tbuckley/cabot-search huggingface dataset:
Immunogenicity of Pluripotent Stem Cells and Their Derivatives
Authors: Patricia E. de Almeida, Julia D. Ransohoff, Abu Nahid, Joseph C. Wu
Journal: Circulation Research (2013)

The ability of pluripotent stem cells to self-renew and differentiate into all somatic cell types brings great prospects to regenerative medicine and human health. However, before clinical applications, much translational research is necessary to ensure that their therapeutic progenies are functional and nontumorigenic, that they are stable and do not dedifferentiate, and that they do not elicit immune responses that could threaten their survival in vivo. For this, an in-depth understanding of their biology, genetic, and epigenetic make-up and of their antigenic repertoire is critical for predicting their immunogenicity and for developing strategies needed to assure successful long-term engraftment. Recently, the expectation that reprogrammed somatic cells would provide an autologous cell therapy for personalized medicine has been questioned. Induced pluripotent stem cells display several genetic and epigenetic abnormalities that could promote tumorigenicity and immunogenicity in vivo. Understanding the persistence and effects of these abnormalities in induced pluripotent stem cell derivatives is critical to allow clinicians to predict graft fate after transplantation, and to take requisite measures to prevent immune rejection. With clinical trials of pluripotent stem cell therapy on the horizon, the importance of understanding immunologic barriers and devising safe, effective strategies to bypass them is further underscored. This approach to overcome immunologic barriers to stem cell therapy can take advantage of the validated knowledge acquired from decades of hematopoietic stem cell transplantation.
Myelomatous pleural effusion: Clinical course and immunologic characterization of the pleural fluid cells
Authors: Daniel C. Scullin, Harvey Jay Cohen
Journal: American Journal of Hematology (1979)

Abstract Multiple myeloma is a disease that infrequently involves nonreticuloendothelial tissues and rarely causes pleural effusion. A 59‐year‐old woman had pleural effusion as the major manifestation of multiple myeloma. Light microscopy of her pleural fluid with Wright stained preparations showed all cells to be bizarre and often multinucleated plasmacytes. Electron microscopy confirmed these results. Intracellular immunofluorescence revealed IgG‐kappa immunoglobulin (Ig) in greater than 90% of these cells. Surface immunofluorescence using anti‐Ig sera was seen on less than 5% of the pleural fluid cells. 3 H leucine incorporation into Ig in vitro was measured for these cells, and secretory curves were obtained that have the typical secretory kinetics of bone marrow plasmacytes. This demonstrates that such cells are viable and are able to synthesize and release immunoglobulin. Treatment of our patient with prednisone, melphalan, and cyclophosphamide resulted in symptomatic improvement and complete resolution of her pleural effusion. Pleural effusion is an unusual but important complication of multiple myeloma and does not necessarily carry the grave prognosis implied in previous reports.
Heterologous Antisera and Antivenins Are Essential Biologicals: Perspectives on a Worldwide Crisis
Authors: Henry Wilde
Journal: Annals of Internal Medicine (1996)

Active immunization against infectious disease is important.However, much of our world faces poverty, social injustice, and warfare, all of which cause universal immunization to remain a distant dream. Agents that provide passive immunity thus remain essential biologicals. The most important of these are human or equine antisera against rabies, tetanus, diphtheria, and snake antivenins. Homologous products are either unavailable or unaffordable in places where they are needed the most. Less expensive heterologous (equine) antisera can be purified and are safe to use, but these antisera are also in short supply. Monoclonal antibodies have been developed but are even less likely to be affordable in poor countries. Several traditional sources of equine antisera are becoming depleted as a result of economic disincentives; a poor reputation based on the high adverse reaction rates of the old, unpurified products; and the activities of animal rights activists who object to the use of horses as blood donors. Purified, pepsin-digested equine antisera are preferred; but developing countries sometimes are forced to make crude products that are less safe or have no specific therapy available at all.
Interferon receptor 2 gene variants are associated with liver fibrosis in patients with chronic hepatitis C infection
Authors: B. Nalpas, R. Lavialle-Meziani, S. Plancoulaine, E. Jouanguy, A. Nalpas, M. Munteanu, F. Charlotte, B. Ranque, E. Patin, S. Heath, H. Fontaine, A. Vallet-Pichard, D. Pontoire, M. Bourliere, J.-L. Casanova, M. Lathrop, C. Brechot, T. Poynard, F. Matsuda, S. Pol, L. Abel
Journal: Gut (2010)

<h3>Background</h3> Only a minority of patients with chronic hepatitis C virus (HCV) infection develops severe liver fibrosis, a process that may be controlled by human genetic factors. <h3>Objective</h3> To investigate the role of 384 single nucleotide polymorphisms (SNPs) located in 36 candidate genes related to the fibrogenesis/fibrolysis process. <h3>Methods</h3> Patients with chronic HCV infection were gathered from two French cohorts (prospectively and retrospectively). The overall sample consisted of 393 HCV-infected subjects without known risk factors for fibrosis progression, including 134 patients with severe liver fibrosis and 259 without severe fibrosis. <h3>Results</h3> Only two SNPs in strong linkage disequilibrium (LD) in the interferon γ receptor 2 gene (<i>IFNGR2</i>) were significantly associated with liver fibrosis in both the prospective and the retrospective samples. The strongest association (p=8×10<sup>−5</sup>) was observed with the G/A SNP rs9976971 with an OR of severe fibrosis for AA versus AG or GG subjects at 2.95 (95% CI 1.70 to 5.11). This effect was higher (p=9×10<sup>−7</sup>) when taking into account the time of follow-up, and the hazard ratio of progression towards severe fibrosis for AA patients was 2.62 (1.76 to 3.91). Refined sequencing and analysis of the <i>IFNGR2</i> region identified two additional variants in strong LD with rs9976971. No haplotypes derived from this cluster of four variants provided stronger evidence for association than rs9976971 alone. <h3>Conclusions</h3> This identification of a cluster of four <i>IFNGR2</i> variants strongly associated with fibrosis progression in chronic HCV infection underlines the role of IFNγ in the development of liver fibrosis that may pave the way for new treatments.
Repression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL
Authors: Xiaoyu Li, Takaomi Sanda, A. Thomas Look, Carl D. Novina, Harald von Boehmer
Journal: The Journal of Experimental Medicine (2011)

The NOTCH1 signaling pathway is a critical determinant of cell fate decisions and drives oncogenesis through mechanisms that are incompletely understood. Using an established mouse model of T cell acute lymphoblastic leukemia (T-ALL), here we report that induction of intracellular Notch1 (ICN1) leads to repression of miR-451 and miR-709. ICN1 decreases expression of these miRNAs by inducing degradation of the E2a tumor suppressor, which transcriptionally activates the genes encoding miR-451 and miR-709. Both miR-451 and miR-709 directly repress Myc expression. In addition, miR-709 directly represses expression of the Akt and Ras-GRF1 oncogenes. We also show that repression of miR-451 and miR-709 expression is required for initiation and maintenance of mouse T-ALL. miR-451 but not miR-709 is conserved in humans, and human T-ALLs with activating NOTCH1 mutations have decreased miR-451 and increased MYC levels compared with T-ALLs with wild-type NOTCH1. Thus, miR-451 and miR-709 function as potent suppressors of oncogenesis in NOTCH1-induced mouse T-ALL, and miR-451 influences MYC expression in human T-ALL bearing NOTCH1 mutations.
ERBB3 is a marker of a ganglioneuroblastoma/ganglioneuroma-like expression profile in neuroblastic tumours
Authors: Annica Wilzén, Cecilia Krona, Baldur Sveinbjörnsson, Erik Kristiansson, Daniel Dalevi, Ingrid Øra, Katleen De Preter, Raymond L Stallings, John Maris, Rogier Versteeg, Staffan Nilsson, Per Kogner, Frida Abel
Journal: Molecular Cancer (2013)

Abstract Background Neuroblastoma (NB) tumours are commonly divided into three cytogenetic subgroups. However, by unsupervised principal components analysis of gene expression profiles we recently identified four distinct subgroups, r1-r4. In the current study we characterized these different subgroups in more detail, with a specific focus on the fourth divergent tumour subgroup (r4). Methods Expression microarray data from four international studies corresponding to 148 neuroblastic tumour cases were subject to division into four expression subgroups using a previously described 6-gene signature. Differentially expressed genes between groups were identified using Significance Analysis of Microarray (SAM). Next, gene expression network modelling was performed to map signalling pathways and cellular processes representing each subgroup. Findings were validated at the protein level by immunohistochemistry and immunoblot analyses. Results We identified several significantly up-regulated genes in the r4 subgroup of which the tyrosine kinase receptor ERBB3 was most prominent (fold change: 132–240). By gene set enrichment analysis (GSEA) the constructed gene network of ERBB3 (n = 38 network partners) was significantly enriched in the r4 subgroup in all four independent data sets. ERBB3 was also positively correlated to the ErbB family members EGFR and ERBB2 in all data sets, and a concurrent overexpression was seen in the r4 subgroup. Further studies of histopathology categories using a fifth data set of 110 neuroblastic tumours, showed a striking similarity between the expression profile of r4 to ganglioneuroblastoma (GNB) and ganglioneuroma (GN) tumours. In contrast, the NB histopathological subtype was dominated by mitotic regulating genes, characterizing unfavourable NB subgroups in particular. The high ErbB3 expression in GN tumour types was verified at the protein level, and showed mainly expression in the mature ganglion cells. Conclusions Conclusively, this study demonstrates the importance of performing unsupervised clustering and subtype discovery of data sets prior to analyses to avoid a mixture of tumour subtypes, which may otherwise give distorted results and lead to incorrect conclusions. The current study identifies ERBB3 as a clear-cut marker of a GNB/GN-like expression profile, and we suggest a 7-gene expression signature (including ERBB3 ) as a complement to histopathology analysis of neuroblastic tumours. Further studies of ErbB3 and other ErbB family members and their role in neuroblastic differentiation and pathogenesis are warranted.
Is maternal asthma a life or death issue for the baby?
Authors: M. Schatz
Journal: Thorax (2009)

Asthma is probably the most common potentially serious medical problem to complicate pregnancy. In recent national surveys in the USA, 8.4–8.8% of pregnant women reported current asthma.1 Since 1970, many published articles have suggested that women with asthma experience more complications of pregnancy than women who do not have asthma. The most commonly reported increased risks have been for pre-eclampsia,2–12 preterm birth2 5 6 8 9 13–15 and infants with low birth weight or intrauterine growth restriction.2 5 6 8–10 12 15 16The most severe complication of pregnancy from the infant standpoint is fetal or neonatal death. Although one study from the USA in 1970 reported a significant 80% increased risk of perinatal mortality in infants of women with asthma compared with those without asthma,17 and another study from Sweden in 1972 reported a more than doubling of neonatal mortality in infants of mothers with asthma,2 11 studies published between 1988 and 2007 did not demonstrate a significant increased risk of fetal mortality, neonatal mortality, or both (perinatal mortality) in the infants of women with asthma compared with women without asthma.3 7 10 15 16 18–23 Since the prevalence of perinatal mortality is fortunately low, a type 2 error due to low statistical power could explain many of these negative results. Indeed, sample sizes for women with asthma in 7 of the 11 negative studies were less than 2000.3 10 16 18–20 22 Moreover, a significant 21% increased risk of perinatal mortality was reported in the second largest cohort of women with asthma studied to date (n = 36 965).6

Against this background, the study by Breton et al 24 in the current issue of Thorax ( see page 101 ) of a database cohort …
Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42 103 individuals
Authors: Malcolm G Dunlop, Albert Tenesa, Susan M Farrington, Stephane Ballereau, David H Brewster, Thibaud Koessler, Paul Pharoah, Clemens Schafmayer, Jochen Hampe, Henry Völzke, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Susanna von Holst, Simone Picelli, Annika Lindblom, Mark A Jenkins, John L Hopper, Graham Casey, David Duggan, Polly A Newcomb, Anna Abulí, Xavier Bessa, Clara Ruiz-Ponte, Sergi Castellví-Bel, Iina Niittymäki, Sari Tuupanen, Auli Karhu, Lauri Aaltonen, Brent Zanke, Tom Hudson, Steven Gallinger, Ella Barclay, Lynn Martin, Maggie Gorman, Luis Carvajal-Carmona, Axel Walther, David Kerr, Steven Lubbe, Peter Broderick, Ian Chandler, Alan Pittman, Steven Penegar, Harry Campbell, Ian Tomlinson, Richard S Houlston
Journal: Gut (2012)

<h3>Objective</h3> Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data. <h3>Design</h3> Nine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39 266) and in combination with gender, age and FH (n=11 324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks. <h3>Results</h3> The median number of risk alleles was greater in cases than controls (10 vs 9, p&lt;2.2×10<sup>−16</sup>), confirmed in external validation sets (Sweden p=1.2×10<sup>−6</sup>, Finland p=2×10<sup>−5</sup>). The mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05 to 1.13). Discriminative performance was poor across the risk spectrum (area under curve for genotypes alone 0.57; area under curve for genotype/age/gender/FH 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with &gt;5% predicted 10-year absolute risk. <h3>Conclusion</h3> Genotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance.
How has healthcare research performance been assessed? A systematic review
Authors: Vanash M Patel, Hutan Ashrafian, Kamran Ahmed, Sonal Arora, Sejal Jiwan, Jeremy K Nicholson, Ara Darzi, Thanos Athanasiou
Journal: Journal of the Royal Society of Medicine (2011)

Objectives Healthcare research performance is increasingly assessed through research indicators. We performed a systematic review to identify the indicators that have been used to measure healthcare research performance. We evaluated their feasibility, validity, reliability and acceptability; and finally assessed the utility of these indicators in terms of measuring performance in individuals, specialties, institutions and countries. Design A systematic review was performed by searching EMBASE, PsycINFO, Ovid MEDLINE and Cochrane Library databases between 1950 and September 2010. Setting Studies of healthcare research were appraised. Healthcare was defined as the prevention, treatment and management of illness and the preservation of mental and physical wellbeing through the services offered by the medical and allied health professions. Participants All original studies that evaluated research performance indicators in healthcare were included. Main outcome measures Healthcare research indicators, data sources, study characteristics, results and limitations for each study were studied. Results The most common research performance indicators identified in 50 studies were: number of publications ( n = 38), number of citations ( n = 27), Impact Factor ( n = 15), research funding ( n = 10), degree of co-authorship ( n = 9), and h index ( n = 5). There was limited investigation of feasibility, validity, reliability and acceptability, although the utility of these indicators was adequately described. Conclusion Currently, there is only limited evidence to assess the value of healthcare research performance indicators. Further studies are required to define the application of these indicators through a balanced approach for quality and innovation. The ultimate aim of utilizing healthcare research indicators is to create a culture of measuring research performance to support the translation of research into greater societal and economic impact.
A good approach to neural and behavioural development but would be even better if set in a broader context
Authors: Patrick Bateson
Journal: Behavioral and Brain Sciences (2008)

Abstract An attractive feature of Neuroconstructivism, Vol. I: How the Brain Constructs Cognition is its emphasis on the active role of the individual in neural and behavioural development and the importance of the interplay with the environment. Certain aspects of development are omitted, however, such as specializations for the distinctive ecologies of infancy and childhood and the scaffolding-like features of behaviour seen during development. It was also a pity that so little credit was given to many scientists who have contributed to just those aspects of development on which the authors focus.
P173 Etiological Factors For Adult Bronchiectasis Identified By A Specialized Investigation Protocol
Authors: A Creamer, J Elliot, J Ryan, J French, H Barker, DS Wat, H Baxendale, A Exley, CS Haworth, RA Floto
Journal: Thorax (2012)

<h3>Rationale</h3> Numerous factors have been identified as contributing to the development of bronchiectasis although their relative prevalence remains poorly understood. The Cambridge Centre for Lung Infection (CCRI) at Papworth Hospital has one of the largest specialist bronchiectasis units in Europe. All new patients referred with recurrent or severe chest infections undergo a systematic investigation protocol to determine an underlying cause for their lung disease involving: high-resolution CT (HRCT) scan; full pulmonary function tests; sweat testing and CFTR sequencing; nasal nitric oxide measurements; immunological test including serum immunoglobulins, specific antibody levels pre-and post vaccination, auto-antibody screening; Aspergillus serology and multiple sputum sample testing for conventional and mycobacterial microscopy and culture. We undertook an analysis of the results of these investigations to determine the relative contributions of causal factors in patients with bronchiectasis. <h3>Methods</h3> We examined the results and case notes of all 352 patients referred to the CCRI with recurrent chest infections between January 1st 2009 and May 31st 2011. Of these, 202 individuals had HRCT evidence of bronchiectasis. The results of their initial investigations were analysed to determine the proportion of patients we could ascribe a likely cause for their bronchiectasis and whether this affected their subsequent management. <h3>Results</h3> Using our investigation strategy, we were able to identify a likely cause in 139/202 (69%) patients, with 31% remaining idiopathic. Identifying an underlying cause frequently influenced subsequent patient management. Common causes included post-infection (22%), aspiration (7%), primary and secondary immune-deficiencies (4 and 6% respectively), and allergic broncho-pulmonary aspergillosis (6%). 5 new diagnoses of cystic fibrosis were made in patients aged 23, 26, 35, 53 and 64. <h3>Conclusion</h3> This study represents the largest analysis of causative factors of bronchiectasis to date. Using our current investigation algorithm, we can ascribe a cause for bronchiectasis in almost 70% of new patients. Many of the underlying conditions diagnosed require specialist management.
Multimeric Hemoglobin of the Australian Brine Shrimp Parartemia
Authors: Michele Coleman, Charles M. Matthews, Clive N. A. Trotman
Journal: Molecular Biology and Evolution (2001)

The hemoglobin molecule of the commercially important brine shrimp Artemia sp. has been used extensively as a model for the study of molecular evolution. It consists of nine globin domains joined by short linker sequences, and these domains are believed to have originated through a series of duplications from an original globin gene. In addition, in Artemia, two different polymers of hemoglobin, called C and T, are found which differ by 11.7% at the amino acid level and are believed to have diverged about 60 MYA. This provides a set of data of 18 globin domain sequences that have evolved in the same organism. The pattern of amino acid substitution between these two polymers is unusual, with pairs of equivalent domains displaying differences of up to 2.7-fold in total amino acid substitution. Such differences would reflect a similar range of molecular-clock rates in what appear to be duplicate, structurally equivalent domains. In order to provide a reference outgroup, we sequenced the cDNA for a nine-domain hemoglobin (P) from another genus of brine shrimp, Parartemia zietziana, which differs morphologically and ecologically from Artemia and is endemic to Australia. Parartemia produces only one hundredth the amount of hemoglobin that Artemia produces and does not upregulate production in response to low oxygen partial pressure. Comparison of the globin domains at the amino acid and DNA levels suggests that the Artemia globin T gene has accumulated substitutions differently from the Parartemia P and Artemia C globin genes. We discuss the questions of accelerated evolution after duplication and possible functions for the Parartemia globin.