bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PL-1: Genome-Directed Therapeutics for Endocrine Therapy Resistant ER+ Breast Cancer
Authors: Ellis Matthew J. 
Published: May 2015

Abstract
As a result of improvements in DNA and RNA sequencing techniques the genomic structure of estrogen receptor positive breast cancer is increasingly well documented, but extracting clinically actionable information from these complex data sets has proved fraught with difficulties. Barriers to progress include the lack of pharmacological hypotheses for novel luminal breast cancer tumor suppressor genes (e.g. MAP3K1, MLL3, SF3B1); 2) a lack of a full understanding of interactions between mutation status, the prognosis of ER+ breast cancer, and the effectiveness of endocrine therapy; 3) an inadequate collection of patient-derived xenograft (PDX) models for luminal breast cancer that fully encompass the heterogeneity of the disease; 4) the logistical barriers of developing adjuvant strategies to exploit rare drivers present in less than 5% of tumor samples; 5) insufficient genomic discovery efforts directed towards samples accrued from patients suffering from endocrine therapy resistant disease progression and 6) an incomplete understanding of how complex somatic genotypes drive the biochemical events responsible for the “hallmarks” of luminal cancer.
To better address these issues, five areas of investigation will be discussed: 1) somatic mutation diagnosis in DNA from primary breast cancer samples from patients treated with adjuvant tamoxifen and followed for over 20 years; 2) DNA and RNA sequencing of samples accrued from patients treated with neoadjuvant endocrine therapy to define the molecular origins of intrinsic aromatase inhibitor resistance and to identify pharmacological hypothesis; 3) efforts to expand and catalog patient-derived xenografts from ER+ breast cancers, including the use of mass spectrometry-based analysis of their proteomes and phosphoproteomes to expand our knowledge of the biochemistry of individual tumors; 4) a functional and pharmacological investigation of mutations in ESR1, including resistance-activating chromosomal translocations, and 5) the development of a neoadjuvant endocrine therapy strategy that identifies patients with intrinsic endocrine therapy resistance within a month of starting treatment so that they can be triaged to mutation-matched investigational treatment.
Citation Format: Matthew J. Ellis. Genome-Directed Therapeutics for Endocrine Therapy Resistant ER+ Breast Cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PL-1.
Abstract S3-05: Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in NSABP trial B-31
Authors: Paik Soonmyung , Pogue-Geile Katherine L , Song Nan , Gavin Patrick G , Kim Seong-Rim 
Published: May 2015

Abstract
Purpose: Considerable molecular heterogeneity exists among HER2-positive breast cancer regarding gene expression and mutation profiling. Evidence from preclinical, clinical neoadjuvant, and metastatic clinical trials suggested PIK3CA mutational status and PAM50 intrinsic subtype of a tumor were markers of response to anti-HER2 therapies. We evaluated the predictive value of these two biomarkers in the adjuvant setting using archived tumor blocks from NSABP trial B-31.
Methods: Expression data for 49 genes using the nCounter platform was used to generate PAM50 intrinsic subtypes for 1,578 archived tumor blocks from B-31. Five PIK3CA hotspot mutations were examined by mass spectrometry of the primer extension products in a randomly selected subset (N=671). We examined the heterogeneity of trastuzumab treatment effect across different subsets defined by each marker using Cox regression and disease free survival as the endpoint.
Results: 741/1578 (47.0%) tumors were classified as HER2E subtype; and 166/671 (24.7%) had PIK3CA mutations. Hazard ratios (HR) for trastuzumab in HER2E and other subtypes were 0.44 (95%CI: 0.34-0.58, p&lt;0.001) and 0.47 (95% CI: 0.35-0.62, p&lt;0.001), respectively (interaction p=0.67). HRs for trastuzumab in PIK3CA wild type and mutated were 0.51 (95%CI: 0.37-0.71, p&lt;0.001) and 0.44 (95%CI: 0.24-0.82, p=0.009), respectively (interaction p=0.64).
Conclusion: Unlike results seen in the metastatic and neoadjuvant clinical trials, PIK3CA and PAM50 intrinsic subtypes were not biomarkers for differential response to trastuzumab in NSABP B-31. These data suggest that results from the metastatic and neoadjuvant setting may not be always applicable to the adjuvant setting.
Support: National Cancer Institute, Department of Health and Human Services, Public Health Service, Grants U10-CA-12027, U10-CA-69651, U10-CA-37377, and U10-CA-69974, and by a grant from the Pennsylvania State Department of Health. The latter Department specifically disclaims responsibility for any analysis, interpretations or conclusions.
Citation Format: Soonmyung Paik, Katherine L Pogue-Geile, Nan Song, Patrick G Gavin, Seong-Rim Kim. Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in NSABP trial B-31 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S3-05.
Next-Generation Sequencing of Stage IV Squamous Cell Lung Cancers Reveals an Association of PI3K Aberrations and Evidence of Clonal Heterogeneity in Patients with Brain Metastases
Authors: Paik Paul K. , Shen Ronglai , Won Helen , Rekhtman Natasha , Wang Lu , Sima Camelia S. , Arora Arshi , Seshan Venkatraman , Ladanyi Marc , Berger Michael F. , Kris Mark G. 
Published: May 2015

Abstract
Large-scale genomic characterization of squamous cell lung cancers (SQCLC) has revealed several putative oncogenic drivers. There are, however, little data to suggest that these alterations have clinical relevance. We performed comprehensive genomic profiling (including next-generation sequencing) of 79 stage IV SQCLCs and analyzed differences in the clinical characteristics of two major SQCLC subtypes: FGFR1 amplified and PI3K aberrant. Patients with PI3K-aberrant tumors had aggressive disease marked by worse survival (median overall survival, 8.6 vs. 19.1 months, P &lt; 0.001), higher metastatic burden (&gt;3 organs, 18% vs. 3%, P = 0.025), and greater incidence of brain metastases (27% vs. 0% in others, P &lt; 0.001). We performed whole-exome and RNA sequencing on paired brain metastases and primary lung cancers to elucidate the metastatic process to brain. SQCLC primaries that gave rise to brain metastases exhibited truncal PTEN loss. SQCLC brain metastases exhibited a high degree of genetic heterogeneity and evidence of clonal differences between their primary sites.
Significance: We performed next-generation sequencing of metastatic SQCLCs and primary lung–brain metastasis pairs, identifying PI3K-aberrant tumors as an aggressive subset associated with brain metastases. We identified genetic heterogeneity between lung primaries–brain metastases as well as clonal populations that may highlight alterations important in the metastatic process. Cancer Discov; 5(6); 610–21. ©2015 AACR.
This article is highlighted in the In This Issue feature, p. 565
Protective Role of Peroxisome Proliferator–Activated Receptor-γ in the Development of Intracranial Aneurysm Rupture
Authors: Shimada Kenji , Furukawa Hajime , Wada Kosuke , Korai Masaaki , Wei Yuan , Tada Yoshiteru , Kuwabara Atsushi , Shikata Fumiaki , Kitazato Keiko T. , Nagahiro Shinji , Lawton Michael T. , Hashimoto Tomoki 
Published: May 2015

Background and Purpose—
Inflammation is emerging as a key component of the pathophysiology of intracranial aneurysms. Peroxisome proliferator–activated receptor-γ (PPARγ) is a nuclear hormone receptor of which activation modulates various aspects of inflammation.

Methods—
Using a mouse model of intracranial aneurysm, we examined the potential roles of PPARγ in the development of rupture of intracranial aneurysm.

Results—
A PPARγ agonist, pioglitazone, significantly reduced the incidence of ruptured aneurysms and the rupture rate without affecting the total incidence aneurysm (unruptured aneurysms and ruptured aneurysms). PPARγ antagonist (GW9662) abolished the protective effect of pioglitazone. The protective effect of pioglitazone was absent in mice lacking macrophage PPARγ. Pioglitazone treatment reduced the mRNA levels of inflammatory cytokines (monocyte chemoattractant factor-1, interleukin-1, and interleukin-6) that are primarily produced by macrophages in the cerebral arteries. Pioglitazone treatment reduced the infiltration of M1 macrophage into the cerebral arteries and the macrophage M1/M2 ratio. Depletion of macrophages significantly reduced the rupture rate.

Conclusions—
Our data showed that the activation of macrophage PPARγ protects against the development of aneurysmal rupture. PPARγ in inflammatory cells may be a potential therapeutic target for the prevention of aneurysmal rupture.
Protease-Activated Receptor 1 and 4 Signal Inhibition Reduces Preterm Neonatal Hemorrhagic Brain Injury
Authors: Lekic Tim , Klebe Damon , McBride Devin W. , Manaenko Anatol , Rolland William B. , Flores Jerry J. , Altay Orhan , Tang Jiping , Zhang John H. 
Published: May 2015

Background and Purpose—
This study examines the role of thrombin’s protease-activated receptor (PAR)-1, PAR-4 in mediating cyclooxygenase-2 and mammalian target of rapamycin after germinal matrix hemorrhage.

Methods—
Germinal matrix hemorrhage was induced by intraparenchymal infusion of bacterial collagenase into the right ganglionic eminence of P7 rat pups. Animals were treated with PAR-1, PAR-4, cyclooxygenase-2, or mammalian target of rapamycin inhibitors by 1 hour, and ≤5 days.

Results—
We found increased thrombin activity 6 to 24 hours after germinal matrix hemorrhage, and PAR-1, PAR-4, inhibition normalized cyclooxygenase-2, and mammalian target of rapamycin by 72 hours. Early treatment with NS398 or rapamycin substantially improved long-term outcomes in juvenile animals.

Conclusions—
Suppressing early PAR signal transduction, and postnatal NS398 or rapamycin treatment, may help reduce germinal matrix hemorrhage severity in susceptible preterm infants.
Sulcal Effacement With Preserved Gray–White Junction
Authors: Haussen Diogo C. , Lima Andrey , Frankel Michael , Anderson Aaron , Belagaje Samir , Nahab Fadi , Rangaraju Srikant , Nogueira Raul G. 
Published: May 2015

Background and Purpose—
Sulcal effacement with preserved underlying gray–white matter junction (isolated sulcal effacement [ISE]) in acute ischemic stroke may not represent irreversible parenchymal injury. We aimed to evaluate the frequency and significance of ISE in patients with large vessel occlusion acute ischemic stroke.

Methods—
Consecutive acute ischemic stroke patients with middle cerebral artery M1 or internal carotid artery terminus occlusions who underwent computed tomography angiogram/perfusion followed by intra-arterial therapy were screened for ISE.

Results—

Out of the 568 patients who underwent intra-arterial therapy between March 2011 and September 2014, 108 fulfilled inclusion criteria. ISE was present in 8 (7.4%) patients (age 55.7±10.5 years, 6 female, baseline National Institutes of Health Stroke Scale 16.1±3.8, 5 middle cerebral artery-M1, and 3 internal carotid artery terminus occlusions). Computed tomography angiogram revealed engorged/dilated leptomeningeal vessels obliterating the sulci within the areas of effacement, whereas computed tomography perfusion indicated normal-to-increased cerebral blood volume and prolonged
T
max
in all patients. Modified treatment in cerebral ischemia (mTICI) 2b-3 reperfusion was achieved in all patients. Follow-up imaging confirmed no infarct in the ISE area in all patients, and 5 (62%) had modified Rankin Scale 0 to 2 at 3 months.

Conclusions—
Sulcal effacement with preserved gray–white delineation is occasionally visualized in patients with proximal occlusion strokes, relates to robust leptomeningeal collaterals, and indicates preserved underlying parenchyma. ISE should not be used to exclude patients from thrombectomy.
Improved Prediction of Bay of Bengal Tropical Cyclones through Assimilation of Doppler Weather Radar Observations
Authors: Osuri Krishna K. , Mohanty U. C. , Routray A. , Niyogi Dev 
Published: May 2015

Abstract
The impact on tropical cyclone (TC) prediction from assimilating Doppler weather radar (DWR) observations obtained from the TC inner core and environment over the Bay of Bengal (BoB) is studied. A set of three operationally relevant numerical experiments were conducted for 24 forecast cases involving 5 unique severe/very severe BoB cyclones: Sidr (2007), Aila (2009), Laila (2010), Jal (2010), and Thane (2011). The first experiment (CNTL) used the NCEP FNL analyses for model initial and boundary conditions. In the second experiment [Global Telecommunication System (GTS)], the GTS observations were assimilated into the model initial condition while the third experiment (DWR) used DWR with GTS observations. Assimilation of the TC environment from DWR improved track prediction by 32%–53% for the 12–72-h forecast over the CNTL run and by 5%–25% over GTS and was consistently skillful. More gains were seen in intensity, track, and structure by assimilating inner-core DWR observations as they provided more realistic initial organization/asymmetry and strength of the TC vortex. Additional experiments were conducted to assess the role of warm-rain and ice-phase microphysics to assimilate DWR reflectivity observations. Results indicate that the ice-phase microphysics has a dominant impact on inner-core reflectivity assimilation and in modifying the intensity evolution, hydrometeors, and warm core structure, leading to improved rainfall prediction. This study helps provide a baseline for the credibility of an observational network and assist with the transfer of research to operations over the India monsoon region.
Quality of life in rheumatological patients
Authors: Uguz Faruk , Kucuk Adem , Cicek Erdinc , Kayhan Fatih , Salli Ali , Guncu Hatice , Çilli Ali Savas 
Published: May 2015

Objective Rheumatological diseases are associated with lower quality of life (QoL) levels. Psychiatric disturbances are frequently observed in these patients. This study examined the impact of personality disorders on the QoL of patients with rheumatological diseases. Method The study sample consisted of 142 participants including patients suffering from rheumatological disease with a personality disorder ( n = 30), without any personality disorder ( n = 112), and healthy control participants without physical or psychiatric disorders ( n = 60). The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID-I) and the Structured Clinical Interview for DSM, Revised Third Edition Personality Disorders (SCID-II) were used to determine Axis I and Axis II psychiatric disorders, respectively. QoL levels were assessed by means of the World Health Organization QoL Assessment-Brief. Results The subscale scores of physical health, psychological health, and social relationships were significantly lower in patients with rheumatological disease regardless of the existence of personality disorder compared with the control participants. Rheumatological patients with a personality disorder had significantly lower subscale scores of psychological health ( p = 0.003) and social relationships ( p < 0.003) compared with patients without any personality disorder. Conclusions Personality disorders seem to be a relevant factor that maybe associated with QoL in patients suffering from rheumatological disease.
Hemodynamics of 17-mm vs. 19-mm St. Jude Medical Regent and annulus enlargement
Authors: Prifti Edvin , Bonacchi Massimo , Baboci Arben , Giunti Gabriele , Esposito Giampiero , Krakulli Klodian , Ademaj Fadil , Kajo Efrosina , Vanini Vitttorio 
Published: May 2015

Objective We aimed to compare early and midterm clinical and hemodynamic outcomes of 17-mm vs. 19-mm St. Jude Medical Regent valves with concomitant aortic annulus enlargement. Methods Between 1999 and 2012, 20 patients (group 1) underwent first-time aortic valve replacement with a 17-mm St. Jude Medical Regent valve, and 35 patients (group 2) had a 19-mm valve and concomitant aortic annulus enlargement. The mean follow-up was 81 ± 37 months (range 20–110 months). Results There was one death in group 1 vs. 4 in group 2 ( p > 0.05). The mean postoperative transprosthetic gradient was 17.5 ± 4.5 in group 1 and 17 ± 6.4 mm Hg in group 2 ( p = 0.83), and 37 ± 10.7 and 32 ± 13 mm Hg, respectively, under stress ( p = 0.17). Left ventricular mass and left ventricular mass index were reduced and similar in both groups. Postoperative effective orifice area index was higher in group 2 (0.85 ± 0.17 cm2 m−2) than group 1 (0.76 ± 0.2 cm2 m−2; p > 0.05). A multivariate Cox model identified a 19-mm valve with aortic annulus enlargement ( p = 0.032), functional class ( p = 0.025), reoperation ( p = 0.04), ejection fraction < 35% ( p = 0.042), and combined surgery ( p = 0.04) as strong predictors of poorer overall event-free survival. Conclusions The 17-mm St. Jude Medical Regent valve may be employed with satisfactory postoperative clinical and hemodynamic outcomes in patients with a small aortic annulus, as an alternative to a larger prothesis with aortic annulus enlargement.
Results of a transparent expert consultation on patient and public involvement in palliative care research
Authors: Daveson Barbara A , de Wolf-Linder Susanne , Witt Jana , Newson Kirstie , Morris Carolyn , Higginson Irene J , Evans Catherine J 
Published: May 2015

Background: Support and evidence for patient, unpaid caregiver and public involvement in research (user involvement) are growing. Consensus on how best to involve users in palliative care research is lacking. Aim: To determine an optimal user-involvement model for palliative care research. Design: We hosted a consultation workshop using expert presentations, discussion and nominal group technique to generate recommendations and consensus on agreement of importance. A total of 35 users and 32 researchers were approached to attend the workshop, which included break-out groups and a ranking exercise. Descriptive statistical analysis to establish consensus and highlight divergence was applied. Qualitative analysis of discussions was completed to aid interpretation of findings. Setting/participants: Participants involved in palliative care research were invited to a global research institute, UK. Results: A total of 12 users and 5 researchers participated. Users wanted their involvement to be more visible, including during dissemination, with a greater emphasis on the difference their involvement makes. Researchers wanted to improve productivity, relevance and quality through involvement. Users and researchers agreed that an optimal model should consist of (a) early involvement to ensure meaningful involvement and impact and (b) diverse virtual and face-to-face involvement methods to ensure flexibility. Conclusion: For involvement in palliative care research to succeed, early and flexible involvement is required. Researchers should advertise opportunities for involvement and promote impact of involvement via dissemination plans. Users should prioritise adding value to research through enhancing productivity, quality and relevance. More research is needed not only to inform implementation and ensure effectiveness but also to investigate the cost-effectiveness of involvement in palliative care research.
Epidemiology of Overuse Injuries in Collegiate and High School Athletics in the United States
Authors: Roos Karen G. , Marshall Stephen W. , Kerr Zachary Y. , Golightly Yvonne M. , Kucera Kristen L. , Myers Joseph B. , Rosamond Wayne D. , Comstock R. Dawn 
Published: May 2015

Background: Overuse injuries result from microtrauma due to repetitive loading combined with insufficient tissue recovery time and can result in both immediate and long-term time loss from sports. Hypothesis: Overuse injury rates and patterns differ across college and high school populations, sport, and sex. Study Design: Descriptive epidemiology study. Methods: Surveillance data for 16 sports from the National Collegiate Athletic Association’s Injury Surveillance System (NCAA ISS; 2004-2005 through 2008-2009) and 14 sports from High School Reporting Information Online (High School RIO; 2006-2007 through 2012-2013) were analyzed. All reported injuries had an injury mechanism of overuse/gradual onset (college) or overuse/chronic (high school). Overuse injury incidence rates were calculated, and rate ratios with 95% CIs were used to compare subgroups. Results: The rate of overuse injury was 3.28 times higher in college than high school sports (95% CI, 3.12-3.44). The rate of overuse injury among sex-comparable sports was higher in female than male athletes in both populations (college rate ratio, 1.25; 95% CI, 1.16-1.35; high school rate ratio, 1.55; 95% CI, 1.43-1.68). The lower extremity was the most commonly injured body site (college, 69.4%; high school, 70.4%). A larger proportion of overuse injuries among college athletes resulted in time loss of more than 21 days (college, 20.4%; high school, 7.7%) and surgery (college, 5.2%, high school, 2.5%). Conclusion: Overuse injuries can impose a significant burden on college and high school athletes. Interventions addressing prevention of overuse injury are needed.
Lyn sustains oncogenic signaling in chronic lymphocytic leukemia by strengthening SET-mediated inhibition of PP2A
Authors: Zonta Francesca , Pagano Mario Angelo , Trentin Livio , Tibaldi Elena , Frezzato Federica , Trimarco Valentina , Facco Monica , Zagotto Giuseppe , Pavan Valeria , Ribaudo Giovanni , Bordin Luciana , Semenzato Gianpietro , Brunati Anna Maria 
Published: May 2015

Key PointsCytosolic HSP90-bound Lyn mediates resistance to apoptosis by strengthening PP2A/SET interaction in CLL cells. FTY720-analogues antagonizing the PP2A/SET interaction and Lyn inhibitors may provide a therapeutic approach of CLL.
A systematic review of transfusion-associated graft-versus-host disease
Authors: Kopolovic Ilana , Ostro Jackie , Tsubota Hideki , Lin Yulia , Cserti-Gazdewich Christine M. , Messner Hans A. , Keir Amy K. , DenHollander Neal , Dzik Walter S. , Callum Jeannie 
Published: May 2015

Key PointsFifty percent of TA-GVHD cases occur in patients who would not be predicted to be at risk for TA-GVHD by current guidelines for blood irradiation. Donor lymphocytes whose HLA antigens are all shared by the recipient dominate in TA-GVHD cases, particularly in immune-competent recipients.