tbuckley/cabot-search huggingface dataset:
Abstract LB-40: Inducible <i>in vivo</i> silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition
Authors: Jessica Bolden, Nilgun Tasdemir, Lukas Dow, Johan H. van Es, John E. Wilkinson, Zhen Zhao, Hans Clevers, Scott W. Lowe
Journal: Cancer Research (2014)

Abstract BET family proteins are novel therapeutic targets for cancer and inflammation and represent the first epigenetic readers against which small-molecule inhibitors have been developed. First generation BET inhibitors have shown some therapeutic efficacy in pre-clinical models, however the consequences of disrupting BET protein function in normal tissues are largely unknown. Using an inducible and reversible transgenic RNAi mouse model targeting the BET family protein Brd4, we show that acute suppression of Brd4 in adult animals has immediate and dramatic effects in multiple tissues. Brd4-depleted mice displayed epidermal hyperplasia, alopecia, and decreased cellular diversity and stem cell depletion in the small intestine. To test whether the loss of intestinal stem cells induced by Brd4 suppression would have consequences in combination with agents that induce acute gut toxicity, we subjected mice to a sub-lethal irradiation. Whereas control mice showed intestinal recovery 4-5 days following irradiation, Brd4-depleted mice showed dramatic and continued crypt-villus atrophy, implying that potent BET protein inhibition in combination with cytotoxic chemotherapy may show significantly enhanced toxicity in the clinic. These findings provide important insight into Brd4 function in normal tissues and importantly, predict several potential outcomes associated with potent and sustained inhibition of BET protein function. Citation Format: Jessica Bolden, Nilgun Tasdemir, Lukas Dow, Johan H. van Es, John E. Wilkinson, Zhen Zhao, Hans Clevers, Scott W. Lowe. Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-40. doi:10.1158/1538-7445.AM2014-LB-40
Target Heart Failure Populations for Newer Therapies
Authors: Lynne Warner Stevenson, Gregory Couper, Barbara Natterson, Gregg Fonarow, Michele A. Hamilton, Mary Woo, Julie W. Creaser
Journal: Circulation (1995)

Background The scarcity of donor hearts has created a large population of heart failure patients who are unlikely to undergo transplantation. Newer surgical therapies that might sustain such patients at home previously have been applied in critical situations in which early outcome is jeopardized by multiorgan failure. The optimal population for studies of extended support would be ambulatory patients with low operative risk but high risk of later unfavorable outcome. Methods and Results Baseline clinical, echocardiographic, and hemodynamic data were collected prospectively between 1988 and 1993 in 500 patients who were discharged on tailored medical therapy after evaluation for transplantation. Specific criteria were examined to identify high risk of death or need for urgent transplantation during the next 2 years. In 265 patients with ejection fraction ≤25% and initial New York Heart Association class IV symptoms, survival at 2 years was 55% (without urgent transplantation, 45%). Lower cardiac index or higher filling pressures at the time of referral did not confer higher risk, which was predicted by persistence of higher pressures after therapy. Serum sodium below 133 was associated with 34% 2-year survival without urgent transplantation, and ventricular dimension &gt;80 mm with a rate of 25%. Patients with initial peak oxygen consumption &gt;10 mL/kg per minute had a 2-year event-free rate of 72% compared with 48% for those with &lt;10 mL/kg per minute and 32% for those unable to exercise at referral. Demonstration of a 30% decrease in mortality with a controlled trial of new therapy in patients with ejection fraction ≤25% would require 600 patients with class III symptoms or almost 300 patients with class IV symptoms unless another criterion were added. Conclusions Ambulatory populations with high predicted event rates can be identified at initial evaluation, when hemodynamic criteria may be less useful than ventricular dimension, serum sodium, and ability to exercise. The use of outcome data from previous eras may lead to overestimation of benefits from newer therapies and underestimation of the sample size required in a prospective trials.
Bilateral Nodular Pulmonary Granulomas and Retroperitoneal Fibrosis
Authors: John R. Benfield
Journal: JAMA (1962)

AN APPARENTLY HOPELESS SITUATION L thought to be due to malignant neoplasm occasionally is deceiving and, therefore, irrefutable pathologic evidence of malignancy is sought before one is resigned to therapeutic nihilism. The following report of a case supports this principle, as the patient was admitted to the University of Chicago Hospitals almost 3 years ago, anuric and with bilateral pulmonary masses presumed to be metastases. She is alive and well today without evidence of malignant disease and represents, to our knowledge, the first case of spontaneous remission in proved retroperitoneal fibrosis as well as an example of unusual, multiple, bilateral, nodular, pulmonary granulomas. Report of a Case First Hospital Admission, Sept. 21, 1959.—A 51-year-old white woman with anuria of 2 days' duration was well until 5 months prior to admission, when she noted bilateral low back pain which became progressively worse but was not associated with dysuria, hematuria, or fever.
CYTOGENETIC STUDIES OF LEUKEMIA INDUCED BY 6,8,12- AND 7,8,12-TRIMETHYLBENZ(A)ANTHRACENE
Authors: Taketoshi Sugiyama, Filomena P. Brillantes
Journal: The Journal of Experimental Medicine (1970)

Cytogenetic studies on 64 rat leukemias induced with 7,8,12- and 6,8,12-trimethylbenz(a)anthracene were performed. Highly distinctive changes were found repeatedly in one special pair of chromosomes. 10 leukemias (15.6%) showed the presence of stemline(s) with trisomy of the largest telocentric chromosome (C-1 trisomy). Another chromosome abnormality, elongation of one of the pairs of the same chromosome (long C-1), was found in 5 leukemias (7.8%) as the predominant stemline and in 7 other cases as a small cell population. This chromosome abnormality, despite slight differences in their elongation rate, was defined as a new specific chromosome abnormality. Other chromosome abnormalities not related with C-1 chromosome were found in 8 cases (12.5%). The remaining 41 leukemias (64.1%) had the predominant stemline with normal karyotype. From this study it appears that three structurally different hydrocarbon carcinogens, 7,12-dimethylbenz(a)anthracene and 7,8,12- and 6,8,12-trimethylbenz(a)anthracene act on blood-forming cells by a common specific mechanism.
704-2 Comparative Relation of Neurohormonal Activation to Hemodynamics in Primary or Precapillary Secondary Pulmonary Hypertension
Authors: Nazzareno Galié, Maria L. Borgatti, Gianpaolo Ussia, Riccardo Parlangeli, Stefano Boschi, Alberto Bargossi, Angelo Branzi, Bruno Magnani
Journal: Journal of the American College of Cardiology (1995)
Rural GPs earn 10 000 more a year than their urban counterparts
Authors: H. Mooney
Journal: BMJ (2009)

Latest figures show that doctors who work in the country earn more than doctors based in urban areas of England.

According to newly published statistics from the NHS Information Centre, rural GPs earnt £10 000 (€11 383; $15 668) more than those working in cities, at an average of more than £115 000 before tax.

The report, GP Earnings and Expenses Enquiry 2006/07 analysed the tax returns for contractor GPs, which show that those working in …
Expression of pituitary tumor-transforming gene 1 (PTTG1)/securin in hepatitis B virus (HBV)-associated liver diseases: Evidence for an HBV X protein-mediated inhibition of PTTG1 ubiquitination and degradation
Authors: Francisca Molina-Jiménez, Ignacio Benedicto, Miki Murata, Samuel Martín-Vílchez, Toshihito Seki, José Antonio Pintor-Toro, María Tortolero, Ricardo Moreno-Otero, Kazuichi Okazaki, Kazuhiko Koike, José Luchi Barbero, Koichi Matsuzaki, Pedro L. Majano, Manuel López-Cabrera
Journal: Hepatology (2009)

Chronic infection with hepatitis B virus (HBV) is strongly associated with hepatocellular carcinoma (HCC), and the viral HBx protein plays a crucial role in the pathogenesis of liver tumors. Because the protooncogene pituitary tumor–transforming gene 1 (PTTG1) is overexpressed in HCC, we investigated the regulation of this protein by HBx. We analyzed PTTG1 expression levels in liver biopsies from patients chronically infected with HBV, presenting different disease stages, and from HBx transgenic mice. PTTG1 was undetectable in biopsies from chronic hepatitis B patients or from normal mouse livers. In contrast, hyperplastic livers from transgenic mice and biopsies from patients with cirrhosis, presented PTTG1 expression which was found mainly in HBx-expressing hepatocytes. PTTG1 staining was further increased in HCC specimens. Experiments in vitro revealed that HBx induced a marked accumulation of PTTG1 protein without affecting its messenger RNA levels. HBx expression promoted the inhibition of PTTG1 ubiquitination, which in turn impaired its degradation by the proteasome. Glutathione S-transferase pull-down and co-immunoprecipitation experiments demonstrated that the interaction between PTTG1 and the Skp1–Cul1–F-box ubiquitin ligase complex (SCF) was partially disrupted, possibly through a mechanism involving protein–protein interactions of HBx with PTTG1 and/or SCF. Furthermore, confocal analysis revealed that HBx colocalized with PTTG1 and Cul1. We propose that HBx promotes an abnormal accumulation of PTTG1, which may provide new insights into the molecular mechanisms of HBV-related pathogenesis of progressive liver disease leading to HCC development. (Hepatology 2010;51:777–787.)
A Reduction in Some Vasodilator Responses in Free-standing Man
Authors: J. G. Mosley
Journal: Cardiovascular Research (1969)

Journal Article A Reduction in Some Vasodilator Responses in Free-standing Man Get access J. G. Mosley J. G. Mosley * From the Department of Physiology, The Queen's University of Belfast, Northern Ireland * Supported by a grant from the Medical Research Council. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 3, Issue 1, January 1969, Pages 14–21, https://doi.org/10.1093/cvr/3.1.14 Published: 01 January 1969 Article history Received: 07 March 1968 Published: 01 January 1969
Bringing the Hospital Home: Ethical and Social Implications of High-Tech Home Care
Authors: B. Jennett
Journal: BMJ (1996)

Ed John D Arras Johns Hopkins University Press, pounds sterling33, pp 259 ISBN 08018 4990 X

Accounts of trends in medical care in the United States that focus on the inequities and commercialism of medical provision in that country are often dismissed as irrelevant to Britain. However, recent organisational changes in the NHS mean that the problems of US medicine are likely to spread across the Atlantic sooner rather than later. In Bringing the Hospital Home American doctors, ethicists, and economists highlight …
Severity Of Illness Models For Respiratory Syncytial Virus–Associated Hospitalization
Authors: FRANK W. MOLER, SUZANNE E. OHMIT
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

The objective of this investigation was to examine the feasibility of multivariate severity of illness models for pediatric patients hospitalized with respiratory syncytial virus (RSV) infection. From a preexisting retrospective cohort study database, all infants and children 2 yr of age or younger with community-acquired RSV infection admitted to the University of Michigan's C. S. Mott Children's Hospital during nine epidemics were examined. The study group consisted of 802 hospitalized patients younger than 2 yr of age with community-acquired RSV infection; 182 (23%) patients had prolonged hospital length of stay defined as 7 d or greater. Multivariate logistic regression modeling of nine variables measurable during the first hospital day was strongly associated with prolonged hospitalization (p < 0.0001). Receiver operator characteristic curve analysis resulted in an area under the curve of 0.894, indicating excellent model discrimination. Goodness-of-fit testing indicated excellent model calibration for observed versus predicted outcomes (p = 0.216). We conclude that severity of illness models for RSV-associated hospitalization with excellent predictive properties in terms of classification, discrimination, and calibration are possible. Further study is required to determine if such models are generalizable across multiple centers and epidemics.
Pathologist faces GMC hearing over altered autopsy report
Authors: Owen Dyer
Journal: BMJ (2005)

A Home Office pathologist has admitted to the General Medical Council that he altered the autopsy report of a patient who died during surgery before the surgeon stood trial for her manslaughter.

Kenneth Shorrock's initial report appeared to exonerate the surgeon, Hurais Ramis Syed, of blame, but at the trial he submitted a second report in which that conclusion was missing. He is contesting the GMC's charge of serious professional misconduct. He acknowledges that he produced two different reports but denies that he had “no sufficient reason” to change his view.

Mr Syed, a …
Histology of the Nervous System of Man and Vertebrates
Authors: Frank R. Freemon
Journal: JAMA (1996)

Santiago Ramón y Cajal (1852-1934) mastered the Golgi stain to become the greatest neurohistologist to date. His autobiography has been reviewed in these pages.<sup>1</sup>The Spanish histologist's great masterpiece on the structure of nerve cells was published in French in two volumes in 1909 and 1911. This work evolved from a series of invited lectures that were published in Spanish in 1904. Ramón y Cajal worked closely with a French translator and added more than 100 figures, so that<i>Histologie du Système Nerveux</i>was really a new work. Now two Americans have translated this historical text into English and republished the work, complete with its original illustrations. The translators have transposed the complex French into American-style English with modern anatomical terms, but have resisted the temptation to correct or amplify Ramón y Cajal's observations. The work includes a thorough index using both modern and historical terminology. The figures are
453 PATIENTS WITH RECURRENT HCV INFECTION AND UNDER ANGIOTENSIN RECEPTOR BLOCKERS AFTER LIVER TRANSPLANTATION HAVE SLOWER HISTOLOGICAL PROGRESSION
Authors: E. Cholongitas, A. Quaglia, D. Samonakis, P. Manousou, G. Papatheodoridis, M. Senzolo, D. Patch, A. Dhillon, A. Burroughs
Journal: Journal of Hepatology (2009)
Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation
Authors: Stefan O. Ciurea, Peter F. Thall, Xuemei Wang, Sa A. Wang, Ying Hu, Pedro Cano, Fleur Aung, Gabriela Rondon, Jeffrey J. Molldrem, Martin Korbling, Elizabeth J. Shpall, Marcos de Lima, Richard E. Champlin, Marcelo Fernandez-Vina
Journal: Blood (2011)
NHS regulator doubts that Morecambe trust can improve maternity services
Authors: N. Hawkes
Journal: BMJ (2011)

Failings in maternity services at University Hospitals of Morecambe Bay NHS Foundation Trust have forced the regulator Monitor to play its strongest card and declare the trust in breach of its authorisation.

This means that Monitor has doubts about whether the trust’s management and board have the competence to put things right. Last month the other NHS regulator in England, the Care Quality Commission (CQC), issued a warning notice about the standards of care in maternity services at the trust, identifying major concerns with staffing levels, risk management, and outdated facilities ( BMJ 2011;343:d5777, doi:10.1136/bmj.d5777).

The commission made unannounced visits in July to the three hospitals in the trust a month after a coroner had issued an official notice to Furness General Hospital in Barrow to take action to deal with failings in care. His intervention came after he had …
Pulmonic Regurgitation Following Staphylococcal Endocarditis
Authors: HUGH S. LEVIN, VINCENT RUNCO, CHARLES F. WOOLEY, JOSEPH M. RYAN
Journal: Circulation (1964)

Isolated pulmonic regurgitation was found in a 30-year-old man 5 years after an episode of bacteriologically proved and successfully treated staphylococcal endocarditis. Intracardiac phonocardiography was useful in confirming the diagnosis, and simultaneous intracardiac pressure and sound recording afforded a plausible explanation for the unusual murmur of organic pulmonic insufficiency.
Tumor Cell-Derived Nitric Oxide Is Involved in the Immune-Rejection of an Immunogenic Murine Lymphoma
Authors: De-En Hu, Stephanie O. M. Dyke, Alistair M. Moore, Lindy L. Thomsen, Kevin M. Brindle
Journal: Cancer Research (2004)

Abstract The roles played by host-derived nitric oxide (NO) in the growth and subsequent immune rejection of a immunogenic murine lymphoma were investigated by growing the tumor in mice in which the gene for either inducible NO synthase (iNOS) or endothelial NOS (eNOS) had been ablated. This showed that NO from tumor-infiltrating host cells had no significant effect on either tumor growth or immune rejection, although measurements of tumor nitrite levels and protein nitration showed that there had been significant NO production in the rejected tumors, in both the eNOS and iNOS knockout mice. Inhibition of both tumor and host NOS activities, with an iNOS-selective inhibitor (1400W), a nonselective NOS inhibitor [Nω-nitro-l-arginine methyl ester (L-NAME)], or scavenging NO with a ruthenium-based scavenger, significantly delayed tumor rejection, while having no appreciable effect on tumor growth. Incubation of tumor cells with medium taken from cultured splenocytes, that had been isolated from immunized animals and activated by incubating them with irradiated tumor cells, resulted in an increase in tumor cell NOS activity and an increase in tumor cell apoptosis, which could be inhibited using L-NAME. We propose that, during the immune rejection of this tumor model, there is induction of tumor NOS activity by cytokines secreted by activated lymphocytes within the tumor and that this results in increased levels of tumor NO that induce tumor cell apoptosis and facilitate immune rejection of the tumor.
Absence of platelet-activating factor receptor protects mice from osteoporosis following ovariectomy
Authors: Hisako Hikiji, Satoshi Ishii, Hideo Shindou, Tsuyoshi Takato, Takao Shimizu
Journal: Journal of Clinical Investigation (2004)

While platelet-activating factor (PAF) is produced in various diseases associated with bone resorption, its functions in bone metabolism remain unknown. Using PAF receptor–deficient mice, we evaluated the role of PAF in the development of bone resorption following ovariectomy, a model of postmenopausal osteoporosis. Through observations of bone mineral density and histomorphometric parameters, it was found that bone resorption was markedly attenuated in PAF receptor–deficient mice, indicating that PAF links estrogen depletion and osteoporosis in vivo. Osteoclasts expressed higher amounts of the enzymes required for PAF biosynthesis than osteoblasts. TNF-α and IL-1β increased the acetyl-coenzyme A:lyso-PAF acetyltransferase activity in osteoclasts. Osteoclasts, but not osteoblasts, expressed the functional PAF receptor. PAF receptor stimulation prolonged the survival of osteoclasts in vitro. Furthermore, osteoclasts treated with a PAF receptor antagonist, and also those from PAF receptor–deficient mice, showed reductions in survival rate and Ca resorption activity. Consistently, in organ cultures, bone resorption was significantly suppressed by a PAF receptor antagonist treatment or genetic PAF receptor deficiency. Thus, these results suggest that, through the inflammatory cytokines, estrogen depletion enhances PAF production as a unique autocrine factor for osteoclast functions. Inhibition of PAF function might pave the way for a new strategy to prevent postmenopausal bone loss without disturbing osteoblast functions.
Changes of laboratory variables with time in cirrhosis: Prognostic and therapeutic significance
Authors: Erik Christensen, Poul Schlichting, Lis Fauerholdt, Erik Juhl, Hemming Poulsen, Niels Tygstrup
Journal: Hepatology (1985)

The time change of laboratory variables in cirrhosis was studied by analysis of data from 488 patients with cirrhosis included in a controlled clinical trial of long-term prednisone vs. placebo. In the placebo group, a marked regression towards normal was seen within 3 months of entry into the trial (increase in serum albumin, acetylcholinesterase, cholesterol, hemoglobin and decrease in erythrocyte sedimentation rate). The subsequent course did not show a clear pattern, except for a slight increase in serum bilirubin and decrease in albumin. When studied in relation to the time of death in patients dying from a "hepatic" cause, marked increase in bilirubin and decrease in prothrombin index, albumin and cholesterol were seen in the year prior to death with little change before that time. In the prednisone group, a more marked decrease in bilirubin, SGOT, alkaline phosphatase, gamma-globulin, sulfobromophthalein retention, erythrocyte sedimentation rate and increase in leukocytes, prothrombin index and cholesterol were seen during the first 3 months. In relation to time of death from a "hepatic" cause, similar changes were seen as in the placebo group except that alkaline phosphatase increased and cholesterol did not decrease. A beneficial effect of prednisone on survival, as expressed by a previously developed therapeutic index, was associated with decrease in SGOT, alkaline phosphatase and gamma-globulin within the first 3 months. An increase in SGOT during prednisone seemed to be associated with harmful effects of therapy.
THOUGHTS ON THE APPENDIX.
Authors: S. T. HARDISON
Journal: JAMA (1898)

For the last decade the mind of the medical world has been turned to the region of the appendix, and possibly no part of the body has been so often before the profession for attention, both medical and surgical. The professional gentleman who has not had numerous cases of appendicitis to treat has either been careless in his diagnosis and investigations, or has had a clientele that is far behind in medical fads and fancies. The increased frequency of troubles that involve the appendix either primarily or secondarily, has caused much thought and many theories in regard to its treatment both medical and surgical, conservative and radical. Many learned men of wide experience have espoused the conservative course, but possibly a greater number favor prompt surgical interference. Quite a degree of success has been attained, and many are almost entitled to be called experts in its management, and if failure
Fallacy in Direct Cystourethrography
Authors: NIELS TROMHOLT, BIRGER HESSE, SUSANNE MUNCK, BIRTHE VEJE
Journal: Clinical Nuclear Medicine (1991)

Voiding cystourethrography is widely used in children to detect vesicoureteral reflux disease. A case of radionuclide voiding cystourethrography is reported, where the initial location of the catheter tip in an open ureter ostium might have lead to erroneous interpretation. Recommendations for catheter technique and control of imaging in voiding cystourethrography are given.