tbuckley/cabot-search huggingface dataset:
Identification of a new exon 2-skipped TNFR1 transcript: regulation by three functional polymorphisms of the TNFR-associated periodic syndrome (TRAPS) gene
Authors: Cécile Rittore, Elodie Sanchez, Stephan Soler, Mouna Barat-Houari, Marieke Albers, Laura Obici, Michael F McDermott, Isabelle Touitou, Sylvie Grandemange
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Mutations in the <i>TNFRSF1A</i> gene encoding the tumour necrosis factor α cell surface receptor, TNFR1<i>,</i> cause TNFR-associated periodic syndrome (TRAPS) and polymorphisms in <i>TNFRSF1A,</i> including rs4149570, rs767455 and rs1800692, are associated with inflammatory diseases. <h3>Objectives</h3> To describe a new exon 2-spliced transcript—TNFR1-d2—and the impact of these three single nucleotide polymorphisms on exon 2 splicing, transcriptional activity of <i>TNFRSF1A</i> and TRAPS phenotype. <h3>Methods</h3> Expression of <i>TNFRSF1A</i> transcripts was performed by reverse-transcription-PCR in a range of human cells and tissues. Exon 2 splicing and transcriptional activity were analysed in HEK293T and SW480 cells by in vitro alternative splicing and luciferase assays, respectively. We constructed haplotypes containing rs4149570, rs767455 and rs1800692 in controls (n=72), patients with TRAPS (n=111) and in TRAPS-like patients (n=450) to compare their distribution and association with clinical features of TRAPS. <h3>Results</h3> TNFR1-d2 was expressed in a tissue-specific manner, whereas TNFR1 expression was ubiquitous. Alternative splicing assays showed that the T-A-T haplotype at rs4149570–rs767455–rs1800692 had a significantly higher expression of exon 2-skipping product (p=0.02) compared with the G-G-C haplotype. Transcriptional activity from the T-T haplotype at rs4149570–rs1800692 was increased compared with the G-C haplotype (p=0.03). In patients with TRAPS, rs1800692 T/T homozygotes were excessively rare (p&lt;10<sup>−4</sup>) and TRAPS-like patients with this genotype experienced less fever. <h3>Conclusions</h3> Our study provides a new mechanism of <i>TNFRSF1A</i> regulation whereby three polymorphisms in the promoter, exon 1 and intron 4 have a functional and combined effect on exon 2 splicing, via a coupling mechanism between transcription and splicing. These polymorphisms may affect the phenotype of TRAPS and TRAPS-like patients.
Treatment of Human Tumor Xenografts with Monoclonal Antibody 806 in Combination with a Prototypical Epidermal Growth Factor Receptor–Specific Antibody Generates Enhanced Antitumor Activity
Authors: Rushika M. Perera, Yoshitaka Narita, Frank B. Furnari, Hui K. Gan, Carmel Murone, Marika Ahlkvist, Rodney B. Luwor, Antony W. Burgess, Elisabeth Stockert, Achim A. Jungbluth, Lloyd J. Old, Webster K. Cavenee, Andrew M. Scott, Terrance G. Johns
Journal: Clinical Cancer Research (2005)

Abstract Monoclonal antibody (mAb) 806 is a novel epidermal growth factor receptor (EGFR) antibody with significant antitumor activity that recognizes a mutant EGFR commonly expressed in glioma known as delta2-7 EGFR (de2-7 EGFR or EGFRvIII) and a subset of the wild-type (wt) EGFR found in cells that overexpress the receptor. We have used two human xenograft mouse models to examine the efficacy of mAb 806 in combination with mAb 528, a prototypical anti-EGFR antibody with similar specificity to cetuximab. Treatment of nude mice, bearing s.c. or i.c. tumor human xenografts expressing the wt or de2-7 EGFR, with mAbs 806 and 528 in combination resulted in additive and in some cases synergistic, antitumor activity. Interestingly, mAb 528 was also effective against xenografts expressing the ligand independent de2-7 EGFR when used as a single agent, showing that its antitumor activity is not merely mediated through inhibition of ligand binding. When used as single agents, neither mAbs 806 or 528 induced down-regulation of the de2-7 EGFR either in vitro or in vivo. In contrast, the combination of antibodies produced a rapid and dramatic decrease in the total cell surface de2-7 EGFR both in vitro and in xenografts. Consistent with this decrease in total cell surface de2-7 EGFR, we observed up-regulation of the cell cycle inhibitor p27KIP1 and a decrease in tumor cell proliferation as measured by Ki-67 immunostaining when the antibodies were used in combination in vivo. Thus, mAb 806 can synergize with other EGFR-specific antibodies thereby providing a rationale for its translation into the clinic.
Support and stimulation of epidermal cell outgrowth from porcine skin explants by platelet factors
Authors: PATRICIA A. HEBDA, STEPHANIE P. ALSTADT, W.T. HILEMAN, W.H. EAGLSTEIN
Journal: British Journal of Dermatology (1986)

Journal Article Support and stimulation of epidermal cell outgrowth from porcine skin explants by platelet factors Get access PATRICIA A. HEBDA, PATRICIA A. HEBDA University of Pittsburgh, School of Medicine, Department of Dermatology, Pittsburgh, Pennsylvania, U.S.A. Patricia A.Hebda, Ph.D., University of Pittsburgh School of Medicine, Department of Dermatology, RC‐513 Scaife Hall, Pittsburgh, PA 15261, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar STEPHANIE P. ALSTADT, STEPHANIE P. ALSTADT University of Pittsburgh, School of Medicine, Department of Dermatology, Pittsburgh, Pennsylvania, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar W.T. HILEMAN, W.T. HILEMAN University of Pittsburgh, School of Medicine, Department of Dermatology, Pittsburgh, Pennsylvania, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar W.H. EAGLSTEIN W.H. EAGLSTEIN University of Pittsburgh, School of Medicine, Department of Dermatology, Pittsburgh, Pennsylvania, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 115, Issue 5, 1 November 1986, Pages 529–541, https://doi.org/10.1111/j.1365-2133.1986.tb05762.x Published: 01 November 1986 Article history Accepted: 10 April 1986 Published: 01 November 1986
Dermatological manifestations of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome
Authors: S.M. Collins, M. Dominguez, T. Ilmarinen, C. Costigan, A.D. Irvine
Journal: British Journal of Dermatology (2006)

Background Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome (APECED; OMIM 240300) is a rare autosomal recessive disorder defined by a variable combination of endocrine failure, chronic mucocutaneous candidiasis (CMC), and dystrophy of the dental enamel and nails. APECED is caused by mutations in the autoimmune regulator gene (AIRE). Alopecia areata (AA) and vitiligo are diseases with autoimmune pathogeneses, and have been recognized as part of the APECED complex. There are rare reports of other cutaneous manifestations. Objectives We sought to delineate the dermatological features of APECED in an Irish case series with emphasis on timing of their appearance and association with disease severity. Furthermore, we looked for evidence of genotype: phenotype correlation. Finally, we wanted to determine if the ectodermal changes described represent a primary ectodermal dysplasia or whether the ectodermal manifestations are secondary phenomena. Methods Irish patients with APECED were invited to attend a multidisciplinary clinic (Dermatology, Endocrinology, Dentistry and Ophthalmology) held in Our Lady's Hospital for Sick Children, Dublin. Clinical data were compiled from case notes and questionnaires. All patients had a detailed cutaneous examination. Blood samples were obtained for mutational analysis. Results Eighteen patients (seven males and 11 females) from 15 families were interviewed and examined. The mean age at diagnosis was 6 years (range 8 months–18 years). All patients had evidence of CMC, 13 (72%) had candidal onychomycosis or paronychia, six (33%) had AA and two had vitiligo. In the case of two patients the diagnosis was made on recognition of dermatological manifestations and confirmed by mutational analysis. Both patients developed Addison's disease on follow-up. CMC was an early feature, often predating diagnosis (10 of 18). AA and vitiligo presented later, and may reflect more severe disease in these cases. There was no correlation between the AIRE mutations identified on mutational analysis and the clinical presentation. We found no evidence of an isolated nail dystrophy or features consistent with a primary ectodermal dysplasia. Conclusions APECED is a rare but complex and potentially life-threatening autoimmune disease. CMC is a common and early feature; diagnosis at this stage may pre-empt life-threatening endocrinological crises. It is important for dermatologists to be aware of this association as they are likely to be the earliest clinicians who encounter these children. AA and vitiligo in our series occurred in the setting of established disease. The term 'ectodermal dystrophy' is misleading as the ectodermal features described in our series and in the literature are most likely to be secondary phenomena.
Cost-Effectiveness Analysis of Hypertension Guidelines in South Africa
Authors: Thomas A. Gaziano, Krisela Steyn, David J. Cohen, Milton C. Weinstein, Lionel H. Opie
Journal: Circulation (2005)

Hypertension is responsible for more deaths worldwide than any other cardiovascular risk factor. Guidelines based on blood pressure level for initiation of treatment of hypertension may be too costly compared with an approach based on absolute cardiovascular disease (CVD) risk, especially in developing countries.Using a Markov CVD model, we compared 6 strategies for initiation of drug treatment--2 different blood pressure levels (160/95 and 140/90 mm Hg) and 4 different levels of absolute CVD risk over 10 years (40%, 30%, 20%, and 15%)--with one of no treatment. We modeled a hypothetical cohort of all adults without CVD in South Africa, a multiethnic developing country, over 10 years. The incremental cost-effectiveness ratios for treating those with 10-year absolute risk for CVD >40%, 30%, 20%, and 15% were 700 dollars, 1600 dollars, 4900 dollars, and 11,000 dollars per quality-adjusted life-year gained, respectively. Strategies based on a target blood pressure level were both more expensive and less effective than treatment decisions based on the strategy that used absolute CVD risk of >15%. Sensitivity analysis of cost of treatments, prevalence estimates of risk factors, and benefits expected from treatment did not change the ranking of the strategies.In South Africa, current guidelines based on blood pressure levels are both more expensive and less effective than guidelines based on absolute risk of cardiovascular disease. The use of quantitative risk-based guidelines for treatment of hypertension could free up major resources for other pressing needs, especially in developing countries.
Preclinical Pharmacokinetics and Safety of Sym004: A Synergistic Antibody Mixture Directed against Epidermal Growth Factor Receptor
Authors: Niels Jørgen Østergaard Skartved, Helle Jane Jacobsen, Mikkel Wandahl Pedersen, Pernille Foged Jensen, Jette Wagtberg Sen, Thomas Kjærsgaard Jørgensen, Adam Hey, Michael Kragh
Journal: Clinical Cancer Research (2011)

Sym004 is a novel therapeutic antibody mixture product comprising two unmarketed monoclonal antibodies (mAb) targeting the epidermal growth factor receptor (EGFR). In previous preclinical proof-of-concept studies, Sym004 was shown to elicit superior cancer cell growth inhibition activities compared with marketed anti-EGFR mAbs. This article describes the design and results of the preclinical safety program conducted to support early clinical development of Sym004.Tissue cryosections from various species were stained with Sym004 to evaluate tissue cross reactivity. The pharmacokinetics of Sym004 were evaluated in a mouse xenograft model and in Cynomolgus monkeys. Monkeys received once weekly intravenous infusions of Sym004 in the range 2 to 24 mg/kg for 6 to 8 weeks. Cetuximab (a marketed anti-EGFR mAb) and the individual antibodies comprising Sym004 were included in the repeat-dose toxicity studies at single-dose level.Sym004 had a staining pattern similar to cetuximab in tissue panels from both human and non-human primates. Once weekly dosing of Sym004 to Cynomolgus monkeys did not cause accumulation, whereas administration of the individual antibodies resulted in prolonged half-life and accumulation. In direct comparisons with cetuximab, Sym004 did not induce any distinct or novel adverse findings in the animals. However, an early onset of pronounced, reversible, and anticipated anti-EGFR-mediated pharmacologic effects, such as skin rash, dehydration, and liquid feces, was observed. Only minor adverse effects were recorded in animals treated with the individual antibodies comprising Sym004.Sym004 was well tolerated and did not induce any unexpected toxicities. The preclinical safety data enabled initiation of the ongoing clinical development.
Impact of Implantable Cardioverter-Defibrillator, Amiodarone, and Placebo on the Mode of Death in Stable Patients With Heart Failure
Authors: Douglas L. Packer, Jordan M. Prutkin, Anne S. Hellkamp, L. Brent Mitchell, Robert C. Bernstein, Freda Wood, John P. Boehmer, Mark D. Carlson, Robert P. Frantz, Steve E. McNulty, Joseph G. Rogers, Jill Anderson, George W. Johnson, Mary Norine Walsh, Jeanne E. Poole, Daniel B. Mark, Kerry L. Lee, Gust H. Bardy
Journal: Circulation (2009)

The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated that implantable cardioverter-defibrillator (ICD) therapy reduces all-cause mortality in patients with New York Heart Association class II/III heart failure and a left ventricular ejection fraction < or =35% on optimal medical therapy. Whether ICD therapy reduced sudden death caused by ventricular tachyarrhythmias without affecting heart failure deaths in this population is unknown.
Leptospirosis in New England
Authors: E. Donald Andrew
Journal: JAMA (1977)

Although rarely reported in humans in New England, leptospirosis is enzootic in western and central Massachusetts. Recently there were three cases of<i>Leptospira interrogans</i>, serotype var<i>pomona</i>, in Easthampton, Mass. Our study and others indicate a potential for waterborne epidemics in humans. (<i>JAMA</i>238:2027-2028, 1977)
The Homeobox Gene <i>Gax</i> Inhibits Angiogenesis through Inhibition of Nuclear Factor-κB–Dependent Endothelial Cell Gene Expression
Authors: Sejal Patel, Alejandro D. Leal, David H. Gorski
Journal: Cancer Research (2005)

Abstract The growth and metastasis of tumors are heavily dependent on angiogenesis, but much of the transcriptional regulation of vascular endothelial cell gene expression responsible for angiogenesis remains to be elucidated. The homeobox gene Gax is expressed in vascular endothelial cells and inhibits proliferation and tube formation in vitro. We hypothesized that Gax is a negative transcriptional regulator of the endothelial cell angiogenic phenotype and studied its regulation and activity in vascular endothelial cells. Several proangiogenic factors caused a rapid down-regulation of Gax mRNA in human vascular endothelial cells, as did conditioned media from breast cancer cell lines. In addition, Gax expression using a replication-deficient adenoviral vector inhibited human umbilical vein endothelial cell migration toward proangiogenic factors in vitro and inhibited angiogenesis in vivo in Matrigel plugs. To identify putative downstream targets of Gax, we examined changes in global gene expression in endothelial cells due to Gax activity. Gax expression resulted in changes in global gene expression consistent with a quiescent, nonangiogenic phenotype, with increased expression of cyclin kinase inhibitors and decreased expression of genes implicated in endothelial cell activation and angiogenesis. Further analysis revealed that Gax down-regulated numerous nuclear factor-κB (NF-κB) target genes and decreased the binding of NF-κB to its target sequence in electrophoretic mobility shift assays. To our knowledge, Gax is the first homeobox gene described that inhibits NF-κB activity in vascular endothelial cells. Because NF-κB has been implicated in endothelial cell activation and angiogenesis, the down-regulation of NF-κB–dependent genes by Gax suggests one potential mechanism by which Gax inhibits the angiogenic phenotype.
Pancreatic gastrin stimulates islet differentiation of transforming growth factor alpha-induced ductular precursor cells.
Authors: T C Wang, S Bonner-Weir, P S Oates, M Chulak, B Simon, G T Merlino, E V Schmidt, S J Brand
Journal: Journal of Clinical Investigation (1993)

Gastrin is transiently expressed in fetal islets during a critical period of their development from protodifferentiated islet pre- cursors in fetal pancreatic ducts.To examine the possible role of gastrin as an islet cell growth factor, postnatal islet growth was studied in transgenic mice which overexpress gastrin and TGFa in their pancreas.Overexpression of a TGFa transgene causes metaplastic ductules containing numerous insulin ex- pressing cells that resemble protodifferentiated precursors of the fetal pancreas.However, islet mass of the TGFa transgenic mice was not increased.Pancreatic overexpression of gastrin from a chimeric insulin/gastrin transgene transcribed from the insulin promoter markedly decreased the TGFa-stimulated in- crease in pancreatic duct mass.Furthermore, pancreatic coex- pression of both gastrin and TGFa significantly increased islet mass in mice expressing both transgenes.These findings indi- cate that TGFa and gastrin can act synergistically to stimulate islet growth, although neither peptide alone is sufficient.Islet growth may possibly be stimulated through gastrin promoting the differentiation of insulin-positive cells in the TGFa-induced metaplastic ducts.This transgenic study suggests that islet neogenesis can be reactivated in the ductular epithelium of the adult pancreas by local expression of two growth factors, gastrin and TGFa.(
Reduced Myocardial Ischemia-Reperfusion Injury in Toll-Like Receptor 4-Deficient Mice
Authors: Jun-ichi Oyama, Charles Blais, Xiaoli Liu, Minying Pu, Lester Kobzik, Ralph A. Kelly, Todd Bourcier
Journal: Circulation (2004)

Myocardial ischemia and reperfusion-induced tissue injury involve a robust inflammatory response, but the proximal events in reperfusion injury remain incompletely defined. Toll-like receptor 4 (TLR4) is a proximal signaling receptor in innate immune responses to lipopolysaccharide of Gram-negative pathogens. TLR4 is also expressed in the heart and vasculature, but a role for TLR4 in the myocardial response to injury separate from microbial pathogens has not been examined. This study assessed the role of TLR4 in myocardial infarction and inflammation in a murine model of ischemia-reperfusion injury.Myocardial ischemia-reperfusion (MIR) was performed on 2 strains of TLR4-deficient mice (C57/BL10 ScCr and C3H/HeJ) and controls (C57/BL10 ScSn and C3H/OuJ). Mice were subjected to 1 hour of coronary ligation, followed by 24 hours of reperfusion. TLR4-deficient mice sustained significantly smaller infarctions compared with control mice given similar areas at risk. Fewer neutrophils infiltrated the myocardium of TLR4-deficient Cr mice after MIR, indicated by less myeloperoxidase activity and fewer CD45/GR1-positive cells. The myocardium of TLR4-deficient Cr mice contained fewer lipid peroxides and less complement deposition compared with control mice after MIR. Serum levels of interleukin-12, interferon-gamma, and endotoxin were not increased after ischemia-reperfusion. Neutrophil trafficking in the peritoneum was similar in all strains after injection of thioglycollate.TLR4-deficient mice sustain smaller infarctions and exhibit less inflammation after myocardial ischemia-reperfusion injury. The data suggest that in addition to its role in innate immune responses, TLR4 serves a proinflammatory role in murine myocardial ischemia-reperfusion injury.
Pilot Trial of Combined BRAF and EGFR Inhibition in <i>BRAF</i>-Mutant Metastatic Colorectal Cancer Patients
Authors: Rona Yaeger, Andrea Cercek, Eileen M. O'Reilly, Diane L. Reidy, Nancy Kemeny, Tamar Wolinsky, Marinela Capanu, Marc J. Gollub, Neal Rosen, Michael F. Berger, Mario E. Lacouture, Efsevia Vakiani, Leonard B. Saltz
Journal: Clinical Cancer Research (2015)

BRAF-mutant metastatic colorectal cancer (mCRC) forms an aggressive subset of colorectal cancer with minimal response to selective RAF inhibitors. Preclinical data show that reactivation of EGFR signaling occurs in colorectal tumor cells treated with RAF inhibitors and that the addition of an EGFR inhibitor enhances antitumor activity. These data suggest that combined therapy with RAF and EGFR inhibitors could be an effective strategy for treating BRAF V600E mCRC.We undertook a pilot trial to assess the response rate and safety of the BRAF inhibitor vemurafenib combined with anti-EGFR antibody panitumumab in patients with BRAF-mutant mCRC. Patients received standard approved doses of panitumumab and vemurafenib.Fifteen patients were treated. Performance status was Eastern Cooperative Oncology Group (ECOG) 0 in 4 patients (27%) and ECOG 1 in 11 patients (73%). All patients had progressed through at least one standard treatment regimen, and 8 (53%) had received previous fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. Treatment was well tolerated, with less cutaneous toxicity than would be expected with either agent, and no cases of keratoacanthomas/squamous cell carcinomas. Tumor regressions were seen in 10 of 12 evaluable patients with partial responses in 2 patients (100% and 64% regression lasting 40 and 24 weeks, respectively), and stable disease lasting over 6 months in 2 patients.Combined RAF and EGFR inhibition is well tolerated, with less cutaneous toxicity than would be expected with either agent, and results in modest clinical activity in this highly aggressive and chemoresistant subset of CRC.