tbuckley/cabot-search huggingface dataset:
Restoration of APC gene function in colorectal cancer cells by aminoglycoside- and macrolide-induced read-through of premature termination codons
Authors: A. Zilberberg, L. Lahav, R. Rosin-Arbesfeld
Journal: Gut (2009)

Adenomatous polyposis coli (APC) is a multifunctional tumour suppressor protein that negatively regulates the Wnt signalling pathway. The APC gene is ubiquitously expressed in tissues and organs, including the large intestine and central nervous system. The majority of patients with sporadic and hereditary colorectal cancer have mutations in the gene encoding APC. Approximately 30% of these mutations are single nucleotide changes that result in premature stop codons (nonsense mutations). A potential therapeutic approach for treatment of this subset of patients is the use of aminoglycosides and macrolides that induce nonsense mutation read-through and restore levels of full-length protein. We have used reporter plasmids and colorectal cancer cell lines to demonstrate that several aminoglycosides and tylosin, a member of the macrolide family, induced read-through of nonsense mutations in the APC gene. In xenograft experiments and in the Apc(Min/+) mouse model, these compounds ameliorated the tumorigenic clinical symptoms caused by nonsense mutations in the APC gene.
A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival
Authors: S. Ugurel, C. Loquai, K. Kähler, J. Hassel, C. Berking, L. Zimmer, I. Haubitz, I. Satzger, T. Müller-Brenne, N.C. Mikhaimer, J.C. Becker, K.J. Kilian, D. Schadendorf, L. Heinzerling, M. Kaatz, J. Utikal, D. Göppner, C. Pföhler, A. Pflugfelder, R. Mössner, R. Gutzmer
Journal: Annals of Oncology (2014)
Long-Term Smoking Cessation Outcomes Among Childhood Cancer Survivors in the Partnership for Health Study
Authors: Karen M. Emmons, Elaine Puleo, Ann Mertens, Ellen R. Gritz, Lisa Diller, Frederick P. Li
Journal: Journal of Clinical Oncology (2008)

Partnership for Health (PFH) was found to increase smoking cessation among smokers in the Childhood Cancer Survivors Study (CCSS) at the 8- and 12-month postbaseline follow-up. This report provides outcomes at 2 to 6 years postbaseline; the primary outcome is a four-category smoking status variable (quit at all follow-ups, quit at final follow-up only, smoker at all follow-ups, and smoker at final follow-up only); quit attempts among those who reported smoking at the final follow-up is a secondary outcome.PFH was a randomized control trial with two conditions, peer phone counseling (PC) and self-help (SH), that involved smokers (n = 796) enrolled in the CCSS cohort.Long-term quit rates were higher in PC versus SH participants. Long-term smoking cessation outcomes were lower among those who were nicotine dependent, of lower educational levels, and among men, and were higher among those who used nicotine replacement therapy and who had higher levels of situational self-efficacy. There were no significant differences in relapse rates between conditions or in quit attempts among continued smokers.Cessation rates continue to be significantly higher among participants in the PC condition versus SH, although the differences were not large. This article highlights differences in long-term engagement with smoking cessation among those who received the intervention.
A de novo lineage switch from B‐cell acute lymphoblastic leukemia to acute myelocytic leukemia: A case report
Authors: Ashok C. Shende, Ann L. Zaslav, Arlene Redner, Vincent R. Bonagura, Lynda Hatam, Carole Paley, Philip Lanzkowsky
Journal: American Journal of Hematology (1995)
Impact of the HIV Epidemic on the Incidence Rates of Anal Cancer in the United States
Authors: Meredith S. Shiels, Ruth M. Pfeiffer, Anil K. Chaturvedi, Aimee R. Kreimer, Eric A. Engels
Journal: JNCI Journal of the National Cancer Institute (2012)

BackgroundThe risk of anal cancer is substantially increased in HIV-infected individuals. Thus, the HIV epidemic may have influenced the increasing anal cancer trends in the United States. We estimated the impact of the HIV epidemic on trends in anal cancer incidence in the United States during 1980–2005.
Immunological studies of aging. II. Loss of IgG and high avidity plaque-forming cells and increased suppressor cell activity in aging mice.
Authors: E A Goidl, J B Innes, M E Weksler
Journal: The Journal of Experimental Medicine (1976)

The magnitude and heterogeneity of the immune response to dinitrophenylated bovine gamma globulin was measured in aged and young mice at a cellular level using an inhibition of plaque-forming cell assay. The primary and secondary responses of 24-mo-old mice were markedly depressed in magnitude and restricted in avidity for the DNP determinant when compared to 2-mo-old animals. Bacterial lipopolysaccharide given at the time of immunization increased the restriction in heterogeneity seen in 12- and 24-mo-old mice. Indirect PFCs were more severely depressed than direct PFCs in 24-mo-old mice. Syngeneic, lethally irradiated, 2-mo-old mice reconstituted with aged spleen cells exhibit the depressed and restricted response to DNP-BGG seen in old mice. When 10(8) young thymus cells were given together with old spleen cells the heterogeneity of the response was increased. When 2-mo- and 24-mo-old spleen cells were transferred together into young recipients the magnitude of the response to the young spleen cells markedly reduced. Thus, there appears to be a loss of thymic-helper cells and an increase in suppressor activity in aged animals.
In vivo suppression of delayed hypersensitivity: prolongation of desensitization in guinea pigs.
Authors: J M Dwyer, F S Kantor
Journal: The Journal of Experimental Medicine (1975)

Administering moderate (milligram) amounts of antigen to a guinea pig immunized with thatntigen leads to a transient loss of all delayed hypersensitivity (DH) responses in that animal. In this study, we demonstrate that this "desentization" can be prolonged for 10 days by repeated injection of antigen. At this time, tolerance to the desensitizing antigen develops in both the humoral and cellular systems of the immune response and DH responsiveness to other antigens returns. Repeated cycles of sensitization and desensitization produce repeated episodes of generalized anergy. Neither cells nor serum from desensitized animals could be shown to exert a suppressor effect when transferred to immunized animals and the cells responded normally to antigen and mitogen in tissue culture. The best generalized depression of DH was seen in those animals producing the best DH before desensitization. The inability of antigen to react with tolerant cells to produce desensitization suggests that this phenomenon is an active rather than a passive one and may represent an exaggeration of a normal regulatory mechanism for DH triggered by a regimen of antigen administration that activates suppressor cells to produce a systemic effect.
The Airway Mucins Muc5b and Muc4 Are Endogenous Ligands For Siglec-F and Induce Mouse Eosinophil Death
Authors: Takumi Kiwamoto, Toshihiko Katoh, Christopher Evans, Mary E. Brummet, Sherry Hudson, Zhou Zhu, Michael Tiemeyer, Bruce S. Bochner
Journal: Journal of Allergy and Clinical Immunology (2014)
A Prospective Study of Meat and Meat Mutagens and Prostate Cancer Risk
Authors: Amanda J. Cross, Ulrike Peters, Victoria A. Kirsh, Gerald L. Andriole, Douglas Reding, Richard B. Hayes, Rashmi Sinha
Journal: Cancer Research (2005)

Abstract High-temperature cooked meat contains heterocyclic amines, including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and polycyclic aromatic hydrocarbons, such as benzo(a)pyrene (BaP). In rodents, a high intake of PhIP induces prostate tumors. We prospectively investigated the association between meat and meat mutagens, specifically PhIP, and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Diet was assessed using a 137-item food frequency questionnaire and a detailed meat-cooking questionnaire linked to a database for BaP and the heterocyclic amines 2-amino-3,8-dimethylimidazo[4,5-b]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), and PhIP. During follow-up, we ascertained a total of 1,338 prostate cancer cases among 29,361 men; of these, 868 were incident cases (diagnosed after the first year of follow-up) and 520 were advanced cases (stage III or IV or a Gleason score of ≥7). Total, red, or white meat intake was not associated with prostate cancer risk. More than 10 g/d of very well done meat, compared with no consumption, was associated with a 1.4-fold increased risk of prostate cancer [95% confidence interval (95% CI), 1.05-1.92] and a 1.7-fold increased risk (95% CI, 1.19-2.40) of incident disease. Although there was no association with MeIQx and DiMeIQx, the highest quintile of PhIP was associated with a 1.2-fold increased risk of prostate cancer (95% CI, 1.01-1.48) and a 1.3-fold increased risk of incident disease (95% CI, 1.01-1.61). In conclusion, very well done meat was positively associated with prostate cancer risk. In addition, this study lends epidemiologic support to the animal studies, which have implicated PhIP as a prostate carcinogen. (Cancer Res 2005; 65(24): 11779-84)
Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children
Authors: Susan V. Lynch, Robert A. Wood, Homer Boushey, Leonard B. Bacharier, Gordon R. Bloomberg, Meyer Kattan, George T. O’Connor, Megan T. Sandel, Agustin Calatroni, Elizabeth Matsui, Christine C. Johnson, Henry Lynn, Cynthia M. Visness, Katy F. Jaffee, Peter J. Gergen, Diane R. Gold, Rosalind J. Wright, Kei Fujimura, Marcus Rauch, William W. Busse, James E. Gern
Journal: Journal of Allergy and Clinical Immunology (2014)
Colitis and colonic mucosal barrier dysfunction.
Authors: K R Gardiner, N H Anderson, B J Rowlands, A Barbul
Journal: Gut (1995)

Trauma, infection, neoplasia, and inflammation can all disrupt the intact intestinal mucosal barrier to intraluminal bacteria and bacterial antigens. This study investigated the relation between colonic inflammation and colonic mucosal barrier function in three experimental models of colitis. There were significantly increased systemic endotoxin concentrations in rats with acetic acid (7.5 (1.7-119.5) pg/ml), ethanol (13.7 (0-111.2) pg/ml), and hapten induced (14.4 (5-31.1) pg/ml) colitis compared with saline controls (3.3 (0-13.7) pg/ml). Data expressed as median (range). There were significant correlations between the systemic endotoxin concentration and both the severity of colitis and of illness in acetic acid induced colitis. A significant increase in colonic permeability to 14C-polyethylene glycol was shown in rats with acetic acid (3.42 (1.36-5.63)%) and hapten induced colitis (2.86 (1.03-8.10)%) compared with saline controls (1.20 (0.67-1.36)%). Data expressed as median (range) of percentage of the intracolonic bolus excreted in urine. There was a significant positive correlation between the severity of colitis and % colonic permeability to 14C-polyethylene glycol. This and other studies provide evidence that mucosal barrier dysfunction is a feature of colitis irrespective of aetiology or species. Such barrier dysfunction may be responsible for the systemic inflammatory response and complications seen in patients with inflammatory bowel disease.
Ex vivo perfusion of human spleens maintains clearing and processing functions
Authors: Pierre A. Buffet, Geneviève Milon, Valentine Brousse, Jean-Michel Correas, Bertrand Dousset, Anne Couvelard, Reza Kianmanesh, Olivier Farges, Alain Sauvanet, François Paye, Marie-Noëlle Ungeheuer, Catherine Ottone, Huot Khun, Laurence Fiette, Ghislaine Guigon, Michel Huerre, Odile Mercereau-Puijalon, Peter H. David
Journal: Blood (2005)
The role of genetic polymorphisms regulating vitamin D levels in rheumatoid arthritis outcome: a Mendelian randomisation approach
Authors: Sebastien Viatte, Annie Yarwood, Kate McAllister, Shibeb Al-Mudhaffer, Bo Fu, Edward Flynn, Deborah P M Symmons, Adam Young, Anne Barton
Journal: Annals of the Rheumatic Diseases (2014)

Vitamin D has an important immunoregulatory function,1 ,2 and there is suggestive evidence for its role in the aetiology of autoimmune diseases, including rheumatoid arthritis (RA).3 Vitamin D levels are reduced in individuals with severe RA,4 ,5 but it is difficult to determine whether this reduction is cause or effect. The onset of arthritis during winter is associated with greater radiographic progression at 6 months, which would be compatible with a causative role.6 Single nucleotide polymorphisms (SNPs) in four vitamin D metabolism genes (GC, DHCR7/NADSYN1, CYP2R1 and CYP24A1) are associated at genome-wide significance with circulating vitamin D levels.7 ,8 Since vitamin D level is associated with RA severity, an association between those SNPs and RA severity would establish causality. Testing the association of genetic variants in genes that control circulating vitamin D levels provides, therefore, an instrument to obtain an unbiased test of the hypothesis that vitamin D levels are aetiologically linked to RA outcome by controlling unmeasured confounding (Mendelian randomisation9). Hence, we tested SNPs previously associated with vitamin D metabolism,7 ,8 and SNPs in these …
The cellular basis of the impaired autologous mixed lymphocyte reaction in patients with systemic lupus erythematosus.
Authors: M M Kuntz, J B Innes, M E Weksler
Journal: Journal of Clinical Investigation (1979)

The autologous mixed lymphocyte reaction is impaired in patients with systemic lupus erythematosus. This is because nonthymus-derived (T)-lymphocyte preparations from such patients do not stimulate autologous T-lymphocyte proliferation normally. This defect may explain the impaired generation of suppressor activity in systemic lupus erythematosus and thereby the occurrence of autoantibodies in this disease.
Strength of Selection Pressure Is an Important Parameter Contributing to the Complexity of Antibiotic Resistance Evolution
Authors: Tugce Oz, Aysegul Guvenek, Sadik Yildiz, Enes Karaboga, Yusuf Talha Tamer, Nirva Mumcuyan, Vedat Burak Ozan, Gizem Hazal Senturk, Murat Cokol, Pamela Yeh, Erdal Toprak
Journal: Molecular Biology and Evolution (2014)

Revealing the genetic changes responsible for antibiotic resistance can be critical for developing novel antibiotic therapies. However, systematic studies correlating genotype to phenotype in the context of antibiotic resistance have been missing. In order to fill in this gap, we evolved 88 isogenic Escherichia coli populations against 22 antibiotics for 3 weeks. For every drug, two populations were evolved under strong selection and two populations were evolved under mild selection. By quantifying evolved populations' resistances against all 22 drugs, we constructed two separate cross-resistance networks for strongly and mildly selected populations. Subsequently, we sequenced representative colonies isolated from evolved populations for revealing the genetic basis for novel phenotypes. Bacterial populations that evolved resistance against antibiotics under strong selection acquired high levels of cross-resistance against several antibiotics, whereas other bacterial populations evolved under milder selection acquired relatively weaker cross-resistance. In addition, we found that strongly selected strains against aminoglycosides became more susceptible to five other drug classes compared with their wild-type ancestor as a result of a point mutation on TrkH, an ion transporter protein. Our findings suggest that selection strength is an important parameter contributing to the complexity of antibiotic resistance problem and use of high doses of antibiotics to clear infections has the potential to promote increase of cross-resistance in clinics.
Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study
Authors: Shailender Bhatia, Brendan Curti, Marc S Ernstoff, Michael Gordon, Elisabeth I Heath, Wilson H Miller, Igor Puzanov, David I Quinn, Thomas W Flaig, Peter VanVeldhuizen, Kelly Byrnes-Blake, Jeremy A Freeman, Rachel Bittner, Naomi Hunder, Sonia Souza, John A Thompson
Journal: Journal for ImmunoTherapy of Cancer (2014)

Despite the positive impact of targeted therapies on metastatic renal cell carcinoma (mRCC), durable responses are infrequent and an unmet need exists for novel therapies with distinct mechanisms of action. We investigated the combination of recombinant Interleukin 21 (IL-21), a cytokine with unique immunostimulatory properties, plus sorafenib, a VEGFR tyrosine kinase inhibitor.In this phase 1/2 study, 52 mRCC patients received outpatient treatment with oral sorafenib 400 mg twice daily plus intravenous IL-21 (10-50 mcg/kg) on days 1-5 and 15-19 of each 7-week treatment course. The safety, antitumor activity, pharmacokinetic and pharmacodynamic effects of the combination were evaluated.In phase 1 (n = 19), the maximum tolerated dose for IL-21 with the standard dose of sorafenib was determined to be 30 mcg/kg/day; grade 3 skin rash was the only dose-limiting toxicity. In phase 2, 33 previously-treated patients tolerated the combination therapy well with appropriate dose reductions; toxicities were mostly grade 1 or 2. The objective response rate was 21% and disease control rate was 82%. Two patients have durable responses that are ongoing, despite cessation of both IL-21 and sorafenib, at 41+ and 30+ months, respectively. The median progression-free survival in phase 2 was 5.6 months. The pharmacokinetic and pharmacodynamic properties of IL-21 appeared to be preserved in the presence of sorafenib.IL-21 plus sorafenib has antitumor activity and acceptable safety in previously treated mRCC patients. IL-21 may represent a suitable immunotherapy in further exploration of combination strategies in mRCC.ClinicalTrials.gov Identifier: NCT00389285.
Efficient TGF-β/SMAD signaling in human melanoma cells associated with high c-SKI/SnoN expression
Authors: Delphine Javelaud, Leon van Kempen, Vasileia I Alexaki, Erwan Le Scolan, Kunxin Luo, Alain Mauviel
Journal: Molecular Cancer (2011)

Abstract Background SKI and SnoN proteins have been shown to inhibit TGF-β signaling, acting both as transcriptional co-repressors in the cell nucleus, and as sequestrators of SMAD proteins in the cytoplasm. TGF-β, on the other hand, induces rapid, proteasome-mediated, degradation of both proteins. How elevated SKI and SnoN protein levels co-exist with active autocrine TGF-β signaling in cancer cells is yet to be understood. Results In this study, we found elevated SKI and SnoN protein levels in a panel of melanoma cell lines, as compared to normal melanocytes. There was no correlation between SKI protein content and the capacity of melanoma cells to invade Matrigel™, to form subcutaneous tumors, or to metastasize to bone after intracardiac inoculation into nude mice. Nor did we find a correlation between SKI expression and histopathological staging of human melanoma. TGF-β induced a rapid and dose-dependent degradation of SKI protein, associated with SMAD3/4 specific transcriptional response and induction of pro-metastatic target genes, partially prevented by pharmacologic blockade of proteasome activity. SKI knockdown in 1205Lu melanoma cells did not alter their invasive capacity or transcriptional responses to TGF-β, and did not allow p21 expression in response to TGF-β or reveal any growth inhibitory activity of TGF-β. Conclusions Despite high expression in melanoma cells, the role of SKI in melanoma remains elusive: SKI does not efficiently interfere with the pro-oncogenic activities of TGF-β, unless stabilized by proteasome blockade. Its highly labile nature makes it an unlikely target for therapeutic intervention.
Anglo-French contributions to the recognition of rheumatoid arthritis
Authors: K. J. Fraser
Journal: Annals of the Rheumatic Diseases (1982)

Early descriptions of rheumatoid arthritis in the English and French literature are reviewed. Charcot pointed out that the disease was recognised as distinct from gout in eighteenth century England, and pictorial evidence for this is presented. His own work on arthritis led to a series of noteworthy interactions with Alfred Baring Garrod, which are discussed.
Thrombin Induces the Preproendothelin-1 Gene in Endothelial Cells by a Protein Tyrosine Kinase–Linked Mechanism
Authors: Tobias A. Marsen, Michael S. Simonson, Michael J. Dunn
Journal: Circulation Research (1995)

Abstract Thrombin stimulates synthesis and secretion of endothelin-1 (ET-1), a vasoactive peptide that triggers responses in the vascular endothelium and smooth muscle. We investigated the signal transduction pathways by which thrombin stimulates preproET-1 gene expression and ET-1 peptide secretion in macrovascular cells (human umbilical vein endothelial cells [HUVECs] and bovine pulmonary artery endothelial cells [BPAECs]) and microvascular cells (human microvascular endothelial cell line [HMEC-1]). Thrombin (4 U/mL) stimulated maximal induction of ET-1 peptide secretion and preproET-1 mRNA after 2 hours in HUVECs and BPAECs and after 1 hour in HMEC-1. A synthetic thrombin receptor activator peptide confirmed ligand-specific receptor actions to induce preproET-1 mRNA. Protein kinase C (PKC) activation by phorbol ester transiently induced preproET-1 mRNA but had no effect on ET-1 peptide synthesis. PKC inhibitors sangivamycin and calphostin C and PKC depletion failed to suppress thrombin-stimulated preproET-1 mRNA. Adenylate cyclase and cAMP-dependent protein kinase did not participate in thrombin-induced preproET-1 gene activation. Thrombin stimulated a rapid increase in phosphotyrosine-containing proteins, suggesting a role for tyrosine phosphorylation in thrombin signaling. These data demonstrate that thrombin induces the preproET-1 gene and ET-1 peptide synthesis by a PKC-independent PTK-dependent pathway in macrovascular and microvascular endothelial cells. Protein tyrosine kinase inhibitors herbimycin A and genistein blocked thrombin-stimulated preproET-1 mRNA and peptide secretion, whereas daidzein, which lacks inhibitory activity, did not suppress thrombin-induced ET-1.