bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overexpression of the Trehalase Gene AtTRE1 Leads to Increased Drought Stress Tolerance in Arabidopsis and Is Involved in Abscisic Acid-Induced Stomatal Closure
Authors: Van Houtte Hilde , Vandesteene Lies , López-Galvis Lorena , Lemmens Liesbeth , Kissel Ewaut , Carpentier Sebastien , Feil Regina , Avonce Nelson , Beeckman Tom , Lunn John E. , Van Dijck Patrick 
Published: January 2013

Abstract
Introduction of microbial trehalose biosynthesis enzymes has been reported to enhance abiotic stress resistance in plants but also resulted in undesirable traits. Here, we present an approach for engineering drought stress tolerance by modifying the endogenous trehalase activity in Arabidopsis (Arabidopsis thaliana). AtTRE1 encodes the Arabidopsis trehalase, the only enzyme known in this species to specifically hydrolyze trehalose into glucose. AtTRE1-overexpressing and Attre1 mutant lines were constructed and tested for their performance in drought stress assays. AtTRE1-overexpressing plants had decreased trehalose levels and recovered better after drought stress, whereas Attre1 mutants had elevated trehalose contents and exhibited a drought-susceptible phenotype. Leaf detachment assays showed that Attre1 mutants lose water faster than wild-type plants, whereas AtTRE1-overexpressing plants have a better water-retaining capacity. In vitro studies revealed that abscisic acid-mediated closure of stomata is impaired in Attre1 lines, whereas the AtTRE1 overexpressors are more sensitive toward abscisic acid-dependent stomatal closure. This observation is further supported by the altered leaf temperatures seen in trehalase-modified plantlets during in vivo drought stress studies. Our results show that overexpression of plant trehalase improves drought stress tolerance in Arabidopsis and that trehalase plays a role in the regulation of stomatal closure in the plant drought stress response.
SlARF4, an Auxin Response Factor Involved in the Control of Sugar Metabolism during Tomato Fruit Development
Authors: Sagar Maha , Chervin Christian , Mila Isabelle , Hao Yanwei , Roustan Jean-Paul , Benichou Mohamed , Gibon Yves , Biais Benoît , Maury Pierre , Latché Alain , Pech Jean-Claude , Bouzayen Mondher , Zouine Mohamed 
Published: January 2013

AbstractSuccessful completion of fruit developmental programs depends on the interplay between multiple phytohormones. However, besides ethylene, the impact of other hormones on fruit quality traits remains elusive. A previous study has shown that down-regulation of SlARF4, a member of the tomato (Solanum lycopersicum) auxin response factor (ARF) gene family, results in a dark-green fruit phenotype with increased chloroplasts (Jones et al., 2002). This study further examines the role of this auxin transcriptional regulator during tomato fruit development at the level of transcripts, enzyme activities, and metabolites. It is noteworthy that the dark-green phenotype of antisense SlARF4-suppressed lines is restricted to fruit, suggesting that SlARF4 controls chlorophyll accumulation specifically in this organ. The SlARF4 underexpressing lines accumulate more starch at early stages of fruit development and display enhanced chlorophyll content and photochemical efficiency, which is consistent with the idea that fruit photosynthetic activity accounts for the elevated starch levels. SlARF4 expression is high in pericarp tissues of immature fruit and then undergoes a dramatic decline at the onset of ripening concomitant with the increase in sugar content. The higher starch content in developing fruits of SlARF4 down-regulated lines correlates with the up-regulation of genes and enzyme activities involved in starch biosynthesis, suggesting their negative regulation by SlARF4. Altogether, the data uncover the involvement of ARFs in the control of sugar content, an essential feature of fruit quality, and provide insight into the link between auxin signaling, chloroplastic activity, and sugar metabolism in developing fruit.
Males Are Overrepresented among Life Science Researchers Committing Scientific Misconduct
Authors: Fang Ferric C. , Bennett Joan W. , Casadevall Arturo 
Published: January 2013

ABSTRACTA review of the United States Office of Research Integrity annual reports identified 228 individuals who have committed misconduct, of which 94% involved fraud. Analysis of the data by career stage and gender revealed that misconduct occurred across the entire career spectrum from trainee to senior scientist and that two-thirds of the individuals found to have committed misconduct were male. This exceeds the overall proportion of males among life science trainees and faculty. These observations underscore the need for additional efforts to understand scientific misconduct and to ensure the responsible conduct of research.IMPORTANCEAs many of humanity’s greatest problems require scientific solutions, it is critical for the scientific enterprise to function optimally. Misconduct threatens the scientific enterprise by undermining trust in the validity of scientific findings. We have examined specific demographic characteristics of individuals found to have committed research misconduct in the life sciences. Our finding that misconduct occurs across all stages of career development suggests that attention to ethical aspects of the conduct of science should not be limited to those in training. The observation that males are overrepresented among those who commit misconduct implies a gender difference that needs to be better understood in any effort to promote research integrity.
Personalized Chemotherapy Profiling Using Cancer Cell Lines from Selectable Mice
Authors: Kamiyama Hirohiko , Rauenzahn Sherri , Shim Joong Sup , Karikari Collins A. , Feldmann Georg , Hua Li , Kamiyama Mihoko , Schuler F. William , Lin Ming-Tseh , Beaty Robert M. , Karanam Balasubramanyam , Liang Hong , Mullendore Michael E. , Mo Guanglan , Hidalgo Manuel , Jaffee Elizabeth , Hruban Ralph H. , Jinnah H.A. , Roden Richard B.S. , Jimeno Antonio , Liu Jun O. , Maitra Anirban , Eshleman James R. 
Published: January 2013

Abstract
Purpose: High-throughput chemosensitivity testing of low-passage cancer cell lines can be used to prioritize agents for personalized chemotherapy. However, generating cell lines from primary cancers is difficult because contaminating stromal cells overgrow the malignant cells.
Experimental Design: We produced a series of hypoxanthine phosphoribosyl transferase (hprt)-null immunodeficient mice. During growth of human cancers in these mice, hprt-null murine stromal cells replace their human counterparts.
Results: Pancreatic and ovarian cancers explanted from these mice were grown in selection media to produce pure human cancer cell lines. We screened one cell line with a 3,131-drug panel and identified 77 U.S. Food and Drug Administration (FDA)–approved drugs with activity, and two novel drugs to which the cell line was uniquely sensitive. Xenografts of this carcinoma were selectively responsive to both drugs.
Conclusion: Chemotherapy can be personalized using patient-specific cell lines derived in biochemically selectable mice. Clin Cancer Res; 19(5); 1139–46. ©2012 AACR.
PD-L1 on Tumor Cells Is Induced in Ascites and Promotes Peritoneal Dissemination of Ovarian Cancer through CTL Dysfunction
Authors: Abiko Kaoru , Mandai Masaki , Hamanishi Junzo , Yoshioka Yumiko , Matsumura Noriomi , Baba Tsukasa , Yamaguchi Ken , Murakami Ryusuke , Yamamoto Ayaka , Kharma Budiman , Kosaka Kenzo , Konishi Ikuo 
Published: January 2013

AbstractPurpose: Ovarian cancer often progresses by disseminating to the peritoneal cavity, but how the tumor cells evade host immunity during this process is poorly understood. Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be expressed in cancer cells. The purpose of this study is to elucidate the function of PD-L1 in peritoneal dissemination.Experimental Design: Ovarian cancer cases were studied by microarray and immunohistochemistry. PD-L1 expression in mouse ovarian cancer cell line in various conditions was assessed by flow cytometry. PD-L1–overexpression cell line and PD-L1–depleted cell line were generated, and cytolysis by CTLs was analyzed, and alterations in CTLs were studied by means of timelapse and microarray. These cell lines were injected intraperitoneally to syngeneic immunocompetent mice.Results: Microarray and immunohistochemistry in human ovarian cancer revealed significant correlation between PD-L1 expression and peritoneal positive cytology. PD-L1 expression in mouse ovarian cancer cells was induced upon encountering lymphocytes in the course of peritoneal spread in vivo and coculture with lymphocytes in vitro. Tumor cell lysis by CTLs was attenuated when PD-L1 was overexpressed and promoted when it was silenced. PD-L1 overexpression inhibited gathering and degranulation of CTLs. Gene expression profile of CTLs caused by PD-L1–overexpressing ovarian cancer was associated with CTLs exhaustion. In mouse models, PD-L1 depletion resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival.Conclusion: PD-L1 expression in tumor cell promotes peritoneal dissemination by repressing CTL function. PD-L1–targeted therapy is a promising strategy for preventing and treating peritoneal dissemination. Clin Cancer Res; 19(6); 1363–74. ©2012 AACR.
HIC1 Modulates Prostate Cancer Progression by Epigenetic Modification
Authors: Zheng Jianghua , Wang Jinglong , Sun Xueqing , Hao Mingang , Ding Tao , Xiong Dan , Wang Xiumin , Zhu Yu , Xiao Gang , Cheng Guangcun , Zhao Meizhong , Zhang Jian , Wang Jianhua 
Published: January 2013

Abstract
Purpose: Prostate cancer is the second leading cause of cancer deaths among men in Western counties, which has also occurred in Chinese male with markedly increasing incidence in recent years. Although the mechanism underlying its progression still remains unclear, epigenetic modifications are important ethological parameters. The purpose of this study is to determine the methylation status and function of hypermethylatioted in cancer 1 (HIC1) in prostate cancer progression.
Experimental Design: The methylation status of HIC1 promoter was assayed in cell lines, tissues, and plasma of patients with prostate cancer by using methylation-specific PCR and bisulfate sequencing PCR. The ability of HIC1 to regulate proliferation, migration, and invasion was assessed by MTT, scratch-healing assay, and reconstituted extracellular matrices in porous culture chambers. Tumorigenesis, metastases, and bone destruction were analyzed in mice bearing prostate cancer cells restoring HIC1 by using Xenogen IVIS with radiographic system and small-animal positron emission tomography computed tomographic images. Microarrays were searched for genes that had correlated expression with HIC1 mRNA. Reporter gene assays were used to determine whether HIC1 affected the expression of CXCR7, and chromatin immunoprecipitation was used to determine whether HIC1 bound to CXCR7 promoters. All P values were determined using 2-sided tests.
Results: The methylation status of 11 CpG sites within HIC1 promoter was abundantly methylated in cell lines, tissues, and plasma of patients with prostate cancer compared with those of respective normal controls. Restoring HIC1 expression in prostate cancer cells markedly inhibited proliferation, migration, and invasion and induced the apoptosis in these cells. Moreover, mice bearing prostate cancer–restoring HIC1 cells had a marked effect on reducing tumor growth, multiple tissue metastases, and bone destruction. Notably, we also identified that the chemokine receptor CXCR7 is a direct downstream target gene of HIC1. Finally, we showed that CXCR7 promoter in prostate cancer cells is negatively regulated by HIC1, which may be responsible for prostate cancer progression.
Conclusions: Our data show for the first time that hypermethylation of HIC1 promoter results in loss of its repressive function, responsible for prostate cancer progression and invasion. These findings suggest that therapies targeting epigenetic events regulating HIC1 expression may provide a more effective strategy for prostate cancer treatment. Clin Cancer Res; 19(6); 1400–10. ©2012 AACR.
Establishment and Validation of Circulating Tumor Cell–Based Prognostic Nomograms in First-Line Metastatic Breast Cancer Patients
Authors: Giordano Antonio , Egleston Brian L. , Hajage David , Bland Joseph , Hortobagyi Gabriel N. , Reuben James M. , Pierga Jean-Yves , Cristofanilli Massimo , Bidard Francois-Clement 
Published: January 2013

Abstract
Purpose: Circulating tumor cells (CTC) represent a new outcome-associated biomarker independent from known prognostic factors in metastatic breast cancer (MBC). The objective here was to develop and validate nomograms that combined baseline CTC counts and the other prognostic factors to assess the outcome of individual patients starting first-line treatment for MBC.
Experimental Design: We used a training set of 236 patients with MBCs starting a first-line treatment from the M.D. Anderson Cancer Center (Houston, TX) to establish nomograms that calculated the predicted probability of survival at different time points: 1, 2, and 5 years for overall survival (OS) and 6 months and 1 and 2 years for progression-free survival (PFS).The covariates computed in the model were age, disease subtype, visceral metastases, performance status, and CTC counts by CellSearch. Nomograms were independently validated with 210 patients with MBCs from the Institut Curie (Paris, France) who underwent first-line chemotherapy. The discriminatory ability and accuracy of the models were assessed using Harrell c-statistic and calibration plots at different time points in both training and validation datasets.
Results: Median follow-up was of 23 and 29 months in the MD Anderson and Institut Curie cohorts, respectively. Nomograms showed good c-statistics: 0.74 for OS and 0.65 for PFS and discriminated OS prediction at 1, 2, and 5 years, and PFS prediction at 6 months and 1 and 2 years.
Conclusions: Nomograms, which relied on CTC counts as a continuous covariate, easily facilitated the use of a web-based tool for estimating survival, supporting treatment decisions and clinical trial stratification in first-line MBCs. Clin Cancer Res; 19(6); 1596–602. ©2013 AACR.
Personalized Immune-Interception of Cancer and the Battle of Two Adaptive Systems—When Is the Time Right?
Authors: Dhodapkar Madhav V. 
Published: January 2013

Abstract
A growing body of evidence points to a coevolutionary model of cancer, wherein the cross-talk between tumor cells (or their subclones) and the host determine the malignant potential of individual tumors. Most of this natural history is clinically invisible and includes preneoplastic states. The capacity of the immune system to recognize these incipient lesions provides the basis for targeting them immunologically to arrest the development of preneoplasia toward clinical cancer. Kimura and colleagues provide evidence of immunogenicity of a potential cancer vaccine in patients with a history of advanced colon adenomas. These studies provide proof-of-principle or feasibility of such an approach in the clinic. Here, we discuss emerging opportunities and challenges in harnessing the immune system to “intercept” the precursor or preneoplastic lesions. Both cancer cells as well as the immune system represent independent and complex systems with plasticity and adaptive potential. It is therefore likely that specific aspects of the cross-talk between tumor cells and host may differ between individual tumors and determine the evolution of both tumors and the host response. We try to make the case to consider individualized approaches based on the genetic make-up of tumor cells and properties of the host response. Such strategies may be needed to optimally position the immune system to prevent cancers. Cancer Prev Res; 6(3); 173–6. ©2013 AACR.
Preinfarction Angina Reduces Infarct Size in ST-Elevation Myocardial Infarction Treated With Percutaneous Coronary Intervention
Authors: Reiter Ronald , Henry Timothy D. , Traverse Jay H. 
Published: January 2013

Background—
Preinfarction angina may act as a clinical surrogate of ischemic preconditioning that may reduce infarct size and improve mortality in the setting of thrombolytic therapy for ST-elevation myocardial infarction. However, the benefits of preinfarction angina in the setting of primary percutaneous coronary intervention with stenting is inconclusive because of the greater achievement of infarct artery patency and speed of reperfusion.

Methods and Results—

To identify a homogeneous population, we performed a retrospective analysis of 1031 patients admitted with a first ST-elevation myocardial infarction with ischemic times between 1 and 6 hours who received primary percutaneous coronary intervention. We identified 245 patients who had occluded arteries on presentation, of which 79 patients had documented preinfarction angina defined as chest pain within 24 hours of infarction. Infarct size was measured as the peak creatine kinase level, a metric supported in a subgroup by late enhancement on cardiac magnetic resonance imaging. Patients with preinfarction angina (n=79) had a 50% reduction in infarct size compared with those patients without preinfarction angina (n=166) by both peak creatine kinase (1094±75 IU/L versus 2270±102 IU/L;
P
<0.0001) and creatine kinase area under curve (18 420±18 941 versus 36 810±21 741 IU/h per liter;
P
<0.0001) despite having identical ischemic times (185±8 minutes versus 181±5 minutes;
P
=0.67) and angiographic area at risk (24.1±1.2% versus 25.3±0.9%;
P
=0.43). There was an absolute 4% improvement in left ventricular ejection fraction before discharge in those patients with preinfarction angina (
P
<0.02).

Conclusions—
The occurrence of preinfarction angina is associated with significant myocardial protection in the setting of primary percutaneous coronary intervention with stenting during ST-elevation myocardial infarction. Because preinfarction angina is relatively common, it is important that these patients be identified in clinical trials investigating therapies designed to reduce reperfusion injury and infarct size.
Amino Terminal Pro–B-Type Natriuretic Peptide, Secondary Stroke Prevention, and Choice of Antithrombotic Therapy
Authors: Longstreth W.T. , Kronmal Richard A. , Thompson John L.P. , Christenson Robert H. , Levine Steven R. , Gross Rebecca , Brey Robin L. , Buchsbaum Richard , Elkind Mitchell S.V. , Tirschwell David L. , Seliger Stephen L. , Mohr J.P. , deFilippi Christopher R. 
Published: January 2013

Background and Purpose—
Because of its association with atrial fibrillation and heart failure, we hypothesized that amino terminal pro–B-type natriuretic peptide (NT-proBNP) would identify a subgroup of patients from the Warfarin–Aspirin Recurrent Stroke Study, diagnosed with inferred noncardioembolic ischemic strokes, where anticoagulation would be more effective than antiplatelet agents in reducing risk of subsequent events.

Methods—
NT-proBNP was measured in stored serum collected at baseline from participants enrolled in Warfarin–Aspirin Recurrent Stroke Study, a previously reported randomized trial. Relative effectiveness of warfarin and aspirin in preventing recurrent ischemic stroke or death over 2 years was compared based on NT-proBNP concentrations.

Results—

About 95% of 1028 patients with assays had NT-proBNP below 750 pg/mL, and among them, no evidence for treatment effect modification was evident. For 49 patients with NT-proBNP >750 pg/mL, the 2-year rate of events per 100 person-years was 45.9 for the aspirin group and 16.6 for the warfarin group, whereas for 979 patients with NT-proBNP ≤750 pg/mL, rates were similar for both treatments. For those with NT-proBNP >750 pg/mL, the hazard ratio was 0.30 (95% confidence interval: 0.12–0.84;
P
=0.021) significantly favoring warfarin over aspirin. A formal test for interaction of NT-proBNP with treatment was significant (
P
=0.01).

Conclusions—
For secondary stroke prevention, elevated NT-proBNP concentrations may identify a subgroup of ischemic stroke patients without known atrial fibrillation, about 5% based on the current study, who may benefit more from anticoagulants than antiplatelet agents.

Clinical Trial Registration—
This trial was not registered because enrollment began before 2005.
The developmental and social history of repetitively aggressive mental health patients
Authors: Grenyer Brin FS , Lewis Kate L , Ilkiw-Lavalle Olga , Deane Rebecca , Milicevic Denise , Pai Nagesh 
Published: January 2013

Objective: A small subgroup of patients is primarily responsible for the large number of aggressive and violent incidents in psychiatric inpatient units. This study aims to identify the developmental, social and interpersonal histories of repeatedly aggressive patients in order to better understand their treatment needs. Methods: A total of 1269 consecutive inpatients were studied over 18 months, identifying 64 who were repeatedly aggressive; 128 non-aggressive patients were randomly matched to the aggressive patients by age, sex and diagnosis. Developmental, social, interpersonal and familial histories were obtained from a chart review. Results: Repeatedly aggressive patients were significantly more likely to have had a history of aggression, physical and sexual abuse, and experienced interpersonal problems and parental divorce. Conclusions: Aggressive patients do not just need short-term skills training, but interventions that target interpersonal and personality disorder deficits associated with their developmental histories.
In vitro evaluation of sedative drug losses during extracorporeal membrane oxygenation
Authors: Mulla H , Lawson G , von Anrep C , Burke M D , Upton D U , Firmin R K , Killer H 
Published: January 2013

Sedative agents are routinely administered to critically ill patients, both on and off extracorporeal membrane oxygenation (ECMO), to enable patients to be comfortable and facilitate patient management. It has been observed empirically in our paediatric intensive care unit that doses of sedative drugs required to achieve desired levels of sedation in ECMO patients are far greater than those used in non-ECMO patients. These differences could not simply be accounted for by differences in patient types, clinical status or sedation levels. We therefore undertook an in vitro evaluation of drug binding in ECMO circuits. This study investigated how the polyvinyl chloride (PVC) and silicone rubber components of neonatal ECMO circuits affect drug delivery in patients through drug sorption. Phase 1 investigated drug uptake by the two polymers in static solutions of known concentrations of four commonly used sedative drugs: lorazepam, midazolam, diazepam and propofol. Phase 2 involved the setting up of a complete neonatal ECMO circuit, injecting the drug solutions pre-reservoir at a flow rate of 350 ml/min and collecting samples post-oxygenator for analysis. Phase 1 results revealed significant uptake of drugs with losses in the range 40-98% and in the order propofol • diazepam • midazolam • lorazepam. Phase 2 results were similar and in the first 40 min of running an ECMO circuit only 10% of propofol passed through the circuit. These results may help to explain observed clinical phenomena and raise important issues regarding drug dosing in ECMO patients.