tbuckley/cabot-search huggingface dataset:
Abstract 4521: Discovery of novel small molecule inhibitors of the antiapoptotic protein Mcl-1 through high-throughput screening approach
Authors: Meilan Liu, Chenxi Shen, Martha Larsen, Chao-Yie Yang, Su Qiu, York Tomita, Krzysztof Krajewski, Peter P. Roller, Jeanne Stuckey, Shaomeng Wang, Zaneta Nikolovska-Coleska
Journal: Cancer Research (2010)

Abstract Myeloid cell leukemia (Mcl-1) is a multidomain, anti-apoptotic protein, member of the Bcl-2 family proteins, an important survival factor for many cancers. Mcl-1 has a critical and distinct role(s) in maintaining cell survival and emerging as an independent and promising therapeutic target. Through high throughout screening (HTS) of 53,300 structurally diverse synthetic organic compounds, we have discovered a number of novel inhibitors of Mcl-1. The hits identified by HTS were evaluated in a series of complementary biochemical, biophysical, functional and cellular assays to eliminate false positives and to determine the specificity and mechanism of action of these new compounds and 23 compounds were found to be inhibitors of Mcl-1. The most promising compounds, 59 and 62, have diverse chemical scaffolds. We have shown that these small molecule inhibitors bind to the BH3 binding site in Mcl-1 with IC50 values of 1,200 nM and 200 nM, respectively, and compete with BH3 peptides derived from Bid, Bim, or Noxa proteins. They bind to the Mcl-1 protein showing selectivity over two other Bcl-2 family members, Bcl-2 and Bcl-xL. NMR spectroscopy shows that 59 and 62 bind to the same BH3 domain of Mcl-1 as the Bim BH3 peptide. These initial lead compounds antagonize Mcl-1 on the functional level and they induce release of cytochrome c, inhibit cell growth and induce apoptosis in pancreatic and melanoma cancer cells with high levels of Mcl-1. We have tested several analogues of 59 and 62, both synthetic and commercially available, and established initial structure-activity relationships. One of the compounds tested (77), an analogue of 59, has improved binding affinity to Mcl-1 protein, as well as potent activity in inhibition of cell growth in cancer cells. Furthermore, by using murine embryonic fibroblasts (MEFs), wild type and deficient in both Bax and Bak (double knock out), it was demonstrated that the cytotoxic activity and induction of apoptosis by several analogues of the lead compound 59, depend on Bax and/or Bak, suggesting that they function as BH3 mimetics. Collectively, these findings provide good promise for chemical modifications of the new identified lead compounds, 59 and 62, and their further optimization toward developing a new class of anticancer drugs, Mcl-1 inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4521.
Continuing Education — A British View
Authors: J. G. M. Hamilton
Journal: New England Journal of Medicine (1964)

I AM tempted to answer the question "Whose responsibility?" very succinctly, "His own." Medical education cannot and should not be forced upon anyone. The responsible adult who is the practicing physician must recognize his own needs and seek freely his own means of satisfying them. However, I accept that this curt answer only begs the question, and I shall attempt to go a little farther.The continuing education of the practicing physician is a subject that is exercising the minds of those concerned with medical education all over the world, not least in Great Britain, where intense thought, discussion and . . .
Gangrenous cholecystitis - a rare complication of ERCP
Authors: R. Itah, R. Bruck, M. Santo, Y. Skornick, S. Avital
Journal: Endoscopy (2007)

A 56-year-old male underwent an elective endoscopic retrograde cholangiopancreatography (ERCP) following an episode of cholangitis. Abdominal ultrasound prior to ERCP showed contracted acalculus gallbladder. ERCP revealed normal bile ducts ([Figure 1]). Sphincterotomy was performed. The procedure was uneventful. The patient was admitted to the hospital 48 hours later due to increasing abdominal pain. Physical examination revealed right abdominal tenderness with normal vital signs. Liver function tests were normal; white blood cell (WBC) count was 14 600/mm3. Computed tomography (CT) scan demonstrated small air bubbles adjacent to the duodenum and a gallbladder filled with contrast material ([Figure 2 a, b]).
Suicide and attempted suicide.
Authors: W H Trethowan
Journal: BMJ (1979)

which may be observed even when their intrauterine growth, assessed by the mean birth weight, is reduced.This argument is compelling when considering populations in whom normal growth of totally breast-fed babies occurs.It is highly questionable whether a purely nutritional explanation of intrauterine growth retardation is compatible with successful lactation as judged by good growth in early infancy.Thus good maternal nutrition during pregnancy is not the only prerequisite for normal fetal growth: it is also important that the mother is not subjected to heavy physical demands and is allowed adequate periods of rest in the weeks before birth.
Use of clonazepam in mania and schizoaffective disorders
Authors: B S Victor, N A Link, R L Binder, I R Bell
Journal: American Journal of Psychiatry (1984)

The authors report three cases in which clonazepam controlled the acute symptoms in one manic and two schizoaffective patients. Clonazepam treatment led to a decrease in agitation and logorrhea, without the side effects associated with neuroleptics.
Development of immunoassays for biomonitoring of hexamethylene diisocyanate exposure.
Authors: R Lemus, L Lukinskeine, M E Bier, A V Wisnewski, C A Redlich, M H Karol
Journal: Environmental Health Perspectives (2001)

Hexamethylene diisocyanate (HDI) is used widely to manufacture polyurethanes for paints and coatings. It is an irritant and a chemical asthmagen. The U.S. Occupational Safety and Health Administration time-weighted average permissible exposure limit is 5 ppb and the ceiling limit is 20 ppb. We sought to develop a sensitive and specific immuno-bioassay to supplement workplace air monitoring and detect recent HDI exposure. For this, we produced rabbit antiserum to HDI-adducted keyhole limpet hemocyanin (HDI-KLH). The specificity of the antiserum was demonstrated by its reaction with a variety of HDI-conjugated proteins and the absence of reactions with conjugates of other diisocyanates, namely toluene diisocyanate and diphenyl methylene diisocyanate. Four immunoassays were developed and compared for their ability to detect decreasing quantities of HDI-adducted human serum albumin (HSA) containing 2 mol HDI adduct per mol HSA (HDI(2)-HSA) as determined by matrix-assisted laser desorption time-of-flight (MALDI-TOF) mass spectrometry. The sensitivities of some of the assays are within the range (0.82-45 nM) of current analytic methods. A Western analysis procedure has a sensitivity of 600 nM HDI adduct on HSA. ELISA inhibition assay, in which microtiter plates are coated with the HDI(2)-HSA antigen, has a sensitivity of 300 nM HDI adduct. An immunoblot assay has a sensitivity of 9 nM HDI adduct. The most sensitive bioassay (1.8 nM HDI adduct) is a three-antibody sandwich ELISA in which wells of microtiter plates are coated with the IgG fraction of the anti-HDI-KLH antisera. Compared with analytic methods for HDI biomonitoring, the immunoassays are faster and less costly and accommodate numerous samples simultaneously. The assays have the potential to affect industrial biomonitoring programs significantly.
Postremission Therapy in Acute Promyelocytic Leukemia: Room for Improvement?
Authors: Jeffrey E. Lancet
Journal: Journal of Clinical Oncology (2014)

Article Tools ONCOLOGY GRAND ROUNDS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2014.56.5549 Journal of Clinical Oncology - published online before print September 22, 2014 PMID: 25245443 Postremission Therapy in Acute Promyelocytic Leukemia: Room for Improvement? Jeffrey E. LancetxJeffrey E. LancetSearch for articles by this author Show More H. Lee Moffitt Cancer Center, Tampa, FL https://doi.org/10.1200/JCO.2014.56.5549 First Page Full Text PDF Figures and Tables Supplements © 2014 by American Society of Clinical Oncology
THE PHYSIOLOGICAL SIGNIFICANCE OF THE SECRETION OF ENDOGENOUS INSULIN INTO THE PORTAL CIRCULATION. III. EVIDENCE FOR A DIRECT IMMEDIATE EFFECT OF INSULIN ON THE BALANCE OF GLUCOSE ACROSS THE LIVER*†
Authors: Leonard L. Madison, Burton Combes, Reuben Adams, William Strickland
Journal: Journal of Clinical Investigation (1960)

There is at present general agreement, based upon abundant in vitro and in tvvo experimental evidence, that insulin exerts an immediate and profound effect on glucose utilization by muscle and adipose tissue (1-5).On the other hand, a direct hepatic action of insulin is disclaimed by most investigators since innumerable studies both in vitro and in vivo have failed to demonstrate clearly a consistent and reproducible effect of insulin upon hepatic glucose metabolism (5-12).Recent observations from this laboratory sug- gested that the site (13) and the rate ( 14) of insulin administration are important factors in eliciting a hepatic effect.However, in these as in all previous in vivo studies (11,(15)(16)(17)(18)(19), the conclusions regarding the hepatic action of insulin were inferential, since the net balance of glucose across the liver was not ascertained by direct measurement.Any experiments designed to elucidate the ef- fect of insulin on hepatic carbohydrate metabolism should fulfill the following prerequisites:1. Hepatic, in contrast to splanchnic, glucose metabolism should be measured.In view of the marked sensitivity of the extrahepatic splanchnic tissues to insulin (1-5, 11, 12), separation of the effects of insulin on these tissues from its effects on the liver is mandatory.This, in turn, re-
Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis: the Duration of Anticoagulation based on Compression UltraSonography (DACUS) study
Authors: Sergio Siragusa, Alessandra Malato, Raffaela Anastasio, Valeria Cigna, Glauco Milio, Corrado Amato, Mario Bellisi, Maria Teresa Attanzio, Oreste Cormaci, Massimo Pellegrino, Alberto Dolce, Alessandra Casuccio, Guido Bajardi, Guglielmo Mariani
Journal: Blood (2008)
RRM2 Regulates Bcl-2 in Head and Neck and Lung Cancers: A Potential Target for Cancer Therapy
Authors: Mohammad Aminur Rahman, A.R.M. Ruhul Amin, Dongsheng Wang, Lydia Koenig, Sreenivas Nannapaneni, Zhengjia Chen, Zhibo Wang, Gabriel Sica, Xingming Deng, Zhuo (Georgia) Chen, Dong M. Shin
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Ribonucleotide reductase subunit M2 (RRM2) plays an active role in tumor progression. Recently, we reported that depletion of RRM2 by systemic delivery of a nanoparticle carrying RRM2-specific siRNA suppresses head and neck tumor growth. The aim of this study is to clarify the underlying mechanism by which RRM2 depletion inhibits tumor growth. Experimental Design: siRNA-mediated gene silencing was carried out to downregulate RRM2. Immunoblotting, reverse-transcriptase PCR, confocal microscopy, tissue fractionation, gene overexpression and knockdown were employed to analyze critical apoptosis signaling. Conventional immunohistochemistry and quantum dot-based immunofluorescence were applied to detect RRM2 and Bcl2 expression and localization in tissue samples from patients and mice. Results: Knockdown of RRM2 led to apoptosis through the intrinsic pathway in head and neck squamous cell carcinoma (HNSCC) and non–small cell lung cancer (NSCLC) cell lines. We showed that Bcl-2 is a key determinant controlling apoptosis, both in vitro and in vivo, and that RRM2 depletion significantly reduces Bcl-2 protein expression. We observed that RRM2 regulates Bcl-2 protein stability, with RRM2 suppression leading to increased Bcl-2 degradation, and identified their colocalization in HNSCC and NSCLC cells. In a total of 50 specimens each from patients with HNSCC and NSCLC, we identified the colocalization of Bcl-2 and RRM2 and found a significant positive correlation between their expression in HNSCC (R = 0.98; P &amp;lt; 0.0001) and NSCLC (R = 0.92; P &amp;lt; 0.0001) tumor tissues. Conclusions: Our novel findings add to the knowledge of RRM2 in regulating expression of the antiapoptotic protein Bcl-2 and reveal a critical link between RRM2 and Bcl-2 in apoptosis signaling. Clin Cancer Res; 19(13); 3416–28. ©2013 AACR.
Sleep and Hypnotics: Further Experiments
Authors: J. I. Evans, O. Ogunremi
Journal: BMJ (1970)

Two experiments compatible with that used to investigate the effect of clinical doses (200 mg.) of amylobarbitone were set up to investigate the effects of clinical doses of chloral hydrate (800 mg.), dichloral phenazone (1,300 mg.), and Mandrax (methaqualone 250 mg. and diphenhydramine 25 mg.) over a period of one to two weeks. Four healthy male subjects were used in each experiment and received placebo or drug throughout a period of six to eight weeks when control records, drug records, and drug withdrawal records were obtained. Chloral hydrate was found to depress rapid eye movement (R.E.M.) sleep appreciably though less consistently than amylobarbitone. No withdrawal R.E.M. sleep rebound was found. Neither dichloralphenazone nor Mandrax was found consistently to depress R.E.M. sleep, though occasional nights when R.E.M. sleep was low occurred more often with Mandrax. In the light of other experiments it is postulated that there exists a “threshold” in the dose of a hypnotic, and that when this is exceeded the drug will produce R.E.M. reduction. Thus it may be possible to prescribe a drug which is clinically useful while avoiding withdrawal effects.
The ‘Echo Heart Failure Score’: an echocardiographic risk prediction score of mortality in systolic heart failure
Authors: Erberto Carluccio, Frank Lloyd Dini, Paolo Biagioli, Rosanna Lauciello, Anca Simioniuc, Cinzia Zuchi, Gianfranco Alunni, Gianpaolo Reboldi, Mario Marzilli, Giuseppe Ambrosio
Journal: European Journal of Heart Failure (2013)
Organisation and committees
Authors: Katje Lemke
Journal: British Journal of Sports Medicine (2013)

ORGANISATION 

Congress Chairman 

Prof. Dr. Heinz Lohrer

Sportmedizinisches Institut Frankfurt am Main

Otto-Fleck-Schneise 10, 60528 Frankfurt am Main, Germany 

Convenors 

Dr. Tanja Nauck

Sportmedizinisches Institut Frankfurt am Main

Nikos G. Malliaropolous

Sports Medicine Physician-EJU Medical Committee

Member MD, Msc Dipl in SEM, Phd. FFIMS, F.FSEM

(UK) General Secretary ECOSEP 

Organization/Sponsoring/Industry exhibition 

kongress & kommunikation gGmbH

Katja Lemke, Project Manager

Hanferstr. 4, 79108 Freiburg, Germany

Tel +49 (0)761-216 808 18

Fax +49 (0)761-216 808 …
Many double mastectomies are not clinically indicated, study finds
Authors: M. McCarthy
Journal: BMJ (2014)

Nearly seven in 10 women with breast cancer who have contralateral prophylactic mastectomy are not at significant risk of developing a new breast cancer in the contralateral breast, according to a new study.1

The study, published in JAMA Surgery , was led by Sarah T Hawley of the University of Michigan Medical School in Ann Arbor, US.

In recent years, the number of women choosing to have a contralateral prophylactic mastectomy as part of their initial treatment for breast cancer in the United States has risen steadily.

However, in most patients removal of the unaffected breast has not been shown to prolong survival, and the procedure is generally recommended only for women with a higher than average risk, such as those with genetic mutations of BRCA1 or BRCA2 or with at least two …
Electrical Stability of Acutely Ischemic Myocardium
Authors: KENNETH M. KENT, ELDON R. SMITH, DAVID R. REDWOOD, STEPHEN E. EPSTEIN
Journal: Circulation (1973)

Previous investigations have shown that a slower heart rate (HR) and myocardial ischemia independently diminish the electrical stability of the heart. It therefore was suggested that increasing heart rate during myocardial infarction might diminish the incidence of serious ventricular arrhythmias. However, since increased HR during experimental acute myocardial ischemia augments the degree of ischemia, an evaluation of the presumed "protective" effects of increased HR on the electrical stability of acutely ischemic myocardium was undertaken. The differences in refractory periods (RP) of eight contiguous areas of the left ventricle were determined as a function of HR. In nonischemic myocardium, the disparity of RP was less at an HR of 180 than 60. However, in ischemic myocardium the disparity increased in three of six animals as the HR was increased from 60 to 90, in seven of 10 animals as HR was increased from 60 to 120, and in all animals when the HR was increased from 60 to 180. The increased disparity of RP is believed to favor development of reentrant arrhythmia. The vulnerability of the heart to develop ventricular fibrillation was assessed by determining ventricular fibrillation threshold (VFT). During ischemia, VFT was not only an inverse function of HR but also was found to be independently influenced by electrical stimulation of the cervical vagus nerves. In the absence of vagal stimulation VFT was lowered in only one of four dogs as HR was increased from 50 to 90, but decreased 30% ( P &lt; 0.01) as HR reached 120 and 74% at 180 beats/min. When vagal stimulation was used to control HR VFT was lowered 37% as HR was increased from 50 to 60 to 90 ( P &lt; 0.05). We conclude that increasing HR within a physiologic range by diminishing vagal tone during myocardial ischemia decreases electrical stability of the ventricle by (1) increasing ischemia consequent to the rate-induced increase in myocardial oxygen requirements, and (2) a direct electrophysiologic action of the vagus on the ventricular myocardium.
A Preclinical Large Animal Model of Adenovirus-Mediated Expression of the Sodium–Iodide Symporter for Radioiodide Imaging and Therapy of Locally Recurrent Prostate Cancer
Authors: Roisin M. Dwyer, Stephen M. Schatz, Elizabeth R. Bergert, Rae M. Myers, Mary E. Harvey, Kelly L. Classic, Michael C. Blanco, Craig S. Frisk, Ronald J. Marler, Brian J. Davis, Michael K. O'Connor, Stephen J. Russell, John C. Morris
Journal: Molecular Therapy (2005)

The sodium–iodide symporter (NIS) is primarily a thyroid protein, providing for the accumulation of iodide for biosynthesis of thyroid hormones. Native NIS expression has made possible the use of radioactive iodide to image and treat thyroid disease successfully. The current study, using adult male beagle dogs, was carried out in preparation for a Phase I clinical trial of adenovirus-mediated NIS gene (approved symbol SLC5A5) therapy for prostate cancer. Direct intraprostatic injection of virus (Ad5/CMV/NS) was followed by iv injection of 3 mCi 123I and serial image acquisition. The dogs were then given a therapeutic dose of 131I (116 mCi/m2) and observed for 7 days. SPECT/CT fusion imaging revealed clear images of the NIS-transduced prostates. Dosimetry calculations revealed an average absorbed dose to the prostate of 23 ± 42 cGy/mCi 131I, with acceptably low radiation doses to other organs. This study demonstrated the successful introduction of localized NIS expression in the prostate gland of dogs, with no vector-related toxicity observed. None of the animals experienced any surgical complications, and serum chemistry panels showed no significant change following therapy. The results presented provide further evidence of the safety and efficacy of NIS as a therapeutic gene and support translation of this work into the clinical setting.
Gaucher's Disease: Neurologic Disorder in Adult Siblings
Authors: J. D. MILLER
Journal: Annals of Internal Medicine (1973)

Two adult siblings with biochemically and histologically documented Gaucher's disease as well as a similar diffuse neurologic disorder are presented. The family history suggests that a third, deceased sibling also had a similar neurologic disorder associated with Gaucher's disease. There have been no previous reports of a similar neurologic disorder in adult-type Gaucher's disease.
Flutamide-induced photosensitivity: is it a forme fruste of lupus?
Authors: C. Kaur, G.P. Thami
Journal: British Journal of Dermatology (2003)

Journal Article Flutamide‐induced photosensitivity: is it a forme fruste of lupus? Get access C. Kaur, C. Kaur Department of Dermatology and Venereology, Government Medical College and Hospital, Sector 32 B, Chandigarh 160030, India E‐mail: drgurvinder@mantraonline.com Search for other works by this author on: Oxford Academic Google Scholar G.P. Thami G.P. Thami Department of Dermatology and Venereology, Government Medical College and Hospital, Sector 32 B, Chandigarh 160030, India E‐mail: drgurvinder@mantraonline.com Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 148, Issue 3, 1 March 2003, Pages 603–604, https://doi.org/10.1046/j.1365-2133.2003.05209_11.x Published: 01 March 2003
Importance of bruising associated with paediatric fractures: prospective observational study
Authors: M O Mathew, N Ramamohan, G C Bennet
Journal: BMJ (1998)

Editorial by Eastwood 

Few data are published on the bruising seen in association with paediatric fractures. What little can be found is set in the context of non-accidental injury. Differing opinions about the importance of bruising have been expressed by those working on medicolegal cases. 1–3 The force necessary to fracture a normal bone is thought to result invariably in external evidence of trauma. 1 The absence of such bruising has been taken to imply that minimalforce was required to produce the fracture—that is, the fracture occurred because of metabolic bone disease or osteogenesis imperfecta. 2 3

We prospectively assessed 93 acute fractures in 88 normal …
Henry Rex Marrett
Authors: Richard E Shaw
Journal: BMJ (2004)

Consultant anaesthetist Coventry Group of Hospitals 1947-79 (b 1915; q St Bartholomew's Hospital, London, 1940; DA, FRCA), d 7 March 2003.​2003.




Figure 1




After training at Barts Rex joined the hospital's anaesthetic department under Dr Langton Hewer, who was engaged in assessing the potential of trilene as an anaesthetic. Rex designed a portable machine for possible use in war, and when called up to the Royal Army Medical Corps he took it with him. Rex took part in the Normandy invasion. His apparatus proved highly effective, and his senior officers agreed it was a great improvement on the standard army machine. Consequently at the end of the war the army commissioned him to design a prototype for a field anaesthetic machine. His plans were patented and the machine went into production. At Coventry Rex played a large part in the introduction of halothane and continued to improve the “Marrett” machine. He leaves a wife, Jackie; two sons; and two grandchildren.
Human phagocyte defect caused by a Rac2 mutation detected by means of neonatal screening for T-cell lymphopenia
Authors: Deborah Accetta, Grant Syverson, Benedetta Bonacci, Sreelatha Reddy, Christine Bengtson, Jill Surfus, Ronald Harbeck, Anna Huttenlocher, William Grossman, John Routes
Journal: Journal of Allergy and Clinical Immunology (2010)