tbuckley/cabot-search huggingface dataset:
Progress and problems in the biology, diagnostics, and therapeutics of prion diseases
Authors: Adriano Aguzzi, Mathias Heikenwalder, Gino Miele
Journal: Journal of Clinical Investigation (2004)

The term "prion" was introduced by Stanley Prusiner in 1982 to describe the atypical infectious agent that causes transmissible spongiform encephalopathies, a group of infectious neurodegenerative diseases that include scrapie in sheep, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle. Over the past twenty years, the word "prion" has been taken to signify various subtly different concepts. In this article, we refer to the prion as the transmissible principle underlying prion diseases, without necessarily implying any specific biochemical or structural identity. When Prusiner started his seminal work, the study of transmissible spongiform encephalopathies was undertaken by only a handful of scientists. Since that time, the "mad cow" crisis has put prion diseases on the agenda of both politicians and the media. Significant progress has been made in prion disease research, and many aspects of prion pathogenesis are now understood. And yet the diagnostic procedures available for prion diseases are not nearly as sensitive as they ought to be, and no therapeutic intervention has been shown to reliably affect the course of the diseases. This article reviews recent progress in the areas of pathogenesis of, diagnostics of, and therapy for prion diseases and highlights some conspicuous problems that remain to be addressed in each of these fields.
Sequence of exons and the flanking regions of human bilirubin-UDP-glucuronosyltransferase gene complex and identification of a genetic mutation in a patient with Crigler-Najjar syndrome, type I
Authors: Piter J. Bosma, Namita Roy Chowdhury, Bart G. Goldhoorn, Martin H. Hofker, Ronald P. J. Oude Elferink, Peter L. M. Jansen, Jayanta Roy Chowdhury
Journal: Hepatology (1992)

Crigler-Najjar syndrome, type I is a heterogeneous disorder that may result from mutations of various regions of the bilirubin-UDP-glucuronosyltransferase gene complex that encodes two bilirubin-UDP-glucuronosyltransferase isoforms and a phenol-UDP-glucuronosyltransferase isoform in the human liver. The two bilirubin-UDP-glucuronosyltransferase messenger RNAs and the phenol-UDP-glucuronosyltransferase messenger RNA have identical 3′ regions derived from four consecutive exons. The 5′ region of each messenger RNA is unique and is derived from distinct single exons. By screening a human genomic library with probes corresponding to various regions of the messenger RNAs, we have isolated five cosmid clones containing overlapping segments of this large gene complex that spans at least 84 kb of the human genome. To facilitate the amplification of each exon by polymerase chain reaction and their adjacent splice junctions, we have delineated the intron-exon boundaries of the four common region exons and the two single exons that encode the unique regions of the two bilirubin-UDP-glucuronosyltransferase isoforms and have described sequences of the regions flanking each exon. All exons encoding the two bilirubin-UDP-glucuronosyltransferase isoforms and their splice junctions were amplified from the DNA of two control subjects and a Crigler-Najjar syndrome, type I patient. The DNA from the Crigler-Najjar syndrome, type I patient revealed a point mutation in exon 3 (a common region exon) resulting in a stop codon. RNA blot showed that the two bilirubin-UDP-glucuronosyltransferase messenger RNAs in the liver of the Crigler-Najjar syndrome, type I patient were of normal length but were reduced in concentration. As expected, the mutation was found in the common region of both bilirubin-UDP-glucuronosyltransferase messenger RNAs in the liver of the patient. The premature stop codon is predicted to encode truncated and inactive bilirubin-UDP-glucuronosyltransferase forms. Bilirubin-UDP-glucuronosyltransferase proteins were not detectable by immunotransblot in the liver of the Crigler-Najjar syndrome, type I patient. The single mutation in a common region exon explains the simultaneous loss of activity of both bilirubin-UDP-glucuronosyltransferase isoforms and marked reduction of UDP-glucuronosyltransferase activity toward phenol. (HEPATOLOGY 1992;15:941–947).
ANCA-associated vasculitis is linked to carriage of the Z allele of α<sub>1</sub> antitrypsin and its polymers
Authors: H Morris, M D Morgan, A M Wood, S W Smith, U I Ekeowa, K Herrmann, J U Holle, L Guillevin, D A Lomas, J Perez, C D Pusey, A D Salama, R Stockley, S Wieczorek, A J McKnight, A P Maxwell, E Miranda, J Williams, C O Savage, L Harper
Journal: Annals of the Rheumatic Diseases (2011)

Background Small studies have linked α1 antitrypsin (α1AT) deficiency to patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Objective To test the validity and the mechanism of this association between α1AT and AAV. Methods The distribution of α1AT deficiency alleles Z and S was compared between 856 White Europeans with AAV and 1505 geographic and ethnically matched healthy controls. Genotyping was performed by allelic discrimination assay. Results were compared between cases and controls using χ 2 tests. The serum and renal biopsies for α1AT polymers were compared using the polymer-specific 2C1 antibody. The role of α1AT polymers in promoting inflammation was investigated by examining their ability to prime neutrophils for ANCA activation as assessed by CD62L shedding, superoxide production and myeloperoxidase degranulation. Results The Z but not the S allele was over-represented in the patients compared with controls (HR=2.25, 95% CI 1.60 to 3.19). Higher concentrations of polymers of α1AT were detected in serum from patients carrying the Z allele than in those not carrying the Z allele (median (IQR) 1.40 (0.91–3.32) mg/dl vs 0.17 (0.06–0.28) mg/dl, p&lt;0.001); polymers of α1AT were also seen in the renal biopsy of a patient with vasculitic glomerulonephritis. Polymers of α1AT primed neutrophils with CD62L shedding and increased superoxide production following ANCA activation. Carriage of the Z allele was not associated with disease severity, survival or relapse. Conclusions The Z but not the S deficiency allele is associated with AAV. Polymers of α1AT are present in the serum and glomeruli of at least some patients with the Z allele, which may promote inflammation through priming of neutrophils.
Arabinogalactan isolated from cowshed dust extract protects mice from allergic airway inflammation and sensitization
Authors: Marcus Peters, Marion Kauth, Olaf Scherner, Kirsten Gehlhar, Imke Steffen, Pia Wentker, Erika von Mutius, Otto Holst, Albrecht Bufe
Journal: Journal of Allergy and Clinical Immunology (2010)
A gene expression profile indicative of early stage HER2 targeted therapy response
Authors: Fiona O’Neill, Stephen F Madden, Martin Clynes, John Crown, Padraig Doolan, Sinéad T Aherne, Robert O’Connor
Journal: Molecular Cancer (2013)

Efficacious application of HER2-targetting agents requires the identification of novel predictive biomarkers. Lapatinib, afatinib and neratinib are tyrosine kinase inhibitors (TKIs) of HER2 and EGFR growth factor receptors. A panel of breast cancer cell lines was treated with these agents, trastuzumab, gefitinib and cytotoxic therapies and the expression pattern of a specific panel of genes using RT-PCR was investigated as a potential marker of early drug response to HER2-targeting therapies.Treatment of HER2 TKI-sensitive SKBR3 and BT474 cell lines with lapatinib, afatinib and neratinib induced an increase in the expression of RB1CC1, ERBB3, FOXO3a and NR3C1. The response directly correlated with the degree of sensitivity. This expression pattern switched from up-regulated to down-regulated in the HER2 expressing, HER2-TKI insensitive cell line MDAMB453. Expression of the CCND1 gene demonstrated an inversely proportional response to drug exposure. A similar expression pattern was observed following the treatment with both neratinib and afatinib. These patterns were retained following exposure to traztuzumab and lapatinib plus capecitabine. In contrast, gefitinib, dasatinib and epirubicin treatment resulted in a completely different expression pattern change.In these HER2-expressing cell line models, lapatinib, neratinib, afatinib and trastuzumab treatment generated a characteristic and specific gene expression response, proportionate to the sensitivity of the cell lines to the HER2 inhibitor.Characterisation of the induced changes in expression levels of these genes may therefore give a valuable, very early predictor of the likely extent and specificity of tumour HER2 inhibitor response in patients, potentially guiding more specific use of these agents.
Potentiation of C1 Esterase Inhibitor by StcE, a Metalloprotease Secreted by <i>Escherichia coli</i> O157:H7
Authors: Wyndham W. Lathem, Tessa Bergsbaken, Rodney A. Welch
Journal: The Journal of Experimental Medicine (2004)

The complement system is an essential component of host defense against pathogens. Previous research in our laboratory identified StcE, a metalloprotease secreted by Escherichia coli O157:H7 that cleaves the serpin C1 esterase inhibitor (C1-INH), a major regulator of the classical complement cascade. Analyses of StcE-treated C1-INH activity revealed that surprisingly, StcE enhanced the ability of C1-INH to inhibit the classical complement-mediated lysis of sheep erythrocytes. StcE directly interacts with both cells and C1-INH, thereby binding C1-INH to the cell surface. This suggests that the augmented activity of StcE-treated C1-INH is due to the increased concentration of C1-INH at the sites of potential lytic complex formation. Indeed, removal of StcE abolishes the ability of C1-INH to bind erythrocyte surfaces, whereas the proteolysis of C1-INH is unnecessary to potentiate its inhibitory activity. Physical analyses showed that StcE interacts with C1-INH within its aminoterminal domain, allowing the unaffected serpin domain to interact with its targets. In addition, StcE-treated C1-INH provides significantly increased serum resistance to E. coli K-12 over native C1-INH. These data suggest that by recruiting C1-INH to cell surfaces, StcE may protect both E. coli O157:H7 and the host cells to which the bacterium adheres from complement-mediated lysis and potentially damaging inflammatory events.
Increased CD8+ T-cell Function following Castration and Immunization Is Countered by Parallel Expansion of Regulatory T Cells
Authors: Shuai Tang, Miranda L. Moore, Jason M. Grayson, Purnima Dubey
Journal: Cancer Research (2012)

Abstract Although androgen ablation therapy is effective in treating primary prostate cancers, a significant number of patients develop incurable castration-resistant disease. Recent studies have suggested a potential synergy between vaccination and androgen ablation, yet the enhanced T-cell function is transient. Using a defined tumor antigen model, UV-8101-RE, we found that concomitant castration significantly increased the frequency and function of antigen-specific CD8+ T cells early after the immunization of wild-type mice. However, at a late time point after immunization, effector function was reduced to the same level as noncastrated mice and was accompanied by a concomitant amplification in CD4+CD25+Foxp3+ regulatory T cells (Treg) following immunization. We investigated whether Treg expansion occurred following castration of prostate tumor–bearing mice. In the prostate-specific Pten−/− mouse model of prostate cancer, we observed an accelerated Treg expansion in mice bearing the castration-resistant endogenous prostate tumor, which prevented effector responses to UV-8101-RE. Treg depletion together with castration elicited a strong CD8+ T-cell response to UV-8101-RE in Pten−/− mice and rescued effector function in castrated and immunized wild-type mice. In addition, Treg expansion in Pten−/− mice was prevented by in vivo interleukin (IL)-2 blockade suggesting that increased IL-2 generated by castration and immunization promotes Treg expansion. Our findings therefore suggest that although effector responses are augmented by castration, the concomitant expansion of Tregs is one mechanism responsible for only transient immune potentiation after androgen ablation. Cancer Res; 72(8); 1975–85. ©2012 AACR.
Exposing children to secondhand smoke
Authors: Jenny Pool, Natalya Petrova, Robert Ross Russell
Journal: Thorax (2012)

In the October issue of Thorax , Leonardi-Bee et al reviewed the effects of parental smoking on the uptake of smoking by children.1 They conclude that exposure to smoking within the family is a significant determinant of subsequent smoking.

One area that this study did not address was the effect of the site of the smoking on exposure.

We have studied urinary cotinine levels in children attending an asthma clinic and correlated them with the self-reported smoking habits of their carers. Thirty-six girls and 64 boys aged between …
Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia
Authors: Phil J. Ancliff, Michael P. Blundell, Giles O. Cory, Yolanda Calle, Austen Worth, Helena Kempski, Siobhan Burns, Gareth E. Jones, Jo Sinclair, Christine Kinnon, Ian M. Hann, Rosemary E. Gale, David C. Linch, Adrian J. Thrasher
Journal: Blood (2006)
EGFR Activation Results in Enhanced Cyclooxygenase-2 Expression through p38 Mitogen-Activated Protein Kinase–Dependent Activation of the Sp1/Sp3 Transcription Factors in Human Gliomas
Authors: Kaiming Xu, Hui-Kuo G. Shu
Journal: Cancer Research (2007)

Abstract Expression of cyclooxygenase-2 (COX-2) has been linked to many cancers and may contribute to malignant phenotypes, including enhanced proliferation, angiogenesis, and resistance to cytotoxic therapies. Malignant gliomas are highly aggressive brain tumors that display many of these characteristics. One prominent molecular abnormality discovered in these astrocytic brain tumors is alteration of epidermal growth factor (EGF) receptor (EGFR) through gene amplification and/or mutation resulting in excessive signaling from this receptor. We found that EGF-mediated stimulation of EGFR tyrosine kinase in human glioma cell lines induces expression of both COX-2 mRNA and protein. The p38 mitogen-activated protein kinase (p38-MAPK) pathway was a strong downstream factor in this activation with inhibition of this pathway leading to strong suppression of COX-2 induction. The p38-MAPK pathway can activate the Sp1/Sp3 transcription factors and this seems necessary for EGFR-dependent transactivation of the COX-2 promoter. Analysis of COX-2 promoter/luciferase constructs revealed that transcriptional activation of the COX-2 promoter by EGFR requires the Sp1 binding site located at −245/−240. Furthermore, Sp1/Sp3 binding to this site in the promoter is enhanced by EGFR activation both in vitro and in vivo. Enhanced DNA binding by Sp1/Sp3 requires p38-MAPK activity and correlates with increased phosphorylation of the Sp1 transcription factor. Thus, EGFR activation in malignant gliomas can transcriptionally activate COX-2 expression in a process that requires p38-MAPK and Sp1/Sp3. Finally, treatment of glioma cell lines with prostaglandin E2, the predominant product of COX-2 activity, results in increased vascular endothelial growth factor expression, thus potentially linking elevations in COX-2 expression with tumor angiogenesis in malignant gliomas. [Cancer Res 2007;67(13):6121–9]
Incidence of intestinal amoebiasis.
Authors: F P Antia, H G Desai, K N Jeejeebhoy, A V Borkar
Journal: Gut (1965)

EDITORIAL SYNOPSIS This is an interesting study showing that the incidence of detecting infection is highest when stool is taken for examination at sigmoidoscopy.The use of a saline purge is not recommended.The incidence of intestinal amoebiasis varies mark- edly in different countries and in the different parts of the same country.The incidence also varies with different gastrointestinal symptoms (Shrivastav, 1953; Antia, Chaphekar, Chhabra, Swami, and Borkar, 1961).Although there are a number of reports on the incidence of Entamoeba histolytica alone (Table I), only a few have dealt with the incidence of all types of amoebae (Table II).These reports, except that of Shrivastav, do not mention the incidence in dysentery, non-dysenteric diarrhoea, and asymptomatic patients.Also the patients studied were not drawn from different social strata.Consequently it is the object of this study to analyse
T Cells as a Self-Referential, Sensory Organ
Authors: Mark M. Davis, Michelle Krogsgaard, Morgan Huse, Johannes Huppa, Bjoern F. Lillemeier, Qi-jing Li
Journal: Annual Review of Immunology (2007)

In light of recent data showing that both helper and cytotoxic T cells can detect even a single molecule of an agonist peptide-MHC, alphabeta T cells are clearly a type of sensory cell, comparable to any in the nervous system. In addition, endogenous (self) peptides bound to MHCs are not just important for thymic selection, but also play an integral role in T cell activation in the response to foreign antigens. With the multitude of specificities available to most T cells, they can thus be considered as a sensory organ, trained on self-peptide-MHCs and primed to detect nonself.
Regulation of tumour necrosis factor (TNF) induced apoptosis by soluble TNF receptors in Helicobacter pylori infection
Authors: J Shibata, H Goto, T Arisawa, Y Niwa, T Hayakawa, A Nakayama, N Mori
Journal: Gut (1999)

Tumour necrosis factor (TNF) is a predominant cytokine produced in the gastric mucosa of patients with Helicobacter pylori infection. TNF induces apoptosis in a variety of cells. The soluble TNF receptors (sTNF-Rs) can be divided into sTNF-RI and sTNF-RII, both of which inhibit TNF activity. However, their precise mechanisms remain unclear.To investigate the role of sTNF-Rs in H pylori infection.In 40 patients, production of TNF and sTNF-Rs in gastric mucosa was measured using biopsy specimens. In addition, in gastric epithelial cells, sTNF-R release in response to TNF and the protective effect of sTNF-Rs against the cytotoxic and apoptotic activities of TNF were examined.TNF and sTNF-R expression was significantly higher in H pylori positive than H pylori negative patients. TNF dose-dependently induced sTNF-RI release from gastric epithelial cells. sTNF-RII was also released from the cells. TNF decreased cell viability, but the effect was very small. A combination of anti-sTNF-RI and anti-sTNF-RII monoclonal antibodies significantly increased TNF induced cytotoxicity and apoptosis of gastric epithelial cells.These results show that sTNF-Rs are actively produced in H pylori infected gastric mucosa. sTNF-Rs appear to protect gastric epithelial cells from TNF induced apoptosis in H pylori infection.
Two Functional Epitopes of Pigment Epithelial–Derived Factor Block Angiogenesis and Induce Differentiation in Prostate Cancer
Authors: Stephanie Filleur, Karl Volz, Thomas Nelius, Yelena Mirochnik, Hanhua Huang, Tetiana A. Zaichuk, Maria S. Aymerich, Sofia P. Becerra, Ronald Yap, Dorina Veliceasa, Emelyn H. Shroff, Olga V. Volpert
Journal: Cancer Research (2005)

Pigment epithelial-derived factor (PEDF), an angiogenesis inhibitor with neurotrophic properties, balances angiogenesis in the eye and blocks tumor progression. Its neurotrophic function and the ability to block vascular leakage is replicated by the PEDF 44-mer peptide (residues 58-101). We analyzed PEDFs' three-dimensional structure and identified a potential receptor-binding surface. Seeking PEDF-based antiangiogenic agents we generated and tested peptides representing the middle and lower regions of this surface. We identified previously unknown antiangiogenic epitopes consisting of the 34-mer (residues 24-57) and a shorter proximal peptide (TGA, residues 16-26) with the critical stretch L19VEEED24 and a fragment within the 44-mer (ERT, residues 78-94), which retained neurotrophic activity. The 34-mer and TGA, but not the 44-mer reproduced PEDF angioinhibitory signals hinged on c-jun-NH2-kinase-dependent nuclear factor of activated T cell deactivation and caused apoptosis. Conversely, the ERT, but not the 34-mer/TGA induced neuronal differentiation. For the 44-mer/ERT, we showed a novel ability to cause neuroendocrine differentiation in prostate cancer cells. PEDF and the peptides bound endothelial and PC-3 prostate cancer cells. Bound peptides were displaced by PEDF, but not by each other, suggesting multiple receptors. PEDF and its active fragments blocked tumor formation when conditionally expressed by PC-3 cells. The 34- and 44-mer used distinct mechanisms: the 34-mer acted on endothelial cells, blocked angiogenesis, and induced apoptosis whereas 44-mer prompted neuroendocrine differentiation in cancer cells. Our results map active regions for the two PEDF functions, signaling via distinct receptors, identify candidate peptides, and provide their mechanism of action for future development of PEDF-based tumor therapies.
Detection of hepatitis C virus with RNA polymerase chain reaction in fulminant hepatic failure*1
Authors: F VILLAMIL
Journal: Hepatology (1995)

The role of hepatitis C virus (HCV) infection in fulminant hepatic failure is controversial. The frequency of serum HCV RNA positivity in previously reported patients with fulminant hepatic failure (FHF) of indeterminate cause ranged from 0 to 12% in the United States and Europe and from 43% to 59% in Asia. We assessed serum HCV RNA using polymerase chain reaction (PCR) and oligoprimers from the 5'UTR of the HCV genome in 26 consecutive patients with FHF. Another laboratory independently performed PCR on 21 of the serum samples using different oligoprimers from the 5'UTR and NS3 region of the HCV genome. Serum HCV RNA was detected in two of seven (28%) patients with hepatitis B, 9 of 15 (60%) with an indeterminate cause, and in none with hepatitis A (n = 2) or drug-induced hepatotoxicity (n = 2). HCV RNA PCR results were concordant between both laboratories in 17 of 21 (81%) of samples. In patients with an indeterminate cause, HCV RNA positivity was significantly associated with the transmission risk factor of low socioeconomic status and Hispanic ethnicity. Eighteen patients underwent liver transplantation (LT) and 15 (83%) survived. Among patients with FHF of indeterminate cause, recurrent or acquired HCV infection after transplantation occurred in three of five (60%) and one of four (25%) patients, respectively. Three of four (75%) patients with hepatitis C virus infection post-LT also developed histologic hepatitis. HCV appears to be the causative agent of a substantial number of cases of FHF classified as indeterminate in the Los Angeles area. Differences in patient populations or risk factors may explain the discordant incidences of HCV infection in FHF observed among different programs.
Relationship Between “Morning Dipping” in Peak Expiratory Flow (PEF) or Peak Expiratory Flow Variability (PEFV) and Study Withdrawals: Post Hoc Analysis of a Randomized 12-Week Study in Patients with Moderate to Severe Asthma
Authors: J.G. Zangrilli, U.J. Martin
Journal: Journal of Allergy and Clinical Immunology (2011)
Hemodialysis and Transplantation in Adults With Polycystic Renal Disease
Authors: J. Michael Lazarus
Journal: JAMA (1971)

Thirty-six patients with chronic renal failure due to polycystic kidney disease have been placed in the dialysis-transplant program at the Peter Bent Brigham Hospital since 1960. Hematuria and pyelonephritis occurred more frequently in this group of patients and sometimes required bilateral nephrectomy for control. When compared with other patients receiving dialysis, polycystic patients who did not undergo nephrectomy maintained higher hematocrit values and required fewer transfusions. Polycystic patients had posttransplant courses similar to those of other transplant patients, and extrarenal polycystic disease is not a contraindication to transplantation. These patients are usually good candidates for long-term hemodialysis or renal transplantation or both.