tbuckley/cabot-search huggingface dataset:
Abstract 15098: Impact of Early Initiation of Intravenous Prostanoid Therapy in Patients With Eisenmenger Syndrome
Authors: Nishtha Sodhi, Vedant Gupta, Kathryn Stackhouse, Omar Minai, Raed Dweik, Richard A Krasuski
Journal: Circulation (2013)

Background: Eisenmenger Syndrome (ES) is the most advanced form of shunt-related pulmonary vascular disease and associated with considerable morbidity and mortality. While advanced oral therapy is ...
Abstract 15454: Inhibition of Mechanistic Target of Rapamycin by Heterozygous Deletion of Raptor Ameliorates Pressure-overload Induced Heart Failure and the Associated Proteomics Remodeling
Authors: Dao Fu Dai
Journal: Circulation (2014)

Background: We reported that inhibition of mechanistic target of rapamycin (mTOR) by short-term rapamycin or caloric restriction ameliorates age-dependent cardiac hypertrophy and diastolic dysfunction. Although inhibition of mTOR signaling is well known to regulate metabolism and suppress protein synthesis, the mechanisms of beneficial effect of mTOR inhibition in cardiac hypertrophy and failure are not fully understood. Method: To investigate the mechanisms underlying beneficial effect of mTOR inhibition, we used the transverse aortic constriction (TAC)-induced heart failure model and examined the effect of heterozygous deletion of Raptor (Raptor het), a component of mTOR complex 1, and transgenic overexpression of cardiac specific wild type or mutant 4EBP1, one of the main downstream target of mTOR complex 1. Global proteomics analysis was performed using an improved label-free quantitative shotgun approach, followed by Ingenuity Pathway analysis. Results: In wild-type mice with TAC-induced heart failure, global proteomics analysis revealed decreased abundance of proteins involved in mitochondrial function, electron transport chain, citric acid cycle and fatty acid metabolism and increased abundance of proteins involved in several signaling pathways (RhoA, actin, integrin) as well as oxidative stress response and protein ubiquitin pathways. Raptor het attenuate TAC induced heart failure, accompanied by better preservation of proteomics remodeling, especially the proteins involved in mitochondrial function, citric acid cycle and protein ubiquitination pathways. In contrast, either transgenic overexpression of wild type 4EBP1 or mutant 4EBP1 abolish the adaptive hypertrophy in response to TAC by suppressing protein translation, and thereby aggravate heart failure, in parallel with adverse remodeling of left ventricular proteomes. Neonatal cardiomyocyte experiments reveal that PGC1-α and Sirt3 are among the candidate signaling mechanisms linking the mTOR inhibition and mitochondrial metabolism. Conclusion: mTOR inhibition by Raptor heterozygous deletion, but not overexpression of 4EBP1, ameliorates TAC-induced heart failure and associated with better preservation of mitochondrial proteome.
Cox-2 inhibition and chemoradiation for squamous cell carcinoma of the head and neck
Authors: S. Spencer, L. Nabell, J. Bonner, G. Peters, W. L. Carroll, R. Meredith, L. Clemons, R. Ove
Journal: Journal of Clinical Oncology (2008)

6065 Background: Concurrent chemoradiation is accepted as a standard option for locally advanced squamous cell carcinoma of the head and neck (SCCHN). Other strategies however are needed in order to improve local regional control and ultimate outcomes. Cyclo-oxygenase 2 (Cox-2) inhibition induces radiosentization and chemosentization. We conducted a Phase I/II trial using chemoradiation with Celecoxib in advanced SCCHN and reported the results after a 4 year median follow-up. Methods: From 12/02- 7/06 30 patients with locally advanced or recurrent SCCHN were entered. The objectives were to evaluate toxicity, determine the local control and disease free survival. Patients were treated with weekly carboplatin (AUC=2.0), paclitaxel (30mg/m2), radiotherapy (70Gy) and celecoxib 400mg bid. The celecoxib was started 1 week prior to the initiation of the concurrent chemoradiotherapy. Initially the celecoxib was given for a total of 2 years. After reports of concerns for cardiotoxicity, we discontinued the study 12/04. The study was restarted in 5/06. Celecoxib was used only during chemoradiotherapy thereafter. Results: Twenty-seven patients with newly diagnosed SCCHN and 3 patients with recurrent disease were treated. Seven patients were treated after study modification. The acute grade >3 toxicity was as follows: Febrile neutropenia 23%, mucositis 33%, dysphagia 63%, nausea/vomiting 17%, dermatitis 30%. Ten patients were unable to complete prescribed chemotherapy secondary to myelosuppression. There were 2 deaths during the treatment phase of the trial, both in the absence of neutropenia. One person expired secondary to delirious tremors and infection and another secondary to unknown causes. Nineteen of 30 patients are currently NED (63%) four of which required surgical salvage. Twenty of 30 patients achieved initial local control with 5 developing distant metastasis only. Conclusions: Concurrent chemoradiotherapy plus celecoxib was associated with an increased incidence of neutropenia. Control rates were similar to previously published concurrent chemoradiotherapy trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb, ImClone Systems Incorporated
Doug Lowy Becomes Acting Director of National Cancer Institute
Authors: C. Schmidt
Journal: JNCI Journal of the National Cancer Institute (2015)

April 1.He takes over during rapid advances in cancer research, but also when the NCI budget is lower today than a decade ago when adjusted for inflation.Known as a consensus builder and for groundbreaking research that led to vaccines against human papillomavirus (HPV)-a cause of cervical cancer-Lowy succeeds Harold Varmus, M.D., a Nobel Prize winner and NCI director since 2010.Varmus shaped an agenda that emphasized global health, precision medicine, and creation of NCI's National Clinical Trials Network.Lowy served as Varmus' deputy director, and said he doesn't plan any major changes."I'm looking forward to continuing most of the current policies that we already have, but with the flexibility to adapt to changing needs and opportunities over time," Lowy said."It's a big job, and the challenge is to be as strategic as possible and to support the most meritorious research."John Schiller, Ph.D., deputy chief of NCI's laboratory of cellular oncology partnered with Lowy on the HPV research."Lowy recognizes good science when he sees it, and that's crucially important for someone in his position," Schiller said."I marvel at the number of things he can juggle in his head in a single day-he not only keeps track of things, he synthesizes them in a very big-picture way.We're lucky to have him.
Abstract 093: Adrenergic Stimulation Induces Mitochondrial Fragmentation and Cell Injury through PKD1-dependent Phosphorylation of DLP1 in H9c2 Cardiac Myoblasts.
Authors: Bong Sook Jhun, Jin O-Uchi, Stephen Hurst, Shey-Shing Sheu
Journal: Circulation Research (2013)

Introduction: Regulation of mitochondrial morphology and dynamics is crucial for the maintenance of various cellular functions in cardiac myocytes. Abnormal mitochondrial morphologies concomitant with mitochondrial dysfunction are frequently observed in various pathophysiological states of human heart such as heart failure, where the catecholamine level is elevated. However, it is still unclear what kinds of cardiac signaling pathways regulate mitochondrial morphology and function under pathophysiological conditions. Hypothesis: Adrenergic signaling induces cardiac mitochondrial morphology changes and mitochondrial dysfunction, which simultaneously contribute to cardiac injury. Methods: H9c2 cardiac myoblasts were stimulated by α 1 -adrenoceptor (α 1 -AR) agonist phenylephrine and mitochondrial morphology was monitored by confocal microscopy. Translocation and phosphorylation of a mitochondrial fission protein, dynamin-like protein 1 (DLP1) was observed from whole cell lysates, cytosolic proteins and mitochondrial proteins by western blotting. Results: We found that persistent α 1 -AR stimulation induced mitochondrial fragmentation, followed by an increase in the production of mitochondrial reactive oxygen species (ROS) and the release of cytochrome c from mitochondria to the cytosol in H9c2 cardiac myoblasts. These effects were abolished by the treatment of α 1 -AR antagonist, prazosin. Further, mitochondrial fragmentation by α 1 -AR stimulation was inhibited by expression of the dominant-negative fission mutant DLP1-K38A, suggesting that the mitochondrial fission is required for mitochondrial fragmentation observed in α 1 -AR stimulation. We also found that DLP1 was translocated from cytosol to mitochondria under α 1 -AR stimulation. In addition, activation of protein kinase D1 (PKD1), a protein kinase downstream of α 1 -AR signaling, led to the phosphorylation of DLP1 at serine 637 which lies within a putative PKD phosphorylation consensus motif. Conclusion: α 1 -AR signaling induces mitochondrial fragmentation and cell injury, possibly through PKD1-dependent phosphorylation of DLP1.
Automated longitudinal monitoring of in vivo protein aggregation in neurodegenerative disease C. elegans models
Authors: Matteo Cornaglia, Gopalan Krishnamani, Laurent Mouchiroud, Vincenzo Sorrentino, Thomas Lehnert, Johan Auwerx, Martin A. M. Gijs
Journal: Molecular Neurodegeneration (2016)

While many biological studies can be performed on cell-based systems, the investigation of molecular pathways related to complex human dysfunctions – e.g. neurodegenerative diseases – often requires long-term studies in animal models. The nematode Caenorhabditis elegans represents one of the best model organisms for many of these tests and, therefore, versatile and automated systems for accurate time-resolved analyses on C. elegans are becoming highly desirable tools in the field. We describe a new multi-functional platform for C. elegans analytical research, enabling automated worm isolation and culture, reversible worm immobilization and long-term high-resolution imaging, and this under active control of the main culture parameters, including temperature. We employ our platform for in vivo observation of biomolecules and automated analysis of protein aggregation in a C. elegans model for amyotrophic lateral sclerosis (ALS). Our device allows monitoring the growth rate and development of each worm, at single animal resolution, within a matrix of microfluidic chambers. We demonstrate the progression of individual protein aggregates, i.e. mutated human superoxide dismutase 1 - Yellow Fluorescent Protein (SOD1-YFP) fusion proteins in the body wall muscles, for each worm and over several days. Moreover, by combining reversible worm immobilization and on-chip high-resolution imaging, our method allows precisely localizing the expression of biomolecules within the worms' tissues, as well as monitoring the evolution of single aggregates over consecutive days at the sub-cellular level. We also show the suitability of our system for protein aggregation monitoring in a C. elegans Huntington disease (HD) model, and demonstrate the system's ability to study long-term doxycycline treatment-linked modification of protein aggregation profiles in the ALS model. Our microfluidic-based method allows analyzing in vivo the long-term dynamics of protein aggregation phenomena in C. elegans at unprecedented resolution. Pharmacological screenings on neurodegenerative disease C. elegans models may strongly benefit from this method in the near future, because of its full automation and high-throughput potential.
Risk factors for hospitalization in elderly cancer patients receiving chemotherapy
Authors: J. M. Kleiner, E. Culakova, D. C. Dale, J. Crawford, M. S. Poniewierski, D. A. Wolff, H. Lyman
Journal: Journal of Clinical Oncology (2007)

9035 Background: Chemotherapy-associated hospitalization is a major source of morbidity and cost in cancer care, particularly for elderly (age ≥ 65) cancer patients. Hospitalization in the elderly often leads to an irreversible decline in functional status unrelated to the acute event that prompted hospital admission. Currently, little is known about the risk factors that may lead to increased risk of hospitalization in elderly patients receiving chemotherapy (CTX). Methods: 871 patients with solid tumors or lymphoma initiating a new CTX regimen were prospectively enrolled at 60 randomly selected US community oncology sites between 8/2004 and 10/2005. Of these, 361 elderly patients aged 65–91 were identified and followed. Primary endpoint of this investigation was hematologic toxicity and hospitalization was secondary. Pre- CTX patient data were analyzed for increased risk of hospitalization in univariate analysis using the chi-square test. Results: A total of 155 (18%) patients were hospitalized resulting in 215 hospitalizations. Median time to first hospitalization was the second cycle of CTX. 81/361 (22%) of elderly patients were hospitalized compared to only 74/510 (15%) of younger patients (p=0.003). The rate of hospitalization increased in a linear fashion between ages 65–80. Reasons for hospitalization in the elderly included infection, fever, or febrile neutropenia (36%), cardiopulmonary disease (CPD) (12%), vomiting or dehydration (13%), other gastrointestinal (11%), transfusion (8%), thrombosis (4%), CTX administration (4%), and other (13%). Major independent pre-CTX factors that predicted hospitalization in the elderly included male gender (p=0.0004), hemoglobin &lt;11 g/dL (p=0.02), abnormal platelet count (&lt;150k or &gt;350k) (p=0.05), CPD (p=0.03), creatinine &gt;1.5 mg/dL (p=0.05), and ≥ 2 concomitant medications (p=0.0008). Elderly patients with lung cancer (p=0.001) and lymphoma (p=0.05) had significantly higher rates of hospitalization when compared to other solid tumors. Conclusions: These data suggest that the risk of hospitalization increases in elderly cancer patients with age and that pre-CTX factors may be useful in identifying a subpopulation at increased risk for hospitalization. No significant financial relationships to disclose.
GSK is fined £38m for delaying generic paroxetine
Authors: Clare Dyer
Journal: BMJ (2016)

GlaxoSmithKline, the United Kingdom’s biggest drug maker, has been fined more than £37.6m (€48m; $55m) for striking deals between 2001 and 2004 to stifle competition from generic drug manufacturers with its blockbuster antidepressant paroxetine.

The UK’s Competition and Markets Authority has fined GSK for entering “pay for delay” deals with smaller manufacturers to keep generic forms of paroxetine off the market.

In the UK 4.2 million prescriptions were issued in 2000 for Seroxat, GSK’s branded version of paroxetine, and in 2001 Seroxat was one of GSK’s best selling drugs, with sales exceeding £90m. That year Generics (UK) and …
Sequential versus alternating chemotherapy and radiotherapy in stage III-IV squamous cell carcinoma of the head and neck: a phase III study.
Authors: M Merlano, R Rosso, M R Sertoli, L Bonelli, G Margarino, A Grimaldi, M Benasso, G Gardin, R Corvó, D Scarpati
Journal: Journal of Clinical Oncology (1988)

A cooperative randomized study was begun in August 1983 to compare a sequential program of induction chemotherapy followed by definitive treatment, arm A, with an alternation of chemotherapy and radiotherapy (three courses of 20 Gy in ten daily fractions), arm B. The same chemotherapy was used in both arms: 6 mg/m2, vinblastine, hour 0; 30 mg, bleomycin, hour 6; 200 mg, methotrexate, hours 24 to 26; 45 mg, leucovorin, hour 48. One hundred sixteen patients entered the study, 55 in arm A and 61 in arm B. The patients all had previously untreated squamous cell carcinoma of the head and neck (SCCHN). Forty-five patients had stage III and 71 had stage IV disease. The two arms were fully comparable. As of April 1986, 116 patients were evaluable for survival, while 112 were evaluable for toxicity and 105 for response. Response analysis shows that there were 14 complete responses (CR) and 11 partial responses (PR), for an overall response rate (ORR) of 52% in arm A, and 30 CRs and seven PRs, for an ORR of 64.9% in arm B. The difference in terms of CR between the two arms was statistically significant (P less than .03). Progression-free survival (PFS) was also statistically different, with an advantage for arm B (P less than .05), but without differences in overall survival. Arm B correlates with a significant increase in mucositis compared with arm A (P less than .001).
Agreement between direct and estimated maximum ventilatory ventilation in health subjects: A multicentric study
Authors: Ingrid Azevedo, Palomma Araujo, Vanessa Resqueti, Maria Goes, Rencio Florencio, Marlene Moreno, Ester Silva, Armele Andrade, Guilherme Fregonezi
Journal: European Respiratory Journal (2014)

Aim: To study the agreement between direct and estimated maximum ventilatory ventilation values in healthy subjects. Methods: Two hundred and sixteen healthy subjects (105 male) FEV1: 3.08 ± 0.82 L, FEV1/ FVC: 0.86±0.34, BMI: 26.04±3.69 Kg/m2, age: 47±16.82 years, from three cities of Brazil (Natal, Recife and Piracicaba) performed spirometry and maximum ventilatory ventilation (MVV) following the Brazilian Thoracic Association guidelines. Agreements between direct MVV and MVV obtained indirectly by multiplying FEV1 by 35, 37.5 and 40 were analyzed through Bland-Altman plot. Results: The BIAS and Limits of Agreement (LA) results for FEV1 multiplied by 35, 37.5 and 40 were, respectively: 20.66 ± 23.19 L/min (LA: -24.79 to 66.11 L/min), 11.33 ± 23.13 L/min (LA: -34.01 to 56.68 L/min) and 2.0 ± 23.23 L/min (LA: -43.52 to 47.53 L/min), as showed in figure 1.

![Figure][1] 



Conclusion: In healthy subjects, we observed a poor agreement between the direct MVV and estimated MVV.

 [1]: pending:yes
T Cell Receptor Cross-Reactivity between Similar Foreign and Self Peptides Influences Naive Cell Population Size and Autoimmunity
Authors: Ryan W. Nelson, Daniel Beisang, Noah J. Tubo, Thamotharampillai Dileepan, Darin L. Wiesner, Kirsten Nielsen, Marcel Wüthrich, Bruce S. Klein, Dmitri I. Kotov, Justin A. Spanier, Brian T. Fife, James J. Moon, Marc K. Jenkins
Journal: Immunity (2015)
Phase I Trial of Eribulin/S-1 Combination Therapy for Advanced/Recurrent Breast Cancer
Authors: Tsutomu Iwasa, Tsutomu Sakiyama, Junji Tsurutani, Kaoru Tanaka, Takeshi Yoshida, Yoshikane Nonagase, Yasuhito Fujisaka, Takayasu Kurata, Yoshifumi Komoike, Kazuhiko Nakagawa
Journal: Annals of Oncology (2014)
Intensity-modulated radiation therapy for pediatric head and neck rhabdomyosarcoma: French preliminary results.
Authors: J. Leseur, V. Bernier, J. Habrand, A. Laprie, M. Mahe, S. Supiot, G. Truc, E. Le Prisé, L. Claude, C. Carrie
Journal: Journal of Clinical Oncology (2010)

9549 Background: In head-and-neck rhabdomyosarcoma (RMS), radiotherapy have an important place because tumors are rarely available to complete surgical resection. Intensity-modulated- radiotherapy (IMRT) is an advanced technology that allows a better dose homogeneity inside the tumor while sparing normal tissue. The purpose is to evaluate initial clinical results of IMRT for pediatric head-and-neck RMS in France. Methods: From 2003 until 2008, 27 children, mean age 10 years (8 months-20 years), with head-and neck RMS were treated with IMRT in 6 French departments of Radiation. Eighteen patients had a parameningeal RMS (PM-RMS) and 9 orbital. Thirteen patients had embryonal histologic tumor, 11 alveolar, 3 botryoid. The mean tumor size was 50 mm (22–71 mm). Four patients had nodal involvement and 7 patients had initially metastatic disease. All patients had undergone chemotherapy according to cooperative group RMS protocols. Outcome and toxicities were evaluated in medical records on each cancer center. Results: Median follow-up was 25 months (9-54). The median dose was 50.4 Gy (36- 55.8). Among orbit tumors, 1 failure occurred in reduced fields and 1 patient aged of 8 months had progressive disease during treatment and developed meningeal carcinomatosis. Three failures occurred in high dose region among PM-RMS, and 1 patient developed a marginal failure with synchronous metastasis. No failure in regional lymph nodes was observed. Disease-free survival at 3 years were 51%, and 67% for PM-RMS and for orbital RMS, respectively. Overall survival at 3 years were 88%, and 89% for PM-RMS and for orbital RMS, respectively. Radiation Therapy Oncology Group acute mucosal toxicity grade 3 concerned 2 patients and 1 patient presented a corneal ulcer. No patients developed acute toxicity Grade 4 or 5. The late toxicities observed were 3 keratitis, 2 trismus, 1 hypothyroidism. No secondary solid tumor was observed. Conclusions: Our initial clinical results of IMRT for pediatric head-and-neck RMS revealed no excessive marginal failure for parameningeal RMS. But the failure in reduced fields among orbital tumour conduce to be careful with undercoverage. Long-term-follow-up is needed to evaluate late toxicities. No significant financial relationships to disclose.
Role of Thyroid Hormones in Skeletal Development and Bone Maintenance
Authors: J. H. Duncan Bassett, Graham R. Williams
Journal: Endocrine Reviews (2016)

The skeleton is an exquisitely sensitive and archetypal T3-target tissue that demonstrates the critical role for thyroid hormones during development, linear growth, and adult bone turnover and maintenance. Thyrotoxicosis is an established cause of secondary osteoporosis, and abnormal thyroid hormone signaling has recently been identified as a novel risk factor for osteoarthritis. Skeletal phenotypes in genetically modified mice have faithfully reproduced genetic disorders in humans, revealing the complex physiological relationship between centrally regulated thyroid status and the peripheral actions of thyroid hormones. Studies in mutant mice also established the paradigm that T3 exerts anabolic actions during growth and catabolic effects on adult bone. Thus, the skeleton represents an ideal physiological system in which to characterize thyroid hormone transport, metabolism, and action during development and adulthood and in response to injury. Future analysis of T3 action in individual skeletal cell lineages will provide new insights into cell-specific molecular mechanisms and may ultimately identify novel therapeutic targets for chronic degenerative diseases such as osteoporosis and osteoarthritis. This review provides a comprehensive analysis of the current state of the art.