tbuckley/cabot-search huggingface dataset:
Hematopoietic cell phosphatase, SHP-1, is constitutively associated with the SH2 domain-containing leukocyte protein, SLP-76, in B cells.
Authors: K Mizuno, T Katagiri, K Hasegawa, M Ogimoto, H Yakura
Journal: The Journal of Experimental Medicine (1996)

Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1; previously named HCP, PTP1C, SH-PTP1, and SHP) is a cytosolic protein tyrosine phosphatase that contains two SH2 domains. Recent data have demonstrated that the gene encoding SHP-1 is mutated in motheaten (mc) and viable motheaten (mc') mice resulting in autoimmune disease. More recently, SHP-1 has been shown to negatively regulate B cell antigen receptor (BCR)-initiated signaling. To elucidate potential mechanisms of SHP-1 action in BCR signal transduction, we studied proteins that interact with SHP-1 in B cells. Both anti-SHP-1 antibody and the two SH2 domains of SHP-1 expressed as glutathione S-transferase fusion proteins precipitated at least three phosphoproteins of approximately 75, 110, and 150 kD upon anti-immunoglobulin M stimulation of the WEHI-231 immature B cell line. Binding of SHP-1 to the 75- and 110-kD proteins appeared to be mediated mainly by the NH2-terminal SH2 domain of SHP-1, whereas both the NH2- and COOH-terminal SH2 domains are required for maximal binding to the 150-kD protein. Immunoprecipitation and Western blot analysis revealed that the SHP-1-associated 75-kD protein is the hematopoietic cell-specific, SH2-containing protein SLP-76. Further, this protein-protein association was constitutively observed and stable during the early phase of BCR signaling. However, significant tyrosine phosphorylation of SLP-76 as well as of SHP-1 was observed after BCR ligation. Constitutive association of SHP-1 with SLP-76 could also be detected in normal splenic B cells. Collectively, these results suggest possible mechanisms by which SHP-1 may modulate signals delivered by BCR engagement.
Chlorhexidine maternal-vaginal and neonate body wipes in sepsis and vertical transmission of pathogenic bacteria in South Africa: a randomised, controlled trial
Authors: Clare L Cutland, Shabir A Madhi, Elizabeth R Zell, Locadiah Kuwanda, Martin Laque, Michelle Groome, Rachel Gorwitz, Michael C Thigpen, Roopal Patel, Sithembiso C Velaphi, Peter Adrian, Keith Klugman, Anne Schuchat, Stephanie J Schrag
Journal: The Lancet (2009)
Secondary cutaneous lymphoma: comparative clinical features and survival outcome analysis of 106 cases according to lymphoma cell lineage
Authors: W.J. Lee, K.H. Won, C.H. Won, S.E. Chang, J.H. Choi, K.C. Moon, C.-S. Park, J. Huh, C. Suh, M.W. Lee
Journal: British Journal of Dermatology (2014)

The relative frequency, clinical features and survival outcomes of secondary cutaneous lymphoma remain poorly understood.To determine the clinical characteristics and survival outcomes of secondary cutaneous lymphoma.The present retrospective cohort study included all 106 patients who presented with secondary cutaneous lymphoma. Patient medical records were reviewed to determine the clinical features, survival outcomes and prognostic factors. Survival outcomes were analysed by using the Kaplan-Meier method and comparisons between lymphoma cell lineages [T or natural killer (T-/NK)-cell vs. B-cell lymphoma] were performed using the log-rank test.Secondary cutaneous lymphomas consisted of mature T-/NK-cell lymphomas (56%), mature B-cell lymphomas (35%), immature haematopoietic malignancies (8%) and Hodgkin lymphoma (1%). The T-/NK-cell lineage lymphoma cases were more likely to have multiple and disseminated skin lesions than the B-cell lineage lymphoma cases. The lymphoma cell lineage did not significantly influence survival outcomes. Patients who showed cutaneous involvement within 6 months of the initial diagnosis of primary disease had a poorer overall survival (OS) outcome than patients who developed cutaneous dissemination 6 or more months after the initial diagnosis (P < 0.001). Patients with disseminated skin lesions had a poorer OS than patients with localized skin lesions (P = 0.028). The two lymphoma cell lineages differed in terms of prognostic factors that influenced survival.Skin lesion characteristics such as time point of appearance and extent affect the survival outcomes of secondary cutaneous lymphoma. Cell lineage did not influence survival outcomes but the two lineages are associated with different prognostic factors.
Hepatic perfusion changes in patients with liver metastases: comparison with those patients with cirrhosis.
Authors: E Leen, J A Goldberg, J R Anderson, J Robertson, B Moule, T G Cooke, C S McArdle
Journal: Gut (1993)

Previous studies using dynamic scintigraphy have shown that the measurement of changes in hepatic perfusion may be exploited to detect liver metastases. Similar hepatic haemodynamic changes also occur in cirrhosis, however, thereby reducing the diagnostic power of the technique. The ability of duplex colour Doppler sonography (DCDS) to differentiate between the changes in liver perfusion in patients with cirrhosis and those with hepatic metastases was assessed. Hepatic arterial and portal venous blood flows were measured in 30 control subjects, 20 patients with cirrhosis, and 55 patients with overt liver metastases. The Doppler perfusion index (DPI) (the rate of hepatic arterial to total liver blood flow) and the congestive index (ratio of the cross sectional area of the vessel to time averaged velocity of blood flow in the vessel) of the hepatic artery (HCI) and portal vein (PCI) were calculated. The hepatic arterial blood flow of the cirrhotic and metastatic groups was significantly raised compared with that of controls, and the portal venous blood flow of the former groups were reduced (p &lt; 0.0001). The DPIs of the cirrhotic and metastatic groups were therefore significantly raised compared with those of controls (p &lt; 0.0001). No significant difference was noted in HCI values between the three groups. The PCI values of the cirrhotic group, however, were significantly raised compared with those of controls and patients with metastases (p &lt; 0.0001). The data suggest that DCDS measurement of PCI may be of value in differentiating between the hepatic perfusion changes caused by cirrhosis and those resulting from hepatic metastases, thereby increasing the diagnostic power of this technique.
Polymorphisms in XRCC1 and Glutathione S-Transferase Genes and Hepatitis B-Related Hepatocellular Carcinoma
Authors: Ming-Whei Yu, Shi-Yi Yang, I-Jen Pan, Chih-Lin Lin, Chun-Jen Liu, Yun-Fan Liaw, Shi-Ming Lin, Pei-Jer Chen, Shou-Dong Lee, Chien-Jen Chen
Journal: JNCI Journal of the National Cancer Institute (2003)

Chronic infection with hepatitis B virus (HBV) causes DNA damage. An arginine (Arg)-to-glutamine (Gln) polymorphism at codon 399 in the XRCC1 gene is putatively associated with DNA damage. In a case–control study of 577 HBV surface antigen carriers with hepatocellular carcinoma (HCC) and 389 HBV carrier control subjects, we investigated the association between this polymorphism and the risk of HCC and assessed whether this association varied with glutathione S-transferase (GST) status; GSTs are involved in carcinogen metabolism. All statistical tests were two-sided. The XRCC1 Gln allele was associated with a dose-dependent increased risk of early-onset HCC (<50 years) but not with the risk of late-onset HCC (Ptrend = .01). The GSTT1-null genotype alone did not affect risk, but the GSTM1-null genotype was associated with a decreased risk for early-onset HCC. Various combinations of GSTM1 and GSTT1 genotypes differentially modified the association of XRCC1 with HCC (Pinteraction = .005); e.g., for individuals with the GSTT1-null/GSTM1-present genotype, the risk of HCC was greater for those with the Gln/Gln genotype (odds ratio = 8.07, 95% confidence interval = 1.67 to 38.93) than for those with the Arg/Arg genotype. Thus, GST status appears to affect the risk of HCC associated with this XRCC1 polymorphism.
Carcinoembryonic Antigen Interacts with TGF-β Receptor and Inhibits TGF-β Signaling in Colorectal Cancers
Authors: Ying Li, Hong Cao, Zhongxian Jiao, Suresh B. Pakala, Divijendra Natha Reddy Sirigiri, Wenpin Li, Rakesh Kumar, Lopa Mishra
Journal: Cancer Research (2010)

Abstract As a tumor marker for colorectal cancers, carcinoembryonic antigen (CEA) enhances the metastatic potential of cancer cells. CEA functions as an intercellular adhesion molecule and is upregulated in a wide variety of human cancers. However, the molecular mechanisms by which CEA mediates metastasis remain to be understood. Transforming growth factor-β (TGF-β) signaling regulates both tumor suppression and metastasis, and also contributes to the stimulation of CEA transcription and secretion in colorectal cancer cells. However, it remains unknown whether CEA, in turn, influences TGF-β functions and if a regulatory cross-talk exists between CEA and the TGF-β signaling pathway. Here, we report that CEA directly interacts with TGF-β receptor and inhibits TGF-β signaling. Targeting CEA with either CEA-specific antibody or siRNA rescues TGF-β response in colorectal cancer cell lines with elevated CEA, thereby restoring the inhibitory effects of TGF-β signaling on proliferation. CEA also enhances the survival of colorectal cancer cells in both local colonization and liver metastasis in animal study. Our study provides novel insights into the interaction between CEA and TGF-β signaling pathway and establishes a negative feedback loop in amplifying the progression of colon cancer cells to more invasive phenotypes. These findings offer new therapeutic opportunities to inhibit colorectal cancer cell proliferation by cotargeting CEA in promoting tumor-inhibitory action of the TGF-β pathway. Cancer Res; 70(20); 8159–68. ©2010 AACR.
Twain: Differences of Opinion on the Worthiest of All Occupations
Authors: Richard L. Golden
Journal: Annals of Internal Medicine (1997)

Letters15 July 1997Twain: Differences of Opinion on the Worthiest of All OccupationsRichard L. Golden, MDRichard L. Golden, MDState University of New York at Stony Brook School of Medicine; Stony Brook, NY 11794Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-127-2-199707150-00037 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I read with interest Dr. Ober's informative and entertaining paper [1]. Although the medical practices of the 19th century, particularly as viewed through the acerbic wit of Mark Twain, appear crude and often dangerous, it seems inappropriate to state that “Nineteenth century medicine was as stagnant as it was toxic; therapeutic bloodletting had been championed in James' Medicinal Dictionary of 1743, and it was still being strongly advocated in 1892 by William Osler.” In a broad sense, the therapeutics of the 19th century saw the discovery of emetine, chloral, pilocarpine, antipyrine, ephedrine, suprarenal extract, general anesthesia, antisepsis, ...References1. Ober KP. The pre-Flexnerian reports: Mark Twain's criticism of medicine in the United States. Ann Intern Med. 1997; 126:152-6. Google Scholar2. Osler W. The Principles and Practice of Medicine. New York: D. Appleton; 1892:530. Google Scholar3. Osler W. The Principles and Practice of Medicine. 3rd ed. New York: D. Appleton; 1898:135. Google Scholar4. Osler W. Typed letter signed to G. Gregory. Oxford: 25 July 1910. Google Scholar5. Twain M. Pudd'nhead Wilson: a tale. In: Cardwell G, ed. Mississippi Writings. Library of America; 1982:1029. Google Scholar Author, Article, and Disclosure InformationAuthors: Richard L. Golden, MDAffiliations: State University of New York at Stony Brook School of Medicine; Stony Brook, NY 11794 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 15 July 1997Volume 127, Issue 2Page: 171KeywordsGeneral anesthesiaHemochromatosisPhlebotomyPneumoniaPolycythemiaPorphyriaRacial and ethnic issuesRadiation therapy ePublished: 15 August 2000 Issue Published: 15 July 1997 Copyright & PermissionsCopyright © 1997 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Tumor necrosis factor-α blockade for the treatment of acute GVHD
Authors: Daniel Couriel, Rima Saliba, Krystal Hicks, Cindy Ippoliti, Marcos de Lima, Chitra Hosing, Issa Khouri, Borje Andersson, James Gajewski, Michele Donato, Paolo Anderlini, Dimitrios P. Kontoyiannis, Agueda Cohen, Thomas Martin, Sergio Giralt, Richard Champlin
Journal: Blood (2004)
Targeting the PI3K Pathway in the Brain—Efficacy of a PI3K Inhibitor Optimized to Cross the Blood–Brain Barrier
Authors: Laurent Salphati, Timothy P. Heffron, Bruno Alicke, Merry Nishimura, Kai Barck, Richard A. Carano, Jonathan Cheong, Kyle A. Edgar, Joan Greve, Samir Kharbanda, Hartmut Koeppen, Shari Lau, Leslie B. Lee, Jodie Pang, Emile G. Plise, Jenny L. Pokorny, Hani Bou Reslan, Jann N. Sarkaria, Jeffrey J. Wallin, Xiaolin Zhang, Stephen E. Gould, Alan G. Olivero, Heidi S. Phillips
Journal: Clinical Cancer Research (2012)

Glioblastoma (GBM), the most common primary brain tumor in adults, presents a high frequency of alteration in the PI3K pathway. Our objectives were to identify a dual PI3K/mTOR inhibitor optimized to cross the blood-brain barrier (BBB) and characterize its brain penetration, pathway modulation in the brain and efficacy in orthotopic xenograft models of GBM.Physicochemical properties of PI3K inhibitors were optimized using in silico tools, leading to the identification of GNE-317. This compound was tested in cells overexpressing P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). Following administration to mice, GNE-317 plasma and brain concentrations were determined, and phosphorylated biomarkers (pAkt, p4EBP1, and pS6) were measured to assess PI3K pathway suppression in the brain. GNE-317 efficacy was evaluated in the U87, GS2, and GBM10 orthotopic models of GBM.GNE-317 was identified as having physicochemical properties predictive of low efflux by P-gp and BCRP. Studies in transfected MDCK cells showed that GNE-317 was not a substrate of either transporter. GNE-317 markedly inhibited the PI3K pathway in mouse brain, causing 40% to 90% suppression of the pAkt and pS6 signals up to 6-hour postdose. GNE-317 was efficacious in the U87, GS2, and GBM10 orthotopic models, achieving tumor growth inhibition of 90% and 50%, and survival benefit, respectively.These results indicated that specific optimization of PI3K inhibitors to cross the BBB led to potent suppression of the PI3K pathway in healthy brain. The efficacy of GNE-317 in 3 intracranial models of GBM suggested that this compound could be effective in the treatment of GBM.
THE UPTAKE AND DIGESTION OF IODINATED HUMAN SERUM ALBUMIN BY MACROPHAGES IN VITRO
Authors: Barbara A. Ehrenreich, Zanvil A. Cohn
Journal: The Journal of Experimental Medicine (1967)

Mouse peritoneal macrophages take up I*-HSA from their medium during in vitro cultivation. Conditions which promote I*-HSA uptake are the same as those which stimulate formation of pinocytic vesicles. Autoradiography of cells pulsed with (125)I-HSA showed that intracellular isotope is localized in perinuclear granules, or secondary lysosomes. Following a pulse of (125)I-HSA, intracellular radioactivity decreases and the amount of TCA-soluble isotope in the medium increases correspondingly. About 50% of the intracellular isotope is lost in 5 hr. The release of isotope from pulsed cells is not inhibited by parafluorophenylalanine, 2,4-dinitrophenol or by a reduction of the serum concentration of the medium. However, the processing of ingested (125)I-HSA is reversibly inhibited by reduced temperature. The TCA-soluble radioactive material excreted by pulsed macrophages was identified as monoiodotyrosine.
Bevacizumab and Subtype-Adapted Chemotherapy Backbone in Neuroendocrine Tumors
Authors: Julien Hadoux, Michel Ducreux
Journal: Journal of Clinical Oncology (2013)

mide in combination with bevacizumab in 34 patients with locally advanced or metastatic neuroendocrine tumors (NETs) treated in four institutions in Boston, MA. This chemotherapy regimen led to a 15% response rate (RR) and 65% stable disease overall, with a better outcomeforpatientswithpancreaticNETs(pNETs;RR,33%;median progression-free survival [PFS], 14.3 months) than patients with carcinoid tumors (RR, 0%; median PFS, 7.3 months). We agree with the authors’ main conclusions, in particular with the importance of the role of antiangiogenic therapy in this disease. We think that this study highlights some important issues in clinical research for patients with NETs. First,aspointedoutbytheauthors,thesmallnumberofaccrued patientsinthisstudywasanissue,makingitdifficulttodrawdefinitive statistical conclusions. Neuroendocrine tumors are rare, with an ageadjustedannualincidenceoffive/100,000patientsintheUnitedStates (SEER 17 registry 2000-2004) for all stages and 1.03/100,000 for metastatic disease. 2 Thus, it is important to conduct multicenter clinical trials for this disease to achieve sufficient enrollment. Therefore, nationwide networks dedicated to treatment and clinical research in neuroendocrine tumors are of particular importance. For example, the Reseau National des Tumeurs Endocrines (RENATEN), a neuroendocrine tumors network in France, gathers data from 17 tertiary care centers all over the country and has several goals: to increase the qualityofcare,toorganizeacentralexpertpathologicreviewforevery
Impaired Alveolar Macrophage Response to <i>Haemophilus</i> Antigens in Chronic Obstructive Lung Disease
Authors: Charles S. Berenson, Catherine T. Wrona, Lori J. Grove, Jane Maloney, Mary Alice Garlipp, Paul K. Wallace, Carleton C. Stewart, Sanjay Sethi
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: Interactions of nontypeable Haemophilus influenzae (NTHI) with macrophages are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the immunologic mechanisms that mediate NTHI-macrophage inflammation are poorly understood. Outer membrane protein (OMP) P6 and lipooligosaccharide (LOS) of NTHI are potent immunomodulators. We theorized that alveolar macrophages in COPD possess fundamental immune defects that permit NTHI to evade host responses.Objective: To test this hypothesis, we obtained human alveolar and blood macrophages from exsmokers with COPD, exsmokers without COPD, and nonsmokers.Methods: Alveolar and blood macrophages from each donor were incubated with purified LOS and OMP P6 and with OMP P2 and the total outer membrane preparation (0.1–1 μg/ml).Measurements: Supernatants (24 h) were assayed for IL-1β, TNF-α, IL-10, IL-12, and IL-8 by multianalyte multiplexed flow cytometry.Results: Comparative induction of COPD and non-COPD alveolar macrophages by LOS and OMP P6 revealed diminished IL-8, TNF-α, and IL-1β responses of COPD alveolar macrophages (p ⩽ 0.03 for each). COPD alveolar macrophages also had diminished responses to total outer membrane (p ⩽ 0.03 for each). In contrast, COPD blood macrophages had no significant differences among donor groups in IL-8, TNF-α, or IL-1β responsiveness to NTHI antigens. Diminished IL-12 responses of COPD blood macrophages to NTHI antigens, compared with nonsmokers, could not be independently dissociated from group differences in age and pack-years.Conclusions: These findings support a paradigm of defective immune responsiveness of alveolar macrophages, but not blood macrophages, in COPD.
Cumulative life course impairment in psoriasis: patient perception of disease-related impairment throughout the life course
Authors: R.B. Warren, C.E. Kleyn, W.P. Gulliver
Journal: British Journal of Dermatology (2011)

Psoriasis is associated with significant physical, psychological, social and economic burden, the cumulative effect of which may result in failure to achieve 'full life potential' in some patients, termed 'cumulative life course impairment' (CLCI). In this concept, the burden of stigmatization, and physical and psychological comorbidities (risk factors for cumulative impairment) and coping strategies and external factors (having potential moderating effects), interact to cause lifetime impairment. Components of CLCI are supported by cross‐sectional data; however, the cumulative nature of impairment in patients with psoriasis is not yet established. Nonetheless, CLCI makes intuitive sense to many dermatologists who recognize the cumulative impact of psoriasis on the lives of some patients. This supplement explores the causes and mechanisms of CLCI qualitatively by presenting cases which are representative of typical patients with moderate‐to‐severe psoriasis. These cases demonstrate the effect of psoriasis in influencing major life‐changing decisions and altering the course of patients' lives, preventing patients from attaining their life goals, pursuing their chosen career, gaining a desired educational level, developing social relationships, gaining full pleasure from family life or having children. All these patients believe that their lives would have taken a different course had they not had psoriasis. Additional research to determine how CLCI occurs and to identify the risk factors for cumulative impairment is required. Understanding the key risk factors for CLCI may help physicians identify patients who are more vulnerable to the cumulative impact of psoriasis, resulting in more appropriate treatment decisions earlier in the disease course.
New Oral Therapies for Type 2 Diabetes Mellitus: The Glitazones or Insulin Sensitizers
Authors: Sunder Mudaliar, Robert R. Henry
Journal: Annual Review of Medicine (2001)

Type 2 diabetes mellitus is a growing problem not only in the United States but also across the world. There is now strong evidence that intensive control of blood glucose can significantly reduce and retard the microvascular complications of retinopathy, nephropathy, and neuropathy. Ultimately however, up to 80% of type 2 diabetics die from macrovascular cardiovascular disease. This increased incidence of atherosclerotic disease is intricately associated with insulin resistance, which is a major pathophysiologic abnormality in type 2 diabetes. There is strong evidence that insulin resistance is involved in the development of not only hyperglycemia, but also dyslipidemia, hypertension, hypercoagulation, vasculopathy, and ultimately atherosclerotic cardiovascular disease. This cluster of metabolic abnormalities has been termed the insulin resistance or cardiovascular dysmetabolic syndrome. The thiazolidinediones (rosiglitazone and pioglitazone), a new class of oral antidiabetic agents, are "insulin sensitizers" and exert direct effects on the mechanisms of insulin resistance. These effects not only improve insulin sensitivity and glycemic control with reduced insulin requirements, but also have potentially favorable effects on other components of the cardiovascular dysmetabolic syndrome. Long-term studies are needed to determine whether the insulin-sensitizing effects of the glitazones can prevent or delay premature atherosclerotic cardiovascular disease, morbidity, and death.
Immunization of apoE–/– mice with aldehyde-modified fibronectin inhibits the development of atherosclerosis
Authors: Pontus Dunér, Fong To, Karsten Beckmann, Harry Björkbacka, Gunilla Nordin Fredrikson, Jan Nilsson, Eva Bengtsson
Journal: Cardiovascular Research (2011)

AimsOxidation of low-density lipoprotein in the extracellular matrix of the arterial wall results in the formation of malondialdehyde (MDA) that modifies surrounding matrix proteins. This is associated with the activation of an immune response against modified extracellular matrix proteins present in atherosclerotic plaques. Clinical studies have revealed an inverse association between antibodies to MDA-modified fibronectin and risk for development of cardiovascular events. To determine the functional role of these immune responses in atherosclerosis, we performed studies in which apoE-deficient mice were immunized with MDA-modified fibronectin.