tbuckley/cabot-search huggingface dataset:
Genetic Research and Health Disparities
Authors: Pamela Sankar
Journal: JAMA (2004)

Alleviating health disparities in the United States is a goal with broad support.Medical research undertaken to achieve this goal typically adopts the well-established perspective that racial discrimination and poverty are the major contributors to unequal health status.However, the suggestion is increasingly made that genetic research also has a significant role to play in alleviating this problem, which likely overstates the importance of genetics as a factor in health disparities.Overemphasis on genetics as a major explanatory factor in health disparities could lead researchers to miss factors that contribute to disparities more substantially and may also reinforce racial stereotyping, which may contribute to disparities in the first place.Arguments that promote genetics research as a way to help alleviate health disparities are augmented by several factors, including research funding initiatives and the distinct demographic patterns of health disparities in the United States.
Crizotinib in Advanced, Chemoresistant Anaplastic Lymphoma Kinase–Positive Lymphoma Patients
Authors: Carlo Gambacorti Passerini, Francesca Farina, Alessandra Stasia, Sara Redaelli, Monica Ceccon, Luca Mologni, Cristina Messa, Luca Guerra, Giovanni Giudici, Elena Sala, Lara Mussolin, Dries Deeren, Michael H. King, Michael Steurer, Rainer Ordemann, Amos M. Cohen, Matthias Grube, Lea Bernard, Gianpaolo Chiriano, Laura Antolini, Rocco Piazza
Journal: JNCI Journal of the National Cancer Institute (2014)

Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and in vivo and was administered as monotherapy to 11 ALK+ lymphoma patients who were resistant/refractory to cytotoxic therapy. The overall response rate was 10 of 11 (90.9%; 95% confidence interval [CI] = 58.7% to 99.8%). Disease status at the latest follow-up is as follows: four patients are in complete response (CR) (months >21, >30, >35, >40) under continuous crizotinib administration; 4 patients had progression of disease (months 1, 2, 2, 2); 1 patient obtained CR on crizotinib, received an allogeneic bone marrow transplant, and is in CR; 2 patients (treated before and/or after allogeneic bone marrow transplant) obtained and are still in CR but they have stopped crizotinib. Overall and progression-free survival rates at 2 years are 72.7% (95% CI = 39.1% to 94.0%) and 63.7% (95% CI = 30.8% to 89.1%), respectively. ALK mutations conferring resistance to crizotinib in vitro could be identified in relapsed patients. Crizotinib exerted a potent antitumor activity with durable responses in advanced, heavily pretreated ALK+ lymphoma patients, with a benign safety profile.
Phase I Pharmacokinetic and Pharmacodynamic Study of LAQ824, a Hydroxamate Histone Deacetylase Inhibitor with a Heat Shock Protein-90 Inhibitory Profile, in Patients with Advanced Solid Tumors
Authors: Johann S. de Bono, Rebecca Kristeleit, Anthony Tolcher, Peter Fong, Simon Pacey, Vasilios Karavasilis, Monica Mita, Heather Shaw, Paul Workman, Stan Kaye, Eric K. Rowinsky, Wynne Aherne, Peter Atadja, Jeffrey W. Scott, Amita Patnaik
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To determine the safety, maximum tolerated dose, and pharmacokinetic-pharmacodynamic profile of a histone deacetylase inhibitor, LAQ824, in patients with advanced malignancy. Patients and Methods: LAQ824 was administered i.v. as a 3-h infusion on days 1, 2, and 3 every 21 days. Western blot assays of peripheral blood mononuclear cell lysates and tumor biopsies pretherapy and posttherapy evaluated target inhibition and effects on heat shock protein-90 (HSP90) client proteins and HSP72. Results: Thirty-nine patients (22 male; median age, 53 years; median Eastern Cooperative Oncology Group performance status 1) were treated at seven dose levels (mg/m2): 6 (3 patients), 12 (4 patients), 24 (4 patients), 36 (4 patients), 48 (4 patients), 72 (19 patients), and 100 (1 patient). Dose-escalation used a modified continual reassessment method. Dose-limiting toxicities were transaminitis, fatigue, atrial fibrillation, raised serum creatinine, and hyperbilirubinemia. A patient with pancreatic cancer treated at 100 mg/m2 died on course one at day 18 with grade 3 hyperbilirubinemia and neutropenia, fever, and acute renal failure. The area under the plasma concentration curve increased proportionally with increasing dose; median terminal half-life ranged from 8 to 14 hours. Peripheral blood mononuclear cell lysates showed consistent accumulation of acetylated histones posttherapy from 24 mg/m2; higher doses resulted in increased and longer duration of pharmacodynamic effect. Changes in HSP90 client protein and HSP72 levels consistent with HSP90 inhibition were observed at higher doses. No objective response was documented; 3 patients had stable disease lasting up to 14 months. Based on these data, future efficacy trials should evaluate doses ranging from 24 to 72 mg/m2. Conclusions: LAQ824 was well tolerated at doses that induced accumulation of histone acetylation, with higher doses inducing changes consistent with HSP90 inhibition.
Inhibition of Endogenous Mst1 Prevents Apoptosis and Cardiac Dysfunction Without Affecting Cardiac Hypertrophy After Myocardial Infarction
Authors: Mari Odashima, Soichiro Usui, Hiromitsu Takagi, Chull Hong, Jing Liu, Mitsuhiro Yokota, Junichi Sadoshima
Journal: Circulation Research (2007)

Mammalian sterile 20–like kinase-1 (Mst1) plays an important role in mediating cardiac myocyte apoptosis in response to ischemia/reperfusion. Whether or not Mst1 is also involved in the long-term development of heart failure after myocardial infarction (MI) is unknown. We addressed this issue using transgenic mice with cardiac specific overexpression of dominant negative Mst1 (Tg-DN-Mst1). The left coronary artery was permanently ligated, and the size of MI was similar between Tg-DN-Mst1 and nontransgenic controls (NTg). After 4 weeks, Mst1 was significantly activated in the remodeling area in NTg, but not in Tg-DN-Mst1. Although left ventricular (LV) enlargement was significantly attenuated in Tg-DN-Mst1 compared with NTg, neither LV weight/body weight nor myocyte cross sectional area was statistically different between Tg-DN-Mst1 and NTg. LV ejection fraction was significantly greater in Tg-DN-Mst1 than in NTg (53 versus 38%, P &lt;0.01), whereas LV end-diastolic pressure (6 versus 12 mm Hg, P &lt;0.05) and lung weight/body weight (9.8 versus 12.2 P &lt;0.05) were significantly smaller in Tg-DN-Mst1 than in NTg. The number of TUNEL-positive myocytes (0.17 versus 0.28%, P &lt;0.05) and amount of interstitial fibrosis (5.0 versus 7.1%, P &lt;0.05) in the remodeling area were significantly less in Tg-DN-Mst1 than in NTg. Upregulation of matrix metalloproteinase 2 and proinflammatory cytokines was significantly attenuated in Tg-DN-Mst1. These results indicate that endogenous Mst1 plays an important role in mediating cardiac dilation, apoptosis, fibrosis, and cardiac dysfunction, but not cardiac hypertrophy, after MI. Inhibition of Mst1 improves cardiac function without attenuating cardiac hypertrophy. Thus, Mst1 may be an important target of heart failure treatment.
Targeting GPCR-Mediated p70S6K Activity May Improve Head and Neck Cancer Response to Cetuximab
Authors: Neil E. Bhola, Sufi M. Thomas, Maria Freilino, Sonali Joyce, Anirban Sahu, Jessica Maxwell, Athanassios Argiris, Raja Seethala, Jennifer R. Grandis
Journal: Clinical Cancer Research (2011)

Epidermal growth factor receptor (EGFR) overexpression is correlated with decreased survival in head and neck cancer (HNC) where the addition of EGFR inhibition to standard chemoradiation approaches has improved treatment responses. However, the basis for the limited efficacy of EGFR inhibitors in HNC is incompletely understood. G-protein-coupled receptors (GPCR) have been shown to be overexpressed in HNC where GPCR activation induces HNC growth via both EGFR-dependent and -independent pathways. We hypothesized that targeting GPCR-induced EGFR-independent signaling would improve the efficacy of EGFR inhibition.Using a high-throughput phosphoproteome array, we identified proteins that were phosphorylated in HNC cells where EGFR expression was downmodulated by RNA interference (RNAi) in the presence or absence of a GPCR ligand. We confirmed the findings from the array by Western blotting followed by in vitro and in vivo phenotypic assays.p70S6K phosphorylation was elevated approximately sixfold in EGFR siRNA-transfected cells treated with a GPCR ligand. In addition to RNAi-mediated EGFR downmodulation, GPCR-mediated phosphorylation of p70S6K was modestly increased by EGFR inhibitor cetuximab approved by the Food and Drug Administration. Biopsies from cetuximab-treated patients also displayed increased phospho-p70S6K staining compared with pretreatment biopsies. HNC cells were growth inhibited by both genetic and pharmacologic p70S6K targeting strategies. Furthermore, p70S6K targeting in combination with cetuximab resulted in enhanced antitumor effects in both in vitro and in vivo HNC models.These results indicate that increased phosphorylation of p70S6K in cetuximab-treated patients may be due to increased GPCR signaling. Therefore, the addition of p70S6K targeting strategies may improve treatment responses to EGFR inhibition.
Rheumatoid arthritis, HLA identity, and age at menarche.
Authors: C M Deighton, H Sykes, D J Walker
Journal: Annals of the Rheumatic Diseases (1993)

To determine whether women with rheumatoid arthritis (RA) had differences in obstetric and gynaecological histories when compared with sisters without RA (controls)Ninety eight RA discordant sister pairs, 36 of whom were identical for histocompatibility locus antigen (HLA-A, HLA-B, and HLA-Cw) types, were asked to recall their age of menarche, duration of use of contraceptive pill, pregnancy history, and age of menopause.The 98 siblings with RA had an older mean age of menarche (13.90 (95% confidence interval (95% CI) 13.56 to 14.24) years) than their sisters (13.49 (95% CI 13.22 to 13.76) years; mean difference within pairs 0.41, 95% CI 0.09 to 0.73 years, paired t test t = 2.54, p = 0.013). When the pairs were divided into identical HLA and non-identical HLA groups, the first showed no significant difference (mean difference 0.17 (95% CI -0.40 to 0.73) years), whereas the second did (mean difference 0.55 (95% CI 0.16 to 0.94) years, t = 2.80, p = 0.007). A multiple regression analysis to predict differences in menarche in the non-identical HLA sibling pairs failed to show any demographic or reproductive confounding variables. In 19 RA concordant sibling pairs, the seven HLA identical pairs had similar ages of menarche, whereas the 12 non-identical HLA pairs had interpair differences that narrowly missed significance (p = 0.054). All other obstetric and gynaecological variables were not significantly different within the pairs.The interpretations of these results are that either delayed menarche may predispose to or act as a marker of RA, or HLA linked genes are important in determining the age of menarche irrespective of disease state. This study fails to support a significant role for other obstetric and gynaecological variables in RA.
Changes in Diet and Lifestyle and Long-Term Weight Gain in Women and Men
Authors: Dariush Mozaffarian, Tao Hao, Eric B. Rimm, Walter C. Willett, Frank B. Hu
Journal: New England Journal of Medicine (2011)

Specific dietary and other lifestyle behaviors may affect the success of the straightforward-sounding strategy "eat less and exercise more" for preventing long-term weight gain.We performed prospective investigations involving three separate cohorts that included 120,877 U.S. women and men who were free of chronic diseases and not obese at baseline, with follow-up periods from 1986 to 2006, 1991 to 2003, and 1986 to 2006. The relationships between changes in lifestyle factors and weight change were evaluated at 4-year intervals, with multivariable adjustments made for age, baseline body-mass index for each period, and all lifestyle factors simultaneously. Cohort-specific and sex-specific results were similar and were pooled with the use of an inverse-variance-weighted meta-analysis.Within each 4-year period, participants gained an average of 3.35 lb (5th to 95th percentile, -4.1 to 12.4). On the basis of increased daily servings of individual dietary components, 4-year weight change was most strongly associated with the intake of potato chips (1.69 lb), potatoes (1.28 lb), sugar-sweetened beverages (1.00 lb), unprocessed red meats (0.95 lb), and processed meats (0.93 lb) and was inversely associated with the intake of vegetables (-0.22 lb), whole grains (-0.37 lb), fruits (-0.49 lb), nuts (-0.57 lb), and yogurt (-0.82 lb) (P≤0.005 for each comparison). Aggregate dietary changes were associated with substantial differences in weight change (3.93 lb across quintiles of dietary change). Other lifestyle factors were also independently associated with weight change (P<0.001), including physical activity (-1.76 lb across quintiles); alcohol use (0.41 lb per drink per day), smoking (new quitters, 5.17 lb; former smokers, 0.14 lb), sleep (more weight gain with <6 or >8 hours of sleep), and television watching (0.31 lb per hour per day).Specific dietary and lifestyle factors are independently associated with long-term weight gain, with a substantial aggregate effect and implications for strategies to prevent obesity. (Funded by the National Institutes of Health and others.).
Abstract 3496: Self-renewal as a therapeutic target in human colorectal cancer
Authors: Antonija Kreso, Peter van Galen, Thomas Davis, Eva Szentgyorgyi, Catherine O'Brien, John E. Dick
Journal: Cancer Research (2012)

Abstract Tumor recurrence following treatment remains a major clinical challenge. Evidence from xenograft models and human trials indicates selective enrichment of cancer-initiating cells (C-ICs) in tumors that survive therapy. Together with recent reports showing that C-IC gene signatures influence patient survival, these studies predict that targeting self-renewal, the key stemness property unique to C-ICs, may represent a new paradigm in cancer therapy. Here we demonstrate that tumor formation, and more specifically human colorectal C-IC function are dependent on the canonical self-renewal regulator BMI-1. Down-regulation of BMI-1 inhibits the ability of colorectal C-ICs to self-renew resulting in the abrogation of their tumorigenic potential. Treatment of primary colorectal cancer xenografts with small molecule BMI-1 inhibitors resulted in colorectal C-IC loss with long-term and irreversible impairment of tumor growth. Targeting the Bmi-1 related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3496. doi:1538-7445.AM2012-3496
Increased Fasting Triglyceride Levels Are Associated With Hepatic Insulin Resistance in Caucasian but Not African-American Adolescents
Authors: Robert P. Hoffman
Journal: Diabetes Care (2006)

ncreased lipid levels are related to insulin resistance in children and adults (1-3).Insulin resistance occurs due to an inability to suppress hepatic glucose production (HGP) or to stimulate peripheral glucose uptake.It is not clear whether hyperlipidemia primarily affects hepatic or peripheral insulin sensitivity.In this study, the stable-labeled, frequently sampled intravenous glucose tolerance test (4 -7) was used to measure total-body insulin sensitivity (S i ), peripheral insulin sensitivity (S i *) (5), and hepatic insulin resistance (HIR) (8) in African-American and Caucasian adolescents.RESEARCH DESIGN AND METHODS -Healthy, Tanner stage 1-5, Caucasian (n ϭ 18, age 14.0 Ϯ 2.6 years, BMI 23.0 Ϯ 3.2 kg/m 2 ) and African-American (n ϭ 10, age 14.1 Ϯ 2.3, BMI 25.6 Ϯ 5.1) subjects were studied.Informed written consent and
Ectopic localization of FOXO3a protein in Lewy bodies in Lewy body dementia and Parkinson's disease
Authors: Bo Su, Haihua Liu, Xinglong Wang, Shu G Chen, Sandra L Siedlak, Eisaku Kondo, Raymond Choi, Atsushi Takeda, Rudy J Castellani, George Perry, Mark A Smith, Xiongwei Zhu, Hyoung-gon Lee
Journal: Molecular Neurodegeneration (2009)

Lewy bodies and Lewy neurites constitute the cardinal neuropathological features of both Parkinson's disease (PD) and Lewy body dementia (LBD). Whereas alpha-synuclein has been found to be the major component of the Lewy body, the mechanisms by which neurons degenerate, as well as basic mechanisms involved in the formation of alpha-synuclein-related inclusions, remain obscure. We have suggested previously that potential mechanisms are likely to leave a "molecular signature" or protein adduct within the Lewy body, and have found examples of such signatures in previous studies. In this study, we demonstrate increased FOXO3 in association with Lewy bodies and Lewy neurites in LBD and PD brain tissue. Since FOXO proteins are involved in several pathways responsible for the regulation of cell death, cell proliferation, and cell metabolism, the ectopic localization of FOXO3 to Lewy bodies provides evidence that aberrations in basic cellular biochemistry may contribute to inclusion formation, which is likely more complex than a simple "gain of function" toxicity as is commonly opined. In light of the known interaction of FOXO3 and 14-3-3, basic protein-protein interaction between these proteins and alpha-synuclein may be key.
Osteonecrosis of the humerus related to pregnancy.
Authors: L McGuigan, A Fleming
Journal: Annals of the Rheumatic Diseases (1983)

A case of osteonecrosis of the head of the humerus is described in which the only likely precipitant was pregnancy. The association of pregnancy and osteonecrosis is reviewed. This is the first reported case of osteonecrosis of the humerus alone associated with pregnancy.
Efficacy of monochromatic excimer laser radiation (308 nm) in the treatment of early stage mycosis fungoides
Authors: S. Nistico, A. Costanzo, R. Saraceno, S. Chimenti
Journal: British Journal of Dermatology (2004)

Background Various reports have recently shown the efficacy of narrowband ultraviolet (UV) B phototherapy at 311 nm in the treatment of early stage mycosis fungoides (MF). Objectives To examine the effectiveness and tolerability of monochromatic excimer light (MEL) at 308 nm as a first treatment for early stage MF (stage IA). Methods Ten lesions from five patients with a clinical and histological diagnosis of MF were treated with repeated applications of MEL until complete remission was achieved or up to a maximum of 10 applications, with a cumulative dose of 308 nm UVB of between 6 and 12 J cm−2. All patients were observed every 2 weeks for 2 months, with a 1-year follow-up. Results At present, all patients are in complete remission, with no side-effects. Conclusions Based on these results, MEL can be considered a useful tool in the treatment of early stage MF.
Facial looks: new insight in risk factors involved in looking old
Authors: A.B. Olesen
Journal: British Journal of Dermatology (2015)

Journal Article Facial looks: new insight in risk factors involved in looking old Get access A.B. Olesen A.B. Olesen Department of Dermatology University Hospital of Aarhus Marselisborg Centre P.P. Ørumsgade 11 DK‐8000 Aarhus C Denmark Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 172, Issue 5, 1 May 2015, Pages 1190–1191, https://doi.org/10.1111/bjd.13811 Published: 01 May 2015
Severe immunodeficiency associated with a human immunodeficiency virus 1 NEF/3'-long terminal repeat transgene.
Authors: D Lindemann, R Wilhelm, P Renard, A Althage, R Zinkernagel, J Mous
Journal: The Journal of Experimental Medicine (1994)

We have generated several transgenic mouse strains carrying a human immunodeficiency virus 1 (HIV-1) NEF/3' long terminal repeat (LTR) transgene under control of a T cell-specific promoter-enhancer element, showing a depletion of CD4+ T cells in the thymus and periphery. The immunological functions of the line with the most dramatic changes in lymphocyte populations, B6/338L, were analyzed in greater detail. The presence of the transgene in the heterozygous animal is associated with a dominant severe immunodeficiency. Older animals develop lymph-adenopathy and splenomegaly. CD4+CD8+ and CD4+CD8- single positive thymocytes already are depleted in these mice at the earliest stages in ontogeny, and peripheral T cells are reduced in frequency and present cell surface marker expression, which is characteristic for memory and activated T cells. The immunological response of B6/338L mice to several viral infections is also greatly impaired. Thus, the HIV-1 NEF/3' LTR as transgene in T cells can cause immunodeficiency and disease with striking similarities to a known retrovirus-induced immunodeficiency called murine AIDS (H. C. Morse III, S. K. Chattopadhyay, M. Makino, T. N. Frederickson, A. W. Hügin, and J. W. Hartley. 1992. AIDS. 6:607).
NK CELL RECEPTORS
Authors: Lewis L. Lanier
Journal: Annual Review of Immunology (1998)

▪ Abstract NK cells are regulated by opposing signals from receptors that activate and inhibit effector function. While positive stimulation may be initiated by an array of co-stimulatory receptors, specificity is provided by inhibitory signals transduced by receptors for MHC class I. Three distinct receptor families, Ly49, CD94/NKG2, and KIR, are involved in NK cell recognition of polymorphic MHC class I molecules. A common pathway of inhibitory signaling is provided by ITIM sequences in the cytoplasmic domains of these otherwise structurally diverse receptors. Upon ligand binding and activation, the inhibitory NK cell receptors become tyrosine phosphorylated and recruit tyrosine phosphatases, SHP-1 and possibly SHP-2, resulting in inhibition of NK cell–mediated cytotoxicity and cytokine expression. Recent studies suggest these inhibitory NK cell receptors are members of a larger superfamily containing ITIM sequences, the inhibitory receptor superfamily (IRS).