tbuckley/cabot-search huggingface dataset:
Hepatotoxicity mediated by pyrazole (cytochrome P450 2E1) plus tumor necrosis factor alpha treatment occurs in c-Jun N-terminal kinase 2−/− but not in c-Jun N-terminal kinase 1−/− mice
Authors: Xiaodong Wang, Defeng Wu, Lili Yang, Arthur I. Cederbaum
Journal: Hepatology (2011)

Cytochrome P450 2E1 (CYP2E1) induction and tumor necrosis factor alpha (TNF-α) production are key risk factors in alcoholic liver injury. Increased oxidative stress from CYP2E1 induction by pyrazole in vivo sensitizes the liver to TNF-α-induced hepatotoxicity by a mechanism involving the activation of c-jun N-terminal kinase (JNK) and mitochondrial damage. The aim of this study was to evaluate whether JNK1 or JNK2 plays a role in this potentiated hepatotoxicity. Wild-type (WT), jnk1(-/-) , and jnk2(-/-) mice were used to identify changes of hepatotoxicity, damage to mitochondria, and production of oxidative stress after pyrazole plus TNF-α treatment. Increased serum alanine aminotransferase, inflammatory infiltration, and central necrosis were observed in the jnk2(-/-) and WT mice treated with pyrazole plus TNF-α, but not in the jnk1(-/-) mice. Pyrazole elevated the activity and protein level of CYP2E1 in all mice. There was a significant increase of malondialdehyde, 4-hydroxynonenal adducts, 3-nitrotyrosine, and inducible nitric oxide synthase in the jnk2(-/-) and WT mice, compared to the jnk1(-/-) mice, upon pyrazole plus TNF-α treatment, or compared to mice treated with either pyrazole alone or TNF-α alone. The antioxidants, catalase, phospholipid hydroperoxide glutathione peroxidase, thioredoxin, and glutathione were lowered, and cytochrome c was released from the mitochondria in the jnk2(-/-) and WT mice. Mitochondrial production of superoxide was increased in the jnk2(-/-) and WT mice, compared to the jnk1(-/-) mice, upon pyrazole plus TNF-α treatment. Electron microscopy showed altered mitochondrial structure in the jnk2(-/-) and WT mice, but not the jnk1(-/-) mice.JNK1 plays a role in the hepatotoxicity, mitochondrial dysfunction, and oxidative stress mediated by pyrazole plus TNF-α treatment. These findings raise the question as to the potential mechanisms of JNK1 activation related to alcoholic liver injury.
Long-Term Cause-Specific Mortality of Patients Treated for Hodgkin’s Disease
Authors: Berthe M.P. Aleman, Alexandra W. van den Belt-Dusebout, Willem J. Klokman, Mars B. van’t Veer, Harry Bartelink, Flora E. van Leeuwen
Journal: Journal of Clinical Oncology (2003)

To assess long-term cause-specific mortality of young Hodgkin's disease (HD) patients.The study population consisted of 1,261 patients treated for HD before age 41 between 1965 and 1987. Follow-up was complete until October 2000. For 95% of deaths, the cause was known. Long-term cause-specific mortality was compared with general population rates to assess relative risk (RR) and absolute excess risk (AER) of death.After a median follow-up of 17.8 years, 534 patients had died (55% of HD). The RR of death from all causes other than HD was 6.8 times that of the general population, and still amounted to 5.1 after more than 30 years. RRs of death resulting from solid tumors (STs) and cardiovascular disease (CVD) were increased overall (RR = 6.6 and 6.3, respectively), but especially in patients treated before age 21 (RR = 14.8 and 13.6, respectively). When these patients grew older, this elevated mortality decreased. The overall AER of death from causes other than HD increased throughout follow-up. Patients receiving salvage chemotherapy had a significantly increased RR of death from STs, compared to patients receiving initial therapy only.The main cause of death among HD patients was lymphoma, but after 20 years, HD mortality was negligible. The RRs and AERs of death from second primary cancers (SCs) and CVDs continued to increase after 10 years. Even more than 30 years after diagnosis, HD patients experienced elevated risk of death from all causes other than HD. Increased risk of death from SCs and CVDs was found especially in patients treated before age 21, but these risks seemed to abate with age.
Chronic Active Adolescence
Authors: Christopher M. Callahan
Journal: Annals of Internal Medicine (1997)

On Being a Doctor15 December 1997Chronic Active AdolescenceChristopher M. Callahan, MDChristopher M. Callahan, MDRegenstrief Institute for Health Care; Indianapolis, IN 46202Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-127-12-199712150-00012 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail It was 1980. Michael was sitting in his dormitory room making the final summary sheet for 7 weeks of classroom notes. The notes he had scribbled in haste had been rewritten in a beautiful cursive and then exposed to the scrutiny of yellow and pink fluorescent highlighters. The summary sheet itself was coded in the ink of four different pens. The distilled facts that made it onto his final summary sheet held the key to a final grade of “A.” Michael knew that if he transposed this information onto his brain he would indeed perform heroically on the examination. He ... Author, Article, and Disclosure InformationAuthors: Christopher M. Callahan, MDAffiliations: Regenstrief Institute for Health Care; Indianapolis, IN 46202Corresponding Author: Christopher M. Callahan, MD, Regenstrief Institute for Health Care, Indiana University School of Medicine, 1001 West 10th Street, RG6, Indianapolis, IN 46202. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byProfessionalism and the work-life balance 15 December 1997Volume 127, Issue 12Page: 1124-1125KeywordsAdolescentsCoffeeExerciseFellowshipsForecastingHospitalsIntensive care unitsResidencyRunningSports ePublished: 15 August 2000 Issue Published: 15 December 1997 Copyright & PermissionsCopyright © 1997 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
THE DISTRIBUTION OF 51CR-LABELED LYMPHOCYTES INTO ANTIGEN-STIMULATED MICE
Authors: Marion M. Zatz, Eugene M. Lance
Journal: The Journal of Experimental Medicine (1971)

The localization of syngeneic 51Cr-labeled lymph node cells was investigated in CBA/J mice previously challenged with sheep erythrocytes, Salmonella H antigen, keyhole limpet hemocyanin, C57BL/6J skin, or rat skin. The effect of time, dose, and route of antigen administration on lymphocyte migration was studied in both primary and secondary responses. When the distribution pattern of lymphocytes was examined after 20–24 hr, it was found that increased localization of labeled cells occurred in spleen after intravenous or intraperitoneal antigen injection, and in draining lymph nodes after subcutaneous antigen injection or skin grafting. Increased localization (trapping) of lymphocytes was antigen dose dependent and could be demonstrated when 1–6 hr had elapsed between intravenous antigen administration, or when 24 hr had elapsed between subcutaneous antigen administration and intravenous cell infusion. Trapping was transient, lasting approximately 24 hr. Maximal trapping of lymphocytes in the draining nodes occurred 9 days after skin grafting in the first-set allograft response, and 3 days after grafting in the second-set allograft and first-set xenograft responses. The cell type trapped, the specificity and mechanism of action of the trap, and the role of lymphocyte trapping in the initiation of immune responses are discussed.
Prevalence of Human Immunodeficiency Virus Type 1 p24 Antigen in U.S. Blood Donors — An Assessment of the Efficacy of Testing in Donor Screening
Authors: Harvey J. Alter, Jay S. Epstein, Sally G. Swenson, Mark J. VanRaden, John W. Ward, Richard A. Kaslow, Jay E. Menitove, Harvey G. Klein, S. Gerald Sandler, Merlin H. Sayers, Indira K. Hewlett, Amoz I. Chernoff
Journal: New England Journal of Medicine (1990)

We performed a multicenter study in 1989 to determine whether screening whole-blood donors for human immunodeficiency virus type 1 (HIV-1) p24 antigen would improve transfusion safety by identifying carriers of the virus who are seronegative for HIV-1 antibody.
Comparison of bowel function after ileorectal anastomosis for ulcerative colitis and colonic polyposis.
Authors: C R Newton, W N Baker
Journal: Gut (1975)

Bowel habit has been studied in a group of 92 outpatients with ileorectal anastomosis for ulcerative colitis and compared with that in a group of 45 outpatients with ileorectal anastomosis for colonic polyposis.Bowel frequency ranged from 1.7 to 8.7 stools per 24 hours with a mean of 4.5 in the colitic group compared with a range of 1.3 to 8.1 stools per 24 hours and a mean of 3 5 in the polyposis group.Eighty-two per cent of the colitic group and 95 % of the polyposis group had six or fewer bowel actions per 24 hours.Colitic patients in poor general condition at the time of colectomy seemed more likely to have over six bowel actions per 24 hours than those less severely ill.Urgency of defaecation was rare.Bowel actions every night and occasional faecal incontinence occurred in small but similar percentages of patients in both groups.Fifty-one per cent of patients in the colitic group, as compared with 9 %. in the polyposis group, were taking regular treatment to improve bowel function.Dietary difficulty was rare after ileorectal anastomosis in both colitic and polyposis groups.Although there are several reports of the number of bowel actions per day experienced by patients after ileorectal anastomosis for ulcerative colitis (Aylett,
A Translational, Pharmacodynamic, and Pharmacokinetic Phase IB Clinical Study of Everolimus in Resectable Non–Small Cell Lung Cancer
Authors: Taofeek K. Owonikoko, Suresh S. Ramalingam, Daniel L. Miller, Seth D. Force, Gabriel L. Sica, Jennifer Mendel, Zhengjia Chen, Andre Rogatko, Mourad Tighiouart, R. Donald Harvey, Sungjin Kim, Nabil F. Saba, Allan Pickens, Madhusmita Behera, Robert W. Fu, Michael R. Rossi, William F. Auffermann, William E. Torres, Rabih Bechara, Xingming Deng, Shi-Yong Sun, Haian Fu, Anthony A. Gal, Fadlo R. Khuri
Journal: Clinical Cancer Research (2015)

The altered PI3K/mTOR pathway is implicated in lung cancer, but mTOR inhibitors have failed to demonstrate efficacy in advanced lung cancer. We studied the pharmacodynamic effects of everolimus in resectable non-small cell lung cancer (NSCLC) to inform further development of these agents in lung cancer.We enrolled 33 patients and obtained baseline tumor biopsy and 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging followed by everolimus treatment (5 or 10 mg daily, up to 28 days), or without intervening treatment for controls. Target modulation by everolimus was quantified in vivo and ex vivo by comparing metabolic activity on paired PET scans and expression of active phosphorylated forms of mTOR, Akt, S6, eIF4e, p70S6K, 4EBP1, and total Bim protein between pretreatment and posttreatment tissue samples.There were 23 patients on the treatment arm and 10 controls; median age 64 years; 22 tumors (67%) were adenocarcinomas. There was a dose-dependent reduction in metabolic activity (SUVmax: 29.0%, -21%, -24%; P = 0.014), tumor size (10.1%, 5.8%, -11.6%; P = 0.047), and modulation of S6 (-36.1, -13.7, -77.0; P = 0.071) and pS6 (-41.25, -61.57, -47.21; P = 0.063) in patients treated in the control, 5-mg, and 10-mg cohorts, respectively. Targeted DNA sequencing in all patients along with exome and whole transcriptome RNA-seq in an index patient with hypersensitive tumor was employed to further elucidate the mechanism of everolimus activity.This "window-of-opportunity" study demonstrated measurable, dose-dependent, biologic, metabolic, and antitumor activity of everolimus in early-stage NSCLC.
Overexpressed NF-κB–inducing kinase contributes to the tumorigenesis of adult T-cell leukemia and Hodgkin Reed-Sternberg cells
Authors: Yasunori Saitoh, Norio Yamamoto, M. Zahidunnabi Dewan, Haruyo Sugimoto, Vicente J. Martinez Bruyn, Yuki Iwasaki, Katsuyoshi Matsubara, Xiaohua Qi, Tatsuya Saitoh, Issei Imoto, Johji Inazawa, Atae Utsunomiya, Toshiki Watanabe, Takao Masuda, Naoki Yamamoto, Shoji Yamaoka
Journal: Blood (2008)
Induction of protective immunity after escherichia coli bladder infection in primates. Dependence of the globoside-specific P-fimbrial tip adhesin and its cognate receptor.
Authors: M Söderhäll, S Normark, K Ishikawa, K Karlsson, S Teneberg, J Winberg, R Möllby
Journal: Journal of Clinical Investigation (1997)

Clinical observations suggest that immune mechanisms affect etiology and course of recurrent cystitis. A primate infection model was used to show that primary bladder infection with a uropathogenic P-fimbriated strain (binding to globoside present in the bladder wall) protects against rechallenge with homologous as well as heterologous Escherichia coli strains for up to 5-6 mo. In contrast, mutant derivatives producing P-fimbriae either lacking the tip adhesin protein or carrying an adhesin for which no bladder receptor was present, were unable to induce protection, even though they generated bladder infections of similar duration as the wild type. Therefore, the protective effect mediated by the adhesin seemed to depend upon the presence of its cognate receptor. Since the wild strain also mediated protection against mutants that lacked the adhesin, our data suggest that the globoside-binding PapG adhesin acts as an adjuvant during infection to enhance a specific response against other bacterial antigens. In fact, the globoside-binding strain DS17, but not the mutant DS17-1, unable to bind to membrane-bound globoside, elicited a secretory IgA response to LPS in urine. These in vivo findings suggest that bacterial adhesin-ligand interactions may have signaling functions of importance for the immune response.
Abstract 562: Multi-Kinase Inhibitor: AFPep inhibits the growth and invasion of U87 glioblastoma cells through inhibition of FAK, MAPK, and PKC
Authors: Fassil B. Mesfin, Alexander Riccio, Thomas T. Andersen, James Bennett
Journal: Cancer Research (2011)

Abstract INTRODUCTION: Glioblastomas are the most frequent tumors of the central nervous system. Patients with a diagnosis of glioblastomas have poor prognosis, and new therapeutic agents are in demand for management of this disease. Here, we report on a novel multi-protein kinase inhibitor, AFPep, with regard to its effects on the growth, invasion, and localization in U87 cells. METHODS: Proliferation/Invasion Assay: Cells were seeded into wells of plastic tissue culture plates and treated with various concentrations of AFPep. Crystal violet method was used to determine cell numbers. The Matrigel chemoinvasion assay was used to determine the effect of AFPep on U87 cell invasion. During Xenograft growth assay, U87 cells were solidified in fibrin clot and implanted under the kidney capsule of severe combined immunodeficient (SCID) mice. Various doses of AFPep were administrated i.p and tumor growth was monitored during survival laparotomy. Localization assay was performed by utilizing fluorescent-labeled AFPep. Multi-immunoblotting Assay was performed using Kinexus, the KinetworksTM methodology to screen for protein kinase expression profile in GBM before and after AFPep treatment. RESULTS: AFPep inhibited the growth of U87 cells in culture with it is maximal effect at 10−7 M. Higher concentrations of AFPep (10−6M to 10−4M) inhibited the invasion of U87 cells in a dose dependent manner. Treatment of SCID mice bearing U87 xenografts with 4 mg/Kg/day AFPep resulted in a 50% inhibition of tumor growth. Further, AFPep-Bodipy appeared to be localized in mitochondria and interferes with phosphorylation of FAK, MAPK, and c-kit. CONCLUSION: AFPep has an inhibitory effect on U87 cells. All studies to date have shown no toxicity. As such AFPep is expected to be tolerated and may be a new agent for the treatment of malignant glioblastomas Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 562. doi:10.1158/1538-7445.AM2011-562
Formation of surface reaction products on bioactive glass and their effects on the expression of the osteoblastic phenotype and the deposition of mineralized extracellular matrix
Authors: A. El-Ghannam, P. Ducheyne, I.M. Shapiro
Journal: Biomaterials (1997)

The objective of the study was to examine the effect of alkali ion release, pH control and buffer capacity on the expression of the osteoblastic phenotype. In addition, we determined the importance of modifications of the surface of porous bioactive glass (BG) on the activity of rat calvaria osteoblasts in vitro. We found that at a low tissue culture medium (TCM) volume to BG surface area (Vol/SA) ratio, the products of glass corrosion elevated the pH of the TCM to a value that adversely affected cellular activity; thus, the matrix synthesized by the cells was non-mineralized. On the other hand, when the Vol/SA was high and the buffer capacity of the medium was not exceeded, the cells generated a mineralized extracellular matrix. Addressing the second issue, we observed that modification of the composition of the BG surface markedly influenced osteoblast activity. BG that was coated with either a calcium phosphate-rich layer only or a serum protein layer changed the phenotypic characteristics of the osteoblasts. The presence of either of these surfaces lowered the alkaline phosphatase activity of the attached cells; this finding indicated that the osteoblast phenotype was not conserved. However, when the BG was coated with a bilayer of calcium phosphate and serum proteins, the alkaline phosphatase (AP) activity was elevated and the extracellular matrix contained characteristic bone markers. Our findings indicate that the calcium phosphate-rich layer promotes adsorption and concentration of proteins from the TCM, and it is utilized by the osteoblasts to form the mineralized extracellular matrix.
Benefit of an Early Invasive Management Strategy in Women With Acute Coronary Syndromes
Authors: Ruchira Glaser, Howard C. Herrmann, Sabina A. Murphy, Laura A. Demopoulos, Peter M. DiBattiste, Christopher P. Cannon, Eugene Braunwald
Journal: JAMA (2002)

Women who present with acute coronary syndromes (ACSs) have different characteristics than men. Reports have conflicted about whether different outcomes exist for women with use of a routine invasive management strategy. However, these studies were performed prior to the widespread use of platelet glycoprotein IIb/IIIa inhibitors and intracoronary stents.To determine sex differences in baseline characteristics and outcomes in ACS and whether women benefit from a contemporary early invasive management strategy.Prospective analysis of women and men enrolled in the TACTICS-TIMI 18 randomized trial, conducted December 1997 to December 1999 in 169 centers in 9 countries in North America and Europe, with follow-up at 1 and 6 months.A total of 2220 patients (757 women and 1463 men) with ACS.All patients received aspirin, 325 mg/d; intravenous unfractionated heparin; and tirofiban for 48 hours or until revascularization, with tirofiban administered for at least 12 hours after percutaneous coronary revascularization. Patients assigned to the early invasive strategy (n = 1114) underwent coronary angiography 4 to 48 hours after randomization and revascularization when appropriate. Patients assigned to the early conservative strategy (n = 1106) were treated medically and underwent coronary angiography and appropriate revascularization only if they met specified criteria.Baseline characteristics and the primary composite end point of death, myocardial infarction, or rehospitalization for ACS at 6 months in women and men assigned to early invasive vs conservative management.Women were older and more frequently had hypertension (P<.001 for both). Women less frequently had previous myocardial infarction, coronary artery bypass grafting, and elevations in cardiac markers (P<.001 for all), but there was no difference in distribution of TIMI risk scores (P =.76). Angiography and intervention rates were similar, but women had less severe coronary artery disease, including no critical lesions in 17% of women vs 9% of men (P<.001). Women had a 28% odds reduction in the primary end point with an early invasive strategy (adjusted odds ratio [OR], 0.72; 95% confidence interval [CI], 0.47-1.11), similar to the benefit in men (adjusted OR, 0.64; 95% CI, 0.47-0.88; P =.60 for sex interaction). When adjusted for baseline characteristics, the benefit of invasive therapy in women with elevated troponin T levels was further enhanced (adjusted OR, 0.47; 95% CI, 0.26-0.83).Despite differences between women and men in baseline characteristics, the benefit of an early invasive strategy incorporating tirofiban and intracoronary stents was similar in women and men and was enhanced in women presenting with markers of increased risk.
Better support for investigators is essential
Authors: Sarah Meredith
Journal: BMJ (2004)

Wald's description of his encounter with the new research ethics committee forms provides a graphic illustration of the frustration and bemusement of most researchers when faced with the hurdles that must now be surmounted to conduct a clinical trial. 1 As well as the expansion in the volume of paperwork, the need to understand and comply with the regulatory requirements for good clinical practice, reporting of adverse events, and the supply and labelling of trial drugs make it almost impossible for a clinician to undertake a clinical trial without support.This is not necessarily a bad thing if it leads to better quality studies that are safer for patients, but training and support must be funded and provided if clinical trials in the public interest are to continue.Wald was unfortunate to be initiating a clinical trial in the transitional period before all the systems to implement the new clinical trials regulations were in place. 2 He therefore had to deal with old and new elements and did not benefit from the harmonised competent authority and ethics committee application.Some of the questions he found particularly irritating, because of their apparent irrelevance to ethics, are part of that common data set.Neither the Central Office for Research Ethics Committees nor the Medicines and Healthcare Products Regulatory Agency should be blamed for the content of the forms, most of which is specified in European Commission guidance 3 or the regulations themselves.The exception was Part D of the COREC application (for NHS trust approval), which has since been dropped.However, trust approval is still required and currently each trust has its own application process.For researchers who undertake multisite studies, a single form that does not duplicate information supplied elsewhere would be a boon.
585 ALLOPURINOL PROTECTS AGAINST ACUTE LIVER DAMAGE AND PREVENTS AND REVERSES CIRRHOSIS INDUCED BY CARBON TETRACHLORIDE: ROLE OF CYTOKINES MODULATION AND OXIDATIVE STRESS
Authors: L.R. Aldaba-Muruato, M. Galicia-Moreno, M. Shibayama, M.G. Moreno, P. Muriel
Journal: Journal of Hepatology (2011)
Letter by Vorlat et al Regarding Article, “Statins and the Risk of Cancer After Heart Transplantation”
Authors: Anne Vorlat, Tom Vermeulen, Viviane Conraads
Journal: Circulation (2013)

The findings of the present study reinforce the use of statins in cardiac transplant recipients.Besides providing protection against early severe rejection and coronary vasculopathy, statins may also improve long-term outcome and improve cancer-free survival.