tbuckley/cabot-search huggingface dataset:
Abstract 2677: Novel Hsp90 inhibitor, STA-9090, for combination with radiotherapy
Authors: Jim Sang, Donald Smith, Tim Korbut, Chaohua Zhang, David A. Proia, Yumiko Wada
Journal: Cancer Research (2011)

Abstract Introduction: Radiation is accepted as an important standard therapy for locally unresectable cancers, and as such is given to approximately 60% of cancer patients. However, radio-resistance and repair of sublethal radiation damage can limit its efficacy. Recent studies have shown that Heat Shock Protein 90 (Hsp90), a molecular chaperone that mediates maturation and activation of client proteins, plays a critical role in establishing resistance to radiation therapy. Inhibiting Hsp90 has been reported to sensitize tumors to radiation, resulting in tumor growth suppression and augmenting therapeutic cell death induction. Unfortunately, many of the Hsp90 inhibitors currently in clinical trials exhibit hepatotoxicity as well as ocular toxicity, hindering their clinical use. Taken together, development of clinically acceptable Hsp90 inhibitors for combination with radiation could serve as an important strategy for improving radiotherapy success. STA-9090 is a second generation Hsp90 inhibitor that has shown potent preclinical activity and is currently in twelve Phase II trials across a broad range of indications. STA-9090 has demonstrated encouraging activity in a Phase II trial in patients with stage IIIB and IV non-small cell lung cancer. Importantly, STA-9090 has displayed a favorable safety profile with substantially lower incidence of hepatic or ocular toxicity than that reported for other Hsp90 inhibitors. Results: We evaluated the radiosensitizing potential of STA-9090 in vivo. Monotherapy treatment with either STA-9090 or 2 Gray (Gy) ionizing irradiation resulted in moderate reductions in human tumor growth rates in a mouse xenograft model. Combination of STA-9090 with 2 Gy irradiation resulted in substantial tumor regression. Increasing the dose of radiation in the combination arm to 4 Gy further enhanced tumor regression, resulting in a 50% reduction in tumor volume. In summary, STA-9090 offers a safe and effective strategy for improving the outcome of radiotherapy in human cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2677. doi:10.1158/1538-7445.AM2011-2677
A partial form of recessive STAT1 deficiency in humans
Authors: Ariane Chapgier, Xiao-Fei Kong, Stéphanie Boisson-Dupuis, Emmanuelle Jouanguy, Diana Averbuch, Jacqueline Feinberg, Shen-Ying Zhang, Jacinta Bustamante, Guillaume Vogt, Julien Lejeune, Eleonore Mayola, Ludovic de Beaucoudrey, Laurent Abel, Dan Engelhard, Jean-Laurent Casanova
Journal: Journal of Clinical Investigation (2009)

Complete STAT1 deficiency is an autosomal recessive primary immunodeficiency caused by null mutations that abolish STAT1-dependent cellular responses to both IFN-α/β and IFN-γ. Affected children suffer from lethal intracellular bacterial and viral diseases. Here we report a recessive form of partial STAT1 deficiency, characterized by impaired but not abolished IFN-α/β and IFN-γ signaling. Two affected siblings suffered from severe but curable intracellular bacterial and viral diseases. Both were homozygous for a missense STAT1 mutation: g.C2086T (P696S). This STAT1 allele impaired the splicing of STAT1 mRNA, probably by disrupting an exonic splice enhancer. The misspliced forms were not translated into a mature protein. The allele was hypofunctional, because residual full-length mRNA production resulted in low but detectable levels of normally functional STAT1 proteins. The P696S amino acid substitution was not detrimental. The patients’ cells, therefore, displayed impaired but not abolished responses to both IFN-α and IFN-γ. We also show that recessive STAT1 deficiencies impaired the IL-27 and IFN-λ1 signaling pathways, possibly contributing to the predisposition to bacterial and viral infections, respectively. Partial recessive STAT1 deficiency is what we believe to be a novel primary immunodeficiency, resulting in impairment of the response to at least 4 cytokines (IFN-α/β, IFN-γ, IFN-λ1, and IL-27). It should be considered in patients with unexplained, severe, but curable intracellular bacterial and viral infections.
Human <i>COL7A1</i> -corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa
Authors: Vittorio Sebastiano, Hanson Hui Zhen, Bahareh Haddad, Elizaveta Bashkirova, Sandra P. Melo, Pei Wang, Thomas L. Leung, Zurab Siprashvili, Andrea Tichy, Jiang Li, Mohammed Ameen, John Hawkins, Susie Lee, Lingjie Li, Aaron Schwertschkow, Gerhard Bauer, Leszek Lisowski, Mark A. Kay, Seung K. Kim, Alfred T. Lane, Marius Wernig, Anthony E. Oro
Journal: Science Translational Medicine (2014)

Patients with recessive dystrophic epidermolysis bullosa (RDEB) lack functional type VII collagen owing to mutations in the gene COL7A1 and suffer severe blistering and chronic wounds that ultimately lead to infection and development of lethal squamous cell carcinoma. The discovery of induced pluripotent stem cells (iPSCs) and the ability to edit the genome bring the possibility to provide definitive genetic therapy through corrected autologous tissues. We generated patient-derived COL7A1-corrected epithelial keratinocyte sheets for autologous grafting. We demonstrate the utility of sequential reprogramming and adenovirus-associated viral genome editing to generate corrected iPSC banks. iPSC-derived keratinocytes were produced with minimal heterogeneity, and these cells secreted wild-type type VII collagen, resulting in stratified epidermis in vitro in organotypic cultures and in vivo in mice. Sequencing of corrected cell lines before tissue formation revealed heterogeneity of cancer-predisposing mutations, allowing us to select COL7A1-corrected banks with minimal mutational burden for downstream epidermis production. Our results provide a clinical platform to use iPSCs in the treatment of debilitating genodermatoses, such as RDEB.
Hyperlipidemia after heart transplantation: Report of a 6-year experience, with treatment recommendations
Authors: Christie M. Ballantyne, Branislav Radovancevic, John A. Farmer, O.Howard Frazier, Linda Chandler, Charlotte Payton-Ross, Beth Cocanougher, Peter H. Jones, James B. Young, Antonio M. Gotto
Journal: Journal of the American College of Cardiology (1992)
Marked increased risk of Epstein-Barr virus-related complications with the addition of antithymocyte globulin to a nonmyeloablative conditioning prior to unrelated umbilical cord blood transplantation
Authors: Claudio G. Brunstein, Daniel J. Weisdorf, Todd DeFor, Juliet N. Barker, Jakub Tolar, Jo-Anne H. van Burik, John E. Wagner
Journal: Blood (2006)
Oxygen equilibrium of hemoglobin J Cape Town
Authors: Samuel Charache, Trefor Jenkins
Journal: Journal of Clinical Investigation (1971)

Polycythemia in carriers of hemoglobin J Cape Town or hemoglobin Chesapeake is thought to be produced by increased oxygen affinity of their blood. Both hemoglobins involve substitution of amino acid residue alpha FG-4. Measurements reported here, of the oxygen equilibrium of purified hemoglobin J Cape Town, permit direct comparison of the two hemoglobins. J Cape Town exhibits lower oxygen affinity, and greater heme-heme interaction, than Chesapeake; both exhibit normal Bohr effects. Substitution of one polar amino acid residue for another of opposite charge (arginine --> glutamic acid) thus appears to create less disruption of the interface between alpha- and beta-chains than substitution of a nonpolar residue (arginine --> leucine).
Postural hypotension and tachycardia during hydralazine--isosorbide dinitrate therapy for chronic heart failure.
Authors: B Massie, B Kramer, F Haughom
Journal: Circulation (1981)

Supine and upright hemodynamic measurements were performed in 10 patients with chronic congestive heart failure, before and during vasodilator therapy with hydralazine and isosorbide dinitrate. This combination of drugs produced significant improvement in supine hemodynamic measurements, with the pulmonary capillary wedge pressure decreasing from 26 +/- 5 to 18 +/- 5 mm Hg (mean +/- SD, p less than 0.01) and stroke volume index increasing from 25 +/- 6 to 39 +/- 6 ml/m2 (p less than 0.01), without any significant change in heart rate (HR) or mean arterial pressure (MAP). However, with the patients upright, HR rose significantly (87 +/- 17 to 99 +/- 17 beats/min, p less than 0.05) and MAP fell (84 +/- 10 to 66 +/- 11 mm Hg, p less than 0.001) compared with measurements before treatment. These patients also exhibited potentially deleterious postural changes in HR, MAP, cardiac output, stroke volume index and stroke work index during therapy with the combination of hydralazine and isosorbide dinitrate. Although diuretic therapy (which had been withheld for 12 hours in eight subjects but only for 6 hours in two others) may have played a role in producing these changes, postural hypotension or tachycardia was not noted before vasodilator therapy or during therapy with nitrates or hydralazine. Repeat catheterization after 3 months in six patients revealed a lessening of the postural effects. These findings indicate the need to perform upright as well as supine hemodynamic measurements during the initiation of vasodilator therapy and suggest the need for particular caution in patients with ischemic heart disease.
Temporary placement of a covered metal stent for the management of a bleeding aortoesophageal fistula
Authors: D. Park, J. Park, S.-H. Lee, S.-H. Park, H.-S. Kim, S.-J. Kim
Journal: Endoscopy (2007)

An aortoesophageal fistula is a life-threatening cause of gastrointestinal bleeding [1] [2] [3]. Until now, temporary endoscopic hemostatic treatment for a bleeding aortoesophageal fistula prior to definitive treatment has been a great challenge because the endoscopic procedure that is conventionally used for this condition is not always effective [3] [4] [5]. We report here a patient with a bleeding aortoesophageal fistula in whom temporary hemostasis was successfully achieved using a covered metal stent.
Determinants of Survival After Coronary Artery Bypass Surgery
Authors: JOHN J. COLLINS, LAWRENCE H. COHN, EDMUND H. SONNENBLICK, MICHAEL V. HERMAN, PETER F. COHN, RICHARD GORLIN
Journal: Circulation (1973)

Review of our first 180 consecutive patients undergoing myocardial revascularization surgery at the Peter Bent Brigham Hospital shows that the over-all surgical mortality was 5.5%. Mortality in patients not in shock at the time of operation was 2.3%. The only major determinant of surgical survival appeared to be adequacy of left ventricular contraction, as indicated primarily by an ejection fraction above 40%. Of 116 patients operated on for relief of chronic angina pectoris or the intermediate coronary syndrome, 71% were free of angina 6 to 24 months (average 8.9) after surgery. The aggregate operative and late mortality in this group during the period of follow-up was 4.3%.
Calcium channel blockers inferior to cheaper drugs
Authors: D. Josefson
Journal: BMJ (2000)

Calcium channel blockers are inferior to less expensive antihypertensive drugs in preventing cardiovascular complications of high blood pressure, according to a new meta-analysis presented at the European Society of Cardiology's meeting in Amsterdam.

The research was a joint effort of investigators at Wake Forest University School of Medicine in North Carolina, the University of Washington in Seattle, and the Albert Einstein College of Medicine in New York.

The study analysed the results of nine randomised clinical trials that compared long acting calcium channel blockers with others classes of antihypertensives, such as diuretics, b blockers, and angiotensin converting enzyme inhibitors.

Data from 27743 patients were collected, amounting …
Guidelines for the prevention of falls in people over 65
Authors: Gene Feder, Colin Cryer, Sheila Donovan, Yvonne Carter
Journal: BMJ (2000)

General practice p 994 

Older people frequently fall. This is a serious public health problem, with a substantial impact on health and healthcare costs.1 These guidelines translate trial evidence about prevention of falls into recommendations that can be implemented in different settings, with the aim of reducing the rate of falls and injurious falls in people over 65 (see boxes 2 3).

#### Summary points

Multifaceted interventions reduce falls in older people (those over 65)

Home assessment of older people at risk of falls without referral or direct intervention is not recommended

Assessment of high risk residents in nursing homes with relevant referral is effective

Evidence from well designed single trials shows that assessment and modification of risk factors of older people who have presented to an accident and emergency department after a fall and the provision of hip protectors in residents of nursing homes are effective

We updated two previous systematic reviews to include any new evidence up to March 1998. 4 5 We electronically searched Medline for all randomised controlled trials and systematic reviews by using the terms fall(s), accidental falls, fracture, elderly, aged, older, and senior. We followed up relevant references in papers, and we contacted researchers in prevention of falls for information about other trial evidence and about studies from journals not catalogued by the National Library of Medicine. For inclusion, studies had to be randomised controlled trials of interventions designed to minimise or prevent exposure to the risk factors for falling (or fracture) in people aged 65 years or over living in either community or residential care. Outcomes had to include the number of people who had fallen or the number of falls or fractures. We excluded drug or dietary treatments for the prevention of fractures. Trials that fulfilled the inclusion criteria were reviewed and summarised …
The Current Status of Phenothiazines
Authors: John Kinross-Wright
Journal: JAMA (1967)

Phenothiazines assumed the rank of major chemotherapeutic agents 14 years ago. Throughout these years they have remained the object of controversy concerning their effectiveness, mode of action, toxicity, and method of use. This is perhaps because they have a spectrum of pharmacological activity and a formidable array of side effects unrivaled by any other class of compounds. The introduction of a factor of this complexity into the arena of mental illness, noted for its preponderance of hypothetical beliefs over scientific fact, was bound to produce controversy. Further, it happened at a time when the public conscience was recognizing its shortcomings in regard to the mentally ill. This has made it difficult to know how much of the change in the status of the mentally ill is due to pharmacotherapy and how much to other factors. The issue is further compounded by the propensity of the phenothiazines to give rise to
Whole Body Hematocrit in Women with Idiopathic Edema: Evidence of an Abnormal Plasma Distribution.
Authors: George D. Webster
Journal: Annals of Internal Medicine (1965)

s1 November 1965Whole Body Hematocrit in Women with Idiopathic Edema: Evidence of an Abnormal Plasma Distribution.George D. Webster Jr., M.D., F.A.C.P., William Siegel, M.D., Emanuel G. Tulsky, M.D.George D. Webster Jr., M.D., F.A.C.P.Search for more papers by this author, William Siegel, M.D.Search for more papers by this author, Emanuel G. Tulsky, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-63-5-921_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptIdiopathic edema is a syndrome of obscure and perhaps diverse etiologies. It is characterized by edema formation, frequently cyclic in nature, occurring almost exclusively in women and not related to detectable parenchymal disease of the cardiovascular, renal, or endocrine systems. Its milder forms merge with the fluid retention associated with the menstrual cycle. Physiologic studies in these patients are relatively few; excessive aldosterone production and an inability to excrete a standard water load have been described, and posture, environmental temperature, and psychic stress have been found to play a role.The present studies were undertaken to assess the role of... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: George D. WebsterJr., M.D., F.A.C.P.; William Siegel, M.D.; Emanuel G. Tulsky, M.D.Affiliations: Philadelphia, Pennsylvania PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 November 1965Volume 63, Issue 5Page: 921-921KeywordsBlood plasmaEdemaEndocrine systemEtiologyHematocritMenstrual cyclePostural controlRenal diseasesRenal systemTemperature ePublished: 1 December 2008 Issue Published: 1 November 1965 PDF downloadLoading ...
David Grahame-Smith
Authors: J. Aronson
Journal: BMJ (2011)

David Grahame Grahame-Smith was the clinical pharmacologists’ clinical pharmacologist. He was a perceptive clinician, an innovative progenitor of elegant basic and clinical experiments, an inspiring teacher and solicitous mentor, and a voice of wisdom on medicines policy.

Long before the word “translation” was introduced into medical science, Grahame-Smith developed a paradigm that showed that clinical pharmacology is a supremely translational discipline, building his scientific philosophy as a basic and clinical pharmacologist on four simple questions:

The pharmacological principles that link the last two of those questions encompass actions at the molecular level, actions on cells, tissues, and organs, and outcomes in the whole individual. He applied to this simple schema a deep understanding of both biochemical pharmacology and clinical medicine. It was an important tenet to him that basic experiments should inform clinical practice and that clinical results should …
Association of Colony-Forming Units With Coronary Artery and Abdominal Aortic Calcification
Authors: Susan Cheng, Kenneth S. Cohen, Stanley Y. Shaw, Martin G. Larson, Shih-Jen Hwang, Elizabeth L. McCabe, Roderick P. Martin, Rachael J. Klein, Basma Hashmi, Udo Hoffmann, Caroline S. Fox, Ramachandran S. Vasan, Christopher J. O'Donnell, Thomas J. Wang
Journal: Circulation (2010)

Background— Certain bone marrow–derived cell populations, called endothelial progenitor cells, have been reported to possess angiogenic activity. Experimental data suggest that depletion of these angiogenic cell populations may promote atherogenesis, but limited data are available on their relation to subclinical atherosclerotic cardiovascular disease in humans. Methods and Results— We studied 889 participants of the Framingham Heart Study who were free of clinically apparent cardiovascular disease (mean age, 65 years; 55% women). Participants underwent endothelial progenitor cell phenotyping with an early-outgrowth colony-forming unit assay and cell surface markers. Participants also underwent noncontrast multidetector computed tomography to assess the presence of subclinical atherosclerosis, as reflected by the burden of coronary artery calcification and abdominal aortic calcification. Across decreasing tertiles of colony-forming units, there was a progressive increase in median coronary artery calcification and abdominal aortic calcification scores. In multivariable analyses adjusting for traditional cardiovascular risk factors, each 1-SD increase in colony-forming units was associated with a ≈16% decrease in coronary artery calcification ( P =0.02) and 17% decrease in abdominal aortic calcification ( P =0.03). In contrast, neither CD34 + /KDR + nor CD34 + variation was associated with significant differences in coronary or aortic calcification. Conclusions— In this large, community-based sample of men and women, lower colony-forming unit number was associated with a higher burden of subclinical atherosclerosis in the coronary arteries and aorta. Decreased angiogenic potential could contribute to the development of atherosclerosis in humans.
Loss of doctors from NHS can be stemmed
Authors: C. White
Journal: BMJ (1998)

The exodus of doctors from the NHS could be prevented by better job opportunities, flexible or part time work, and adequate childcare facilities, concludes a report from the Don't Waste Doctors project in the North West region.

The report shows that although women who left the NHS were twice as likely to intend to return as men, both sexes had the same complaints about working practices.

The research focused on a 10 year cohort of medical graduates from the North West region who were no longer working for the NHS …
Dyslipidemia and ischemic heart disease mortality among men and women with diabetes.
Authors: M G Goldschmid, E Barrett-Connor, S L Edelstein, D L Wingard, B A Cohn, W H Herman
Journal: Circulation (1994)

BACKGROUND We investigated whether the greater increased risk of ischemic heart disease mortality associated with diabetes among women compared with men could be explained by their more pronounced lipoprotein abnormalities. METHODS AND RESULTS Seventy-six men and 45 women with diabetes and 327 men and 496 women without diabetes were followed for an average of 16 years in a population-based study. Cox proportional hazards models were used to determine the relative hazard of ischemic heart disease mortality for changes in lipoprotein subfractions after adjustment for age, hypertension, obesity, smoking, exercise, alcohol consumption, and estrogen use (among women). The relative hazard of ischemic heart disease mortality among diabetic women was 1.76 (P = .10) for a 10-mg/dL decrement in high-density lipoprotein cholesterol (HDL-C) and 3.13 (P = .01) for a 1-U increment in log very-low-density lipoprotein cholesterol (VLDL-C). The risk of ischemic heart disease mortality among diabetic women relative to nondiabetic women for an HDL-C level of 50 mg/dL and a log(e) VLDL-C of 3 (about 20 mg/dL) were 4.1 and 3.4, respectively (P &lt; .05). These lipoprotein changes were not associated with ischemic heart disease mortality among men or among nondiabetic women. CONCLUSIONS Excess ischemic heart disease mortality among diabetic women is partially explained by deleterious levels of HDL-C and VLDL-C. HDL-C levels of &lt; or = 50 mg/dL and VLDL-C levels of &gt; or = 20 mg/dL appear to predict ischemic heart disease mortality among these women and may help identify women who would benefit most from intervention.