tbuckley/cabot-search huggingface dataset:
Abstract 1993: Identification of genetic interactors of BRCA2 in mouse embryonic stem cell model.
Authors: Xia Ding, Shyam Sharan
Journal: Cancer Research (2013)

Abstract Breast cancer is the most prevalent cancer in women worldwide and mutations in breast cancer susceptible genes, BRCA1 and BRCA2 are the genetic factors conferring highest risk (40-70%) of developing breast cancer. Although BRCA proteins are known to maintain genomic stability mainly by homologous recombination-mediated DNA repair, detailed mechanisms of how BRCA loss induces tumorigenesis remain unclear. Interestingly, while inactivation of both alleles of BRCA1 or BRCA2 genes is necessary for tumor development, their loss in embryonic cells affects cell viability. To explain this paradox, we hypothesize that cells lacking BRCA1 or 2 are able to survive and are predisposed to tumorigenesis due to mutations in other genes such as those involved in cell cycle regulation or DNA damage response. In the current study, we propose to identify such genes using a mouse embryonic stem (mES) cell-based insertional mutagenesis screen. In mES cells with one mutant allele of Brca2 and the other flanked by loxP sites, cell death can be induced by Cre-mediated loss of the conditional allele. To identify genes whose up-regulation can rescue BRCA2 loss-induced cell death, we transduced these mES cells with murine stem cell retrovirus (MSCV) expressing Cre recombinase. We obtained Brca2-null ES cells that were rescued by the viral insertion and used them to clone the viral insertional sites. We identified several candidate genes that were upregulated in viable ES cells. One of these genes encodes a PDZ domain-containing protein, GIPC3. Expression of Gipc3 was elevated 3 to 4-fold in the rescued clone. Furthermore, we rescued the lethality of Brca2-null ES cells by overexpressing Gipc3. The rescued cells were hypersensitive to DNA damaging agents and exhibited an overall increase in genomic instability. Mechanistically, we found DNA damage-induced p21 expression to be attenuated in GIPC3 over-expressing clones. Because p21 is a key mediator of BRCA2 loss-induced cell death, we hypothesize that GIPC3 overexpression may inhibit p21 expression resulting in viable Brca2-null ES cells. We are now studying the detailed signaling pathway of how GIPC3 affects p21 expression. In addition, we are examining if Gipc3 overxpression can rescue the lethality of Brca2ko/ko embryos and contribute to tumorigenesis in Brca2ko/+ mice. We are also examining the expression of GIPC3 in human BRCA2-deficient tumors. Citation Format: Xia Ding, Shyam Sharan. Identification of genetic interactors of BRCA2 in mouse embryonic stem cell model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1993. doi:10.1158/1538-7445.AM2013-1993
Light chain 2 profile and activity of human ventricular myosin during dilated cardiomyopathy. Identification of a causal agent for impaired myocardial function.
Authors: S S Margossian, H D White, J B Caulfield, P Norton, S Taylor, H S Slayter
Journal: Circulation (1992)

BACKGROUND A number of parameters reflecting the effects of idiopathic dilated cardiomyopathy (IDC) on the structure and function of myosin from the human myocardium were analyzed. METHODS AND RESULTS The content of the regulatory light chain, LC2, was reduced in myopathic heart myosin in contrast to the controls in which it was present in stoichiometric amounts relative to the essential light chain, LC1. In IDC hearts, the absence or significant reduction in amount of LC2 was related to the presence of an active protease, which was isolated and purified about 130-fold. The protease exhibited a significant degree of specificity: It cleaved LC2 almost totally (but not the heavy chains) in human control heart myosin but only partially cleaved LC2 in canine heart or in rabbit skeletal muscle myosins. The protease was present at a very low level or was inactive in control heart tissue. When the LC1/LC2 molar ratio was calculated, it was found to be 1:1.0 in control heart myosin and remained constant in various samples analyzed, whereas in myopathic myosin from different individuals, this ratio varied from 1:0.1 to 1:0.69. The rates of ATP binding to control and myopathic myosins were similar, whereas the Vm of actin-activated ATPase of myopathic myosin was about 25% less than that of the control. However, ATP binding and its hydrolysis by control S1, i.e., the myosin head, were faster by a factor of 2 than that of the myopathic S1. In addition, control myosin synthetic thick filament length as well as turbidity in solution, measured by light scattering, were twice as large as those of the myopathic heart myosin. These effects induced by myopathy in both filament assembly and turbidity were reversed upon reassociation of IDC myosin with LC2. CONCLUSIONS The changes in myosin structure and function were linked to a protease-mediated cleavage of LC2 in myosin; a possible role for the protease in the degenerative effects of idiopathic dilated cardiomyopathy is thus defined.
Transferrin synthesis by small cell lung cancer cells acts as an autocrine regulator of cellular proliferation.
Authors: M Vostrejs, P L Moran, P A Seligman
Journal: Journal of Clinical Investigation (1988)

Since transferrin is required for cellular proliferation, we investigated transferrin synthesis by a small cell lung cancer line (NCI-H510) that survives in serum-free media without added transferrin. Immunoassays for human transferrin demonstrated that these cells contained immunoreactive human transferrin. Immunofluorescence studies showed that the protein is expressed on the surface of cells, presumably bound to transferrin receptor. Media conditioned by NCI-H510 cells support proliferation of human leukemic cells that would not survive in media lacking transferrin. [35S]Methionine incorporation documented transferrin synthesis by NCI-H510 cells as well as three other small cell lines. Transferrin synthesis by NCI-H510 cells increased more than 10-fold when cells entered active phases of the cell cycle, and this increase was seen before large increases in transferrin-receptor expression. Further experiments examining the effects of agents that affect iron metabolism show that the addition of transferrin-iron or hemin to the media is associated with a more rapid initial rate of proliferation and lower rates of transferrin synthesis than control cells. Gallium salts, which inhibit iron uptake, inhibited proliferation of these cells. If the cells recovered from this effect, transferrin synthesis remained greatly increased compared to control. We conclude that transferrin synthesis by these malignant cells is ultimately related to an iron requirement for cellular proliferation. It appears that this synthesized transferrin acts as part of an important autocrine mechanism permitting proliferation of these cells, and perhaps permitting tumor cell growth in vivo in areas not well vascularized.
Directed endothelial cell morphogenesis in micropatterned gelatin methacrylate hydrogels
Authors: Mehdi Nikkhah, Nouran Eshak, Pinar Zorlutuna, Nasim Annabi, Marco Castello, Keekyoung Kim, Alireza Dolatshahi-Pirouz, Faramarz Edalat, Hojae Bae, Yunzhi Yang, Ali Khademhosseini
Journal: Biomaterials (2012)
Thioredoxin: a redox-regulating cellular cofactor for glucocorticoid hormone action. Cross talk between endocrine control of stress response and cellular antioxidant defense system.
Authors: Y Makino, K Okamoto, N Yoshikawa, M Aoshima, K Hirota, J Yodoi, K Umesono, I Makino, H Tanaka
Journal: Journal of Clinical Investigation (1996)

Adaptation to stress evokes a variety of biological responses, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and synthesis of a panel of stress-response proteins at cellular levels: for example, expression of thioredoxin (TRX) is significantly induced under oxidative conditions. Glucocorticoids, as a peripheral effector of the HPA axis, exert their actions via interaction with a ligand-inducible transcription factor glucocorticoid receptor (GR). However, how these stress responses coordinately regulate cellular metabolism is still unknown. In this study, we demonstrated that either antisense TRX expression or cellular treatment with H2O2 negatively modulates GR function and decreases glucocorticoid-inducible gene expression. Impaired cellular response to glucocorticoids is rescued by overexpression of TRX, most possibly through the functional replenishment of the GR. Moreover, not only the ligand binding domain but the DNA binding domain of the GR is also suggested to be a direct target of TRX. Together, we here present evidence showing that cellular glucocorticoid responsiveness is coordinately modulated by redox state and TRX level and propose that cross talk between neuroendocrine control of stress responses and cellular antioxidant systems may be essential for mammalian adaptation processes.
Correlation Between Left Ventricular Hypertrophy and GAA Trinucleotide Repeat Length in Friedreich's Ataxia
Authors: Richard Isnard, Hanna Kalotka, Alexandra Dürr, Mireille Cossée, Michèle Schmitt, Françoise Pousset, Daniel Thomas, Alexis Brice, Michel Koenig, Michel Komajda
Journal: Circulation (1997)

Background Friedreich's ataxia (FA), the most common inherited ataxia, is associated frequently with cardiac hypertrophy, and death is often cardiac related. Recently, the disease has been associated with a mutation that consists of an unstable expansion of GAA repeats in the first intron of the gene encoding frataxin on chromosome 9. Methods and Results We studied 44 consecutive patients with FA, determined the size of GAA expansions in the frataxin gene, and examined the relation between the genotype and cardiac phenotype assessed by M-mode and two-dimensional echocardiography. All the patients were homozygous for the mutation. The size of the GAA expansion on the smaller allele varied from 270 to 1200. We found a correlation between the size of GAA expansion and the left ventricular wall thickness ( r =.51, P &lt;.001) and the left ventricular mass index ( r =.45, P =.002). Left ventricular hypertrophy was observed in 81% of patients with a number of GAA repeats above the median value of 770 compared with only 14% in the other group ( P =.002). Conclusions These data demonstrate that in FA, the severity of left ventricular hypertrophy is related to the number of GAA repeats. These results suggest that abnormalities of the gene encoding frataxin, a protein of unknown function highly expressed in the normal heart, may play an important role in the modulation of cardiac hypertrophy.
Randomised controlled trials in primary care: case study
Authors: S. Wilson, B. C Delaney, A. Roalfe, L. Roberts, V. Redman, A. M Wearn, F D R. Hobbs
Journal: BMJ (2000)

Although over 90% of patient contacts within the NHS occur in primary care, many of the interventions used in this setting remain unproved. 1The relevance of research undertaken in secondary or tertiary care to general practice is questionable, and more research based in primary care is needed. 2Increasing research in primary care will inevitably increase demand for randomised controlled trials in this setting.Some of the trials will be of health service interventions (pragmatic trials), 3 where the focus lies in assessing the cost effectiveness of an intervention rather than efficacy or safety.The difficulties experienced in doing randomised controlled trials in primary care have been reported [4][5][6] and are not restricted to this setting. 7 8We discuss some of the issues that must be considered when conducting and interpreting the results of trials in primary care using examples generated during a trial of the management of dyspepsia (box).Dyspepsia is a common clinical problem.About 2% of the population consult their general practitioner each year with dyspeptic symptoms, 9 and it costs the NHS more than £1bn a year, with a large proportion of these costs relating to drug prescription. 10The evidence base has largely consisted of cohort studies of patients referred to secondary care for investigation 11 12 and economic models. 13In the absence of evidence from primary care, several conflicting consensus guidelines have been generated. 14 15Dyspepsia represents a good example of a chronic disease that is largely managed in primary care and that requires high quality evidence from randomised controlled trials in primary care. Birmingham open access endoscopy studyThe study aimed to evaluate the effectiveness of two management strategies for patients presenting in primary care with symptoms of dyspepsia.Two randomised controlled trials were conducted concurrently, with eligibility being determined by the patient's age at presentation.Randomisation was done at the individual patient level by using sealed opaque, sequentially numbered envelopes during a primary care consultation for dyspepsia.
How Well Does Climate Change and Human Health Research Match the Demands of Policymakers? A Scoping Review
Authors: Jamie Hosking, Diarmid Campbell-Lendrum
Journal: Environmental Health Perspectives (2012)

Background: In 2008, the World Health Organization (WHO) Member States passed a World Health Assembly resolution that identified the following five priority areas for research and pilot projects on climate change and human health: health vulnerability, health protection, health impacts of mitigation and adaptation policies, decision-support and other tools, and costs of health protection from climate change.Objectives: To assess the extent to which recently published research corresponds to these priorities, we undertook a scoping review of original research on climate change and human health. Scoping reviews address topics that are too broad for a systematic review and commonly aim to identify research gaps in existing literature. We also assessed recent publication trends for climate change and health research.Methods: We searched for original quantitative research published from 2008 onward. We included disease burden studies that were specific to climate change and health and included intervention studies that focused on climate change and measured health outcomes. We used MEDLINE, Embase, and Web of Science databases and extracted data on research priority areas, geographic regions, health fields, and equity (systematic differences between advantaged and disadvantaged social groups).Discussion: We identified 40 eligible studies. Compared with other health topics, the number of climate change publications has grown rapidly, with a larger proportion of reviews or editorials. Recent original research addressed four of the five priority areas identified by the WHO Member States, but we found no eligible studies of health adaptation interventions, and most of the studies focused on high-income countries.Conclusions: Climate change and health is a rapidly growing area of research, but quantitative studies remain rare. Among recently published studies, we found gaps in adaptation research and a deficit of studies in most developing regions. Funders and researchers should monitor and respond to research gaps to help ensure that the needs of policymakers are met.
Thoughts on Anniversaries, Jubilees and Centenaries
Authors: John Lister
Journal: New England Journal of Medicine (1958)

IT seems that nearly all ancient people celebrated the return of spring and the death of winter each year, and it was from this custom that anniversaries, jubilees and centenaries have come to be celebrated in commemoration of events of personal, national and political importance. There is always the danger in such commemorations of looking back in complacency rather than looking forward in inspiration, and if the occasion is to be put to good use it is clear that the emphasis must be on the latter.This year, the National Health Service celebrates the tenth anniversary of its inception, and . . .
Studies of a Flatulent Patient
Authors: Michael D. Levitt, Robert B. Lasser, J.S. Schwartz, John H. Bond
Journal: New England Journal of Medicine (1976)

The physician seldom deals rationally with a patient complaining of excessive flatus. Lacking measurements of rectal gas volumes, excessive gas excretion is not documented. Evaluation usually consists of x-ray and endoscopic studies, when, in truth, there is no known cause of excessive flatus that such procedures might identify. As a result, psychologic or medical therapy (or both) is administered without knowledge of the cause of the problem. We studied an unusual patient who documented his flatulence by means of a meticulous recording of the time of each passage of gas.Case Report and ResultsA 28-year-old man had a five-year . . .
Sulphuric Ether in Asphyxia Neonatorum.
Authors: C. F. Hopkins
Journal: JAMA (1901)

Chinook, Mont., June 11, 1901. <h3>To the Editor:</h3> —In a recent case of asphyxia neonatorum, caused by delay in delivery and the use of forceps, I worked faithfully for one hour, using artificial respiration and external stimulants such as rubbing, slapping, hot and cold water, but with poor success, as the heart became more feeble, cyanosis increased, and it seemed altogether a hopeless case. I injected 5 minims sulphuric ether into the thigh. In two or three minutes circulation was fully restored, child was breathing naturally, and it has since done well. Having never seen any note of ether being used in these cases, I send you this, thinking it might possibly be of some value. Respectfully,
THE ROLE OF SYPHILIS AS A CAUSATIVE FACTOR IN THE PRODUCTION OF PYORRHEA ALVEOLARIS.
Authors: A. H. OHMANN-DUMESNIL
Journal: JAMA (1902)

Pyorrhea alveolaris, variously known as Riggs' disease, Fauchard's disease, and by some other names, remains to this day a<i>bete noir</i>to dentists. This is mainly due to the fact that they can not cure it, and the best methods at their command to-day lie in prosthetic dentistry. Without desiring to pose as a carping critic, the method is bad and is surely a<i>petitio in forma pauperis</i>to him who is able to observe and to reason. In this trouble, as well as in others, it is necessary to determine the cause and then properly treat it or eliminate it, and it is to this very question of cause that the present is written. He who has had an opportunity to observe a number of cases of syphilis has not failed to observe that a peculiar manifestation shows itself at first in connection with the lower canine teeth. This
Omeprazole Versus Ranitidine as Adjunct Therapy to Endoscopic Injection in Actively Bleeding Ulcers: a Prospective and Randomized Study
Authors: C. Villanueva, J. Balanzó, X. Torras, S. Sáinz, G. Soriano, D. González, F. Vilardell
Journal: Endoscopy (1995)

Backround and Study Aims: Although high rates of initial hemostasis can be achieved with endoscopic injection therapy in actively bleeding ulcers, the incidence of rebleeding is not negligible. Optimal conditions for clotting may require achieving deep and sustained acid inhibition to avoid the deleterious effect of acid and pepsin secretions on the hemostatic process. The aim of this study was to assess whether omeprazole could improve the efficacy of ranitidine as an adjunct treatment in endoscopic injection therapy to avoid rebleeding.
Defence union will not back libel actions
Authors: C. Dyer
Journal: BMJ (1998)

The Medical Defence Union (MDU) has told its members that it is unlikely to back them financially in bringing libel actions in future after it was landed with a bill thought to be nearly £2m ($3.2m) for both sides' legal costs.

The MDU supported Dr Peter Nixon, a former consultant cardiologist at Charing Cross Hospital, in a libel claim against Channel Four, the investigative journalist …
Effect of Valsalva Maneuver on Oxygen Saturation in Patients with Intracardiac Shunts
Authors: STEFAN A. CARTER, NEWTON C. BIRKHEAD, EARL H. WOOD
Journal: Circulation (1959)

Oxygen saturation of arterial and central venous blood was measured continuously during the Valsalva maneuver in patients with and without intracardiac defects. The majority of patients with atrial septal defects and patients with ventricular septal defects and high right ventricular pressure showed a sharp decrease in saturation of radial artery blood shortly after the maneuver. These changes were not recorded accurately by ear oximetry. The patients with shunts uniformly showed a rapid increase in saturation of pulmonary artery blood during the initial period of increased airway pressure. This effect was not observed in patients without shunts. These reactions may be of special diagnostic value under certain circumstances.
Rehabilitation: An Evolving Concept
Authors: Herbert Berner
Journal: JAMA (1966)

ABSTRACT To the Editor:— In his article Rehabilitation: An Evolving Concept (195:1129, 1966), Dr. Eustace lucidly outlined the progress of rehabilitation medicine especially as it applied to  rehabilitation. He defined the limitations of rehabilitation as presented by the patient, the environment, and the physician. He opposed the abdication of responsibility of the physician to the nonphysician in the management of rehabilitation patients. He indicated the dangers inherent in such a course both ethically and practically.As a corollary to this excellent presentation, it is important to inquire further into the passing of the responsibility from physician to nonphysician. Actual prescriptions and consultation requests found in many hospitals with excellent medical and surgical staffs read give the patient crutches, give the patient electrotherapy, spondylitis, treat the neck, long leg brace, would like some occupational therapy, give heat and massage, fit with a leg, exercise the legs, vocational training. Most frequently,
Long-term Angiographic and Clinical Outcome After Percutaneous Transluminal Coronary Angioplasty and Intracoronary Radiation Therapy in Humans
Authors: Jose A. Condado, Ron Waksman, Orlando Gurdiel, Raul Espinosa, Juan Gonzalez, Bruno Burger, Guillermo Villoria, Harry Acquatella, Ian R. Crocker, K. B. Seung, Samuel F. Liprie
Journal: Circulation (1997)

Background Ionizing radiation has been shown to reduce neointimal formation after balloon angioplasty in experimental models of restenosis. This study was designed to evaluate the feasibility, safety, and effectiveness of intracoronary radiation therapy (ICRT) after percutaneous transluminal coronary angioplasty (PTCA) for preventing restenosis in human coronary arteries. Methods and Results Twenty-one patients (22 arteries) with unstable angina underwent standard balloon angioplasty. ICRT was performed with the use of an 192 Ir source wire that was hand delivered to the angioplasty site. Angiographic follow-up was performed at 24 hours, between 30 and 60 days, and at 6 months. Angioplasty was successful in 19 of 22 lesions, and insertion of the radioactive source wire was successful at all treated sites. Angiographic study at 24 hours demonstrated early late loss of the luminal diameter from 1.92±0.55 to 1.40±0.27 mm. Between 30 and 60 days, repeat angiography demonstrated total occlusion in 2 arteries, a new pseudoaneurysm in 1 artery, and significant dilatation at the treatment site in 2 additional vessels. At ≥6 months’ follow-up, all remaining arteries (n=20) maintained patent, with a mean lumen diameter of 1.65±0.8 mm. The calculated late lumen loss was 0.27±0.56 mm, and the late loss index was 0.19. Clinical events at 1 year included myocardial infarction in 1 patient, repeat angioplasty to the treated site in 3 patients, and persistent angina in 7 patients. Conclusions These preliminary results demonstrate that ICRT after coronary intervention is feasible and is associated with an acceptable degree of complications and lower rates of angiographic restenosis indexes.