tbuckley/cabot-search huggingface dataset:
Abstract 2398: Activity of the PARP inhibitor olaparib in ATM-deficient gastric cancer: from preclinical models to the clinic
Authors: Darren Hodgson, Helen Mason, Lenka Oplustilova, Chris Harbron, Xiaolu Yin, Seock-Ah Im, Helen Jones, Lai Zhongwu, Brian Dougherty, Matthew McLoughlin, James Bradford, Andrew Dickinson, Anitra Fielding, Jane Robertson, Woo-Ho Kim, Chris Womack, Yi Gu, Yung-Jue Bang, Alan Lau, J. Carl Barrett, Mark J. O'Connor
Journal: Cancer Research (2014)

Abstract Olaparib is an oral inhibitor of the Poly-(ADP-ribose)-polymerases (PARP-1, -2 and -3), and has demonstrated clinical activity in trials of patients with BRCA-deficient tumors. The BRCA1 and BRCA2 proteins are both important for the repair of DNA double strand breaks (DSBs) by homologous recombination repair (HRR) and sensitivity to olaparib has further been shown preclinically to extend to other DNA DSB repair factor deficiencies, including those in the ataxia telangiectasia mutated (ATM) protein. We have demonstrated that a high proportion of gastric cancer (GC) cell lines (∼50%) are responsive (IC50 &amp;lt;500 nM) to single agent olaparib and that characterization of their DNA repair status reveals that, as in breast and ovarian cancer, HRR deficiencies (HRD) can account at least in part for this. However, unlike breast and ovarian cancer cell lines, there is no strong correlation with platinum sensitivity, suggesting alternative drivers of response in the GC panel to HRD. Here, we demonstrate that low levels of ATM protein expression correlate with sensitivity of GC cell lines to olaparib, and moreover can be observed in approximately 15-20% of clinical gastric cancer samples when evaluated using ATM immunohistochemistry (IHC). Based on these data, a Phase II GC trial has been carried out that enriches for patients with tumors having low or undetectable ATM IHC scores (H-score equivalent less than or equal to 10). Data from this clinical trial confirm activity (overall survival [OS] benefit HR=0.56, 95% CI: 0.35-0.87; P=0.010) in the overall population, which includes ATM tumor positive patients, and importantly, a substantially better OS benefit in the ATM-negative population (HR=0.35, 95% CI: 0.17-0.71; P=0.003). Together, these data provide an important example of a PARP inhibitor demonstrating both preclinical and clinical activity in a well defined but non-BRCA DNA repair deficient background. Citation Format: Darren Hodgson, Helen Mason, Lenka Oplustilova, Chris Harbron, Xiaolu Yin, Seock-Ah Im, Helen Jones, Lai Zhongwu, Brian Dougherty, Matthew McLoughlin, James Bradford, Andrew Dickinson, Anitra Fielding, Jane Robertson, Woo-Ho Kim, Chris Womack, Yi Gu, Yung-Jue Bang, Alan Lau, J. Carl Barrett, Mark J. O'Connor. Activity of the PARP inhibitor olaparib in ATM-deficient gastric cancer: from preclinical models to the clinic. [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 2398. doi:10.1158/1538-7445.AM2014-2398
Proparacaine Drug Alert
Authors: F. T. Fraunfelder, M. Harvey Johnson
Journal: JAMA (1980)

<h3>To the Editor.—</h3> There are increasing problems for the physician, pharmacist, and patients, not only with similar-sounding names of drugs, but also with similar-appearing dispensing units. A prime example of the latter is shown in the Figure. The Hemoccult slide test has a stabilized solution of hydrogen peroxide and denatured alcohol used for testing occult blood in stool specimens. Unfortunately, the bottle looks almost the same as Ophthaine (proparacaine hydrochloride solution, 0.5%), a local anesthetic used in ophthalmology. Because of this similarity, the Hemoccult slide test now has a paper ring over the neck of the bottle, but this is designed so it can be easily removed. Ophthaine does have a white band on the unopened bottle; however, once the seal is broken and removed, the bottles look strikingly similar. Both bottles are identical in size and shape and have black printing. There have been a number of reports to
Prevalence of the C282Y mutation of the hemochromatosis gene in liver transplant recipients and donors
Authors: Kenneth W. Alanen, Subrata Chakrabarti, Jenna J. Rawlins, William Howson, Gary Jeffrey, Paul C. Adams
Journal: Hepatology (1999)

Hemochromatosis heterozygotes may be predisposed to end-stage liver disease from other causes. The aims of this study were to determine the prevalence of the hemochromatosis mutation, C282Y, in end-stage liver disease and to determine if transplantation of C282Y heterozygous livers adversely affected survival. The C282Y status of patients who underwent hepatic transplantation and, whenever possible, their donors, was determined and correlated with hepatic iron status. Survival was compared in patients who received livers from heterozygotes and normals. Prevalence of C282Y in recipients was compared with 5,211 voluntary blood donors. Twenty-six C282Y heterozygotes were detected among 304 transplant recipients (8.6%) compared with a prevalence of 8.4% in blood donors. Six of 26 heterozygous recipients (23%) had ≥2+ iron staining in their explanted livers compared with 40 of 277 wild-type livers (14%) ( P = ns). There was no significant difference in mean hepatic iron concentration between C282Y heterozygotes and wild-type explanted livers with ≥2+ iron staining. Seven of 31 patients (23%) with alcoholic liver disease were C282Y heterozygotes. Twenty-four heterozygotes were detected in 141 donors (17.0%). Survival did not differ between recipients who received heterozygous or normal livers. The prevalence of C282Y heterozygotes in patients requiring liver transplantation does not differ significantly from the general population. Heterozygotes are not at increased risk of developing end-stage liver disease. Transplantation of C282Y heterozygous livers is a safe, effective practice.
Urban/rural differences in diet and atopy in South Africa
Authors: R. Hooper, J. Calvert, R. L. Thompson, M. E. Deetlefs, P. Burney
Journal: Allergy (2008)

Background: There are large differences in the prevalence of atopic disease between urban and rural areas of developing countries, without good explanation. Diet has been associated with atopic disease, but studies of specific nutrients are contradictory, cross‐sectional studies often being unsupported by trials. We investigated diet as an explanation for the difference in the prevalence of atopy between urban and rural areas in South Africa. Methods: A cross‐sectional analysis of food frequency questionnaires and allergen skin tests from 698 children aged 8–13 years, recruited from 24 schools in Cape Province, South Africa, who were taking part in a case–control study of exercise‐induced bronchospasm. Food frequency data were analysed with a principal components analysis (PCA). Results: The first two principal components of diet explained 25% of the variance, and discriminated almost perfectly between urban and rural subjects. The ‘urban’ component of diet was strongly associated with positive skin tests even after adjusting for urban residence. There were no significant associations between individual foods or nutrients and positive skin tests, allowing for multiple testing. Conclusions: Diet explains part of the difference in prevalence between urban and rural areas. The ability to demonstrate this using PCA, but not by exhaustive analysis of all foods, reflects the value of reducing the number of dietary dimensions. The number of foods and nutrients which can be assessed, and the possibility of confounding and effect modification, make it difficult to identify the features of diet most directly implicated in disease. This may explain inconsistencies in dietary studies.
Cell-to-Cell Transfer of HIV-1 via Virological Synapses Leads to Endosomal Virion Maturation that Activates Viral Membrane Fusion
Authors: Benjamin M. Dale, Gregory P. McNerney, Deanna L. Thompson, Wolfgang Hubner, Kevin de los Reyes, Frank Y.S. Chuang, Thomas Huser, Benjamin K. Chen
Journal: Cell Host & Microbe (2011)
Meta-Analysis: Antibiotic Prophylaxis Reduces Mortality in Neutropenic Patients
Authors: Anat Gafter-Gvili, Abigail Fraser, Mical Paul, Leonard Leibovici
Journal: Annals of Internal Medicine (2005)

Background: Bacterial infections are a major cause of illness and death in patients who are neutropenic after chemotherapy treatment for cancer. Trials have shown the efficacy of antibiotic prophylaxis in decreasing the incidence of bacterial infections but not in reducing mortality rates. Purpose: To evaluate whether antibiotic prophylaxis in neutropenic patients reduces mortality and incidence of infection and to assess related adverse events. Data Sources: The Cochrane Cancer Network register of trials (2004), The Cochrane Library (Issue 4, 2004), EMBASE (1980–2004), MEDLINE (1966–2004), and references of identified studies. Study Selection: Randomized, controlled trials comparing antibiotic prophylaxis with placebo or no intervention or another antibiotic in afebrile neutropenic patients. Data Extraction: Two reviewers independently appraised the quality of trials and extracted data. Data Synthesis: Ninety-five trials performed between 1973 and 2004 met inclusion criteria. Fifty-two trials addressed quinolone prophylaxis. Antibiotic prophylaxis significantly decreased the risk for death when compared with placebo or no treatment (relative risk, 0.67 [95% CI, 0.55 to 0.81]). All prophylactic antibiotics were associated with an increased risk for adverse events (relative risk, 1.69 [CI, 1.14 to 2.50]). Fluoroquinolone prophylaxis reduced the risk for all-cause mortality (relative risk, 0.52 [CI, 0.35 to 0.77]), as well as infection-related mortality, fever, clinically documented infections, and microbiologically documented infections. Fluoroquinolone prophylaxis increased the risk for harboring bacilli resistant to the specific drug after treatment and adverse events, but these results were not statistically significant (relative risks, 1.69 [CI, 0.73 to 3.92]) and 1.30 [CI, 0.61 to 2.76], respectively). Limitations: Most trials involved patients with hematologic cancer. Data on all-cause mortality were missing in 10 of 50 trials comparing prophylaxis with no prophylaxis. Effect estimates were larger in trials of unclear methodologic quality compared with trials of adequate methodologic quality. Conclusions: Antibiotic prophylaxis for neutropenic patients undergoing cytotoxic therapy reduces mortality. Mortality was substantially reduced when analysis was limited to fluoroquinolones. Antibiotic prophylaxis, preferably with a fluoroquinolone, should be considered for neutropenic patients.
F2-isoprostanes mediate high glucose-induced TGF-β synthesis and glomerular proteinuria in experimental type I diabetes
Authors: Angel Montero, Karen A. Munger, Rizwan Z. Khan, José M. Valdivielso, Jason D. Morrow, Antonio Guasch, Fuad N. Ziyadeh, Kamal F. Badr
Journal: Kidney International (2000)

F<sub>2</sub>-isoprostanes mediate high glucose-induced TGF-β synthesis and glomerular proteinuria in experimental type I diabetes. <h3>Background</h3> The recently discovered arachidonic acid derivatives, isoprostanes, are increased in pathological conditions associated with oxidative stress, such as diabetes. No role has yet been described for isoprostanes during the development of diabetic nephropathy. Cell culture in high ambient glucose has been used as a model in elucidating cellular mechanisms underlying diabetic nephropathy. Among the growth factors involved in the effect of high glucose, transforming growth factor-β (TGF-β) has been described as playing a key role in the development of nephropathy. <h3>Methods</h3> Streptozotocin-induced diabetic rats were supplemented in their diet with the antioxidant vitamin E (1000 U/kg diet). Blood and urine samples were taken to determine renal function and isoprostane concentration, as determined by gas chromatography/mass spectrometry. Glomerular mesangial and endothelial cells were cultured in high ambient glucose to determine the synthesis of isoprostanes and the role of isoprostanes in high glucose-induced synthesis of TGF-β. <h3>Results</h3> Streptozotocin-induced diabetic rats had marked increases in plasma levels and urinary excretion rates of F<sub>2</sub>-isoprostanes. Dietary supplementation with vitamin E normalized (plasma) and reduced (urine) isoprostane levels and, surprisingly, improved proteinuria and blood urea nitrogen (BUN) levels. High ambient glucose increased F<sub>2</sub>-isoprostane synthesis in glomerular endothelial and mesangial cells in culture. Incubation of glomerular cells with F<sub>2</sub>-isoprostanes stimulated the production of TGF-β. <h3>Conclusions</h3> Increased F<sub>2</sub>-isoprostane synthesis during diabetes appears to be responsible in part for the increase in renal TGF-β, a well-known mediator of diabetic nephropathy.
THE GROWTH HORMONE OF THE ANTERIOR PITUITARY
Authors: HERBERT McLEAN EVANS
Journal: JAMA (1935)

The earliest description of a hypophyseal disorder, that of acromegaly by Pierre Marie, and its identification with pituitary overactivity by Minkowski, was followed by reference of the reverse condition—dwarfism—to underactivity of the hypophysis by Paltauf. These deductions, based essentially on a hypertrophied or diminished pituitary gland, were, of course, far from demonstrating the existence in the gland of a specific ferment-like substance needed in some fundamental way before the process of growth could take place in any of the higher animals. The study of the effects of the gland substance itself could alone bring such a demonstration.  EXPERIMENTAL PRODUCTION OF DWARFISM  An immense step forward was taken by the experimental production of dwarfism when the gland was removed from young animals. 1 The classic experiments of Aschner, which were done with puppies with littermate controls, showed that an immediate arrest of growth and development was occasioned by the operation.
TGFβ1 Inhibits NF-κB/Rel Activity Inducing Apoptosis of B Cells: Transcriptional Activation of IκBα
Authors: Marcello Arsura, Min Wu, Gail E Sonenshein
Journal: Immunity (1996)

TGFβ1 treatment of B cell lymphomas decreases c-myc gene expression and induces apoptosis. Since we have demonstrated NF-κB/Rel factors play a key role in transcriptional control of c-myc, we explored the effects of TGFβ1 on WEHI 231 immature B cells. A reduction in NF-κB/Rel activity followed TGFβ1 treatment. In WEHI 231 and CH33 cells, we observed an increase in IκBα, a specific NF-κB/Rel inhibitor, due to transcriptional induction. Engagement of surface CD40 or ectopic c-Rel led to maintenance of NF-κB/Rel and c-Myc expression and protection of WEHI 231 cells from TGFβ1-mediated apoptosis. Ectopic c-Myc expression overrode apoptosis induced by TGFβ1. Thus, downmodulation of NF-κB/Rel reduces c-Myc expression, which leads to apoptosis in these immature B cell models of clonal deletion. The inhibition of NF-κB/Rel activity represents a novel TGFβ signaling mechanism.
671. SIV-Derived Lentiviral Vectors Pseudotyped with Modified RD114 Envelope and Containing Mutant MGMT Efficiently Transduce Human CD34+ PBSCs and Allow Selection
Authors: Nora Naumann, Uimook Choi, Suk See De Ravin, Morvarid Moayeri, Larry Lantz, Lanise Cardwell-Miller, Harry L. Malech
Journal: Molecular Therapy (2006)

Lentiviral vectors have become an attractive tool for gene transfer into hematopoietic stem cells (HSCs) because they may more efficiently transduce non-dividing multipotent HSCs. Most lentiviral gene transfer studies use human immunodeficiency virus (HIV) 1- derived vectors pseudotyped with VSV-G envelope. We investigated the ability of vectors based on simian immunodeficiency virus (SIVmac) and pseudotyped with modified RD114 envelope to efficiently transduce human HSCs using both marker constructs and a construct containing the therapeutic gene for X-linked chronic granulomatous disease (CGD) gp91phox. RD114-pseudotyped SIV vector particles transiently produced following transfection of 293T HEK cells were concentrated by high-speed centrifugation. The marker gene construct encoded a green fluorescent protein-mutant methylguanine methyltransferase fusion protein (GFP-MGMT*) which confers resistance to O6-benzylguanine (BG) and a DNA alkylating agent such as 1,3-bis (2-chloroethyl)-1-nitrosurea (BCNU) and retains green fluorescence. Mobilized healthy human CD34+ peripheral blood stem cells (PBSCs) were efficiently transduced (>90% GFP+ on day 4 of culture) and could be selected with BG/ BCNU ex vivo on day 4 of culture (1 hour 5 μM BG followed by 2 hours 7 μM BCNU) to increase stable ex vivo marking to 97%. When non-selected transduced PBSCs were transplanted into NOD/ SCID mice, marking of human cells at 6 weeks post transplant was consistently greater than 50%. In vivo selection of these animals is ongoing. We next created an IRES bicistronic SIV modified RD114 pseudotyped vector encoding both gp91phox and MGMT*, and demonstrated that we could transduce gp91phox-deficient X-linked CGD patient CD34+ PBSCs to a level of 30% ex vivo and this could be increased in culture to 55% following BG/BCNU selection at day 4. Transplant of the unselected cells into NOD/SCID mice resulted in 2.2% marking of the engrafted CGD human myeloid cells and using the ex vivo selected cells marking was 5.1%. Thus, while the therapeutic selective vector did perform, we find that it is more difficult to obtain high pre-concentration titers of this larger bicistronic construct. However, preliminary experiments using significantly higher concentrations of centrifuged vector indicate that low starting titers can be augmented by concentration to achieve much higher transduction rates similar to those seen with the marker vectors and these experiments are ongoing.
Signal transducer and activator of transcription 6 (STAT-6) expression and function in asthmatic bronchial epithelium
Authors: Rebecca E. Mullings, Susan J. Wilson, Sarah M. Puddicombe, James L. Lordan, Fabio Bucchieri, Ratko Djukanović, Peter H. Howarth, Steven Harper, Stephen T. Holgate, Donna E. Davies
Journal: Journal of Allergy and Clinical Immunology (2001)
RESULTS OF HOSPITAL TREATMENT OF ALCOHOLISM
Authors: JAMES H. WALL, EDWARD B. ALLEN
Journal: American Journal of Psychiatry (1944)

1. A study has been made of 100 men suffering from alcoholism, admitted to the New York Hospital, Westchester Division, between 1934 and 1940. 2. A review of the family background has shown the common occurrence of excessive drinking in the relatives, the predominance of small families, and an indulgent, pampering type of mother in 59 instances. 3. The drinking usually began at an early age and continued for an average of 15 years before serious treatment was undertaken. 4. Follow-up studies of these 100 men three to eight years after discharge revealed that 24 were recovered, and 19 were managing better, making a total of 43 who had been definitely benefited by treatment.
"Fit note" is linked to fewer people taking long term sick leave, study finds
Authors: J. Pakpoor
Journal: BMJ (2015)

The introduction of the UK “fit note” is associated with fewer people taking long term sick leave from work, but the proportion of people off sick with mental health issues is rising, a study published in Occupational and Environmental Medicine has found.1

The fit note, which replaced its “sick note” predecessor in 2010, enables GPs to include advice on how a person “may be fit” to work with reasonable workplace adjustments.2 Researchers examined sickness absence data from before and after the introduction of the fit note—obtained from 68 general practices in England, Scotland, and Wales during 2011-13 and from seven …
Scotland may be first UK country to impose minimum alcohol price
Authors: B. Christie
Journal: BMJ (2011)

Legislation on the minimum pricing of alcohol is set to be introduced in Scotland after the resounding victory of the Scottish National Party (SNP) in last week’s Scottish parliamentary election.

The win also signifies a divergence in health policy between Scotland and England. The SNP has rejected the reforms that have created so much unrest in England and promised to protect the Scottish health budget in a “publicly funded and publicly delivered” health service.

However, economists are warning of difficult challenges ahead in paying for …
TCTAP A-109 Clinical Outcome After Endovascular Treatment for Popliteal Artery
Authors: Hideaki Takahashi, Shigeru Nakamura, Tomoko Kobayashi, Atsushi Funatsu, Masahiro Mizobuchi, Yoshifumi Hano, Masamune Otagaki, Satoru Sasaki
Journal: Journal of the American College of Cardiology (2014)
National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for Utilization of Biochemical Markers in Acute Coronary Syndromes and Heart Failure
Authors: Robert H. Christenson
Journal: Circulation (2007)

NACB) Laboratory Medicine Practice Guidelines (LMPG) for use of cardiac markers in coronary artery diseases were published in July 1999 1 .Since production of this initial document, numerous published studies and presented data have added significantly to the knowledge base for biochemical markers of cardiac injury.This increased knowledge has substantially expanded the scope of recommendations for biochemical marker utilization since the 1999 document, and in particular has required the inclusion of recommendations regarding biochemical markers that extend beyond myocardial necrosis.Toward addressing these advances and their impact on biochemical marker utilization in clinical practice, the NACB appointed a chair and members of an LMPG committee that was charged with revising and extending the earlier recommendations by establishing modern guidelines for Utilization of Biochemical Markers in Acute Coronary Syndromes and Heart Failure.These extended recommendations include Clinical Utilization of Biochemical Markers in Acute Coronary Syndromes (ACS); Analytical Issues of ACS Biochemical Markers; Clinical Utilization of Biochemical Markers of Heart Failure and Hemodynamic Stress; Analytical Issues of Heart Failure Biochemical Markers; Point-of-Care Testing and Logistics; and Cardiac Biomarkers and Other Etiologies.Updated draft revisions of the Guidelines were prepared and placed for comment on the NACB World Wide Web site (http://www.aacc.org/AACC/members/nacb/LMPG/OnlineGuide/DraftGuidelines/BioHearFailure/) in August of 2004.
A Randomized Study of the Prevention of Acute Graft-versus-Host Disease
Authors: Norma K. C. Ramsay, John H. Kersey, Leslie L. Robison, Philip B. McGlave, William G. Woods, William Krivit, Tae H. Kim, Anne I. Goldman, Mark E. Nesbit
Journal: New England Journal of Medicine (1982)

Acute graft-versus-host disease is a major problem in allogeneic bone-marrow transplantation. We performed a randomized study to compare the effectiveness of two regimens in the prevention of acute graft-versus-host disease. Thirty-five patients received methotrexate alone, and 32 received methotrexate, antithymocyte globulin, and prednisone. Of the patients who received methotrexate alone, 48 per cent had acute graft-versus-host disease, as compared with 21 per cent of those who received methotrexate, antithymocyte globulin, and prednisone (P = 0.01). The age of the recipient was a significant factor in the development of acute graft-versus-host disease: Older patients had a higher incidence of the disease (P = 0.001). We conclude that the combination of methotrexate, antithymocyte globulin, and prednisone significantly decreased the incidence of acute graft-versus-host disease and should be used to prevent this disorder in patients receiving allogeneic marrow transplants. (N Engl J Med. 1982; 306:392–7.)