tbuckley/cabot-search huggingface dataset:
Abstract 2917: Design, synthesis and biological evaluation of two chemical classes as novel small molecule Mcl-1 inhibitors
Authors: Naval Bajwa, Fardokht Abulwerdi, Chenzhong Liao, Ahmed Mady, Julie Di Bernardo, Asfar Azmi, Tomek Cierpicki, Jeanne Stuckey, Hollis Showalter, Ramzi Mohammad, Zaneta Nikolovska-Coleska
Journal: Cancer Research (2012)

Abstract The anti-apoptotic myeloid cell leukemia protein Mcl-1, a member of the Bcl-2 family proteins, has a critical and distinct role(s) in maintaining cell survival and is emerging as an independent and promising therapeutic target. Using structure-based design, two classes of small molecule Mcl-1 inhibitors were developed with IC50 values ranging from 50 nM to 75 μM, based on the lead compounds identified from high throughput screening. The structure-activity relationships (SAR) of these compounds were analyzed and chemical features of both series that are important for potency and selectivity on Mcl-1 were identified. The HSQC-NMR spectroscopy studies combined with molecular docking and dynamics simulations demonstrated that both classes of compounds occupy the BH3 binding site in Mcl-1 protein mimicking two conserved hydrophobic residues from BH3 binding motif. The most potent analogues antagonize Mcl-1 on the functional level and they induce release of cytochrome c, inhibit cell growth and induce apoptosis in Bax/Bak-dependent manner in pancreatic and melanoma cancer cells with high levels of Mcl-1. The knowledge gained through these studies provides promise for future design and expansion of these series towards development of potent small-molecule Mcl-1 inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2917. doi:1538-7445.AM2012-2917
Aerobic Exercise and Blood Pressure
Authors: Andrew J. Lewin
Journal: JAMA (1986)

<h3>To the Editor.—</h3> The article by Duncan et al<sup>1</sup>is a welcome addition to the growing literature on the relationship of aerobic-conditioning exercise and hypertension. Although a bias in the selection of patients seems to have been eliminated in this study, an important source of bias still may exist. There is no description of attempts to blind the observer of blood pressures from the information regarding the patient's assignment to the experimental or control group. It appears that blood pressure observations were made on a standard mercury sphygmomanometer rather than a random zero-type device to help minimize this bias effect. I would appreciate more clarification by the authors of this methodologic point since it may represent an important source of error in this otherwise fine research study.
A Functional Genomic Approach Identifies FAL1 as an Oncogenic Long Noncoding RNA that Associates with BMI1 and Represses p21 Expression in Cancer
Authors: Xiaowen Hu, Yi Feng, Dongmei Zhang, Sihai D. Zhao, Zhongyi Hu, Joel Greshock, Youyou Zhang, Lu Yang, Xiaomin Zhong, Li-Ping Wang, Stephanie Jean, Chunsheng Li, Qihong Huang, Dionyssios Katsaros, Kathleen T. Montone, Janos L. Tanyi, Yiling Lu, Jeff Boyd, Katherine L. Nathanson, Hongzhe Li, Gordon B. Mills, Lin Zhang
Journal: Cancer Cell (2014)
The Effects of Vasomotor Drugs and of Anemia upon Interarterial Coronary Anastomoses
Authors: PAUL M. ZOLL, LEONA R. NORMAN, SIDNEY CASSIN
Journal: Circulation (1952)

The development of functionally significant interarterial coronary anastomoses was measured in 349 young domestic pigs by injecting the coronary arteries with the lead-agar mass of Schlesinger. By this technic well-developed anastomoses were absent in 132 normal control animals. Among the agents tested, acute coronary artery narrowing, sodium nitrite and anemia were effective in stimulating anastomoses. Anastomoses first began to appear two days after narrowing; they became larger and more frequent after seven days.
CHRONIC PULMONARY TUBERCULOSIS: A NEW CONCEPTION
Authors: R. C. Wingfield
Journal: BMJ (1933)

DRUG RESISTANCE OF TRYPANOSOMES rTHE BRITISH' 179 (MEDICALJOU'RNAIL 0.5 gram of tryparsamide per kilo failed to clear the blood of parasites ; and in the case of the mouse 45 mg. of tryparsa-
Biochemical differences in children with conduct disorder socialized and undersocialized
Authors: Graham A. Rogeness, Jose M. Hernandez, Carlos A. Macedo, Elizabeth L. Mitchell
Journal: American Journal of Psychiatry (1982)

The authors compared plasma dopamine beta-hydroxylase (DBH), platelet monoamine oxidase (MAO), whole blood serotonin, and RBC catechol O-methyltransferase (COMT) in 25 children with conduct disorder and 20 control children. They found that children diagnosed as having conduct disorder undersocialized had significantly lower DBH activity than children diagnosed as having conduct disorder socialized and the control group. The children with conduct disorder socialized had significantly higher COMT activity than the other two groups. When children with a diagnosis of conduct disorder plus a diagnosis of attention deficit disorder were compared with the control group, no significant biochemical differences were found because of the mixing of the two diagnoses.
Violence versus reproductive health care
Authors: J. E Hodgson
Journal: BMJ (1995)

the cost and anxiety entailed by immediate referral-for example, patients with intraocular pressure of 22-25 mmHg but with little or no evidence of the disease.The prevalence of primary open angle glaucoma in this range is seven times higher than that in patients with lower intraocular pressure."Such people should be re-examined regularly.Of course there are problems in effecting improvements in a primary health care function that operates in the market economy.The role of the relevant medical and optical professional bodies is important, as are the policies of the large chains of opticians, which account for a substantial proportion of the nation's sight tests.The government's approach is, however, central.It paid for 6-3 million sight tests in England andWales in 1993-4 and should be negotiating to get better value for money in an activity where the quality of service varies widely.In particular, where the payment recognises the need for regular testing of categories of people at relatively high risk of glaucoma (at present, people with diabetes or those aged over 40 with a family history of glaucoma) use of all the three main tests could reasonably be required.The publicity needed to ensure that citizens know their rights in this respect would promote more general awareness of the value of comprehensive testing for the disease.It would also be rational for the government to support sight tests for the other main groups at higher than average risk ofglaucoma.The main example is that ofborderline cases in which immediate referral is not justified, notably people with intraocular pressure of 22-25 mm Hg (after retesting by
Simultaneous Assessment of Right Ventricular Function and Hypertrophy by Tc-99m MIBI
Authors: KYOJI NISHIJIMA, YOSHIYUKI MIYAHARA, KATSUYUKI FURUKAWA, TETSURO MATSUSHITA, SHIGERU KOHNO
Journal: Clinical Nuclear Medicine (1999)

Tc-99m MIBI allows the simultaneous performance of cardiac blood pool scintigraphy and myocardial SPECT. The authors performed studies to determine whether right ventricular function and hypertrophy can be evaluated simultaneously using Tc-99m MIBI in patients with right heart disease.Using right heart catheterization, several parameters of pulmonary circulation were measured, including right ventricular ejection fraction, in 23 patients with chronic pulmonary disease and pulmonary vascular disease. Within 1 week, right heart blood pool scintigraphy was performed using the first-pass method using Tc-99m MIBI. The right ventricular ejection fraction calculated from right heart blood pool scintigraphy was compared with that measured using right heart catheterization. Myocardial SPECT was performed 1 hour after right heart blood pool scintigraphy. On the short axis images, which allowed optimal visualization of the right ventricle, the right and left ventricular free walls were established as regions of interest. Myocardial wall counts were determined. The right ventricular uptake: left ventricular uptake ratio was calculated to study the relation of that ratio to mean pulmonary artery pressure and total pulmonary resistance.A significant correlation was observed between the right ventricular ejection fraction calculated on right heart catheterization and that calculated on right heart blood pool scintigraphy. The right ventricular uptake:left ventricular uptake ratio correlated positively with pulmonary artery pressure and total pulmonary resistance.These results suggest that Tc-99m MIBI allows simultaneous noninvasive evaluation of cardiac function and structure, which previously was considered impossible in patients with right heart disease.
GROUP PRACTICE WITH SPECIAL REFERENCE TO OBSTETRICS AND GYNECOLOGY
Authors: W. B. Harrell
Journal: JAMA (1952)

To the Editor:  —Group clinic practice is under consideration at present by many physicians in this country. Numerous articles have been published on the subject, but we feel that there should be more recorded experience with this type of clinic practice from the practitioners themselves.  Our clinic is located in Texarkana, which has a population of 50,000, and can be classified as a medical group family practice clinic. We organized in 1946, with a general surgeon, obstetrician-gynecologist, and internist. At present, we have seven physicians and the following departments: general surgery, obstetrics and gynecology, internal medicine, pediatrics, general practice, and industrial surgery. We get some physician referrals locally and from the surrounding communities, but we operate chiefly as an interdepartmental referral clinic type of unit.  A practice of this type means that each clinic partner, regardless of the specialty, will assume the role of family physician for those families that
IMPERFORATE AUDITORY CANALS.Read in the Section of Laryngology and Otology, at the Forty-first Annual Meeting of the American Medical Association, at Nashville, Tenn., May, 1890.
Authors: SETH S. BISHOP
Journal: JAMA (1890)

American medical books on the ear contain so little on the subject of congenital and traumatic anomalies of the external auditory canal, that it seems fair to infer that they are of uncommon occurrence in this country. Only the following four cases of complete and permanent imperviousness of the external meatus have come under my observation during a practice of fourteen years, eight of which have afforded me quite a respectable experience in hospital and dispensary work. <i>Case I</i>was a man 32 years old, who applied for treatment August 15, 1883. Several years previously he had been run over by a railroad train, that severed the auricle from the head. The surgeon in attendance is said to have had no hopes of the man's recovery, but sewed the auricle to the side of the head, to make the subject appear more presentable at his funeral. The result was
Fatal infection with Aeromonas sobria and Plesiomonas shigelloides.
Authors: G V Sawle, B C Das, P R Acland, D A Heath
Journal: BMJ (1986)

African Americans face higher risk of AKI than Caucasians. The extent to which this increased risk is because of differences in clinical, socioeconomic, or genetic risk factors is unknown. We evaluated 10,588 African-American and Caucasian participants in the Atherosclerosis Risk in Communities study, a community-based prospective cohort of middle-aged individuals. Participants were followed from baseline study visit (1996–1999) to first hospitalization for AKI (defined by billing code), ESRD, death, or December 31, 2010. African-American participants were slightly younger (61.7 versus 63.1 years, <i>P</i>&lt;0.001), were more often women (64.5% versus 53.2%, <i>P</i>&lt;0.001), and had higher baseline eGFR compared with Caucasians. Annual family income, education level, and prevalence of health insurance were lower among African Americans than Caucasians. The unadjusted incidence of hospitalized AKI was 7.4 cases per 1000 person-years among African Americans and 5.8 cases per 1000 person-years among Caucasians (<i>P</i>=0.002). The elevated risk of AKI among African Americans persisted after adjustment for demographics, cardiovascular risk factors, kidney markers, and time-varying number of hospitalizations (adjusted hazard ratio, 1.20; 95% confidence interval [95% CI], 1.01 to 1.43; <i>P</i>=0.04); however, accounting for differences in income and/or insurance by race attenuated the association (<i>P</i>&gt;0.05). High-risk <i>APOL1</i> variants did not associate with AKI among African Americans (demographic-adjusted hazard ratio, 1.07; 95% CI, 0.69 to 1.65; <i>P</i>=0.77). In summary, the higher risk of AKI among African Americans may be related to disparities in socioeconomic status.
Resistance to Levofloxacin and Failure of Treatment of Pneumococcal Pneumonia
Authors: Ross Davidson, Rodrigo Cavalcanti, James L. Brunton, Darrin J. Bast, Joyce C.S. de Azavedo, Pamela Kibsey, Christine Fleming, Donald E. Low
Journal: New England Journal of Medicine (2002)

This report describes four patients with pneumococcal pneumonia in whom empirical treatment with levofloxacin failed. In these patients, the isolates of Streptococcus pneumoniae were resistant to levofloxacin, and in two of them the resistance appeared to have been acquired during the current course of treatment with fluoroquinolones.
Using metal-ligand binding characteristics to predict metal toxicity: quantitative ion character-activity relationships (QICARs).
Authors: M C Newman, J T McCloskey, C P Tatara
Journal: Environmental Health Perspectives (1998)

Ecological risk assessment can be enhanced with predictive models for metal toxicity. Modelings of published data were done under the simplifying assumption that intermetal trends in toxicity reflect relative metal-ligand complex stabilities. This idea has been invoked successfully since 1904 but has yet to be applied widely in quantitative ecotoxicology. Intermetal trends in toxicity were successfully modeled with ion characteristics reflecting metal binding to ligands for a wide range of effects. Most models were useful for predictive purposes based on an F-ratio criterion and cross-validation, but anomalous predictions did occur if speciation was ignored. In general, models for metals with the same valence (i.e., divalent metals) were better than those combining mono-, di-, and trivalent metals. The softness parameter (sigma p) and the absolute value of the log of the first hydrolysis constant ([symbol: see text] log KOH [symbol: see text]) were especially useful in model construction. Also, delta E0 contributed substantially to several of the two-variable models. In contrast, quantitative attempts to predict metal interactions in binary mixtures based on metal-ligand complex stabilities were not successful.
Postinfarction ventricular septal rupture: the importance of location of infarction and right ventricular function in determining survival.
Authors: C A Moore, T W Nygaard, D L Kaiser, A A Cooper, R S Gibson
Journal: Circulation (1986)

Over a 5.5 year period, 1264 consecutive patients with acute myocardial infarction as confirmed by enzyme levels were prospectively identified. Of these, 25 (2%) suffered ventricular septal rupture (pulmonary/systemic flow range 1.5 to 6) 7 +/- 7 days after onset of myocardial infarction. Death occurred in 14 patients (56%) and was more common after inferior than anterior myocardial infarction (11 of 15 [73%] vs three of 10 [30%], p less than .05). Among 133 variables analyzed, survivors and nonsurvivors were similar with respect to all premorbid clinical characteristics, infarct size as assessed by peak creatine kinase values, shunt size, two-dimensional echocardiographic and hemodynamic indexes of left ventricular function, and extent of coronary disease. Compared with survivors, the nonsurvivors had greater impairment of right ventricular function as determined by a higher two-dimensional echocardiographically derived right ventricular wall motion index (RVWMI) (0.55 +/- 0.87 vs 1.70 +/- 0.45, p less than .001), greater elevation of right ventricular end-diastolic pressure (11 +/- 6 vs 17 +/- 6, p less than .02), and greater mean right atrial pressure (10 +/- 6 vs 16 +/- 3, p less than .01). Of interest, two of the three patients who presented with anterior myocardial infarction and who died had inferiorly extended infarcts and all had abnormal RVWMIs (greater than or equal to 1.0). As expected, cardiogenic shock shortly after onset of ventricular septal rupture was associated with a 91% mortality, but was more common after inferior than anterior myocardial infarction (60% vs 20%, p less than .05). The mean effective cardiac index was also higher in survivors than nonsurvivors (2.1 +/- 0.5 vs 1.2 +/- 0.5, p less than .001). Finally, multivariate analysis indicated that all nonsurvivors could be identified based on: an effective cardiac index of 1.75 liters/min/m2 or less, the presence of extensive right ventricular and septal dysfunction on the two-dimensional echocardiogram, a mean right atrial pressure of 12 mm Hg or more, and early onset of ventricular septal rupture. Thus, our data demonstrate that: mortality is higher when ventricular septal rupture complicates inferior than when it complicates anterior myocardial infarction, survivors can be distinguished from nonsurvivors and the prediction of outcome is highly accurate, and combined right ventricular and septal dysfunction has a substantial impact on prognosis.
G <sub>βγ</sub> -Independent Recruitment of G-Protein Coupled Receptor Kinase 2 Drives Tumor Necrosis Factor α–Induced Cardiac β-Adrenergic Receptor Dysfunction
Authors: Neelakantan T. Vasudevan, Maradumane L. Mohan, Manveen K. Gupta, Elizabeth E. Martelli, Afshan K. Hussain, Yilu Qin, Unni M. Chandrasekharan, David Young, Arthur M. Feldman, Subha Sen, Gerald W. Dorn, Paul E. DiCorleto, Sathyamangla V. Naga Prasad
Journal: Circulation (2013)

Proinflammatory cytokine tumor necrosis factor-α (TNFα) induces β-adrenergic receptor (βAR) desensitization, but mechanisms proximal to the receptor in contributing to cardiac dysfunction are not known.Two different proinflammatory transgenic mouse models with cardiac overexpression of myotrophin (a prohypertrophic molecule) or TNFα showed that TNFα alone is sufficient to mediate βAR desensitization as measured by cardiac adenylyl cyclase activity. M-mode echocardiography in these mouse models showed cardiac dysfunction paralleling βAR desensitization independent of sympathetic overdrive. TNFα-mediated βAR desensitization that precedes cardiac dysfunction is associated with selective upregulation of G-protein coupled receptor kinase 2 (GRK2) in both mouse models. In vitro studies in β2AR-overexpressing human embryonic kidney 293 cells showed significant βAR desensitization, GRK2 upregulation, and recruitment to the βAR complex following TNFα. Interestingly, inhibition of phosphoinositide 3-kinase abolished GRK2-mediated βAR phosphorylation and GRK2 recruitment on TNFα. Furthermore, TNFα-mediated βAR phosphorylation was not blocked with βAR antagonist propranolol. Additionally, TNFα administration in transgenic mice with cardiac overexpression of Gβγ-sequestering peptide βARK-ct could not prevent βAR desensitization or cardiac dysfunction showing that GRK2 recruitment to the βAR is Gβγ independent. Small interfering RNA knockdown of GRK2 resulted in the loss of TNFα-mediated βAR phosphorylation. Consistently, cardiomyocytes from mice with cardiac-specific GRK2 ablation normalized the TNFα-mediated loss in contractility, showing that TNFα-induced βAR desensitization is GRK2 dependent.TNFα-induced βAR desensitization is mediated by GRK2 and is independent of Gβγ, uncovering a hitherto unknown cross-talk between TNFα and βAR function, providing the underpinnings of inflammation-mediated cardiac dysfunction.
Liver Transplantation and Opioid Dependence
Authors: Monika Koch
Journal: JAMA (2001)

ContextChronic hepatitis C is the leading cause for liver transplantation in the United States. Intravenous drug use, the major risk factor, accounts for approximately 60% of hepatitis C virus transmission. Information from the United Network of Organ Sharing (UNOS) does not address substance use among liver transplantation patients.ObjectiveTo identify addiction-related criteria for admission to the UNOS liver transplantation waiting list and posttransplantation problems experienced by patients who are prescribed maintenance methadone.Design, Setting, and ParticipantsMail survey of all 97 adult US liver transplantation programs (belonging to UNOS) in March 2000 with telephone follow-up conducted in May and June 2000.Main Outcome MeasuresPrograms' acceptance and management of patients with past or present substance use disorder.ResultsOf the 97 programs surveyed, 87 (90%) responded. All accept applicants with a history of alcoholism or other addictions, including heroin dependence. Eighty-eight percent of the responding programs require at least 6 months of abstinence from alcohol; 83% from illicit drugs. Ninety-four percent have addiction treatment requirements. Consultations from substance abuse specialists are obtained by 86%. Patients receiving methadone maintenance are accepted by 56% of the responding programs. Approximately 180 patients receiving methadone maintenance are reported to have undergone liver transplantation.ConclusionsMost liver transplantation programs have established policies for patients with substance use disorders. Opiate-dependent patients receiving opiate replacement therapy seem underrepresented in transplantation programs. Little anecdotal evidence for negative impact of opiate replacement therapy on liver transplantation outcome was found. Policies requiring discontinuation of methadone in 32% of all programs contradict the evidence base for efficacy of long-term replacement therapies and potentially result in relapse of previously stable patients.
Progress in medicinal chemistry. vol. 1
Authors: Dale G. Friend
Journal: JAMA (1962)

This book, devoted to progress in medicinal chemistry, is, as the publishers say, an attempt to present a series of reviews written by outstanding specialists on selected topics prepared in such a way that they will be of interest generally, but also of use to those working in the field, since the reviews are designed to present a reasonably complete summary of the work up to the present time. The book has also been designed to interest the chemist, biochemist, pharmacologist, and clinician. The book consists of 6 chapters which discuss pharmacological screening tests, hypotensive agents, tranquilizers, diuretic drugs, oral hypoglycemics and antifungal agents. Unquestionably, the selection of authors is excellent, and their coverage of the material is very complete. The chapters on tranquilizers and diuretic drugs are most stimulating. In discussing the tranquilizers, M. W. Parks has covered the subject in an exemplary fashion, giving a great deal of