tbuckley/cabot-search huggingface dataset:
Identification of ATR–Chk1 Pathway Inhibitors That Selectively Target p53-Deficient Cells without Directly Suppressing ATR Catalytic Activity
Authors: Masaoki Kawasumi, James E. Bradner, Nicola Tolliday, Renee Thibodeau, Heather Sloan, Kay M. Brummond, Paul Nghiem
Journal: Cancer Research (2014)

Resistance to DNA-damaging chemotherapy is a barrier to effective treatment that appears to be augmented by p53 functional deficiency in many cancers. In p53-deficient cells in which the G1-S checkpoint is compromised, cell viability after DNA damage relies upon intact intra-S and G2-M checkpoints mediated by the ATR (ataxia telangiectasia and Rad3 related) and Chk1 kinases. Thus, a logical rationale to sensitize p53-deficient cancers to DNA-damaging chemotherapy is through the use of ATP-competitive inhibitors of ATR or Chk1. To discover small molecules that may act on uncharacterized components of the ATR pathway, we performed a phenotype-based screen of 9,195 compounds for their ability to inhibit hydroxyurea-induced phosphorylation of Ser345 on Chk1, known to be a critical ATR substrate. This effort led to the identification of four small-molecule compounds, three of which were derived from known bioactive library (anthothecol, dihydrocelastryl, and erysolin) and one of which was a novel synthetic compound termed MARPIN. These compounds all inhibited ATR-selective phosphorylation and sensitized p53-deficient cancer cells to DNA-damaging agents in vitro and in vivo. Notably, these compounds did not inhibit ATR catalytic activity in vitro, unlike typical ATP-competitive inhibitors, but acted in a mechanistically distinct manner to disable ATR-Chk1 function. Our results highlight a set of novel molecular probes to further elucidate druggable mechanisms to improve cancer therapeutic responses produced by DNA-damaging drugs.
Review: Voriconazole for prevention or treatment of invasive fungal infections in cancer with neutropenia
Authors: Andrew M. Morris
Journal: Annals of Internal Medicine (2014)

Source Citation Jørgensen KJ, Gøtzsche PC, Dalbøge CS, Johansen HK. Voriconazole versus amphotericin B or fluconazole in cancer patients with neutropenia. Cochrane Database Syst Rev. 2014;(2):CD004707. 24563222
Effect of coexposure to asbestos and kerosene soot on pulmonary drug-metabolizing enzyme system.
Authors: J M Arif, S G Khan, N Mahmood, M Aslam, Q Rahman
Journal: Environmental Health Perspectives (1994)

This article reports the effect of coexposure to Indian chrysotile asbestos (5 mg/rat) and kerosene soot (5 mg/rat) on the pulmonary phase I and phase II drug-metabolizing enzymes 1, 4, 8, 16, 30, 90, and 150 days after a single intratracheal inoculation. Exposure to soot resulted in a significant induction of the pulmonary microsomal cytochrome P450 and the activity of dependent monooxygenase, benzo(a)pyrene (B[a]P) hydroxylase, and epoxide hydrase at all time intervals. On the other hand, the cytosolic glutathione S-transferase (GST) activity was induced at days 1, 4, 8, 16, and 30 after exposure, followed by inhibition in the enzyme activity. In contrast, chrysotile exposure depleted cytochrome P450, B[a]P hydroxylase, epoxide hydrase, and GST at initial stages, while all these parameters except GST were induced at later stages. However, coexposure to chrysotile and soot led to a significant inhibition in the cytochrome P450 levels, activities of B[a]P hydroxylase, epoxide hydrase, and GST at initial stages of exposure. At advanced stages, however, an additional increase in cytochrome P450, B[a]P hydroxylase, and epoxide hydrase but a decrease in GST was observed. These results clearly show that the intratracheal coexposure to high levels of asbestos and kerosene soot alters the metabolic activity of the lung, which is turn may retain toxins in the system for a longer period, resulting in adverse pathological disorders.
Abstract 2251: Induction of apoptosis in breast cancer cells using <i>Kedrostis foetidissima</i>.
Authors: Lesetja Raymond Motadi
Journal: Cancer Research (2013)

Abstract Kedrostis foetidissima has been used by tribes throught Africa to treat various human livestock ailments. K. foetidissima, has been shown to inhibit the growth of breast cancer cell lines in vitro by induction of apoptosis in previous studies of our group1. With current chemotherapy and radiotherapy continuing to show unwanted side effects the only hope to a better safer medicinal target would include that uses medical plants that induces apoptosis with or without inducing p53 gene2,3. However, the mechanisms of action are not completely understood. In this study we are looking at the role and expressional levels of RBBp6 in breast cancer following treatment with the plant extract. In trying to achieve our objective both human breast cancer tissue and MCF7 cell lines were used to first establish the pattern of expression and then cell lines were treated with medicinal plant to evaluate the expressional patterns using both the immunohistochemistry, RTPCR and Flow cytometer. We observed that protein as well as mRNA level of RBBP6 was inhibited by K. foetidissima in a dose-dependent manner (Fig. 1). However, in both untreated and human breast cancer tissues RBBp6 was found to be highly expressed around cells undergoing cell division. In recent studies, an apoptosis-related gene expression profiling analysis provided a clue that both p53 and bax gene were slightly upregulated at least 2 to 3 fold in response to K. foetidissima treatment in MCF7 cell2. On the other had we have reported in the past that RBBp6 acted as inhibitor of p53 gene. The findings in this study suggest that downregulation of RBBp6 may through small molecules might be a potential therapy in cancer. Citation Format: Lesetja Raymond Motadi. Induction of apoptosis in breast cancer cells using Kedrostis foetidissima. [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 2251. doi:10.1158/1538-7445.AM2013-2251 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Phospholamban phosphorylation sites enhance the recovery of intracellular Ca2+ after perfusion arrest in isolated, perfused mouse heart
Authors: C VALVERDE, C MUNDINAWEILENMANN, M REYES, E KRANIAS, A ESCOBAR, A MATTIAZZI
Journal: Cardiovascular Research (2006)

Objective To investigate the importance of the phosphorylation of Ser16 and Thr17 sites of phospholamban (PLN) on intracellular Ca2+ (Cai2+) handling and contractile recovery of the stunned myocardium.
Severe metabolic alkalosis: a case report.
Authors: S Javaheri, E A Nardell
Journal: BMJ (1981)

A 45-year-old man who was admitted with nausea, vomiting, and abdominal pain was found to have severe metabolic alkalosis, with a PaCO2 of 11.4kPa (85.5 mm Hg), PaO2 of 5.8 kPa (43.5 mm Hg), pH of 7.61, and plasma bicarbonate concentration of 82.0 mmol/l. He was treated with oxygen, intravenous physiological saline, and phenytoin and improved within 48 hours. Radiographs showed gastric outlet obstruction secondary to peptic ulcer, which was treated by surgery. Though sever, the rise in carbon dioxide concentration in this patient was probably lifesaving. The PaCO2 was therefore allowed to fall gradually as the alkalosis was treated. The return of both PaCO2 and plasma bicarbonate values to normal in parallel suggests that hypoventilation compensated for the metabolic alkalosis and emphasises the importance of conservative treatment in cases of metabolic alkalosis.
Altered left ventricular mechanics in patients with valvular aortic stenosis and coarction of the aorta: effects on systolic performance and late outcome.
Authors: K M Borow, S D Colan, A Neumann
Journal: Circulation (1985)

Despite similar degrees of left ventricular systolic hypertension shortening characteristics are usually greater in patients with congenital valvular aortic stenosis (VAS) than in patients with coarctation of the aorta (CoA). We hypothesized that these dissimilarities were caused by differences in myocardial mechanics rather than by alterations in contractile state. Eleven patients with VAS (ages 6 to 41 years) and 11 with CoA were matched for age, body surface area, and peak systolic ejection gradient. Results were compared with data from 22 normal subjects matched for age and body surface area. Echocardiographic tracings of the left ventricle were recorded in conjunction with left ventricular pressure measurements (VAS) or calibrated carotid pulse tracings (CoA and normal subjects). Peak and end-systolic wall stresses as well as left ventricular shortening fraction (% delta D) and rate-corrected velocity of fiber shortening (Vcfc) were calculated. No differences for left ventricular dimensions, heart rate or peak wall stress were present. Ventricular peak systolic pressures and wall mass were higher for the patients with VAS or CoA than for the normal subjects (p less than .001). These parameters did not differ between the VAS and CoA groups. The patients with VAS had higher % delta D and Vcfc than either the CoA or normal groups (p less than .01). Afterload, as quantified by end-systolic stress, was 41% lower than normal for the patients with VAS (p less than .001) and 13% higher than normal for those with CoA (p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer
Authors: Gijs van Haaften, Gillian L Dalgliesh, Helen Davies, Lina Chen, Graham Bignell, Chris Greenman, Sarah Edkins, Claire Hardy, Sarah O'Meara, Jon Teague, Adam Butler, Jonathan Hinton, Calli Latimer, Jenny Andrews, Syd Barthorpe, Dave Beare, Gemma Buck, Peter J Campbell, Jennifer Cole, Simon Forbes, Mingming Jia, David Jones, Chai Yin Kok, Catherine Leroy, Meng-Lay Lin, David J McBride, Mark Maddison, Simon Maquire, Kirsten McLay, Andrew Menzies, Tatiana Mironenko, Lee Mulderrig, Laura Mudie, Erin Pleasance, Rebecca Shepherd, Raffaella Smith, Lucy Stebbings, Philip Stephens, Gurpreet Tang, Patrick S Tarpey, Rachel Turner, Kelly Turrell, Jennifer Varian, Sofie West, Sara Widaa, Paul Wray, V Peter Collins, Koichi Ichimura, Simon Law, John Wong, Siu Tsan Yuen, Suet Yi Leung, Giovanni Tonon, Ronald A DePinho, Yu-Tzu Tai, Kenneth C Anderson, Richard J Kahnoski, Aaron Massie, Sok Kean Khoo, Bin Tean Teh, Michael R Stratton, P Andrew Futreal
Journal: Nature Genetics (2009)
Relief From Pain and the Double Effect-Reply
Authors: John M. Luce
Journal: JAMA (1992)

<h3>In Reply.</h3> —We appreciate the response of Drs Hooyman and Veremakis to our recent study. We agree with their first reservation regarding the use of deeply comatose patients who did not receive drugs as a control group compared with patients who are not deeply comatose and did receive drugs, and we expressed this reservation in our article.<sup>1</sup>However, as Hooyman and Veremakis note, a better control group was not available to us and is unlikely to be available to other investigators in the future. As for their second reservation regarding the principle of double effect, we note that the source we cited on this principle emphasized the importance of the primary motivation, relief of pain and suffering, in ordering and administering sedatives and analgesics. Because such relief was the primary motivation for the physicians and nurses in our study, we stated that their actions were ethically justified. Hooyman and Veremakis
Efficacy and Safety of Umbilical Cord Milking at Birth
Authors: Heidi Al-Wassia, Prakesh S. Shah
Journal: JAMA Pediatrics (2014)

<h3>Importance</h3> Umbilical cord milking (UCM) is suggested to improve neonatal outcomes. <h3>Objectives</h3> To perform a systematic review and meta-analysis of the efficacy and safety of UCM in full-term and preterm neonates. <h3>Data Sources</h3> A systematic search of MEDLINE, EMBASE, CINAHL, the Cochrane Database of Clinical Trials, the clinicaltrails.gov database, and the reference list of retrieved articles from 1940 to 2014. <h3>Study Selection</h3> Randomized clinical trials comparing UCM with other strategies of handling the umbilical cord at birth in full-term and preterm infants. Seven of the 18 initially identified studies were selected. <h3>Data Extraction and Synthesis</h3> Two reviewers independently extracted data and assessed the risk for bias in included trials using the criteria outlined in the<i>Cochrane Handbook for Systematic Reviews of Interventions</i>. <h3>Main Outcomes and Measures</h3> Neonatal mortality before discharge from the hospital. <h3>Results</h3> We included 7 randomized clinical trials involving 501 infants. Infants with a gestational age of less than 33 weeks allocated to UCM compared with control conditions showed no difference in the risk for mortality (risk ratio [RR], 0.75 [95% CI, 0.35 to 1.64]; risk difference [RD], −0.02 [95% CI, −0.09 to 0.04]), hypotension requiring volume expanders (RR, 0.71 [95% CI, 0.41 to 1.25]; RD, −0.09 [95% CI, −0.22 to 0.05]), or inotrope support (RR, 0.77 [95% CI, 0.51 to 1.17]; RD, −0.10 [95% CI, −0.25 to 0.05]). Higher initial levels of hemoglobin (mean difference, 2.0 [95% CI, 1.3-2.7] g/dL) and hematocrit (mean difference, 4.5% [95% CI, 1.5%-7.4%]) were identified in the UCM groups. We found a reduced risk for oxygen requirement at 36 weeks (RR, 0.42 [95% CI, 0.21 to 0.83]; RD, −0.14 [95% CI, −0.25 to −0.04]) and for intraventricular hemorrhage of all grades (RR, 0.62 [95% CI, 0.41 to 0.93]; RD, −0.12 [95% CI, −0.22 to −0.02]) in infants assigned to UCM. Among infants with a gestational age of at least 33 weeks, UCM was associated with higher hemoglobin levels in the first 48 hours in 224 infants (mean difference, 1.2 [95% CI, 0.8-1.5] g/dL) and at 6 weeks of life in 170 infants (mean difference, 1.1 [95% CI, 0.7-1.5] g/dL). <h3>Conclusions and Relevance</h3> Umbilical cord milking was associated with some benefits and no adverse effects in the immediate postnatal period in preterm infants (gestational age, &lt;33 weeks); however, further studies are warranted to assess the effect of UCM on neonatal and long-term outcomes.
718 CONTRAST-ENHANCED CT SCAN DIFFERENTIATES HEPATOCELLULAR CARCINOMA AND INTRAHEPATIC CHOLANGIOCARCINOMA IN CIRRHOSIS
Authors: M. Iavarone, S. Vavassori, A. Sangiovanni, M. Fraquelli, L.V. Forzenigo, G. Ronchi, M. Colombo
Journal: Journal of Hepatology (2012)
The National Resident Matching Program and Antitrust Law
Authors: Frances H. Miller, Thomas L. Greaney
Journal: JAMA (2003)

In May 2002, a group of physicians filed a class action lawsuit alleging that the National Resident Matching Program (NRMP) violates antitrust laws. The plaintiffs contend that NRMP practices have stabilized lower-than-competitive wages and imposed exhausting working conditions on residents. They also maintain that NRMP procedures virtually force applicants for house officer positions to forfeit their right to negotiate for better wages and conditions. The plaintiffs also allege that the defendants have collectively fostered anticompetitive accreditation standards through the Accreditation Council for Graduate Medical Education. Jung v Association of American Medical Colleges could present antitrust law with some difficult challenges. Although the matching program on its face appears to limit competition in a manner that previous cases have found illegal, it operates in the context of important professional activities (medical education and quality improvement) that may generate some judicial deference. At this early stage, no confident prediction can be made about the outcome of the case if it goes to trial; however, the plaintiffs appear to have a plausible case under existing antitrust doctrine, and lengthy litigation is possible. Given the important questions that the litigation will not address, such as the potential costs of a finding of illegality to the government and other payers, and the impact of such a finding on the health care system as a whole, a legislative solution seems highly desirable.
Low incidence of BRCA2 mutations in breast carcinoma and other cancers
Authors: David H.-R Teng, Robert Bogden, Jeffrey Mitchell, Michelle Baumgard, Russell Bell, Simin Berry, Thaylon Davis, Phuong C. Ha, Robert Kehrer, Srikanth Jammulapati, Qian Chen, Kenneth Offit, Mark H. Skolnick, Sean V. Tavtigian, Suresh Jhanwar, Brad Swedlund, Alexander K.C. Wong, Alexander Kamb
Journal: Nature Genetics (1996)
Assessment of Aminopyrine Metabolism in Man by Breath Analysis after Oral Administration of<sup>14</sup>C-Aminopyrine
Authors: Gershon W. Hepner, Elliot S. Vesell
Journal: New England Journal of Medicine (1974)

To determine whether hepatic drug metabolism might be conveniently assessed by a breath analysis technic, 4-dimethyl-14C-amino-antipyrine (aminopyrine) was administered orally to healthy ambulant and nonambulant volunteers and to patients with portal cirrhosis; some of the volunteers were restudied after pretreatment with either phenobarbital or disulfiram. 14CO2 output was estimated semiquantitatively from interval breath samples. Aminopyrine metabolic clearance rate and 12-hour breath 14CO2 output in the healthy volunteers studied before and after drug pretreatment correlated highly(r = 0.91). The metabolic clearance rate was 46 ± 7 ml per minute (mean ± S.E.) in the patients with portal cirrhosis, and 122 ± 20 ml per minute in the healthy controls (p < 0.01). Twelve-hour breath 14CO2 output was 13.8 ± 1.5 per cent in the patients with portal cirrhosis, and 32.6 ± 2.3 per cent in the nonambulant controls (p < 0.01). The data suggest that in vivo breath analysis after administration of 14C-aminopyrine provides useful information about hepatic drug metabolism in health and disease. (N Engl J Med 291:1384–1388, 1974)
Long-term Insulin Treatment in Two Nondiabetic Patients
Authors: Johan Asplund
Journal: JAMA (1981)

TODAY the diagnosis of insulindependent diabetes mellitus seldom presents problems. However, in two patients recently seen by us, renal glucosuria had been wrongly diagnosed as diabetes mellitus 33 and 51 years earlier. Throughout this period, treatment with long-acting insulin of an unpurified type had been administered, and this therapy was withdrawn. It was considered of interest to investigate the B-cell function in nondiabetic subjects after such a long period of insulin therapy. Since it has been suggested that the presence of insulin antibodies may be a factor in the development of diabetic microangiopathy,<sup>1</sup>we also searched for evidence of this condition. <h3>Report of Cases</h3><h3>Case 1.—</h3> In 1946, a 23-year-old man was found to have glucosuria, 1.5% to 4.0%; there was no ketonuria. Despite the absence of classic symptoms of diabetes mellitus and the recording of one normal glucose value, treatment was given, consisting of diet and administration of
The general practitioner; a study of medical education and practice in Ontario and Nova Scotia.
Authors: David W. Wallwork
Journal: JAMA (1963)

This detailed survey of 86 general practices in Ontario and Nova Scotia, conceived by the College of General Practice of Canada, was directed between 1956 and 1960 by Dr. Kenneth F. Clute, pediatrician, using as a guide Peterson's report of a similar survey in North Carolina in 1956. Designed primarily to study quality of practice, the survey was expanded to provide a more complete picture of the background of the practitioner than was provided by Peterson's work. The report deals first with the practitioner's family, economic and social background, his education and training, the vicissitudes of planning and practice, the arrangements for practice in the office, outside the office and in the hospital, intraprofessional and community relationships, finances, personal attributes, and the nature of general practice. Although items of interest are frequent, this portion of the book is arduous reading and might well discourage many to whom the remainder would
Latent Gonorrhea in Women
Authors: Joseph G. Ellis
Journal: JAMA (1969)

<h3>To the Editor:—</h3> The letter of Dr. LeMon Clark (<b>209</b>:563, 1969) expanded on the latent gonorrhea in women and the Desdemona distress of female patients with this problem. The most famous example of this dilemma is described from the man's point of view by James Boswell in<i>Boswell's London Journal</i>, 1762-1763, New York: McGraw-Hill Book Co., Inc., 1950, pp 150-160. Boswell had spent considerable time and effort in the seduction of an actress in order to provide himself with "a winter of safe copulation" and, when signs of gonorrhea appeared, he angrily confronted the young woman, broke off their relationship, and spent the next five weeks in his rooms recovering. Boswell: Pray, Madam, in what state of health have you been in for some time? Louisa: Sir, you amaze me. Boswell: I have but too strong, too plain reason to doubt of your regard. I have for some days
Prognosis of myocardial infarctions involving more than 40% of the left ventricle after acute reperfusion therapy.
Authors: B D McCallister, T F Christian, B J Gersh, R J Gibbons
Journal: Circulation (1993)

BACKGROUND Prior studies based on autopsy data suggest that infarction of more than 40% of the left ventricle necessitates cardiogenic shock and death. METHODS AND RESULTS Technetium-99m Sestamibi tomography was used prospectively to measure infarct size at discharge in 166 patients with acute myocardial infarction. Patients with previous myocardial infarction or revascularization were excluded from the trial. Sixteen patients were identified with final infarct sizes &gt; 40% of the left ventricle despite acute reperfusion therapy. These 16 patients (13 men) had a mean age of 63 +/- 10 years; 44% had a previous history of angina. Ten patients had emergent coronary angioplasty only (mean time to percutaneous transluminal coronary angioplasty [PTCA], 6.0 +/- 3.0 hours); 6 had thrombolysis (mean time to tissue plasminogen activator, 4.0 +/- 1.5 hours), of which 2 had rescue PTCA (5 and 3 hours from onset of pain). Of 15 patients who had angiograms after therapy, 15 had open infarct-related arteries. The left anterior descending artery was the infarct-related artery in 14 (9 proximal and 5 distal lesions). Half the patients had only single-vessel disease. Infarct size measured 50 +/- 7% of the left ventricle (range, 42% to 68%). Ejection fraction by radionuclide angiogram was 0.33 +/- 0.09 and 0.38 +/- 0.07 at discharge and 6 weeks, respectively. Hospital complications included shock (1 patient), pulmonary edema (2), angina (3), symptomatic nonsustained ventricular tachycardia (1), transient complete heart block (2), and transient bifascicular block (1). At follow-up (13 +/- 9 months), the patient with shock had died, but the remaining 15 patients were asymptomatic (1 had late PTCA for angina). CONCLUSIONS In the interventional and thrombolytic era, patients with large residual myocardial infarctions can survive without heart failure.
Use of Prophylactic Antibiotics by Drug Abusers
Authors: Sydria K. Schaffer
Journal: JAMA (1984)

<h3>To the Editor.—</h3> We are becoming increasingly aware that intravenous (IV) drug abusers in the Philadelphia area routinely take prophylactic oral antibiotics. Approximately 60% of all IV drug abusers seen by us during a threemonth period at the emergency rooms of two city hospitals admit to the use of antibiotics to prevent cellulitis, phlebitis, and abscess formation. There may be more who use the drugs but would not admit it to us. Of those patients who do admit to antibiotic use, 100% report taking cephalexin (Keflex). Furthermore, they report receiving the cephalexin from the same supplier from which they receive their IV drugs. The drug is reportedly procured via manipulation of routine prescriptions given by physicians to drug users and their friends for unrelated infections. We therefore urge all physicians to consider using the following guidelines when writing antibiotic prescriptions: (1) limit the prescription of antibiotics, especially cephalexin, to those