tbuckley/cabot-search huggingface dataset:
Overexpression of VEGF <sub>165</sub> b, an Inhibitory Splice Variant of Vascular Endothelial Growth Factor, Leads to Insufficient Angiogenesis in Patients With Systemic Sclerosis
Authors: Mirko Manetti, Serena Guiducci, Eloisa Romano, Claudia Ceccarelli, Silvia Bellando-Randone, Maria Letizia Conforti, Lidia Ibba-Manneschi, Marco Matucci-Cerinic
Journal: Circulation Research (2011)

Systemic sclerosis (SSc) is characterized by widespread microangiopathy, fibrosis, and autoimmunity. Despite the lack of angiogenesis, the expression of vascular endothelial growth factor A (VEGF) was shown to be upregulated in SSc skin and circulation; however, previous studies did not distinguish between proangiogenic VEGF(165) and antiangiogenic VEGF(165)b isoforms, which are generated by alternative splicing in the terminal exon of VEGF pre-RNA.We investigated whether VEGF isoform expression could be altered in skin and circulation of patients with SSc.Here, we show that the endogenous antiangiogenic VEGF(165)b splice variant is selectively overexpressed at both the mRNA and protein levels in SSc skin. Elevated VEGF(165)b expression correlated with increased expression of profibrotic transforming growth factor-β1 and serine/arginine protein 55 splicing factor in keratinocytes, fibroblasts, endothelial cells, and perivascular inflammatory cells. Circulating levels of VEGF(165)b were significantly higher in patients with SSc than in control subjects. Microvascular endothelial cells (MVECs) isolated from SSc skin expressed and released higher levels of VEGF(165)b than healthy MVECs. Transforming growth factor-β1 upregulated the expression of VEGF(165)b and serine/arginine protein 55 in both SSc and healthy MVECs. In SSc MVECs, VEGF receptor-2 was overexpressed, but its phosphorylation was impaired. Recombinant VEGF(165)b and SSc-MVEC-conditioned medium inhibited VEGF(165)-mediated VEGF receptor-2 phosphorylation and capillary morphogenesis in healthy MVECs. The addition of anti-VEGF(165)b blocking antibodies abrogated the antiangiogenic effect of SSc-MVEC-conditioned medium. Capillary morphogenesis was severely impaired in SSc MVECs and could be ameliorated by treatment with recombinant VEGF(165) and anti-VEGF(165)b blocking antibodies.In SSc, a switch from proangiogenic to antiangiogenic VEGF isoforms may have a crucial role in the insufficient angiogenic response to chronic ischemia.
<i>ALK</i> Rearrangements Are Mutually Exclusive with Mutations in <i>EGFR</i> or <i>KRAS</i>: An Analysis of 1,683 Patients with Non–Small Cell Lung Cancer
Authors: Justin F. Gainor, Anna M. Varghese, Sai-Hong Ignatius Ou, Sheheryar Kabraji, Mark M. Awad, Ryohei Katayama, Amanda Pawlak, Mari Mino-Kenudson, Beow Y. Yeap, Gregory J. Riely, A. John Iafrate, Maria E. Arcila, Marc Ladanyi, Jeffrey A. Engelman, Dora Dias-Santagata, Alice T. Shaw
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of non–small cell lung cancer (NSCLC). Recently, several case reports and small series have reported that ALK rearrangements can overlap with other oncogenic drivers in NSCLC in crizotinib-naïve and crizotinib-resistant cancers. Experimental Design: We reviewed clinical genotyping data from 1,683 patients with NSCLC and investigated the prevalence of concomitant EGFR or KRAS mutations among patients with ALK-positive NSCLC. We also examined biopsy specimens from 34 patients with ALK-positive NSCLC after the development of resistance to crizotinib. Results: Screening identified 301 (17.8%) EGFR mutations, 465 (27.6%) KRAS mutations, and 75 (4.4%) ALK rearrangements. EGFR mutations and ALK rearrangements were mutually exclusive. Four patients with KRAS mutations were found to have abnormal ALK FISH patterns, most commonly involving isolated 5′ green probes. Sufficient tissue was available for confirmatory ALK immunohistochemistry in 3 cases, all of which were negative for ALK expression. Among patients with ALK-positive NSCLC who acquired resistance to crizotinib, repeat biopsy specimens were ALK FISH positive in 29 of 29 (100%) cases. Secondary mutations in the ALK kinase domain and ALK gene amplification were observed in 7 of 34 (20.6%) and 3 of 29 (10.3%) cases, respectively. No EGFR or KRAS mutations were identified among any of the 25 crizotinib-resistant, ALK-positive patients with sufficient tissue for testing. Conclusions: Functional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population. This lack of overlap was also observed in ALK-positive cancers with acquired resistance to crizotinib. Clin Cancer Res; 19(15); 4273–81. ©2013 AACR.
Mechanical Unloading Restores β-Adrenergic Responsiveness and Reverses Receptor Downregulation in the Failing Human Heart
Authors: Monique L. Ogletree-Hughes, Linda B. Stull, Wendy E. Sweet, Nicholas G. Smedira, Patrick M. McCarthy, Christine Schomisch Moravec
Journal: Circulation (2001)

Background — Mechanical unloading of the failing human heart with a left ventricular assist device (LVAD) results in clinically documented reversal of chamber dilation and improvement of cardiac function. We tested the hypothesis that LVAD support normalizes the ability of cardiac muscle to respond to sympathetic nervous system stimulation by reversing the downregulation of β-adrenergic receptors. Methods and Results — Human LV tissue was obtained from nonfailing hearts of unmatched organ donors and failing hearts at the time of transplantation, with or without LVAD. Baseline contractile parameters and inotropic response to a β-adrenergic agonist were measured in isolated trabecular muscles. β-Adrenergic receptor density was quantified by radioligand binding. Results showed a significant increase in the response to β-adrenergic stimulation after LVAD (developed tension increased by 0.76±0.09 g/mm 2 in nonfailing, 0.38±0.07 in failing, and 0.68±0.10 in failing+LVAD; P &lt;0.01), accompanied by an increased density of β-adrenergic receptors (58.7±9.6 fmol/mg protein in nonfailing, 26.2±3.8 in failing, and 63.0±8.3 in failing+LVAD; P &lt;0.05). These changes were unrelated to the duration of support. Conclusions — Data demonstrate that mechanically supporting the failing human heart with an LVAD can reverse the downregulation of β-adrenergic receptors and restore the ability of cardiac muscle to respond to inotropic stimulation by the sympathetic nervous system. This indicates that functional impairment of cardiac muscle in human heart failure is reversible.
Multiple Myeloma Involving Skin and Pulmonary Parenchyma after Autologous Stem Cell Transplantation
Authors: Yuan Yuan, Rosemary Wieczorek, David L Green, Perry Cook, Harold Ballard, David J Araten
Journal: Journal of Hematology & Oncology (2009)

Abstract Pulmonary involvement and skin involvement are rare complications of plasma cell neoplasms. Here we describe what may be the first reported case of a patient with relapse in both of these sites following autologous peripheral blood stem cell transplantation.
Allosteric Receptors: From Electric Organ to Cognition
Authors: Jean-Pierre Changeux
Journal: The Annual Review of Pharmacology and Toxicology (2010)

This autobiography covers the past 50 years beginning with the development of the concept of allosteric proteins and its application to pharmacological receptors. It continues with the identification of the nicotinic acetylcholine receptor, the discovery of its molecular organization, the structure of the acetylcholine-binding site and of the ion channel, and the demonstration of its allosteric transitions. The article then traces the origins of the concept of allosteric modulator and its consequences in pharmacology. It proceeds with the theory of selective stabilization of synapses and with experimental studies carried out on the contribution of the nicotinic receptor in the morphogenesis of the neuromuscular junction. The knowledge acquired with the nicotinic receptor is further exploited to reach higher levels of brain organization, and the contribution of nicotinic receptors to the action of nicotine on reward and cognition is explored, in particular, using a novel experimental strategy that combines nicotinic receptor genes knock-out and stereotaxic gene re-expression. Theoretical models of cognitive functions are proposed that link the molecular to the cognitive level. The report ends with a discussion on nicotinic receptors and the pharmacology of the future.
A Very Low-Carbohydrate, Low–Saturated Fat Diet for Type 2 Diabetes Management: A Randomized Trial
Authors: Jeannie Tay, Natalie D. Luscombe-Marsh, Campbell H. Thompson, Manny Noakes, Jon D. Buckley, Gary A. Wittert, William S. Yancy, Grant D. Brinkworth
Journal: Diabetes Care (2014)

To comprehensively compare the effects of a very low-carbohydrate, high-unsaturated/low-saturated fat diet (LC) with those of a high-unrefined carbohydrate, low-fat diet (HC) on glycemic control and cardiovascular disease (CVD) risk factors in type 2 diabetes (T2DM).Obese adults (n = 115, BMI 34.4 ± 4.2 kg/m(2), age 58 ± 7 years) with T2DM were randomized to a hypocaloric LC diet (14% carbohydrate [<50 g/day], 28% protein, and 58% fat [<10% saturated fat]) or an energy-matched HC diet (53% carbohydrate, 17% protein, and 30% fat [<10% saturated fat]) combined with structured exercise for 24 weeks. The outcomes measured were as follows: glycosylated hemoglobin (HbA1c), glycemic variability (GV; assessed by 48-h continuous glucose monitoring), antiglycemic medication changes (antiglycemic medication effects score [MES]), and blood lipids and pressure.A total of 93 participants completed 24 weeks. Both groups achieved similar completion rates (LC 79%, HC 82%) and weight loss (LC -12.0 ± 6.3 kg, HC -11.5 ± 5.5 kg); P ≥ 0.50. Blood pressure (-9.8/-7.3 ± 11.6/6.8 mmHg), fasting blood glucose (-1.4 ± 2.3 mmol/L), and LDL cholesterol (-0.3 ± 0.6 mmol/L) decreased, with no diet effect (P ≥ 0.10). LC achieved greater reductions in triglycerides (-0.5 ± 0.5 vs. -0.1 ± 0.5 mmol/L), MES (-0.5 ± 0.5 vs. -0.2 ± 0.5), and GV indices; P ≤ 0.03. LC induced greater HbA1c reductions (-2.6 ± 1.0% [-28.4 ± 10.9 mmol/mol] vs. -1.9 ± 1.2% [-20.8 ± 13.1 mmol/mol]; P = 0.002) and HDL cholesterol (HDL-C) increases (0.2 ± 0.3 vs. 0.05 ± 0.2 mmol/L; P = 0.007) in participants with the respective baseline values HbA1c >7.8% (62 mmol/mol) and HDL-C <1.29 mmol/L.Both diets achieved substantial improvements for several clinical glycemic control and CVD risk markers. These improvements and reductions in GV and antiglycemic medication requirements were greatest with the LC compared with HC. This suggests an LC diet with low saturated fat may be an effective dietary approach for T2DM management if effects are sustained beyond 24 weeks.
Predictive accuracy of the Framingham coronary risk score in British men: prospective cohort study
Authors: P. Brindle
Journal: BMJ (2003)

To establish the predictive accuracy of the Framingham risk score for coronary heart disease in a representative British population.Prospective cohort study.24 towns in the United Kingdom.6643 British men aged 40-59 years and free from cardiovascular disease at entry into the British regional heart study.Comparison of observed 10 year coronary heart disease mortality and event rates with predicted rates for each individual, using the relevant Framingham risk equation.Of 6643 men, 2.8% (95% confidence interval 2.4% to 3.2%) died from coronary heart disease compared with 4.1% predicted (relative overestimation 47%, P < 0.0001). A fatal or non-fatal coronary heart disease event occurred in 10.2% (9.5% to 10.9%) of the men compared with 16.0% predicted (relative overestimation 57%, P < 0.0001). These relative degrees of overestimation were similar at all levels of coronary heart disease risk, so that overestimation of absolute risk was greatest for those at highest risk. A simple adjustment provided an improved level of accuracy. In a "high risk score" approach, most cases occur in the low risk group. In this case, 84% of the deaths from coronary heart disease and non-fatal events occurred in the 93% of men classified at low risk (< 30% in 10 years) by the Framingham score.Guidelines for the primary prevention of coronary heart disease advocate offering preventive measures to individuals at high risk. Currently recommended risk scoring methods derived from the Framingham study significantly overestimate the absolute coronary risk assigned to individuals in the United Kingdom.
Specific targeting of the antiviral drug 5-Iodo 2′-deoxyuridine to the parenchymal liver cell using lactosylated poly-L-lysine
Authors: Erik A.L. Biessen, Diana M. Beuting, Helene Vietsch, Martin K. Bijsterbosch, Theo J.C. Van Berkel
Journal: Journal of Hepatology (1994)
TGF-β1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II
Authors: Jo El J. Schultz, Sandra A. Witt, Betty J. Glascock, Michelle L. Nieman, Peter J. Reiser, Stacey L. Nix, Thomas R. Kimball, Thomas Doetschman
Journal: Journal of Clinical Investigation (2002)

Angiotensin II (Ang II), a potent hypertrophic stimulus, causes significant increases in TGFb1 gene expression. However, it is not known whether there is a causal relationship between increased levels of TGF-β1 and cardiac hypertrophy. Echocardiographic analysis revealed that TGF-β1–deficient mice subjected to chronic subpressor doses of Ang II had no significant change in left ventricular (LV) mass and percent fractional shortening during Ang IItreatment. In contrast, Ang II–treated wild-type mice showed a >20% increase in LV mass and impaired cardiac function. Cardiomyocyte cross-sectional area was also markedly increased in Ang II–treated wild-type mice but unchanged in Ang II–treated TGF-β1–deficient mice. No significant levels of fibrosis, mitotic growth, or cytokine infiltration were detected in Ang II–treated mice. Atrial natriuretic factor expression was ∼6-fold elevated in Ang II–treated wild-type, but not TGF-β1–deficient mice. However, the α- to β-myosin heavy chain switch did not occur in Ang II–treated mice, indicating that isoform switching is not obligatorily coupled with hypertrophy or TGF-β1. The Ang IIeffect on hypertrophy was shown not to result from stimulation of the endogenous renin-angiotensis system. These results indicate that TGF-β1 is an important mediator of the hypertrophic growth response of the heart to Ang II.
Theranostic Au Cubic Nano-aggregates as Potential Photoacoustic Contrast and Photothermal Therapeutic Agents
Authors: Juan Hu, Xianglong Zhu, Hui Li, Zhenghuan Zhao, Xiaoqin Chi, Guoming Huang, Dengtong Huang, Gang Liu, Xiaomin Wang, Jinhao Gao
Journal: Theranostics (2014)

Multifunctional nanostructures combining diagnosis and therapy modalities into one entity have drawn much attention in the biomedical applications.Herein, we report a simple and cost-effective method to synthesize a novel cubic Au nano-aggregates structure with edge-length of 80 nm (Au-80 CNAs), which display strong near-infrared (NIR) absorption, excellent water-solubility, good photothermal stability, and high biocompatibility.Under 808 nm laser irradiation for 5 min, the temperature of the solution containing Au-80 CNAs (100 µg/mL) increased by ~38 °C.The in vitro and in vivo studies demonstrated that Au-80 CNAs could act as both photothermal therapeutic (PTT) agents and photoacoustic imaging (PAI) contrast agents, indicating that the only one nano-entity of Au-80 CNAs shows great potentials for theranostic applications.Moreover, this facile and cost-effective synthetic method provides a new strategy to prepare stable Au nanomaterials with excellent optical properties for biomedical applications.
Gelsolin Secretion in Interleukin-4–treated Bronchial Epithelia and in Asthmatic Airways
Authors: Giovanni Candiano, Maurizio Bruschi, Nicoletta Pedemonte, Emanuela Caci, Sabrina Liberatori, Luca Bini, Carlo Pellegrini, Mario Viganò, Brian J. O'Connor, Tak H. Lee, Luis J. V. Galietta, Olga Zegarra-Moran
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

The airway surface liquid, the thin layer of liquid covering the airways, is essential for mucociliary clearance and as a barrier against microbial and other noxious agents. Proteins secreted into the airway surface liquid by epithelial and nonepithelial cells may be important in innate immunity and to improve the fluidity of mucous secretions.We aimed to identify proteins specifically secreted into the airway surface liquid by human bronchial epithelial cells, in resting conditions and after treatment with interleukin 4 (IL-4), a cytokine released in asthma.By using a proteomics approach, we found that one of the most abundant proteins was gelsolin, which breaks down actin filaments. Gelsolin mRNA and protein secretion were increased threefold in the airway surface liquid of epithelia treated with IL-4. These results were confirmed at the functional level by measuring actin depolymerization using a fluorescence assay. Gelsolin protein was also upregulated in the airways of subjects with asthma.Our findings indicate that gelsolin is released by epithelial cells into the airways and that its secretion is increased by IL-4 in vitro. In addition, we found that the concentration of both IL-4 and gelsolin were raised in the bronchoalveolar lavage of patients with asthma. These results suggest that gelsolin might improve the fluidity of airway surface liquid in asthma by breaking down filamentous actin that may be released in large amounts by dying cells during inflammation.
A Critique of Thomas S. Szasz's "Myth of Mental Illness"
Authors: STEVEN REISS
Journal: American Journal of Psychiatry (1972)

Thomas Szasz's position that mental illness is a myth is found by the author to involve the following beliefs: 1) the term "mental illness" is universally defined as a biological disease state; 2) because some similarities exist between the mental health movement and the Inquisition, mental illness is as nonexistent as witchcraft; and 3) the value of alleviating suffering is more likely to be abused than is the value of promoting individual rights. Each of these beliefs is challenged. Moreover, Sasz's alternative to mental illness is found to involve concepts that are exceptionally vague.
High protein expression of EZH2 is related to unfavorable outcome to tamoxifen in metastatic breast cancer
Authors: E.A. Reijm, A.M. Timmermans, M.P. Look, M.E. Meijer-van Gelder, C.K. Stobbe, C.H.M. van Deurzen, J.W.M. Martens, S. Sleijfer, J.A. Foekens, P.M.J.J. Berns, M.P.H.M. Jansen
Journal: Annals of Oncology (2014)
Effects of Coresidential Living on the Attitudes, Self-Image, and Role Expectations of College Women
Authors: ELIZABETH AUB REID
Journal: American Journal of Psychiatry (1974)

The author interviewed matched groups of college women to study the effects on women of coresidential dormitory life. As compared to those in all-women's dormitories, women in the coresidential setting were found to have more satisfying relationships with both men and women, higher self-esteem, conceptions of masculinity and femininity that were less stereotyped, and more egalitarian role expectations.
The Importance of Clinical and Angiographic Risk Scores in Development of Atrioventricular Conduction Blocks after Acute Inferior Myocardial Infarction
Authors: İlker Gül, Ahmet Çağrı Aykan, Tayyar Gökdeniz, Faruk Boyacı, Ezgi Kalaycıoğlu, Engin Hatem, Turhan Turan, Mustafa Zungur, Şükrü Çelik
Journal: Journal of the American College of Cardiology (2013)
Haemophilia, hepatitis and porphyria
Authors: J.W. BURNETT, J.M. LAMON, J. LEVIN
Journal: British Journal of Dermatology (1977)

Journal Article Haemophilia, hepatitis and porphyria Get access J.W. BURNETT, J.W. BURNETT Division of Dermatology, University of Maryland School of Medicine, Baltimore, MD 21201; †Metabolism Branch, National Cancer Institute, Bethesda, MD 20014, ‡Hematology Division, Department of Medicine, The Johns Hopkins University School of Medicine and Hospital, Baltimore, MD 21205, U.S.A. Reprints requests to: Dr Joseph W.Burnett, Dermatology, University of Md. Hospital, Baltimore, Maryland 2I20I, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar J.M. LAMON, J.M. LAMON Division of Dermatology, University of Maryland School of Medicine, Baltimore, MD 21201; †Metabolism Branch, National Cancer Institute, Bethesda, MD 20014, ‡Hematology Division, Department of Medicine, The Johns Hopkins University School of Medicine and Hospital, Baltimore, MD 21205, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar J. LEVIN J. LEVIN Division of Dermatology, University of Maryland School of Medicine, Baltimore, MD 21201; †Metabolism Branch, National Cancer Institute, Bethesda, MD 20014, ‡Hematology Division, Department of Medicine, The Johns Hopkins University School of Medicine and Hospital, Baltimore, MD 21205, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 97, Issue 4, 1 October 1977, Pages 453–455, https://doi.org/10.1111/j.1365-2133.1977.tb14258.x Published: 01 October 1977
Cystinuria: Defective Intestinal Transport of Dibasic Amino Acids and Cystine*
Authors: S. O. Thier, S. Segal, M. Fox, A. Blair, L. E. Rosenberg
Journal: Journal of Clinical Investigation (1965)

The clinical manifestations of cystinuria are lo- calized to the urinary tract and result from the formation of cystine calculi.The findings of in- creased excretion of cystine, lysine, arginine, and ornithine in the urine at a time when the plasma levels of these amino acids were normal or low suggested to Dent and Rose (2) that a renal tu- 1)ular reabsorptive site, shared by the involved amino acids, was defective.Investigations from our laboratory (3), using slices of human kidney, failed to confirm the hypothesis of Dent and Rose.Cystine did not compete with the dibasic amino acids in vitro, and although the transport of ly- sine and arginine was defective in cystinuria, cys- tine transport was unimpaired.Although evidence had been accumulating for over 60 years (4-6), it was not until 1960 that the concept of an intestinal transport defect in cystinuria emerged.Milne, Asatoor, and co- workers (7, 8) noted that urinary and fecal ex- cretion of the diamines, cadaverine and putrescine, was elevated in cystinuric subjects fed lysine and ornithine, respectively.These diamines are formed by bacterial decarboxylation of the dibasic amino acids.Hence, it was postulated that lysine and ornithine were poorly absorbed from the small intestine in cystinuria and were presented to colonic bacteria in increased amounts, result- ing in excessive diamine formation and excretion.