Chaves 
Published: September 2014

Objetivo: Identifi car e caracterizar os principais métodos utilizados para a avaliação do desempenho de crianças nas rotinas de autocuidado encontrados na literatura sobre Atividades de Vida Diária (AVD), assim como os contextos em que foram realizadas. Método: A busca foi realizada nas bases de dados eletrônicas BVS, CINAHL e Web of Science. Resultados: a partir dos artigos encontrados no período de 1991 a 2012 (n=2.386), foram selecionados 58 estudos, seguindo os critérios de inclusão e exclusão. Foi observado um aumento nos últimos anos da produção científica sobre o tema, e o uso de métodos padronizados de avaliação (n=50). A maioria dos estudos avaliou populações infantis portadoras de patologias neurológicas (n=31). Em relação ao contexto de avaliação, a maior parte dos trabalhos não descreveu os ambientes de sua realização como fator relevante na discussão dos resultados encontrados. Conclusões: Considera-se que os métodos de avaliação das AVD de crianças podem seguir orientando pesquisas que sirvam não apenas à avaliação funcional para fins terapêuticos, como também à realização de estudos sobre o desenvolvimento em contextos ecológicos de populações infantis em risco social.
Elevated Circulating Lipocalin-2 Levels Independently Predict Incident Cardiovascular Events in Men in a Population-Based Cohort
Authors: Wu Guangyu , Li Huating , Fang Qichen , Jiang Shan , Zhang Lei , Zhang Jing , Hou Xuhong , Lu Junxi , Bao Yuqian , Xu Aimin , Jia Weiping 
Published: September 2014

Objective—
Adipose tissue inflammation and perturbation of adipokine secretion may contribute to the pathogenesis of cardiovascular diseases (CVD). Lipocalin-2 (LCN2), mainly released from adipocytes, has been shown to be positively associated with CVD in cross-sectional studies. We aimed to evaluate the association of LCN2 with CVD involving a population-based cohort recruited from the Shanghai Diabetes Study.

Approach and Results—

Serum LCN2 levels were measured using ELISA. Independent predictors of CVD development were identified using Cox proportion hazards regression. The predictive performances of the various models were assessed by Kaplan–Meier analysis. At baseline, circulating LCN2 was significantly associated with a cluster of traditional cardiovascular risk factors. Baseline LCN2 levels in male subjects who developed CVD events during follow-up were significantly higher than those who did not develop CVD events (
P
=0.012). However, such difference was not significant in female subjects. LCN2 was a predictor of CVD in men, which remained statistically significant after adjustment for traditional cardiovascular risk factors (hazard ratio, 1.038 [95% confidence interval, 1.017–1.060]). LCN2 remained significantly associated with incident CVD even after adjustment for renal function, adiponectin, and high-sensitivity C-reactive protein levels. Kaplan–Meier analysis suggested combination of LCN2 and high-sensitivity C-reactive protein might improve the prediction of CVD events in male subjects.

Conclusions—
Elevated circulating LCN2 level is an independent predictor of CVD events in men in a population-based cohort and adds to the prognostic value of high-sensitivity C-reactive protein, which is currently the most extensively studied biomarker of CVD. Measurement of serum LCN2 might be useful for early detection and intervention of CVD.
Homoarginine and Cardiovascular Outcome in the Population-Based Dallas Heart Study
Authors: Atzler Dorothee , Gore M. Odette , Ayers Colby R. , Choe Chi-un , Böger Rainer H. , de Lemos James A. , McGuire Darren K. , Schwedhelm Edzard 
Published: September 2014

Objective—
The nonproteinogenic amino acid homoarginine has been postulated to have antiatherosclerotic effects as a weak substrate of nitric oxide synthase. This investigation in the population-based Dallas Heart Study (DHS) aimed to evaluate the association of homoarginine with clinical and subclinical cardiovascular outcomes.

Approach and Results—

Plasma homoarginine was measured in 3514 participants of the DHS using liquid chromatography-tandem mass spectrometry. Associations between homoarginine and major adverse cardiovascular events and all-cause mortality were analyzed using Cox proportional hazard models adjusting for cardiovascular risk factors. Linear regression was used to assess cross-sectional associations between homoarginine and subclinical cardiovascular disease, including coronary artery calcium measured by electron beam-computed tomography, and aortic plaque burden and aortic wall thickness by MRI. Median age was 43 (interquartile range, 36–52) years, with 56% women and 52% black participants. Median follow-up was 9.4 (9.0–9.8) years. Median plasma homoarginine was 2.80 (2.14–3.54) μmol/L. In multivariable models, higher homoarginine was associated with lower rate of major adverse cardiovascular events (hazard ratio, 0.86; 95% confidence interval, 0.75–0.98) and lower all-cause mortality (hazard ratio, 0.82; 0.73–0.92; per 1 log SD increase in homoarginine). Homoarginine was inversely and independently associated with aortic wall thickness (β-estimate, −0.04;
P
<0.01) but not with aortic plaque burden and coronary artery calcium.

Conclusions—
Homoarginine is inversely associated with subclinical vascular disease and with risk for cardiovascular disease events. Additional studies are needed to evaluate whether the regulation of plasma homoarginine could emerge as a novel therapeutic option to improve outcomes in cardiovascular disease.
The Hemodynamic Basis of Exercise Intolerance in Tricuspid Regurgitation
Authors: Andersen Mads J. , Nishimura Rick A. , Borlaug Barry A. 
Published: September 2014

Background—
Patients with severe tricuspid regurgitation (TR) frequently present with exertional fatigue and dyspnea, but the hemodynamic basis for exercise limitation in people with TR remains unclear.

Methods and Results—

Twelve subjects with normal left ventricular (LV) ejection fraction and grade ≥3 TR underwent high-fidelity invasive hemodynamic exercise testing with simultaneous expired gas analysis and were compared with 13 age- and sex-matched controls. At rest, TR subjects had lower pulmonary blood flow (3.6±0.4 versus 5.1±1.9 L/min;
P
=0.01), increased right atrial pressure (12±5 versus 4±1 mm Hg;
P
=0.0002), and higher pulmonary capillary wedge pressure (17±5 versus 9±3 mm Hg;
P
=0.0001). However, LV transmural pressure (pulmonary capillary wedge pressure−right atrial pressure), which reflects LV preload independent of right heart congestion and pericardial restraint, was similar in TR and controls (6±3 versus 4±2 mm Hg;
P
=0.3). With exercise, TR subjects displayed lower peak V
O
2
(10.3±2.8 versus 13.8±4.2 mL/min per kg;
P
=0.02), lower pulmonary blood flow (6.4±1.3 versus 10.3±3.3 L/min;
P
=0.001), and less increase in pulmonary blood flow relative to V
O
2
(+4.6±1.1vs +6.2±0.7;
P
=0.001). TR subjects displayed higher pulmonary capillary wedge pressure with exercise, but this was solely because of RA hypertension (27±9 versus 8±3 mm Hg;
P
<0.0001), because LV transmural pressure dropped with exercise in subjects with TR (−5±6 versus +3±3 mm Hg;
P
=0.0007), suggesting inadequate LV diastolic filling, despite high pulmonary capillary wedge pressure.

Conclusions—
Impaired exercise capacity in people with severe TR is related to low cardiac output reserve relative to metabolic needs, coupled with elevated systemic and pulmonary venous pressures. Left heart pressures are elevated with exercise in subjects with TR, despite low LV preload, secondary to enhanced ventricular interaction.
Tbx1 Coordinates Addition of Posterior Second Heart Field Progenitor Cells to the Arterial and Venous Poles of the Heart
Authors: Rana M. Sameer , Théveniau-Ruissy Magali , De Bono Christopher , Mesbah Karim , Francou Alexandre , Rammah Mayyasa , Domínguez Jorge N. , Roux Marine , Laforest Brigitte , Anderson Robert H. , Mohun Timothy , Zaffran Stephane , Christoffels Vincent M. , Kelly Robert G. 
Published: September 2014

Rationale:
Cardiac progenitor cells from the second heart field (SHF) contribute to rapid growth of the embryonic heart, giving rise to right ventricular and outflow tract (OFT) myocardium at the arterial pole of the heart, and atrial myocardium at the venous pole. Recent clonal analysis and cell-tracing experiments indicate that a common progenitor pool in the posterior region of the SHF gives rise to both OFT and atrial myocytes. The mechanisms regulating deployment of this progenitor pool remain unknown.

Objective:

To evaluate the role of
TBX1
, the major gene implicated in congenital heart defects in 22q11.2 deletion syndrome patients, in posterior SHF development.

Methods and Results:

Using transcriptome analysis, genetic tracing, and fluorescent dye-labeling experiments, we show that
Tbx1
-dependent OFT myocardium originates in
Hox
-expressing cells in the posterior SHF. In
Tbx1
null embryos, OFT progenitor cells fail to segregate from this progenitor cell pool, leading to failure to expand the dorsal pericardial wall and altered positioning of the cardiac poles. Unexpectedly, addition of SHF cells to the venous pole of the heart is also impaired, resulting in abnormal development of the dorsal mesenchymal protrusion, and partially penetrant atrioventricular septal defects, including ostium primum defects.

Conclusions:

Tbx1
is required for inflow as well as OFT morphogenesis by regulating the segregation and deployment of progenitor cells in the posterior SHF. Our results provide new insights into the pathogenesis of congenital heart defects and 22q11.2 deletion syndrome phenotypes.
Validity of Hospital Discharge Diagnosis Codes for Stroke
Authors: Jones Sydney A. , Gottesman Rebecca F. , Shahar Eyal , Wruck Lisa , Rosamond Wayne D. 
Published: September 2014

Background and Purpose—
Characterizing International Classification of Disease 9th Revision, Clinical Modification (ICD-9-CM) code validity is essential given widespread use of hospital discharge databases in research. Using the Atherosclerosis Risk in Communities (ARIC) Study, we estimated the accuracy of ICD-9-CM stroke codes.

Methods—
Hospitalizations with ICD-9-CM codes 430 to 438 or stroke keywords in the discharge summary were abstracted for ARIC cohort members (1987–2010). A computer algorithm and physician reviewer classified definite and probable ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Using ARIC classification as a gold standard, we calculated the positive predictive value (PPV) and sensitivity of ICD-9-CM codes grouped according to the American Heart Association/American Stroke Association (AHA/ASA) 2013 categories and an alternative code grouping for comparison.

Results—
Thirty-three percent of 4260 hospitalizations were validated as strokes (1251 ischemic, 120 intracerebral hemorrhage, 46 subarachnoid hemorrhage). The AHA/ASA code groups had PPV 76% and 68% sensitivity compared with PPV 72% and 83% sensitivity for the alternative code groups.
The PPV of the AHA/ASA code group for ischemic stroke was slightly higher among blacks, individuals <65 years, and at teaching hospitals. Sensitivity was higher among older individuals and increased over time. The PPV of the AHA/ASA code group for intracerebral hemorrhage was higher among blacks, women, and younger individuals. PPV and sensitivity varied across study sites.

Conclusions—
A new AHA/ASA discharge code grouping to identify stroke had similar PPV and lower sensitivity compared with an alternative code grouping. Accuracy varied by patient characteristics and study sites.
Hormone Replacement Therapy and Adverse Outcomes in Women With Atrial Fibrillation
Authors: Apostolakis Stavros , Sullivan Renee M. , Olshansky Brian , Lip Gregory Y.H. 
Published: September 2014

Background and Purpose—
Hormone replacement therapy (HRT) use has been related to thromboembolism, but whether HRT increases adverse outcomes in females with atrial fibrillation is uncertain.

Methods—
We used the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial data set that included 1594 women (39.3% of the population, mean age 71±8), of whom 376 (23.6%) were taking HRT at baseline. The primary end point, a composite of all-cause death, stroke, systemic/pulmonary embolism, and myocardial infarction, and secondary outcomes (ie, each individual end point) and major bleeding, were considered.

Results—

HRT was not independently associated with the primary end point (hazard ratio=0.894; 95% confidence interval, 0.658–1.214;
P
=0.473) or any secondary outcome. Age (
P
<0.001), diabetes mellitus (
P
<0.001), previous stroke (
P
=0.011), and heart failure (
P
<0.001) predicted the primary end point. Lack of association between HRT and the primary end point was confirmed in a propensity score–matched control group (hazard ratio=0.966; 95% confidence interval, 0.663–1.409;
P
=0.858).

Conclusions—
HRT does not independently predict mortality, thromboembolism, or bleeding in a large cohort of women with atrial fibrillation.