tbuckley/cabot-search huggingface dataset:
Alcoholism Causes Alveolar Macrophage Zinc Deficiency and Immune Dysfunction
Authors: Ashish J. Mehta, Samantha M. Yeligar, Lisa Elon, Lou Ann Brown, David M. Guidot
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Alcohol use disorders cause oxidative stress in the lower airways and increase susceptibility to pneumonia and lung injury. Currently, no therapeutic options exist to mitigate the pulmonary consequences of alcoholism.We recently determined in an animal model that alcohol ingestion impairs pulmonary zinc metabolism and causes alveolar macrophage immune dysfunction. The objective of this research is to determine the effects of alcoholism on zinc bioavailability and alveolar macrophage function in human subjects.We recruited otherwise healthy alcoholics (n = 17) and matched control subjects (n = 17) who underwent bronchoscopy for isolation of alveolar macrophages, which were analyzed for intracellular zinc, phagocytic function, and surface expression of granulocyte-macrophage colony-stimulating factor receptor; all three of these indices are decreased in experimental models.Alcoholic subjects had normal serum zinc, but significantly decreased alveolar macrophage intracellular zinc levels (adjusted means [SE], 718 [41] vs. 948 [25] RFU/cell; P < 0.0001); bacterial phagocytosis (adjusted means [SE], 1,027 [48] vs. 1,509 [76] RFU/cell; P < 0.0001); and expression of granulocyte-macrophage colony-stimulating factor receptor β subunit (adjusted means [SE], 1,471 [42] vs. 2,114 [35] RFU/cell; P < 0.0001]. Treating alveolar macrophages with zinc acetate and glutathione in vitro increased intracellular zinc levels and improved their phagocytic function.These novel clinical findings provide evidence that alcohol abuse is associated with significant zinc deficiency and immune dysfunction within the alveolar space and suggest that dietary supplementation with zinc and glutathione precursors could enhance airway innate immunity and decrease the risk for pneumonia or lung injury in these vulnerable individuals.
Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis
Authors: H Landau, H Hassoun, M A Rosenzweig, M Maurer, J Liu, C Flombaum, C Bello, E Hoover, E Riedel, S Giralt, R L Comenzo
Journal: Leukemia (2012)
Incorporating Biomarkers Into Cancer and Aging Research
Authors: Joleen M. Hubbard, Harvey J. Cohen, Hyman B. Muss
Journal: Journal of Clinical Oncology (2014)

The challenge in treating the older adult with cancer is accurately accounting for and adapting management to the heterogeneity in health status of the individual patient. Many oncologists recognize that chronological age alone should not be the determinant when deciding on a treatment regimen. Easily measurable markers that provide an assessment of functional age would be ideal to assess frailty, which may predispose the patient to complications from cancer treatment, including increased toxicity, functional decline, decreased quality of life, and poorer survival. Several categories of potential markers, including chronic inflammatory markers, markers of cellular senescence, and imaging to assess muscle mass to detect sarcopenia, may provide insight into the likelihood of treatment-related complications. This article discusses candidate markers and strategies to evaluate these markers in cancer treatment trials, with the aim of developing a method to assess risk of oncologic outcomes and guide management decisions for both the physician and patient.
A Low-Sodium Diet Potentiates the Effects of Losartan in Type 2 Diabetes
Authors: Christine A. Houlihan, Terri J. Allen, Amynta L. Baxter, Sianna Panangiotopoulos, David J. Casley, Mark E. Cooper, George Jerums
Journal: Diabetes Care (2002)

OBJECTIVE—Diabetic subjects have a high prevalence of hypertension, increased total body exchangeable sodium levels, and an impaired ability to excrete a sodium load. This study assessed the effect of dietary sodium restriction on the efficacy of losartan in hypertensive subjects with type 2 diabetes and albumin excretion rates of 10–200 μg/min. RESEARCH DESIGN AND METHODS—In this study, 20 subjects were randomized to losartan 50 mg/day (n = 10) or placebo (n = 10). Drug therapy was given in two 4-week phases separated by a washout period. In the last 2 weeks of each phase, patients were assigned to low- or regular-sodium diets, in random order. In each phase, 24-h ambulatory blood pressure, urinary albumin-to-creatinine ratio (ACR), and renal hemodynamics were measured. RESULTS—Achieved urinary sodium on a low-sodium diet was 85 ± 14 and 80 ± 22 mmol/day in the losartan and placebo groups, respectively. In the losartan group, the additional blood pressure-lowering effects of a low-sodium diet compared with a regular-sodium diet for 24-h systolic, diastolic, and mean arterial blood pressures were 9.7 mmHg (95% confidence interval [CI], 2.2−17.2; P = 0.002), 5.5 mmHg (2.6−8.4; P = 0.002), and 7.3 mmHg (3.3− 11.3; P = 0.003), respectively. In the losartan group, the ACR decreased significantly on a low-sodium diet versus on a regular-sodium diet (−29% [CI −50.0 to −8.5%] vs. + 14% [−19.4 to 47.9%], respectively; P = 0.02). There was a strong correlation between fall in blood pressure and percent reduction in the ACR (r = 0.7, P = 0.02). In the placebo group, there were no significant changes in blood pressure or ACR between regular- and low-sodium diets. There were no significant changes in renal hemodynamics in either group. CONCLUSIONS—These data demonstrated that a low-sodium diet potentiates the antihypertensive and antiproteinuric effects of losartan in type 2 diabetes. The blood pressure reduction resulting from the addition of a low-sodium diet to losartan was of similar magnitude to that predicted from the addition of a second antihypertensive agent.
Risk Factors for Cardiovascular Disease in Homeless Adults
Authors: Tony C. Lee, John G. Hanlon, Jessica Ben-David, Gillian L. Booth, Warren J. Cantor, Philip W. Connelly, Stephen W. Hwang
Journal: Circulation (2005)

Background— Homeless people represent an extremely disadvantaged group in North America. Among older homeless men, cardiovascular disease (CVD) is the leading cause of death. The objective of this study was to examine cardiovascular risk factors in a representative sample of homeless adults and identify opportunities for improved risk factor modification. Methods and Results— Homeless persons were randomly selected at shelters for single adults in Toronto. Response rate was 79%. Participants (n=202) underwent interviews, physical measurements, and blood sampling. The mean age of participants was 42 years, and 89% were men. The prevalence of smoking among homeless subjects (78%; 95% confidence interval [CI], 72% to 84%) was significantly higher than in the general population (standardized morbidity ratio [SMR], 254; 95% CI, 216 to 297). Hypertension, high cholesterol, and diabetes were not more prevalent than in the general population but were often poorly controlled. Homeless men were significantly less likely to be overweight or obese than men in the general population (SMR, 79; 95% CI, 63 to 98). Cocaine use in the last year was reported by 29% of subjects (95% CI, 23% to 36%). CVD was reported by 15% of subjects, fewer than one third of whom reported taking aspirin or cholesterol-lowering medication. According to multiple-risk-factor equations, the median estimated 10-year absolute risk of myocardial infarction or coronary death among homeless men aged 30 to 74 years was 5% (interquartile range, 3% to 9%). Conclusions— Cardiovascular risk factor modification is suboptimal among homeless adults in Toronto, despite universal health insurance. Multiple risk factor equations may underestimate true risk in this population because of inadequate accounting for factors such as cocaine use and heavy smoking.
High Proteinase 3-Anti-Neutrophil Cytoplasmic Antibody (ANCA) Level Measured by the Capture Enzyme-Linked Immunosorbent Assay Method Is Associated with Decreased Patient Survival in ANCA-Associated Vasculitis with Renal Involvement
Authors: Kerstin W. A. Westman, Daina Selga, Per-Erik Isberg, Anna Bladström, Ha[Combining Ring Above]kan Olsson
Journal: Journal of the American Society of Nephrology (2003)

Wegener granulomatosis (WG) and microscopic polyangiitis (MP), diseases associated with antineutrophil cytoplasmic antibodies (ANCA), had an extremely poor prognosis before the introduction of cyclophosphamide and corticosteroids for their treatment. However, there is still reduced patient survival, and some studies have documented severe side effects of the immunosuppressants used. This 10-yr follow-up study assessed 117 consecutive patients with WG or MP with biopsy-confirmed renal involvement. The cumulative relative patient survival was lower: 0.664 for women and 0.648 for men. The causes of death (n = 64) were in most cases registered as associated with the vasculitic disease. Analysis of possible predictive factors for patient survival by multiple Cox regression analysis revealed that a very high level of proteinase 3 (PR3)-ANCA measured by the capture ELISA method, a diagnosis of MP, and older age were factors predicting poorer patient survival. High levels of B-thrombocytes at time of diagnosis were associated with a better prognosis. For patients surviving the first year, remission-sustaining therapy with azathioprine for longer than 12 mo was associated with improved patient survival. Thirty-nine patients developed end-stage renal failure. Elevated serum creatinine at time of diagnosis and a very high level of PR3-ANCA by capture ELISA were factors predicting a higher risk for renal failure during follow-up. The epitope on PR3 assessed by capture ELISA needs to be further analyzed and explored: it seemed to implicate poorer patient and renal survival in WG or MP with renal involvement.
In vitro effect of a mucolytic thiol agent on the activity of polymorphonuclear leucocyte elastase and antileucoprotease.
Authors: J Stolk, J A Kramps, J H Dijkman
Journal: Thorax (1986)

We have studied the effects of the mucolytic thiol agent mercapto-ethanesulphonate (mesna) on the activity of both polymorphonuclear leucocyte (PMN) elastase and antileucoprotease in vitro. In all tests a specific synthetic substrate was used to measure elastase activity, which was then related to enzyme activity in the absence of mesna. The relative elastase activity decreased to 67.5% of control values after the enzyme had been incubated in a 120 mmol/l mesna solution. In the sol phase of purulent sputum, elastase activity decreased to 45% after the sol phase had been incubated in a 600 mmol/l mesna solution. The inability to reverse the inhibition of mesna by increasing the substrate concentration indicated that mesna acts as a non-competitive inhibitor of PMN elastase. Incubation of elastase with antileucoprotease reduced the relative elastase activity to 21%. When antileucoprotease was preincubated in a 60 mmol/l mesna solution under identical assay conditions, a relative elastase activity of 39% was observed. Inhibition experiments with mesna treated antileucoprotease, in which sulphydryl groups were blocked with iodoacetamide, strongly suggested that the dissociation constant (Ki) of the fraction of antileucoprotease that retains activity after the incubation with mesna was not changed. Elastase inhibitory activity in mucoid sol phase, which can be ascribed mainly to antileucoprotease, decreased to 53% after incubation with mesna at a concentration of 960 mmol/l. Incubation of PMN elastase/antileucoprotease complex with mesna did not result in any release of active PMN elastase from the antileucoprotease. It is concluded that mesna and other thiol compounds, when locally administered, may influence the proteinase-antiproteinase balance in the airways by their effect on both PMN elastase and antileucoprotease.
Efficacy of Chemotherapy in <i>BRCA1/2</i> Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study
Authors: Joo Ern Ang, Charlie Gourley, C. Bethan Powell, Hilda High, Ronnie Shapira-Frommer, Vincent Castonguay, Jacques De Greve, Tina Atkinson, Timothy A. Yap, Shahneen Sandhu, Susana Banerjee, Lee-May Chen, Michael L. Friedlander, Bella Kaufman, Amit M. Oza, Ursula Matulonis, Louise J. Barber, Iwanka Kozarewa, Kerry Fenwick, Ioannis Assiotis, James Campbell, Lina Chen, Johann S. de Bono, Martin E. Gore, Christopher J. Lord, Alan Ashworth, Stan B. Kaye
Journal: Clinical Cancer Research (2013)

Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.
Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
Authors: Gizem Karsli-Uzunbas, Jessie Yanxiang Guo, Sandy Price, Xin Teng, Saurabh V Laddha, Sinan Khor, Nada Y. Kalaany, Tyler Jacks, Chang S. Chan, Joshua D. Rabinowitz, Eileen White
Journal: Cancer Discovery (2014)

Abstract Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy related 7 (Atg7), throughout adult mice. Here, we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2 to 3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non–small cell lung cancer (NSCLC) initiation by activation of oncogenic KrasG12D and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with preexisting NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This antitumor activity occurred before destruction of normal tissues, suggesting that acute autophagy inhibition may be therapeutically beneficial in cancer. Significance: We systemically ablated cellular self-cannibalization by autophagy in adult mice and determined that it is dispensable for short-term survival, but required to prevent fatal hypoglycemia and cachexia during fasting, delineating a new role for autophagy in metabolism. Importantly, acute, systemic autophagy ablation was selectively destructive to established tumors compared with normal tissues, thereby providing the preclinical evidence that strategies to inhibit autophagy may be therapeutically advantageous for RAS-driven cancers. Cancer Discov; 4(8); 914–27. ©2014 AACR. See related commentary by Amaravadi and Debnath, p. 873 This article is highlighted in the In This Issue feature, p. 855
Nucleic Acid Testing to Detect HBV Infection in Blood Donors
Authors: Susan L. Stramer, Ulrike Wend, Daniel Candotti, Gregory A. Foster, F. Blaine Hollinger, Roger Y. Dodd, Jean-Pierre Allain, Wolfram Gerlich
Journal: New England Journal of Medicine (2011)

The detection of hepatitis B virus (HBV) in blood donors is achieved by screening for hepatitis B surface antigen (HBsAg) and for antibodies against hepatitis B core antigen (anti-HBc). However, donors who are positive for HBV DNA are currently not identified during the window period before seroconversion. The current use of nucleic acid testing for detection of the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) RNA and HBV DNA in a single triplex assay may provide additional safety.
Confirmation of Association Between Autism and the Mitochondrial Aspartate/Glutamate Carrier <i>SLC25A12</i> Gene on Chromosome 2q31
Authors: Ricardo Segurado, Judith Conroy, Eleanor Meally, Michael Fitzgerald, Michael Gill, Louise Gallagher
Journal: American Journal of Psychiatry (2005)

Autism is a neurodevelopmental disorder with childhood onset and a known major genetic component. A recent study identified a highly significant association between autism and a two-single-nucleotide-polymorphism haplotype in the SLC25A12 gene, with a homozygote genotype relative risk between 2.4 and 4.8. The authors' goal was to investigate this association with autism in Irish affected child-parent trios because replication in an independent sample is essential in the validation of such potentially important findings.Markers rs2056202 and rs2292813 were genotyped in a total of 158 trios (442 individuals). The Transmission Disequilibrium Test was used to examine these markers for association with autism.In agreement with the recent study, the authors found significant association between autism and the C alleles of both rs2056202 and rs2292813 as well as the two-marker haplotype.These findings provide replication of the association between autism and SLC25A12.
Bilateral Prophylactic Mastectomy Reduces Breast Cancer Risk in <i>BRCA1</i> and <i>BRCA2</i> Mutation Carriers: The PROSE Study Group
Authors: Timothy R. Rebbeck, Tara Friebel, Henry T. Lynch, Susan L. Neuhausen, Laura van ’t Veer, Judy E. Garber, Gareth R. Evans, Steven A. Narod, Claudine Isaacs, Ellen Matloff, Mary B. Daly, Olufunmilayo I. Olopade, Barbara L. Weber
Journal: Journal of Clinical Oncology (2004)

Data on the efficacy of bilateral prophylactic mastectomy for breast cancer risk reduction in women with BRCA1 and BRCA2 (BRCA1/2) mutations are limited, despite the clinical use of this risk-management strategy. Thus, we estimated the degree of breast cancer risk reduction after surgery in women who carry these mutations.Four hundred eighty-three women with disease-associated germline BRCA1/2 mutations were studied for the occurrence of breast cancer. Cases were mutation carriers who underwent bilateral prophylactic mastectomy and who were followed prospectively from the time of their center ascertainment and their surgery, with analyses performed for both follow-up periods. Controls were BRCA1/2 mutation carriers with no history of bilateral prophylactic mastectomy matched to cases on gene, center, and year of birth. Both cases and controls were excluded for previous or concurrent diagnosis of breast cancer. Analyses were adjusted for duration of endogenous ovarian hormone exposure, including age at bilateral prophylactic oophorectomy if applicable.Breast cancer was diagnosed in two (1.9%) of 105 women who had bilateral prophylactic mastectomy and in 184 (48.7%) of 378 matched controls who did not have the procedure, with a mean follow-up of 6.4 years. Bilateral prophylactic mastectomy reduced the risk of breast cancer by approximately 95% in women with prior or concurrent bilateral prophylactic oophorectomy and by approximately 90% in women with intact ovaries.Bilateral prophylactic mastectomy reduces the risk of breast cancer in women with BRCA1/2 mutations by approximately 90%.
Serum C reactive protein levels and genetic variation in the <i>CRP</i> gene are not associated with the prevalence, incidence or progression of osteoarthritis independent of body mass index
Authors: Hanneke J M Kerkhof, Sita M A Bierma-Zeinstra, Martha C Castano-Betancourt, Moniek P de Maat, Albert Hofman, Huib A P Pols, Fernando Rivadeneira, Jacqueline C Witteman, André G Uitterlinden, Joyce B J van Meurs
Journal: Annals of the Rheumatic Diseases (2010)

To study the relationship between serum C reactive protein (CRP) levels, genetic variation in the CRP gene and the prevalence, incidence and progression of radiographic osteoarthritis (ROA) in the Rotterdam Study-I (RS-I). A systematic review of studies assessing the relationship between osteoarthritis (OA) and CRP levels was also performed.The association between CRP levels and genetic variation in the CRP gene and ROA was examined in 861 patients with hand OA, 718 with knee OA, 349 with hip OA and 2806 controls in the RS-I using one-way analysis of covariance and logistic regression, respectively. PubMed was searched for articles published between January 1992 and August 2009 assessing the relationship between CRP levels and OA.In RS-I the prevalence of knee OA, but not hip OA or hand OA, was associated with 14% higher serum CRP levels compared with controls (p=0.001). This association disappeared after adjustment for age and especially body mass index (BMI) (p=0.33). Genetic variation of the CRP gene was not consistently associated with the prevalence, incidence or progression of OA within RS-I. The systematic review included 18 studies (including RS-I) on serum CRP levels and the prevalence, incidence or progression of OA. Consistently higher crude CRP levels were found in cases of prevalent knee OA compared with controls. No association was observed between serum CRP levels and the prevalence of knee OA following adjustment for BMI (n=3 studies, meta-analysis p value=0.61).There is no evidence of association between serum CRP levels or genetic variation in the CRP gene with the prevalence, incidence or progression of OA independent of BMI.
Adrenaline for the treatment of anaphylaxis: cochrane systematic review
Authors: A. Sheikh, Y. A. Shehata, S. G. A. Brown, F. E. R. Simons
Journal: Allergy (2009)

Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. Adrenaline is recommended as the initial treatment of choice for anaphylaxis.To assess the benefits and harms of adrenaline in the treatment of anaphylaxis.We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 1), MEDLINE (1966 to March 2007), EMBASE (1966 to March 2007), CINAHL (1982 to March 2007), BIOSIS (to March 2007), ISI Web of Knowledge (to March 2007) and LILACS (to March 2007). We also searched websites listing ongoing trials: http://www.clinicaltrials.gov/, http://www.controlledtrials.com and http://www.actr.org.au/ and contacted pharmaceutical companies and international experts in anaphylaxis in an attempt to locate unpublished material. Randomized and quasi-randomized controlled trials comparing adrenaline with no intervention, placebo or other adrenergic agonists were eligible for inclusion. Two authors independently assessed articles for inclusion.We found no studies that satisfied the inclusion criteria.On the basis of this review, we are unable to make any new recommendations on the use of adrenaline for the treatment of anaphylaxis. In the absence of appropriate trials, we recommend, albeit on the basis of less than optimal evidence, that adrenaline administration by intramuscular injection should still be regarded as first-line treatment for the management of anaphylaxis.