tbuckley/cabot-search huggingface dataset:
Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia
Authors: John C. Byrd, Richard R. Furman, Steven E. Coutre, Ian W. Flinn, Jan A. Burger, Kristie A. Blum, Barbara Grant, Jeff P. Sharman, Morton Coleman, William G. Wierda, Jeffrey A. Jones, Weiqiang Zhao, Nyla A. Heerema, Amy J. Johnson, Juthamas Sukbuntherng, Betty Y. Chang, Fong Clow, Eric Hedrick, Joseph J. Buggy, Danelle F. James, Susan O'Brien
Journal: New England Journal of Medicine (2013)

The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell-receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells.We conducted a phase 1b-2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg.Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%.Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.).
Hyponatremia Induced by a Combination of Amiloride and Hydrochlorothiazide
Authors: Peter H. Strykers
Journal: JAMA (1984)

HYPONATREMIA developing after conventional diuretic therapy has been well documented. Recently, some cases of hyponatremia developing after the administration of an amiloride-hydrochlorothiazide combination, as early as six days after the onset of treatment, have been reported.<sup>1-3</sup>This article reports a case of severe hyponatremia developing after two doses of an amiloride hydrochloride, 5 mg, and hydrochlorothiazide, 50 mg, combination. <h3>Report of a Case</h3> A 78-year-old, generally healthy woman had been treated with hydrochlorothiazide, 50 mg daily, and potassium supplements for hypertension since 1975. In 1982, propranolol hydrochloride, 20 mg twice daily, was added to her regimen. Her serum sodium level has ranged from 132 to 133 mEq/L, with normal potassium levels. On July 12, 1983, to simplify her regimen, hydrochlorothiazide and potassium chloride were changed to one tablet daily of an amiloride hydrochloride, 5 mg, and hydrochlorothiazide, 50 mg, combination. A chemistry screen on the same day revealed a sodium
Interaction between a carboxypeptidase-like protein and neutralizing epitopes of duck hepatitis B virus pres-S protein
Authors: S TONG
Journal: Hepatology (1995)

In clarifying the bonding mechanism and in the in-depth study of the property of coating in cold gas dynamic spray (CGDS), the analysis of multiple impacts techniques is of great importance. The development of atomic-scale structures and Microscopic analysis of the deformation mechanisms have proven to be of many advantages to molecular dynamic simulations. Thus, simulations of molecular dynamics (MD) are performed to determine the effect of temperature and surface configurations on multiple impacts plastic deformation in Pd-Cu composite metal membrane (CMM) interfaces during CGDS. The results suggest that the analysis of temperature and plastic strain at different preheating temperatures showed an understanding of multiple impact behaviour. The interfacial layer thickness increases with temperature. Therefore, Pd-Cu cohesion occurs without melting at the interfacial zone. The interfacial bonding strength during this process emerged to be considerably higher at a higher temperature than that achieved during low temperature because the hydrodynamic behaviour between bonded atoms resulted from the elevated shear strain rate, shear plastic deformation and local fusion (thermal effect) at the interface of the contact region. The surface configurations of the substrate material also shown to have a significant impact on the process of deposition and deformation of the impacting clusters. As the temperature increases, the bonding process involves substantial plastic deformation at the interface, leading to the removal of interstices and total interaction between the contact pair. The Pd-Cu CMM interface obtained in this analysis has very good mechanical characteristics of approximately (0.70, 0.87, 0.96 and 1.06) GPa tensile strength at (300, 450, 550 and 650) K showing a tensile strength that is approximately similar with those from experiments.
Screen detected high blood pressure under 40: a general practice population followed up for 21 years.
Authors: J T Hart, C Edwards, M Hart, J Jones, M Jones, A Haines, G Watt
Journal: BMJ (1993)

OBJECTIVE--To assess hypertension detected under 40 in a general practice population. DESIGN--Prospective case-control study. SETTING AND SUBJECTS--Former coal mining community in south Wales. Systematic case finding for hypertension and associated risk factors applied to a mean total population of 1945 from age 20 on a five year cycle through 21 years. Mean population aged 20-39, 227 men and 213 women. Case criteria: age &lt; 40 and mean systolic pressure &gt; or = 160 mm Hg or diastolic pressure &gt; or = 100 mm Hg. Age and sex matched controls randomly sampled from the same population. MAIN OUTCOME MEASURES--Mean initial pressures and pressures at follow up in 1989 or preceding death, and all cardiovascular events. RESULTS--25 men and 16 women met criteria. Estimated five yearly inceptions were 26/1000 for men and 18/1000 for women. Male group mean initial blood pressure was 164/110 mm Hg for cases, falling to 148/89 mm Hg at follow up. Five male cases died at mean age 47.8, compared with two controls at 49.5. Female group mean initial pressure was 172/107 mm Hg for cases, falling to 145/86 mm Hg at follow up. One female case died aged 50, no controls. 10 male cases had non-fatal cardiovascular events at mean age 40.2, compared with two controls at mean age 50.5. Four female cases had non-fatal events at mean age 47.2, compared with one control aged 58. Male differences were statistically significant. CONCLUSIONS--Hypertension under 40 is dangerous, commoner in men than women, rarely secondary to classic causes, and may be controlled in general practice on a whole community basis.
bHLH-zip Transcription Factor Spz1 Mediates Mitogen-Activated Protein Kinase Cell Proliferation, Transformation, and Tumorigenesis
Authors: Shih-Hsien Hsu, Hsiu-Mei Hsieh-Li, Hsin-Yi Huang, Pei-Hsin Huang, Hung Li
Journal: Cancer Research (2005)

BHLH-zip proteins usually play important regulatory roles in cell growth and differentiation. In this study, we show that Spz1, a bHLH-zip transcription factor, acts downstream of mitogen-activated protein kinase (MAPK, extracellular signal-regulated kinase 1/2) to up-regulate cell proliferation and tumorigenesis. In addition, through an interaction with proliferating cell nuclear antigen (PCNA) promoter, Spz1 induced cell proliferation concomitant with an increase in PCNA gene expression. Spz1-transfected cells formed colony foci on soft agar and developed fibrosarcoma tumors in nude mice. MAPK directly interacted and phosphorylated Spz1 protein, which increased PCNA transcription and cell tumorigenic activities. Reduction of endogenous Spz1 expression via RNA interference decreased cell proliferation in p19 embryonic carcinoma cells. High levels of Spz1 expression were detected in murine tumor cell lines and tumor samples of both human and Spz1 transgenic mice. Thus, Spz1 may act as a proto-oncogene, participating in the MAPK signal pathway, and be a potential therapeutic target in the treatment of Ras-induced tumors.
Abstract 224: The role of Bmi-1 in benzyl isothiocyanate-mediated suppression of breast cancer stem cell self-renewal
Authors: Su-Hyeong Kim, Shivendra V. Singh
Journal: Cancer Research (2014)

Abstract We have shown previously that benzyl isothiocyanate (BITC), a nontoxic small-molecule constituent of edible cruciferous vegetables (eg, garden cress) inhibits breast cancer stem cells (bCSC) in vitro and in vivo but the underlying mechanisms are not fully understood. Bmi-1 is a member of the polycomb group family of proteins that function in the epigenetic silencing of genes governing self-renewal, differentiation, and proliferation. The present study was undertaken to investigate the role of Bmi-1 in BITC-mediated inhibition of bCSC. BITC treatment downregulated protein level of Bmi-1 in cultured human breast cancer cells (MCF-7, SUM159 and MDA-MB-231), and in MDA-MB-231 xenografts in vivo. Ectopic expression of Bmi-1 alone was sufficient to drive stemness in MCF-7 cells. In addition, Bmi-1 overexpression in MCF-7 cells conferred marked protection against BITC-mediated inhibition of bCSC as evidenced by mammosphere frequency and aldehyde dehydrogenase 1 (ALDH1) activity. Consistent with these observations, silencing of Bmi-1 in SUM159 cells remarkably reduced the portion of bCSC. Apoptosis induced by BITC was also partially attenuated by overexpression of Bmi-1 in MCF-7 cells but its silencing had no effect on BITC-induced apoptosis in SUM159 cells. Previous studies have shown that miRNA128 inhibits cell proliferation and self-renewal by direct regulation of Bmi-1. BITC treatment modestly but statistically significantly increased the expression of miRNA128 in both MCF-7 and SUM159 cells. Inhibition of miRNA128 increased the mammosphere formation in MCF-7 and SUM159 cells and partially attenuated BITC-mediated inhibition of mammosphere formation. These observations led us to conclude that Bmi-1 is a novel target of BITC-mediated inhibition of bCSC. This study was supported by the grant RO1 CA129347 awarded by the National Cancer Institute. Citation Format: Su-Hyeong Kim, Shivendra V. Singh. The role of Bmi-1 in benzyl isothiocyanate-mediated suppression of breast cancer stem cell self-renewal. [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 224. doi:10.1158/1538-7445.AM2014-224
Abstract 698: MCL1 dependent cells are sensitive to the CDK inhibitor Dinaciclib.
Authors: Harold Hatch, Robert Booher, Samanthi Perera, Thi Nguyen, Brian Dolinski, Samer Al-Assaad, Lauren Harmonay, Alwin Schuller, Minilik Angagaw, Brian Long, Xianlu Qu, Nathan Miselis, Mark Ayers, Michael Nebozhyn, Heather Hirsch, Danielle Greenawalt, Andrey Loboda, Thorseten Graef, Ellie Im, Rebecca Blanchard, Leigh Zawel, Peter Strack
Journal: Cancer Research (2013)

Abstract Dinaciclib is a potent inhibitor of cyclin dependent kinases (CDKs) 1, 2, 5, and 9 and is currently in Phase 3 for the treatment of refractory chronic lymphocytic leukemia (CLL). To further understand the mechanism of action, identify predictive biomarkers, and find additional cancer types which may benefit from dinaciclib, we evaluated cell viability following 24 hours treatment across a panel of ∼500 cells lines. Hematopoietic cell lines were on average 3-times more sensitive than solid tumor lines. In agreement with previous findings, mRNA expression of the anti-apoptotic family member BCL-xL or the ratio of MCL1-to-BCL-xL continue to be the best predictor of dinaciclib sensitivity in both hematopoietic and solid tumor cell lines. MCL1 appears to be an important target of dinaciclib particularly in MCL1 amplified cell lines. Dependence on MCL1 was established in a panel of 19 breast, NSCLC and SCLC cell lines by depletion of the protein by either dinaciclib treatment or MCL1 RNAi. The NSCLC line H23 was highly dependent on MCL1, as RNAi knockdown decreased viability to &amp;lt;20% and could be rescued by introduction of a non-targeted MCL1 expression construct. In the H23 xenograft, dinaciclib diminished MCL1 levels and induced tumor apoptosis resulting in &amp;gt;80% tumor regression. Cell lines which lacked pro-apoptotic proteins BAX / BAK or harbored a BAX mutation were insensitive to the inhibitor. Using apoptosis defective lines we demonstrate that 24 hours of dinaciclib treatment still impacted cell count by blocking cell cycle progression as measured by FACS. These data demonstrate that both cell cycle block and induction of apoptosis contribute to dinaciclib's mechanism of action. However, the observation that MCL1 and BCL-xL were top genes associated with sensitivity suggests that induction of apoptosis is the predominant mechanism of dinaciclib's anti-tumor effect and warrants further investigation of MCL1 amplification as a predictive biomarker in future clinical studies. Citation Format: Harold Hatch, Robert Booher, Samanthi Perera, Thi Nguyen, Brian Dolinski, Samer Al-Assaad, Lauren Harmonay, Alwin Schuller, Minilik Angagaw, Brian Long, Xianlu Qu, Nathan Miselis, Mark Ayers, Michael Nebozhyn, Heather Hirsch, Danielle Greenawalt, Andrey Loboda, Thorseten Graef, Ellie Im, Rebecca Blanchard, Leigh Zawel, Peter Strack. MCL1 dependent cells are sensitive to the CDK inhibitor Dinaciclib. [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 698. doi:10.1158/1538-7445.AM2013-698
Dextran Sulfate Is Poorly Absorbed after Oral Administration
Authors: Kevin J. Lorentsen
Journal: Annals of Internal Medicine (1989)

Study Objective: To determine whether dextran sulfate (molecular weight, 7000 to 8000 daltons; 17% to 20% sulfur), a synthetic heparin analogue with anti-human immunodeficiency virus (HIV) activity in vitro, is absorbed after oral administration. Design: Open-label, single-center study in two parts. The first part was a bioavailability study in which six subjects received a single 1800-mg oral dose and a single 225- or 300-mg intravenous dose. The second part was a study of the dose-response relation between dextran sulfate and total plasma lipolytic activity in which twelve subjects were given a single infusion of either 0.05, 0.5, 5, or 50 mg of dextran sulfate. Subjects: Eighteen healthy volunteers. Measurements and Main Results: In the bioavailability study, plasma and urine dextran-sulfate concentrations were measured by a competitive binding assay after each dose. In addition, two bioassays were used to assess plasma concentrations: plasma lipolytic activity and activated partial thromboplastin time (APTT). After the oral dose, plasma concentrations were not measurable with the competitive binding assay (lower limit of sensitivity, 1 µg/mL); less than 0.5% of the dose was recovered in the urine, the APTT did not increase, and the median increase in the plasma lipolytic activity was only twofold (maximum increase, 11-fold). In contrast, after the intravenous dose of 225 mg, peak plasma concentrations by competitive binding assay were 26 to 35 µg/mL (median, 28 µg/mL); 25% to 29% (median, 25%) of the dose was recovered in the urine; the APTT increased to 3.5 to 9.2 times the baseline value (median increase, 6.9 times), and the plasma lipolytic activity increased by 185 to 548 times the baseline value (median increase, 438 times). In the dose-response study, intravenous doses as low as 0.5 mg produced significant increases in the plasma lipolytic activity. There was a steep dose-response curve between 0.5 and 50 mg. Conclusion: Dextran sulfate is very poorly absorbed after oral administration.
Who cares for those who care?
Authors: P Thomas
Journal: BMJ (1994)

Doctor AB had worked as a general practitioner in a small market town in Wales for 35 years. His family had lived in the area for generations before and his father held a prominent position in the local community. The only time he had moved away was to go to medical school in England, but he returned to his roots, went into practice, married, and brought up his family. He was a well liked man with a good sense of humour. His patients thought the world of him. He was conscientious and hard working and devoted himself to the health and wellbeing of the community he served. He had always worked to the highest of personal and professional standards. He was not an ambitious man, not a seeker of influence or power, but simply enjoyed doing what he was extremely good at - being a country general practitioner.

Then, over the years, his work gradually changed. The town grew and his list increased. Every summer an influx of holiday makers added to his workload. That was in the 1960s and 1970s. Ten years ago something else happened. Changes in the organisation and management of the health service meant that he and his partners had to face increasing amounts of paperwork. The situation became particularly acute at the start of the 1990s when the partners considered that they should become a fundholding practice. …
Fixed Drug Eruption From Chlorphenesin Carbamate
Authors: Ralph J. Coskey
Journal: JAMA (1982)

To the Editor.—  Fixed drug eruptions tend to recur as circumscribed lesions at the same site or sites after oral or parenteral intake of the offending drug. There are long lists of drugs that may be responsible, the most common of which are anovulatory drugs, barbiturates, meprobamate, phenacetin, phenolphthalein, phenylbutazone, salicylates, sulfonamides, and tetracycline. 1   I would like to report a case of a fixed drug reaction caused by chlorphenesin carbamate (Maolate).  Report of a Case.—  A 54-year-old man was seen on June 15, 1981, because of an hourglass-shaped, 2-cm ulcer on the glans penis and on the shaft of the penis. It had been present for ten days. He had been taking salicylates and chlorphenesin for low back pain. Both dark-field examination and VDRL test results were normal or negative. The patient was treated with soaks, topical and oral antibiotics, and topical corticosteroids. On July 27,1981, he stopped taking
Matchmaking Scheme Solves Tay-Sachs Problem
Authors: Beverly Merz
Journal: JAMA (1987)

THE UNLIKELY combination of biotechnology and ancient cultural tradition has produced a highly effective program to eliminate Tay-Sachs disease. The program was born of despair after an ultra-Orthodox Jewish rabbi in New York realized that his once-healthy infant daughter had Tay-Sachs disease. She would be the fourth of his children to die of the genetic disorder. Like the others, she would suffer progressive neurological deterioration. She would become severely mentally retarded, lose her vision and motor control, have cerebral seizures, and, probably before her sixth birthday, die. To make matters worse, the rabbi knew that his family might not have seen the last of Tay-Sachs. Both he and his wife carried a recessive allele for the disease, so chances were one in four that any additional offspring would be affected. Moreover, ultra-Orthodox law proscribed abortion; contraception is permitted only under certain conditions. He knew his fate was not unique. The
Measures of performance in Scottish maternity hospitals.
Authors: A H Leyland, C W Pritchard, P McLoone, F A Boddy
Journal: BMJ (1991)

To develop measures of hospital performance over time with particular reference to maternal and neonatal care by controlling for case mix.Analysis of computerised records of births.Scotland, 1980-7.Over half a million singleton live births and stillbirths.Numbers of perinatal deaths and caesarean sections.Scottish maternity hospitals perform more or less equally with regard to perinatal mortality. When caesarean sections are considered, there is evidence that hospitals differ in their treatment of different groups of women; in two examples one hospital had an increased rate among women of parity 2 or more and another had a reduced rate of repeat caesarean section.Developing measures of performance over time by controlling for case mix is a valid system for monitoring hospital outcomes and activity, and allows comparison either between hospitals or with data for all Scottish maternity hospitals. Hospital profiles permit identification of differences for particular patient groups after allowance is made for other case mix variables.
Randomized Clinical Trial of Atenolol in Patients with Alcohol Withdrawal
Authors: Mark L. Kraus, Louis D. Gottlieb, Ralph I. Horwitz, Mitchell Anscher
Journal: New England Journal of Medicine (1985)

We conducted a randomized, double-blind clinical trial of atenolol as compared with placebo in the treatment of patients hospitalized with the alcohol withdrawal syndrome. In addition to receiving customary therapy, 61 patients were randomly assigned to receive atenolol, and 59 to receive placebo. Outcome was assessed daily by the measurement of nine features in three categories: vital signs, clinical signs (e.g., tremor), and behavioral signs (e.g., agitation and anxiety). Compared with placebo patients, atenolol patients had a significant reduction in the mean length of hospital stay (four as compared with five days, P less than 0.02). On each treatment day, significantly fewer patients receiving atenolol required concomitant benzodiazepines, and patients receiving placebo required a significantly higher mean daily dose of benzodiazepines. Among patients who had withdrawal symptoms at base line, vital signs became normal more rapidly in the patients receiving atenolol, and their abnormal behavior and clinical characteristics also resolved more rapidly. We conclude that atenolol is helpful in the treatment of patients with the alcohol withdrawal syndrome.
Sage of Science
Authors: Richard A. Stein
Journal: JAMA (2006)

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Smiles about rickets, gloom over whooping cough.
Authors: R M Badminton
Journal: BMJ (1982)

Pertussis immunisation in children admitted to hospital with serious neurological illness and in matched case controls from community lists Immunised more Immunised less than seven days Total immunised Total than seven days but less than less than 28 before date of 28 days before days before admission date of admission date of admission No of children with serious neurological illness ad- mitted to hospital (%) . . 993 (100%) 26 (2 6%) 32 (3-2%) 58 (580°,,) No of matched case controls from community lists (% ) 1976 (100%) 30 (1-5%) 86 (44%) 116 (5 9%)