tbuckley/cabot-search huggingface dataset:
Tissue Transglutaminase Mediated Tumor–Stroma Interaction Promotes Pancreatic Cancer Progression
Authors: Jiyoon Lee, Salvatore Condello, Bakhtiyor Yakubov, Robert Emerson, Andrea Caperell-Grant, Kiyotaka Hitomi, Jingwu Xie, Daniela Matei
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Aggressive pancreatic cancer is commonly associated with a dense desmoplastic stroma, which forms a protective niche for cancer cells. The objective of the study was to determine the functions of tissue transglutaminase (TG2), a Ca2+-dependent enzyme that cross-links proteins through transamidation and is abundantly expressed by pancreatic cancer cells in the pancreatic stroma. Experimental Design: Orthotopic pancreatic xenografts and coculture systems tested the mechanisms by which the enzyme modulates tumor–stroma interactions. Results: We show that TG2 secreted by cancer cells effectively molds the stroma by cross-linking collagen, which, in turn, activates fibroblasts and stimulates their proliferation. The stiff fibrotic stromal reaction conveys mechanical cues to cancer cells, leading to activation of the YAP/TAZ transcription factors, promoting cell proliferation and tumor growth. Stable knockdown of TG2 in pancreatic cancer cells leads to decreased size of pancreatic xenografts. Conclusions: Taken together, our results demonstrate that TG2 secreted in the tumor microenvironment orchestrates the cross-talk between cancer cells and stroma fundamentally affecting tumor growth. Our study supports TG2 inhibition in the pancreatic stroma as a novel strategy to block pancreatic cancer progression. Clin Cancer Res; 21(19); 4482–93. ©2015 AACR.
Cases of child malnutrition double in Gaza because of blockade
Authors: C. Dyer
Journal: BMJ (2002)

The Israeli blockade of Gaza has produced a health crisis among Palestinians, according to the charity Christian Aid, with cases of child malnutrition doubling in just one year.

More than 100 000 Palestinians from Gaza previously earned their living in Israel, but the closing of the border has driven most into unemployment. This loss of income has devastated the fragile Palestinian economy, producing a further 76 000 job losses locally.

Costa Dabbagh, director of the Middle East Council of Churches, which runs two clinics for women and children in Gaza City, said: “We are treating more underweight and malnourished children, and this is a problem of the economy. Gaza suffers from 85% unemployment. Food is available here—we are not short of anything. But it is …
Retinoid Signaling and Activator Protein-1 Expression in Ferrets Given -Carotene Supplements and Exposed to Tobacco Smoke
Authors: X.-D. Wang, C. Liu, R. T. Bronson, D. E. Smith, N. I. Krinsky, R. M. Russell
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Epidemiologic studies have demonstrated that individuals who eat more fruits and vegetables and/or have high levels of serum β-carotene have a lower risk of cancer, especially lung cancer. However, recent human intervention studies using β-carotene supplements have shown an increase in the risk of lung cancer among smokers and asbestos workers. In this study, we used an animal model system to evaluate the hazard associated with a combination of high-dose β-carotene supplementation and tobacco smoking. METHODS: Ferrets were given a β-carotene supplement, exposed to cigarette smoke, or both for 6 months. Cell proliferation and squamous metaplasia in lung tissue were assessed by examination of proliferating-cell nuclear antigen expression and histopathologic examination, respectively. β-Carotene and retinoid concentrations in lung tissue and plasma samples were analyzed by high-performance liquid chromatography. Expression of genes for retinoic acid receptors (RARs) and activator protein-1 (encoded by the c-Jun and c-Fos genes) in lung tissue specimens was examined by western blotting. RESULTS: A strong proliferative response in lung tissue and squamous metaplasia was observed in all β-carotene-supplemented animals, and this response was enhanced by exposure to tobacco smoke. When compared with control groups, all three treatment groups had statistically significantly lower concentrations of retinoic acid in lung tissue, and they exhibited 18%-73% reductions in RARβ gene expression; however, RARα and RARγ gene expression was not reduced. Ferrets given a β-carotene supplement and exposed to tobacco smoke had threefold to fourfold elevated expression of the c-Jun and c-Fos genes. CONCLUSIONS: Diminished retinoid signaling, resulting from the suppression of RARβ gene expression and overexpression of activator protein-1, could be a mechanism to enhance lung tumorigenesis after high-dose β-carotene supplementation and exposure to tobacco smoke.
Differential responses of mast cell Toll-like receptors 2 and 4 in allergy and innate immunity
Authors: Volaluck Supajatura, Hiroko Ushio, Atsuhito Nakao, Shizuo Akira, Ko Okumura, Chisei Ra, Hideoki Ogawa
Journal: Journal of Clinical Investigation (2002)

Toll-like receptor 2 (TLR2) and TLR4 play important roles in the early innate immune response to microbial challenge. To clarify the functional roles of TLRs 2 and 4 in mast cells, we examined bone marrow–derived mast cells (BMMCs) from TLR2 or TLR4 gene-targeted mice. Peptidoglycan (PGN) from Staphylococcus aureus stimulated mast cells in a TLR2-dependent manner to produce TNF-α, IL-4, IL-5, IL-6, and IL-13, but not IL-1β. In contrast, LPS from Escherichia coli stimulated mast cells in a TLR4-dependent manner to produce TNF-α, IL-1β, IL-6, and IL-13, but not IL-4 nor IL-5. Furthermore, TLR2- but not TLR4-dependent mast cell stimulation resulted in mast cell degranulation and Ca2+ mobilization. In a mast cell–dependent model of acute sepsis, TLR4 deficiency of BMMCs in mice resulted in significantly higher mortality because of defective neutrophil recruitment and production of proinflammatory cytokines in the peritoneal cavity. Intradermal injection of PGN led to increased vasodilatation and inflammation through TLR2-dependent activation of mast cells in the skin. Taken together, these results suggest that direct activation of mast cells via TLR2 or TLR4 by respective microligands contributes to innate and allergic immune responses.
Bcl-2 protein expression in follicular lymphomas in absence of 14;18 translocation
Authors: F. Pezzella, K.C. Gatter, D.Y. Mason, C. Bastard, C. Duval, A. Krajewski, G.E. Turner, F.M. Ross, H. Clark, D.B. Jones, D. Leroux, F. LE MARC'HADOUR
Journal: The Lancet (1990)
The Sarcoplasmic Reticulum and the Na <sup>+</sup> /Ca <sup>2+</sup> Exchanger Both Contribute to the Ca <sup>2+</sup> Transient of Failing Human Ventricular Myocytes
Authors: Konstantina Dipla, Julian A. Mattiello, Kenneth B. Margulies, Valluvan Jeevanandam, Steven R. Houser
Journal: Circulation Research (1999)

Abstract —Our objective was to determine the respective roles of the sarcoplasmic reticulum (SR) and the Na + /Ca 2+ exchanger in the small, slowly decaying Ca 2+ transients of failing human ventricular myocytes. Left ventricular myocytes were isolated from explanted hearts of patients with severe heart failure (n=18). Cytosolic Ca 2+ , contraction, and action potentials were measured by using indo-1, edge detection, and patch pipettes, respectively. Selective inhibitors of SR Ca 2+ transport (thapsigargin) and reverse-mode Na + /Ca 2+ exchange activity (No. 7943, Kanebo Ltd) were used to define the respective contribution of these processes to the Ca 2+ transient. Ca 2+ transients and contractions induced by action potentials (AP transients) at 0.5 Hz exhibited phasic and tonic components. The duration of the tonic component was determined by the action potential duration. Ca 2+ transients induced by caffeine (Caf transients) exhibited only a phasic component with a rapid rate of decay that was dependent on extracellular Na + . The SR Ca 2+ -ATPase inhibitor thapsigargin abolished the phasic component of the AP Ca 2+ transient and of the Caf transient but had no significant effect on the tonic component of the AP transient. The Na + /Ca 2+ exchange inhibitor No. 7943 eliminated the tonic component of the AP transient and reduced the magnitude of the phasic component. In failing human myocytes, Ca 2+ transients and contractions exhibit an SR-related, phasic component and a slow, reverse-mode Na + /Ca 2+ exchange–related tonic component. These findings suggest that Ca 2+ influx via reverse-mode Na + /Ca 2+ exchange during the action potential may contribute to the slow decay of the Ca 2+ transient in failing human myocytes.
Reinterpreting Comorbidity: A Model-Based Approach to Understanding and Classifying Psychopathology
Authors: Robert F. Krueger, Kristian E. Markon
Journal: Annual Review of Clinical Psychology (2005)

Comorbidity has presented a persistent puzzle for psychopathology research. We review recent literature indicating that the puzzle of comorbidity is being solved by research fitting explicit quantitative models to data on comorbidity. We present a meta-analysis of a liability spectrum model of comorbidity, in which specific mental disorders are understood as manifestations of latent liability factors that explain comorbidity by virtue of their impact on multiple disorders. Nosological, structural, etiological, and psychological aspects of this liability spectrum approach to understanding comorbidity are discussed.
Microarray-Based Identification of <i>Tenascin C</i> and <i>Tenascin XB</i>, Genes Possibly Involved in Tumorigenesis Associated with Neurofibromatosis Type 1
Authors: Pascale Lévy, Hugues Ripoche, Ingrid Laurendeau, Vladimir Lazar, Nicolas Ortonne, Béatrice Parfait, Karen Leroy, Janine Wechsler, Isabelle Salmon, Pierre Wolkenstein, Philippe Dessen, Michel Vidaud, Dominique Vidaud, Ivan Bièche
Journal: Clinical Cancer Research (2007)

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a complex variety of clinical manifestations. The hallmark of NF1 is the onset of heterogeneous (dermal or plexiform) benign neurofibromas. Plexiform neurofibromas can give rise to malignant peripheral nerve sheath tumors, which are resistant to conventional therapies.To identify new signaling pathways involved in the malignant transformation of plexiform neurofibromas, we applied a 22,000-oligonucleotide microarray approach to a series of plexiform neurofibromas and malignant peripheral nerve sheath tumors. Changes in the expression of selected genes were then confirmed by real-time quantitative reverse transcription-PCR.We identified two tenascin gene family members that were significantly deregulated in both human NF1-associated tumors and NF1-deficient primary cells: Tenascin C (TNC) was up-regulated whereas tenascin XB (TNXB) was down-regulated during tumor progression. TNC activation is mainly due to the up-regulation of large TNC splice variants. Immunohistochemical studies showed that TNC transcripts are translated into TNC protein in TNC-overexpressing tumors. Aberrant transcriptional activation of TNC seems to be principally mediated by activator protein transcription factor complexes.TNXB and TNC may be involved in the malignant transformation of plexiform neurofibromas. Anti-TNC antibodies, already used successfully in clinical trials to treat malignant human gliomas, may be an appropriate new therapeutic strategy for NF1.
The Ubiquitin-Proteasome Pathway and Pathogenesis of Human Diseases
Authors: Alan L. Schwartz, PhD, MD, Aaron Ciechanover, MD, PhD
Journal: Annual Review of Medicine (1999)

The ubiquitin-proteasome pathway plays a pivotal role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation. The pathway involves an enzymatic cascade through which multiple ubiquitin molecules are covalently attached to the protein substrate, which is then degraded by the 26S proteasome complex. The pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman's syndroome, and Liddle syndrome), in immune surveillance/viral pathogenesis, and in the pathology of muscle wasting. The molecular mechanisms that underlie these processes are being unraveled at present.
Body Mass Index and Risk, Age of Onset, and Survival in Patients With Pancreatic Cancer
Authors: Donghui Li, Jeffrey S. Morris, Jun Liu, Manal M. Hassan, R. Sue Day, Melissa L. Bondy, James L. Abbruzzese
Journal: JAMA (2009)

Obesity has been implicated as a risk factor for pancreatic cancer.To demonstrate the association of excess body weight across an age cohort and the risk, age of onset, and overall survival of patients with pancreatic cancer.A case-control study of 841 patients with pancreatic adenocarcinoma and 754 healthy individuals frequency matched by age, race, and sex. The study was conducted at a university cancer center in the United States from 2004 to 2008. Height and body weight histories were collected by personal interview starting at ages 14 to 19 years and over 10-year intervals progressing to the year prior to recruitment in the study.The associations between patients' body mass index (BMI) and risk of pancreatic cancer, age at onset, and overall survival were examined by unconditional logistic regression, linear regression, and Cox proportional hazard regression models, respectively.Individuals who were overweight (a BMI of 25-29.9) from the ages of 14 to 39 years (highest odds ratio [OR], 1.67; 95% confidence interval [CI], 1.20-2.34) or obese (a BMI > or = 30) from the ages of 20 to 49 years (highest OR, 2.58; 95% CI, 1.70-3.90) had an associated increased risk of pancreatic cancer, independent of diabetes status. The association was stronger in men (adjusted OR, 1.80; 95% CI, 1.45-2.23) by mean BMI from the ages of 14 to 59 years than in women (adjusted OR, 1.32; 95% CI, 1.02-1.70) and in ever smokers (adjusted OR, 1.75; 95% CI, 1.37-2.22) than in never smokers (adjusted OR, 1.46; 95% CI, 1.16-1.84). The population-attributable risk percentage of pancreatic cancer based on the mean BMI from the ages of 14 to 59 years was 10.3% for never smokers and 21.3% for ever smokers. Individuals who were overweight or obese from the ages of 20 to 49 years had an earlier onset of pancreatic cancer by 2 to 6 years (median age of onset was 64 years for patients with normal weight, 61 years for overweight patients [P = .02], and 59 years for obese patients [P < .001]). Compared with those with normal body weight and after adjusting for all clinical factors, individuals who were overweight or obese from the ages of 30 to 79 years or in the year prior to recruitment had reduced overall survival of pancreatic cancer regardless of disease stage and tumor resection status (overweight patients: hazard ratio, 1.26 [95% CI, 0.94-1.69], P = .04; obese patients: hazard ratio, 1.86 [95% CI, 1.35-2.56], P < .001).Overweight or obesity during early adulthood was associated with a greater risk of pancreatic cancer and a younger age of disease onset. Obesity at an older age was associated with a lower overall survival in patients with pancreatic cancer.
Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women
Authors: Lori Mosca, Lawrence J. Appel, Emelia J. Benjamin, Kathy Berra, Nisha Chandra-Strobos, Rosalind P. Fabunmi, Deborah Grady, Constance K. Haan, Sharonne N. Hayes, Debra R. Judelson, Nora L. Keenan, Patrick McBride, Suzanne Oparil, Pamela Ouyang, Mehmet C. Oz, Michael E. Mendelsohn, Richard C. Pasternak, Vivian W. Pinn, Rose Marie Robertson, Karin Schenck-Gustafsson, Cathy A. Sila, Sidney C. Smith, George Sopko, Anne L. Taylor, Brian W. Walsh, Nanette K. Wenger, Christine L. Williams
Journal: Circulation (2004)

HomeCirculationVol. 109, No. 5Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women
Proteolytic Mapping of the Adeno-associated Virus Capsid
Authors: Kim Van Vliet, Veronique Blouin, Mavis Agbandje-McKenna, Richard O. Snyder
Journal: Molecular Therapy (2006)

The three-dimensional structures of the viral capsid of three AAV serotypes have previously been determined by X-ray crystallography or cryoelectron microscopy. These studies of AAV and similar studies of autonomous parvoviruses have yielded important structural information about the virions in a low-energy conformation. However, there is little information on the structural properties of AAV virions in solution under physiological conditions. We demonstrate that proteolytic digestion of AAV2 virions with trypsin results in cleavage at a specific site on the capsid surface while the capsid remains intact. The products of digestion were mapped using unique antibodies, protein sequencing, mass spectroscopy, and 3D structure modeling to a region on a surface loop that is common to all three AAV2 structural proteins. Empty AAV2 capsids could be distinguished from full (DNA-containing) capsids, having an increased susceptibility of VP2 to trypsin and being digested more rapidly by chymotrypsin. Proteolytic analysis utilizing trypsin or chymotrypsin was also capable of distinguishing AAV2 from AAV1 and AAV5, as seen by differential susceptibility and unique fragment patterns. These data demonstrate a novel approach for studying the structure of AAV capsids in solution and should be valuable in the testing and engineering of AAV vectors for gene transfer.
Ulcerative perianal lichen planus
Authors: C.M.E.Rowland Payne, J.F.Mc Partlin, P.R. Hawley
Journal: British Journal of Dermatology (1997)

Journal Article Ulcerative perianal lichen planus Get access C.M.E.Rowland Payne, C.M.E.Rowland Payne Dermatology Department, St Saviour's Hospital, Hythe, Kent, U.K. Search for other works by this author on: Oxford Academic Google Scholar J.F.Mc Partlin, J.F.Mc Partlin Department of Surgery, St Saviour's Hospital, Hythe, Kent, U.K. Search for other works by this author on: Oxford Academic Google Scholar P.R. Hawley P.R. Hawley Department of Surgery, St Mark's Hospital, London, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 136, Issue 3, 1 March 1997, Page 479, https://doi.org/10.1111/j.1365-2133.1997.tb14983.x Published: 01 March 1997
RANDOMISED, CONTROLLED TRIAL OF THE COMPARATIVE EFFICACY, AUDITORY TOXICITY, AND NEPHROTOXICITY OF TOBRAMYCIN AND NETILMICIN
Authors: A.Martin Lerner, LawrenceA Cone, Winfried Jansen, MilagrosP Reyes, DonaldC Blair, GraceE Wright, RichardR Lorber
Journal: The Lancet (1983)
Evaluating Hypoxia-Inducible Factor-1α as a Cancer Therapeutic Target via Inducible RNA Interference <i>In vivo</i>
Authors: Leiming Li, Xiaoyu Lin, Michael Staver, Alexander Shoemaker, Dimitri Semizarov, Stephen W. Fesik, Yu Shen
Journal: Cancer Research (2005)

Abstract Validating potential targets is an important step in the drug discovery process. In this study, we tested the feasibility of using inducible RNA interference (RNAi) in vivo to obtain an unbiased evaluation on the efficacy of inhibiting hypoxia-inducible factor-1α (HIF-1α) in established tumors. We showed that HIF-1α inhibition resulted in transient tumor stasis or tumor regression, and inhibiting HIF-1α in early-stage tumors was found to be more efficacious than inhibiting HIF-1α in more established tumors. A differential requirement of HIF-1α for tumor growth was also observed among different tumor types. Examination of tumors resistant to HIF-1α inhibition suggested that the resistance might result from a less hypoxic tumor environment and the level of HIF-1α expression in tumors may be a useful marker for predicting tumor response to HIF-1 inhibition. This study shows that inducible RNAi is a versatile tool for evaluating cancer targets in vivo. In addition to broad implications on in vivo validation of cancer targets, results from this study will also be instructive for practical applications of HIF-1–based cancer therapeutics.
Subpoenas and Science — When Lawyers Force Their Way into the Laboratory
Authors: Bert Black
Journal: New England Journal of Medicine (1997)

Scientists who want no part of lawyers and the judicial system may learn to their horror that a court can subpoena their research results, and perhaps even compel them to testify, if their work has some bearing on a case under litigation. For example, Dr. Sherine Gabriel of the Mayo Clinic, who coauthored an article elsewhere in this issue of the Journal, 1 was served with a subpoena for the primary data on which an earlier article was based.2,3 In federal district courts, the rules governing the conduct of civil litigation — from filing a complaint through the final judgment . . .
Effect of Donor KIR2DL1 Allelic Polymorphism on the Outcome of Pediatric Allogeneic Hematopoietic Stem-Cell Transplantation
Authors: Rafijul Bari, Piya Rujkijyanont, Erin Sullivan, Guolian Kang, Victoria Turner, Kwan Gan, Wing Leung
Journal: Journal of Clinical Oncology (2013)

Killer-cell immunoglobulin-like receptors (KIRs) that regulate natural-killer cells are highly polymorphic. Some KIR2DL1 alleles encode receptors that have stronger signaling function than others. We tested the hypothesis that the clinical outcomes of allogeneic hematopoietic stem-cell transplantation (HSCT) could be affected by donor KIR2DL1 polymorphism.All 313 pediatric patients received allogeneic HSCT at a single institution. Donor KIR2DL1 functional allele typing was retrospectively performed using single nucleotide polymorphism assay.Patients who received a donor graft containing the functionally stronger KIR2DL1 allele with arginine at amino acid position 245 (KIR2DL1-R(245)) had better survival (P = .0004) and lower cumulative incidence of disease progression (P = .001) than those patients who received a donor graft that contained only the functionally weaker KIR2DL1 allele with cysteine at the same position (KIR2DL1-C(245)). The effect of KIR2DL1 allelic polymorphism was similar in patients with acute myeloid leukemia or acute lymphoblastic leukemia among all allele groups (P ≥ .71). Patients who received a KIR2DL1-R(245)-positive graft with HLA-C receptor-ligand mismatch had the best survival (P = .00003) and lowest risk of leukemia progression (P = .0005) compared with those who received a KIR2DL1-C(245) homozygous graft.Donor KIR2DL1 allelic polymorphism affects recipient outcomes after allogeneic HSCT. These findings have substantial implications for prognostication and donor selection.