tbuckley/cabot-search huggingface dataset:
Epidermal Growth Factor–Induced Signaling in Breast Cancer Cells Results in Selective Target Gene Activation by Orphan Nuclear Receptor Estrogen-Related Receptor α
Authors: Janelle B. Barry, Vincent Giguère
Journal: Cancer Research (2005)

Abstract The orphan nuclear hormone receptor estrogen-related receptor α (ERRα, NR3B1) is a constitutive transcription factor that is structurally and functionally related to the classic estrogen receptors. ERRα can recognize both the estrogen response element and its own binding site (ERRE) in either dimeric or monomeric forms. ERRα is also a phosphoprotein whose expression in human breast tumors correlates with that of the receptor tyrosine kinase ErbB2, suggesting that its transcriptional activity could be regulated by signaling cascades. Here, we investigated growth factor regulation of ERRα function and found that it is phosphorylated in MCF-7 breast cancer cells in response to epidermal growth factor (EGF), an event that enhances its DNA binding. Interestingly, treatment with alkaline phosphatase shifts ERRα from a dimeric to a monomeric DNA-binding factor, and only the dimeric form interacts with the coactivator PGC-1α. In vitro, the DNA-binding domain of ERRα is selectively phosphorylated by protein kinase Cδ (PKCδ), which increases its DNA-binding activity, whereas expression of constitutively active PKCδ enhances TFF1 promoter activity via the ERRE. However, whereas treatment of MCF-7 cells with the phorbol ester phorbol-12-myristate 13-acetate also enhances ERRα activation of the TFF1 promoter reporter, it does not affect ERRα activity on its own promoter. In agreement, chromatin immunoprecipitation analysis shows that ERRα and RNA polymerase II are preferentially recruited to the TFF1 promoter after EGF treatment, whereas recruitment of these factors to its own promoter is not affected. These results reveal a mechanism through which growth factor signaling can selectively activate ERRα target genes in breast cancer cells.
An Integrated Computational Model of the Bone Microenvironment in Bone-Metastatic Prostate Cancer
Authors: Arturo Araujo, Leah M. Cook, Conor C. Lynch, David Basanta
Journal: Cancer Research (2014)

Bone metastasis will impact most men with advanced prostate cancer. The vicious cycle of bone degradation and formation driven by metastatic prostate cells in bone yields factors that drive cancer growth. Mechanistic insights into this vicious cycle have suggested new therapeutic opportunities, but complex temporal and cellular interactions in the bone microenvironment make drug development challenging. We have integrated biologic and computational approaches to generate a hybrid cellular automata model of normal bone matrix homeostasis and the prostate cancer-bone microenvironment. The model accurately reproduces the basic multicellular unit bone coupling process, such that introduction of a single prostate cancer cell yields a vicious cycle similar in cellular composition and pathophysiology to models of prostate-to-bone metastasis. Notably, the model revealed distinct phases of osteolytic and osteogenic activity, a critical role for mesenchymal stromal cells in osteogenesis, and temporal changes in cellular composition. To evaluate the robustness of the model, we assessed the effect of established bisphosphonate and anti-RANKL therapies on bone metastases. At approximately 100% efficacy, bisphosphonates inhibited cancer progression while, in contrast with clinical observations in humans, anti-RANKL therapy fully eradicated metastases. Reducing anti-RANKL yielded clinically similar results, suggesting that better targeting or dosing could improve patient survival. Our work establishes a computational model that can be tailored for rapid assessment of experimental therapies and delivery of precision medicine to patients with prostate cancer with bone metastases.
The Common Cytokine Receptor γ Chain Controls Survival of γ/δ T Cells
Authors: Marie Malissen, Pablo Pereira, David J. Gerber, Bernard Malissen, James P. DiSanto
Journal: The Journal of Experimental Medicine (1997)

We have investigated the role of common γ chain (γc)-signaling pathways for the development of T cell receptor for antigen (TCR)-γ/δ T cells. TCR-γ/δ–bearing cells were absent from the adult thymus, spleen, and skin of γc-deficient (γc−) mice, whereas small numbers of thymocytes expressing low levels of TCR-γ/δ were detected during fetal life. Recent reports have suggested that signaling via interleukin (IL)-7 plays a major role in facilitating TCR-γ/δ development through induction of V-J (variable-joining) rearrangements at the TCR-γ locus. In contrast, we detected clearly TCR-γ rearrangements in fetal thymi from γc− mice (which fail to signal in response to IL-7) and reduced TCR-γ rearrangements in adult γc thymi. No gross defects in TCR-δ or TCR-β rearrangements were observed in γc− mice of any age. Introduction of productively rearranged TCR Vγ1 or TCR Vγ1/Vδ6 transgenes onto mice bearing the γc mutation did not restore TCR-γ/δ development to normal levels suggesting that γc-dependent pathways provide additional signals to developing γ/δ T cells other than for the recombination process. Bcl-2 levels in transgenic thymocytes from γc− mice were dramatically reduced compared to γc+ transgenic littermates. We favor the concept that γc-dependent receptors are required for the maintenance of TCR-γ/δ cells and contribute to the completion of TCR-γ rearrangements primarily by promoting survival of cells committed to the TCR-γ/δ lineage.
Epitope Spreading and Autoimmune Glomerulonephritis in Rats Induced by a T Cell Epitope of Goodpasture’s Antigen
Authors: Warren Kline Bolton, Lanlin Chen, Thomas Hellmark, Jo[Combining Diaeresis]rgen Wieslander, Jay W. Fox
Journal: Journal of the American Society of Nephrology (2005)

An amino-terminal region of alpha3 chain of type IV collagen noncollagenous domain [alpha3(IV)NC1] that induces experimental autoimmune glomerulonephritis (EAG) in rats has been identified. Only recombinant antigens that contain a nine-amino acid (AA) span of alpha3(IV)NC1, consistent with a T cell epitope, could induce EAG. It was hypothesized that synthetic peptides of this region should induce EAG. Human and rat peptides of this region were synthesized and rats were immunized to define the nephritogenic epitope. A 13-AA rat peptide induced EAG with proteinuria, decreased renal function, and glomerular basement membrane (GBM)-bound deposits in half of the rats. This peptide induces lymph node cell proliferation and development of antibodies to epitopes of alpha3(IV)NC1 external to the peptide immunogen. Carboxy-terminal extension to 21 amino acids results in all rats' demonstrating anti-GBM antibody and severe EAG. Asparagine at position 19 is critical for EAG induction. None of the 50 rats that were immunized with peptide that contained human sequence with isoleucine at position 19 developed EAG, whereas rat sequence with asparagine 19 induced EAG. Truncation of amino terminal AA of the peptide aborts EAG induction. These studies demonstrate that a T cell epitope of alpha3(IV)NC1 induces lymph node cell proliferation, EAG, and intramolecular epitope spreading; that the length of this peptide influences the formation of anti-GBM antibody; and that the presence of asparagine at position 19 of the peptide is critical to disease induction.
Pharmacodynamic Effects of Seliciclib, an Orally Administered Cell Cycle Modulator, in Undifferentiated Nasopharyngeal Cancer
Authors: Wen-Son Hsieh, Ross Soo, Bee-Keow Peh, Thomas Loh, Difeng Dong, Donny Soh, Lim-Soon Wong, Simon Green, Judy Chiao, Chun-Ying Cui, Yoke-Fong Lai, Soo-Chin Lee, Benjamin Mow, Richie Soong, Manuel Salto-Tellez, Boon-Cher Goh
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Cell cycle dysregulation resulting in expression of antiapoptotic genes and uncontrolled proliferation is a feature of undifferentiated nasopharyngeal carcinoma. The pharmacodynamic effects of seliciclib, a cyclin-dependent kinase (CDK) inhibitor, were studied in patients with nasopharyngeal carcinoma. Experimental Design: Patients with treatment-naïve locally advanced nasopharyngeal carcinoma received seliciclib at 800 mg or 400 mg twice daily on days 1 to 3 and 8 to 12. Paired tumor samples obtained at baseline and on day 13 were assessed by light microscopy, immunohistochemistry, and transcriptional profiling using real-time PCR low-density array consisting of a panel of 380 genes related to cell cycle inhibition, apoptosis, signal transduction, and cell proliferation. Results: At 800 mg bd, one patient experienced grade 3 liver toxicity and another had grade 2 vomiting; no significant toxicities were experienced in 13 patients treated at 400 mg bd. Seven of fourteen evaluable patients had clinical evidence of tumor reduction. Some of these responses were associated with increased tumor apoptosis, necrosis, and decreases in plasma EBV DNA posttreatment. Reduced protein expression of Mcl-1, cyclin D1, phosphorylated retinoblastoma protein pRB (T821), and significant transcriptional down-regulation of genes related to cellular proliferation and survival were shown in some patients posttreatment, indicative of cell cycle modulation by seliciclib, more specifically inhibition of cdk2/cyclin E, cdk7/cyclin H, and cdk9/cyclin T. Conclusions: Brief treatment with this regimen of seliciclib in patients with nasopharyngeal carcinoma is tolerable at 400 mg bd and associated with tumor pharmacodynamic changes consistent with cdk inhibition, and warrants further efficacy studies in this tumor.
Cigarette smoking, TB, and TNF inhibitors
Authors: J Bieber
Journal: Annals of the Rheumatic Diseases (2003)

Accompanying the tremendous excitement about the introduction of TNF inhibitors into the clinic has been caution about potential adverse events that may be associated with the use of these potent immunomodulators. Increased susceptibility to certain infections, particularly Mycobacterium tuberculosis (TB), has been a particular concern.1 Data from animal studies suggest that TNF has a central role in host defence against TB, in part related to effective granuloma formation.2 For infliximab, 277 cases of …
Phase I and Pharmacologic Study of the Novel Indoloquinone Bioreductive Alkylating Cytotoxic Drug E09
Authors: J. H. M. Schellens, A. S. Th. Planting, B. A.C. van Acker, W. J. Loos, M. d. Boer-Dennert, M. E.L. van der Burg, I. Koier, R. T. Krediet, G. Stoter, J. Verweij
Journal: JNCI Journal of the National Cancer Institute (1994)

Background: A novel bioreductive alkylating indolo-quinone compound, E09 [3-hydroxy-5-aziridinyl-l-methyl-2-(lH-indole-4, 7-indione)-prop-F128b-en-a-ol], has been shown to have distinct antitumor activity against solid tumors, excellent activity under hypoxic conditions, but no notable bone marrow toxicity in preclinical models. Purpose: A phase I study was carried out to determine the toxicity, maximum tolerated dose (MTD), pharmacology, and antitumor response of E09. Methods: E09 was administered as a 5-minute intravenous infusion once every 3 weeks to 32 patients with solid tumors. The starting dose of 2.7 mg/m2 was one tenth of the mouse equivalent of lethal dose to 10% of animals (MELD10). Dose was escalated by 100% until the area under the curve (AUC) at the MELD10 was reached, following a Fibonacci-like schedule. The pharmacokinetics of E09 and its metabolite E05A with an open aziridine ring were determined using a new high-pressure liquid chromatographic method and noncom-partmental calculation of kinetic parameters. The sigmoid Emax model was used to fit pharmacokinetic parameters to toxicity. The renal function and proteinuria were quantitated and were further evaluated by determining renal clearance ratios of immunoglobulin G (IgG) to albumin and pancreatic amylase to salivary amylase. Results: The 32 patients were treated with a total of 85 assessable courses of E09. The dose-limiting toxicity was proteinuria, which was accompanied by sodium and water retention. All symptoms were reversible on day 15 except in two patients, who developed acute renal failure. The ratios of IgG to albumin and pancreatic amylase to salivary amylase suggested a loss of glomerular negative charge consistent with a minimal change glomerulopathy. The pharmacokinetics of E09 showed its rapid elimination from the central compartment but with wide interpatient variation in the overall disposition of the drug. Total plasma clearance of E09 ranged from 3.2 to 24 L/min. The AUC of E09 was linearly related to the administered dose. The relationship between the AUC and proteinuria was best fitted by the sigmoid Emax, model (r =.98). In two patients with adenocarcinoma of unknown primary site and in a third patient with bile duct cancer, a partial response was observed. Conclusions: The MTD of E09 was determined to be 27 mg/m2. The standard approach of drug administration is considered unsuitable because of potential renal toxicity and wide variability in the pharmacokinetics of E09. Individual dose adjustments based on plasma concentration measurements are recommended to combine maximally achievable exposure with tolerable toxicity. [J Natl Cancer Inst 86:906–912, 1994]
Small airway dysfunction is associated with poorer asthma control
Authors: Arvind Manoharan, William J. Anderson, Joseph Lipworth, Ibrahim Ibrahim, Brian J. Lipworth
Journal: European Respiratory Journal (2014)

Take home messageIn asthmatics with a preserved FEV 1 , small airways dysfunction defined by FEF 25-75 and R5-R20 was associated with poorer long-term control.
Increased Plasma S-Nitrosothiol Concentrations Predict Cardiovascular Outcomes among Patients with End-Stage Renal Disease
Authors: Ziad A. Massy, Christine Fumeron, Didier Borderie, Philippe Tuppin, Thao Nguyen-Khoa, Marie-Odile Benoit, Christian Jacquot, Claude Buisson, Tilman B. Dru[Combining Diaeresis]eke, Ohvanesse G. Ekindjian, Bernard Lacour, Marie-Christine Iliou
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. The plasma concentrations of S-nitrosothiols, which are circulating nitric oxide metabolites with potential biologic activity, are increased among patients undergoing chronic hemodialysis (HD). However, the ability of S-nitrosothiols to release nitric oxide at physiologically relevant sites may be reduced among HD patients, because of impaired availability and/or activity of factors involved in S-nitrosothiol breakdown. The resultant lack of S-nitrosothiol bioavailability could contribute to the high cardiovascular risk for such patients. A possible relationship between plasma S-nitrosothiol levels and cardiac outcomes, as well as all-cause mortality rates, was investigated in a cohort of 250 chronic HD patients and who were undergoing regular dialysis three times per week were monitored for 1 yr. During that follow-up period, major cardiac events and all-cause deaths were prospectively recorded. At baseline, high plasma S-nitrosothiol levels (>2 μM, corresponding to the top quartile of all measured values) were independently associated with pulse pressure in an adjusted multivariate analysis (odds ratio, 1.03; 95% confidence interval, 1.01 to 1.05; P = 0.007). During the follow-up period, 36 patients died (16 as a result of cardiac causes) and 33 patients experienced major adverse cardiac events. In an adjusted Cox proportional-hazards model, high plasma S-nitrosothiol concentrations (i.e., the top quartile versus the three other quartiles) were an independent predictor of cardiac events (hazard ratio, 3.30; 95% confidence interval, 1.61 to 6.76; P = 0.001) but not of all-cause death. Therefore, among chronic HD patients, markedly elevated plasma S-nitrosothiol levels are associated with pulse pressure and predict cardiovascular outcomes. These findings support the hypothesis that impaired S-nitrosothiol bioavailability in uremia is an important factor for the excessive cardiovascular risk among HD patients.
The risk for cutaneous malignant melanoma, melanoma in situ and intraocular malignant melanoma in relation to tobacco use and body mass index
Authors: Å. Odenbro, P. Gillgren, R. Bellocco, P. Boffetta, N. Håkansson, J. Adami
Journal: British Journal of Dermatology (2006)

The incidence of cutaneous malignant melanoma (CMM) and melanoma in situ (MIS) has been increasing during the last 50 years. Malignant melanoma (MM) is also the most common intraocular malignancy (IMM). Besides ultraviolet radiation, the cause of these tumours is largely unknown.We designed a study to examine the effect of body mass index (BMI) and tobacco use on the risk for MM and MIS.Analyses were performed on a nationwide cohort of 339 802 Swedish construction workers. Exposure information was collected prospectively by questionnaires combined with personal interviews.Follow up yielded a total of 7 663 400 person-years during which 1639 workers developed MM/MIS. The risk for MM/MIS was reduced in current or previous smokers compared with those who had never smoked, both when analysing all smoking tobacco products combined and when analysing cigarette and pipe smokers separately. The risk was further diminished with longer duration of smoking and greater quantity of tobacco smoked. The effect was more evident in CMM/MIS than in IMM. Snuff taking conferred a decreased risk for CMM/MIS, and a BMI over normal weight range conferred an increased risk for CMM.Tobacco smoking was found to be inversely associated with the risk for CMM and MIS. The mechanism of action is unknown but it has been suggested to be due to the immune suppressive effect that tobacco exerts which would be protective against deleterious immune reactions caused by, for example, the sun. Neither is the mechanism behind the higher risk for CMM due to being overweight known. One hypothesis is that it is an effect of a hormonal imbalance. Further studies are required to elucidate these mechanisms.
Oral contraceptives, reproductive factors and risk of inflammatory bowel disease
Authors: Hamed Khalili, Leslie M Higuchi, Ashwin N Ananthakrishnan, James M Richter, Diane Feskanich, Charles S Fuchs, Andrew T Chan
Journal: Gut (2012)

Oral contraceptive use has been associated with risk of Crohn's disease (CD) and ulcerative colitis (UC).
Controlling inflammation
Authors: Roderick J. Flower, Mauro Perretti
Journal: The Journal of Experimental Medicine (2005)

The inflammatory response protects the body against infection and injury but can itself become deregulated with deleterious consequences to the host. It is now clear that several endogenous biochemical pathways activated during defense reactions can counterregulate inflammation. New experimental evidence adds resolvin E1 to this group of endogenous inhibitors and provides further rationale for the beneficial effects of dietary supplementation with fish oils. It also highlights an unexpected twist in the pharmacology of aspirin.
Should the Paradigm Shift for Low-Grade Follicular Non-Hodgkin Lymphoma Be Toward Less Therapy?
Authors: Ian Edwin Haines
Journal: Journal of Clinical Oncology (2013)

TO THE EDITOR: Although the quest for improved cure rates of any cancer is paramount, the suggestion by Cabanillas 1 that it is time for a paradigm shift in our approach to the goals of treatment of patients with advanced indolent or low-grade follicular non-Hodgkin lymphoma (ALGFNHL) toward “cure” does not seem to be supported by an analysis of much of the published evidence over 30 years. Cabanillas 1 states that our paradigm should shift because ALGFNHLs are “characterized by a continuous relapse rate for the first 8 years, with a subsequent plateau in the FFS [failure-free survival] curve at 40%.” 1(p15) However, no randomized studies in the pre– and post– rituximab era show benefit for initial treatment over watch and wait. 2 One of these studies compared initial systemic treatment at diagnosis with a watch and wait policy in 309 patients and found identical overall survival and disease-specific survival between these two approaches. More importantly, the actuarial chance of not needing chemotherapy at 10 years was 19% for all patients and 40% for patients older than age 70 years, the largest subgroup. 3 Another reason advanced for justifying this paradigm shift is that patients have “not been observed long enough to realize that there is indeed a plateau in the FFS curve.” 1(p15) However, Cabanillas cites studies of selected and small numbers of patients. One looked at five treatment cohorts totaling 580 patients for a period of 25 years. 4 The five groups were all young; each had a median age younger than 55 years, well below the overall median for this disease of age 60 years and older. The two cohorts with the best FFS results had median follow-up of only 8.2 and 3.3 years. Longer follow-up of these recent cohorts is required to detect any sustainable plateau in the survival curves. Cabanillas’s other reason for justifying his claim that patients with ALGFNHLs are curable is that they have not previously been treated with effective chemoimmunotherapy. However, a recent systematic review and meta-analysis of prospective randomized trials assessing available evidence suggests that high-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) as part of initial
Gastrointestinal bleeding diagnosed using video capsule endoscopy
Authors: H Sokol, P Seksik, D Wendum, J Bellanger, Y Parc, J Cosnes, L Beaugerie
Journal: Gut (2009)

A 43-year-old patient was referred to our gastroenterology department with haematochezia. Prior to admission to our unit, the patient experienced two episodes of similar rectal bleeding in 1996 and 1997 (the first one after treatment with non-steroidal anti-inflammatory drugs) explored each time unsuccessfully by upper gastrointestinal endoscopy and colonoscopy. He had no other particular medical history. Upon admission, the patient was pale and asthenic. Examination of the abdomen was normal. Blood testing before transfusion showed: haemoglobin, 8.3 g/dl; leucocytes, 8.0×109 …
Chromosome Changes (Trisomies #15 and 17) Associated With Tumor Progression in Leukemias Induced by Radiation Leukemia Virus2
Authors: Francis Wiener, Shinsuke Ohno, Jack Spira, Nechama Haran-Ghera, George Klein
Journal: JNCI Journal of the National Cancer Institute (1978)

Journal Article Chromosome Changes (Trisomies #15 and 17) Associated With Tumor Progression in Leukemias Induced by Radiation Leukemia Virus Get access Francis Wiener, Francis Wiener 3Department of Tumor Biology, Karolinska Institutet, 104 01 Stockholm 60, Sweden. Search for other works by this author on: Oxford Academic PubMed Google Scholar Shinsuke Ohno, Shinsuke Ohno 3Department of Tumor Biology, Karolinska Institutet, 104 01 Stockholm 60, Sweden. Search for other works by this author on: Oxford Academic PubMed Google Scholar Jack Spira, Jack Spira 3Department of Tumor Biology, Karolinska Institutet, 104 01 Stockholm 60, Sweden. Search for other works by this author on: Oxford Academic PubMed Google Scholar Nechama Haran-Ghera, Nechama Haran-Ghera 4Department of Chemical Immunology, The Weizmann Institute of Science, Rehovot, Israel. Search for other works by this author on: Oxford Academic PubMed Google Scholar George Klein George Klein 3Department of Tumor Biology, Karolinska Institutet, 104 01 Stockholm 60, Sweden. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 61, Issue 1, July 1978, Pages 227–237, https://doi.org/10.1093/jnci/61.1.227 Published: 01 July 1978 Article history Received: 20 October 1977 Accepted: 30 January 1978 Published: 01 July 1978