tbuckley/cabot-search huggingface dataset:
Adrenal Metastases Causing Addison's Disease
Authors: C. M. Sheridan
Journal: BMJ (1966)

CD4<sup>+</sup> Th2 development is regulated by the zinc finger transcription factor GATA3. Once induced by acute priming signals, such as IL-4, GATA3 poises the Th2 cytokine locus for rapid activation and establishes a positive-feedback loop that maintains elevated GATA3 expression. Type I IFN (IFN-α/β) inhibits Th2 cells by blocking the expression of GATA3 during Th2 development and in fully committed Th2 cells. In this study, we uncovered a unique mechanism by which IFN-α/β signaling represses the GATA3 gene in human Th2 cells. IFN-α/β suppressed expression of GATA3 mRNA that was transcribed from an alternative distal upstream exon (1A). This suppression was not mediated through DNA methylation, but rather by histone modifications localized to a conserved noncoding sequence (CNS-1) upstream of exon 1A. IFN-α/β treatment led to a closed conformation of CNS-1, as assessed by DNase I hypersensitivity, along with enhanced accumulation of H3K27me3 mark at this CNS region, which correlated with increased density of total nucleosomes at this putative enhancer. Consequently, accessibility of CNS-1 to GATA3 DNA binding activity was reduced in response to IFN-α/β signaling, even in the presence of IL-4. Thus, IFN-α/β disrupts the GATA3-autoactivation loop and promotes epigenetic silencing of a Th2-specific regulatory region within the GATA3 gene.
Lamivudine results in a complete and sustained suppression of hepatitis B virus replication in patients requiring orthotopic liver transplantation for cirrhosis secondary to hepatitis B
Authors: K GUTFREUND
Journal: Hepatology (1995)

Among the acquired immunodeficiency syndrome (AIDS) drugs approved by the FDA for clinical use, two are modified cytosine analogs, Zalcitabine (ddC) and Lamivudine [(−)3TC]. (−)3TC is the only analog containing an unnatural l (−) nucleoside configuration. Similar to other dideoxy nucleosides, these analogs are metabolically activated to the triphosphate that is incorporated into DNA by human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) resulting in DNA chain termination and ultimately cessation of viral replication. The natural d (+) 3TC isomer also acts in a similar manner to inhibit HIV-1 RT. In cell culture, (−)3TC is less toxic than its d (+) isomer, (+)3TC, containing the natural nucleoside configuration, and both are considerably less toxic than 2′,3′-dideoxycytidine (ddC). The mechanistic basis for the stereochemical selectivity and differential toxicity of the isomeric 2′,3′-dideoxy-3′-thiacytidine (3TC) and ddC compounds is not completely understood although a number of factors may clearly come into play. We have previously investigated the mechanistic basis for the differential stereoselective inhibition and toxicity of these three cytosine analogs by comparing the effects of 2′,3′-deoxycytidine-5′-triphosphate (ddCTP), β-d-(+)-2′3′-dideoxy-3′-thiacytidine-5′-triphosphate [(+)3TC-TP] and β-l-(−)-2′3′-dideoxy-3′-thiacytidine-5′-triphosphate [(−)3TC-TP] on the HIV-1 RT as well as a recombinant form of the human mitochondrial DNA polymerase gamma (Pol γ), the holoenzyme polymerase responsible for mitochondrial DNA replication. In this review, we discuss studies which may provide insight into the molecular mechanism for the stereochemical selectivity and differential toxicity.
Oncolytic Sindbis Virus Targets Tumors Defective in the Interferon Response and Induces Significant Bystander Antitumor Immunity In Vivo
Authors: Pong-Yu Huang, Jih-Huong Guo, Lih-Hwa Hwang
Journal: Molecular Therapy (2011)

Sindbis virus (SBV) has been shown to possess oncolytic potential in many human xenograft tumor models in immunocompromised mice. However, the mechanism underlying the tumor selectivity of SBV remains undetermined. In this study, we provide evidence that the tumor tropism of SBV infection is not determined by the levels of SBV receptor but by the status of the type I interferon (IFN) response in the tumors. Our results demonstrate that cells with defects in the IFN response (in either IFN-β production or IFN signaling) were highly susceptible to SBV infection in vitro. The results of oncolysis experiments conducted in immunocompetent animals further confirmed that the success of SBV-mediated oncolysis is greatly dependent on the presence of defects in IFN signaling in tumors. In all cases, viral titers rapidly declined in tumors due to host immune responses in immunocompetent animals. Interestingly, however, tumor-specific immune responses were concomitantly elicited, which might contribute to the sustained antitumor effect observed after the clearance of SBV. These findings indicate that SBV-mediated virotherapy is a promising therapeutic strategy for cancers defective in the IFN response and underscore the importance of bystander antitumor immunity in the efficacy of this virotherapy. Sindbis virus (SBV) has been shown to possess oncolytic potential in many human xenograft tumor models in immunocompromised mice. However, the mechanism underlying the tumor selectivity of SBV remains undetermined. In this study, we provide evidence that the tumor tropism of SBV infection is not determined by the levels of SBV receptor but by the status of the type I interferon (IFN) response in the tumors. Our results demonstrate that cells with defects in the IFN response (in either IFN-β production or IFN signaling) were highly susceptible to SBV infection in vitro. The results of oncolysis experiments conducted in immunocompetent animals further confirmed that the success of SBV-mediated oncolysis is greatly dependent on the presence of defects in IFN signaling in tumors. In all cases, viral titers rapidly declined in tumors due to host immune responses in immunocompetent animals. Interestingly, however, tumor-specific immune responses were concomitantly elicited, which might contribute to the sustained antitumor effect observed after the clearance of SBV. These findings indicate that SBV-mediated virotherapy is a promising therapeutic strategy for cancers defective in the IFN response and underscore the importance of bystander antitumor immunity in the efficacy of this virotherapy.
Gastrointestinal Hormones in the Production of Peptic Ulcer
Authors: David State
Journal: JAMA (1964)

THE ETIOLOGY OF PEPTIC ULCER remains a mystery. The search for the cause has been and continues to be an exciting hygeria. The study of patients with the common garden variety of peptic (ie duodenal) ulcer has taught us frustratingly little other than that in most of the victims there is hypersecretion of acid and pepsin. However, in the experimental laboratory it has been possible to produce ulcers in animals (dogs) which do not ordinarily develop them spontaneously, and nature in its own ingenuous fashion has produced ulcers in man in association with a variety of other conditions—all of which may, with continued study and keener insight, shed some light on the vexing problem of ulcerogenesis. This presentation will concern itself with the possible role of certain gastrointestinal hormones in the production of peptic ulcers and, I have, for the sake of broadening the scope of the subject, taken the liberty of including gastrointestinal humoral
Local and Systemic Protumorigenic Effects of Cancer-Associated Fibroblast-Derived GDF15
Authors: Francesca Bruzzese, Christina Hägglöf, Alessandra Leone, Elin Sjöberg, Maria Serena Roca, Sara Kiflemariam, Tobias Sjöblom, Peter Hammarsten, Lars Egevad, Anders Bergh, Arne Östman, Alfredo Budillon, Martin Augsten
Journal: Cancer Research (2014)

Abstract The tumor stroma is vital to tumor development, progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the abundant cell types in the tumor stroma, but the range of their contributions to cancer pathogenicity has yet to be fully understood. Here, we report a critical role for upregulation of the TGFβ/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found upregulated in situ and in primary cultures of CAF from prostate cancer. Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects on prostate cancer cell migration, invasion, and tumor growth. Notably, GDF15-expressing fibroblasts exerted systemic in vivo effects on the outgrowth of distant and otherwise indolent prostate cancer cells. Our findings identify tumor stromal cells as a novel source of GDF15 in human prostate cancer and illustrate a systemic mechanism of cancer progression driven by the tumor microenvironment. Further, they provide a functional basis to understand GDF15 as a biomarker of poor prognosis and a candidate therapeutic target in prostate cancer. Cancer Res; 74(13); 3408–17. ©2014 AACR.
Pegylated Interferon Alfa-2b Treatment for Patients With Solid Tumors: A Phase I/II Study
Authors: Ronald Bukowski, Marc S. Ernstoff, Martin E. Gore, John J. Nemunaitis, Robert Amato, Samir K. Gupta, Craig L. Tendler
Journal: Journal of Clinical Oncology (2002)

The efficacy of interferon alfa has been established in treating advanced melanoma and renal cell carcinoma (RCC) patients. We conducted a phase I/II study to determine the maximum-tolerated dose (MTD), the safety and tolerability, and the preliminary efficacy of once-weekly pegylated interferon alfa-2b (IFNalpha-2b) in patients with advanced solid tumors (primarily RCC).To determine the MTD, 35 patients with a variety of advanced solid tumors received 0.75 to 7.5 micro g/kg/wk of pegylated IFNalpha-2b by subcutaneous injection for 12 weeks. An additional 35 previously untreated RCC patients received 6.0 and 7.5 micro g/kg/wk for up to 12 weeks. Patients with a response or stable disease after 12 weeks were eligible for the extension protocol and were treated for up to 1 year or until disease progression.The MTD for pegylated IFNalpha-2b at 12 weeks was 6.0 micro g/kg/wk. One year of 6.0 micro g/kg/wk was well tolerated with appropriate dose modification; no grade 3 or 4 fatigue occurred, and safety was comparable with that with nonpegylated IFNalpha-2b. The most common nonhematologic adverse events included mild to moderate nausea, anorexia, and fatigue. Six patients had grade 3 or 4 hematologic toxicity. Twenty-nine patients continued on the extension protocol. Four patients had a complete response, and five patients had a partial response. Among 44 previously untreated RCC patients, the objective response rate was 14%. Median survival for all RCC patients was 13.2 months.Pegylated IFNalpha-2b was active and well tolerated in patients with metastatic solid tumors, including RCC, at doses up to 6.0 micro g/kg/wk.
Evidence for entry of plasma insulin into cerebrospinal fluid through an intermediate compartment in dogs. Quantitative aspects and implications for transport.
Authors: M W Schwartz, R N Bergman, S E Kahn, G J Taborsky, L D Fisher, A J Sipols, S C Woods, G M Steil, D Porte
Journal: Journal of Clinical Investigation (1991)

To study the route by which plasma insulin enters cerebrospinal fluid (CSF), the kinetics of uptake from plasma into cisternal CSF of both insulin and [14C]inulin were analyzed during intravenous infusion in anesthetized dogs. Four different mathematical models were used: three based on a two-compartment system (transport directly across the blood-CSF barrier by nonsaturable, saturable, or a combination of both mechanisms) and a fourth based on three compartments (uptake via an intermediate compartment). The kinetics of CSF uptake of [14C]inulin infused according to an "impulse" protocol were accurately accounted for only by the nonsaturable two-compartment model (determination coefficient [R2] = 0.879 +/- 0.044; mean +/- SEM; n = 5), consistent with uptake via diffusion across the blood-CSF barrier. When the same infusion protocol and model were used to analyze the kinetics of insulin uptake, the data fit (R2 = 0.671 +/- 0.037; n = 10) was significantly worse than that obtained with [14C]inulin (P = 0.02). Addition of a saturable component of uptake to the two-compartment model improved this fit, but was clearly inadequate for a subset of insulin infusion studies. In contrast, the three-compartment model accurately accounted for CSF insulin uptake in each study, regardless of infusion protocol (impulse infusion R2 = 0.947 +/- 0.026; n = 10; P less than 0.0001 vs. each two-compartment model; sustained infusion R2 = 0.981 +/- 0.003; n = 5). Thus, a model in which insulin passes through an intermediate compartment en route from plasma to CSF, as a part of a specialized transport system for the delivery of insulin to the brain, best accounts for the dynamics of this uptake process. This intermediate compartment could reside within the blood-CSF barrier or it may represent brain interstitial fluid, if CNS insulin uptake occurs preferentially across the blood-brain barrier.
Cold-Inducible RNA-Binding Protein Regulates Cardiac Repolarization by Targeting Transient Outward Potassium Channels
Authors: Jun Li, Duanyang Xie, Jian Huang, Fei Lv, Dan Shi, Yi Liu, Li Lin, Li Geng, Yufei Wu, Dandan Liang, Yi-Han Chen
Journal: Circulation Research (2015)

Cold-inducible RNA-binding protein (CIRP) is constitutively expressed at low levels across various tissues. It is rapidly upregulated by multiple stresses, underlying a general role for CIRP in organic adaptations to pathophysiological conditions. However, the role of CIRP in the heart remains unclear.To examine the biofunctions of CIRP in the mammalian heart.Rats with targeted disruption of Cirp were generated using the TALEN (transcription activator-like effector nucleases)-based genome editing technique. The Cirp-knockout rats had structurally and functionally normal hearts. Resting ECG recordings revealed a short rate-corrected QT (QTc) interval in Cirp-null rats without any abnormalities in PR interval, RR interval or QRS waves as compared to wild-type animals. The shortened QTc interval from Cirp ablation was tightly linked to an abbreviated action potential duration in cardiac myocytes, which was attributable to increased transient outward potassium current (Ito). Furthermore, our findings uncovered that CIRP protein selectively bonded to KCND2 and KCND3 mRNAs encoding the functional α-subunits of Ito channel proteins. CIRP deficiency did not change the transcriptional activity of KCND2 or KCND3, but it facilitated their translation. Cirp knockout had no effect on the functional expression of ion channels other than Ito channels.CIRP modulates cardiac repolarization by negatively adjusting the expression and function of Ito channels. Our study may open a window to decipher the potential function of RNA-binding proteins in bioelectric activity.
Aggressive T‐cell large granular lymphocyte leukemia: A case report and review of the literature
Authors: Todd J. Alekshun, Jianguo Tao, Lubomir Sokol
Journal: American Journal of Hematology (2007)

Abstract The majority of patients with T‐cell large granular lymphocyte (LGL) leukemia will have an indolent clinical course. Herein, we report a case of an aggressive T‐cell LGL leukemia in a previously healthy 42‐year‐old Caucasian male who presented with acute onset of B‐symptoms, hepatosplenomegaly, lymphocytosis, moderate anemia, and thrombocytopenia. Immunophenotypically, the malignant cells co‐expressed CD3 + CD8 + CD56 + markers and the T‐cell receptor beta (TCR β) gene demonstrated clonal rearrangement. The patient was treated with an intensive chemotherapeutic regimen (hyper‐CVAD) and he achieved a complete remission. A systematic review of all available English literature revealed 12 well‐described cases of aggressive T‐cell LGL leukemia suggesting that this variant is a new and distinct entity in the spectrum of LGL disorders. Am. J. Hematol., 2007. © 2007 Wiley‐Liss, Inc.
RECONSTRUCTION OF THE COMMON BILE DUCT
Authors: J. SHELTON HORSLEY
Journal: JAMA (1918)

Defects in the common bile duct may result from errors in operative technic, from strictures following ulceration or trauma, or from neoplasms. Since excision of the gallbladder has become a frequent practice, possibilities for injuring the common bile duct, particularly in inexperienced hands, have multiplied. In an effort to devise some method that would be satisfactory in reconstructing the common duct, various procedures have been devised. Sullivan<sup>1</sup>described an operation in which a rubber tube is sutured into the stump of the hepatic or the remaining upper end of the common duct, carried into the duodenum, and surrounded with neighboring tissue and omentum. Molineus, according to Walton, has suggested the use of the appendix for reconstruction of the common duct. However, it is often difficult to secure a satisfactory appendix, the nutrition of the transplanted appendix would be very problematic, and it would carry bacteria it normally contains, which
Degradation pathways of PCB upon gamma irradiation.
Authors: F Lépine, R Massé
Journal: Environmental Health Perspectives (1990)

In order to understand the modifications of the chromatographic profile of Aroclor 1260 upon gamma irradiation, a total of 14 pure polychlorinated biphenyl (PCB) congeners were separately irradiated in solution. Dechlorination was observed, and the generated products were investigated by gas chromatography and mass spectrometry. Degradation proceeds more rapidly in methanol/water mixture than in petroleum ether, but the relative amount of ortho-dechlorinated congeners formed upon irradiation was smaller in the former solvent. Ortho chlorines are preferentially lost in petroleum ether except when they are involved in a 2.5 (or 3.6) substitution pattern, in which case para dechlorination becomes predominant. The precursors of some toxicologically important congeners such as congeners 77, 118, 167, and 189 have been identified. These data are useful to rationalize the modifications of the chromatographic profile of PCB complex mixture upon gamma irradiation.
Case 25-1963
Authors: Conger Williams, Austin L. Vickery
Journal: New England Journal of Medicine (1963)

Presentation of Case First admission. A sixty-four-year-old woman was referred to the hospital because of diarrhea and abdominal cramps of five months' duration. On physical examination the abdomen was minimally tender, and peristaltic activity was normal. The temperature was 99°F.; the blood pressure was 160 systolic, 95 diastolic. The blood, urine and several stool specimens were normal. An x-ray film of the chest showed prominence of the left ventricle; an upper gastrointestinal series, films from a barium-enema examination and intravenous pyelograms were normal. An electrocardiogram showed occasional atrial premature beats, with low T waves in Lead 1 and slightly . . .
Endoscopy and Early Neoplasia: Better but not the Best
Authors: R. Lambert, J. Rey
Journal: Endoscopy (2001)

The secondary prevention of cancer of the digestive system relies on the logical assumption that early detection benefits the patient. Endoscopy is the gold standard procedure in early detection of neoplasia (either confirmed cancer or high-grade and low-grade dysplasia), particularly when the morphology is not polypoid. Furthermore, diagnosis is often accompanied by treatment in the same endoscopy session.
A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo
Authors: Helen S. Bell, Christine Dufes, Jim O’Prey, Diane Crighton, Daniele Bergamaschi, Xin Lu, Andreas G. Schätzlein, Karen H. Vousden, Kevin M. Ryan
Journal: Journal of Clinical Investigation (2007)

The tumor suppressor p53 is a potent inducer of tumor cell death, and strategies exist to exploit p53 for therapeutic gain. However, because about half of human cancers contain mutant p53, application of these strategies is restricted. p53 family members, in particular p73, are in many ways functional paralogs of p53, but are rarely mutated in cancer. Methods for specific activation of p73, however, remain to be elucidated. We describe here a minimal p53-derived apoptotic peptide that induced death in multiple cell types regardless of p53 status. While unable to activate gene expression directly, this peptide retained the capacity to bind iASPP — a common negative regulator of p53 family members. Concordantly, in p53-null cells, this peptide derepressed p73, causing p73-mediated gene activation and death. Moreover, systemic nanoparticle delivery of a transgene expressing this peptide caused tumor regression in vivo via p73. This study therefore heralds what we believe to be the first strategy to directly and selectively activate p73 therapeutically and may lead to the development of broadly applicable agents for the treatment of malignant disease.
Estrogen Metabolism and Excretion in Oriental and Caucasian Women
Authors: H. Adlercreutz, S. L. Gorbach, B. R. Goldin, M. N. Woods, J. T. Dwyer, E. Hamalainen
Journal: JNCI Journal of the National Cancer Institute (1994)

Journal Article Estrogen Metabolism and Excretion in Oriental and Caucasian Women Get access H. Adlercreutz, H. Adlercreutz Department of Clinical Chemistry, University of Helsinki, Meilahti HospitalFinland Search for other works by this author on: Oxford Academic PubMed Google Scholar S. L. Gorbach, S. L. Gorbach Department of Community Health, Nutrition/Infection Unit, Tufts University School of Medicine, New England Medical CenterBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar B. R. Goldin, B. R. Goldin Department of Community Health, Nutrition/Infection Unit, Tufts University School of Medicine, New England Medical CenterBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar M. N. Woods, M. N. Woods Department of Community Health, Nutrition/Infection Unit, Tufts University School of Medicine, New England Medical CenterBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar J. T. Dwyer, J. T. Dwyer Frances Stern Nutrition Center, New England Medical Center Search for other works by this author on: Oxford Academic PubMed Google Scholar E. Håmålåinen E. Håmålåinen * Department of Clinical Chemistry, University of Helsinki, Meilahti HospitalFinland *Correspondence to : H. Adlercreutz, M.D., Ph.D., Department of Clinical Chemistry, University of Helsinki, Meilahti Hospital, FIN-00290 Helsinki, Finland. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 86, Issue 14, 20 July 1994, Pages 1076–1082, https://doi.org/10.1093/jnci/86.14.1076 Published: 20 July 1994 Article history Received: 02 November 1993 Revision received: 28 April 1994 Accepted: 06 May 1994 Published: 20 July 1994
THE ROUTINE TREATMENT OF MALARIA IN UGANDA
Authors: J. A. Taylor
Journal: BMJ (1920)

AmRr more than ten years' experience of the treatment of many thousands of cases of malaria in Uganda, the results I have obtned with smaal doses of quinine have led me to conelusis so different from toe expressed recently in your columns that I hope they may be wortl recording.Mlost of the cases of malaria met with in Uganda are simple subtertian without complications, and the routine treatment I adopted for these was as follows:1. Calomel, in an average dose for an adult of not less than 5,grains, followed in sone hours by a saline.This usually meant that the calowel was given last thing at night, and the salts at 6 a.nm., or when the patient awoke