tbuckley/cabot-search huggingface dataset:
CD4+ T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease
Authors: Antonella De Luca, Rossana G. Iannitti, Silvia Bozza, Remi Beau, Andrea Casagrande, Carmen D’Angelo, Silvia Moretti, Cristina Cunha, Gloria Giovannini, Cristina Massi-Benedetti, Agostinho Carvalho, Louis Boon, Jean-Paul Latgé, Luigina Romani
Journal: Journal of Clinical Investigation (2012)

Aspergillus fumigatus is a model fungal pathogen and a common cause of infection in individuals with the primary immunodeficiency chronic granulomatous disease (CGD). Although primarily considered a deficiency of innate immunity, CGD is also linked to dysfunctional T cell reactivity. Both CD4(+) and CD8(+) T cells mediate vaccine-induced protection from experimental aspergillosis, but the molecular mechanisms leading to the generation of protective immunity and whether these mechanisms are dysregulated in individuals with CGD have not been determined. Here, we show that activation of either T cell subset in a mouse model of CGD is contingent upon the nature of the fungal vaccine, the involvement of distinct innate receptor signaling pathways, and the mode of antigen routing and presentation in DCs. Aspergillus conidia activated CD8(+) T cells upon sorting to the Rab14(+) endosomal compartment required for alternative MHC class I presentation. Cross-priming of CD8(+) T cells failed to occur in mice with CGD due to defective DC endosomal alkalinization and autophagy. However, long-lasting antifungal protection and disease control were successfully achieved upon vaccination with purified fungal antigens that activated CD4(+) T cells through the endosome/lysosome pathway. Our study thus indicates that distinct intracellular pathways are exploited for the priming of CD4(+) and CD8(+) T cells to A. fumigatus and suggests that CD4(+) T cell vaccination may be able to overcome defective antifungal CD8(+) T cell memory in individuals with CGD.
Expression of human ERG K channels in the mouse heart exerts anti-arrhythmic activity
Authors: A ROYER, S DEMOLOMBE, A ELHARCHI, K LEQUANG, J PIRON, G TOUMANIANTZ, D MAZURAIS, C BELLOCQ, G LANDE, C TERRENOIRE
Journal: Cardiovascular Research (2004)

The K(+) channel encoded by the human ether-a-go-go-related gene (HERG) is crucial for repolarization in the human heart. In order to investigate the impact of HERG current (I(Kr)) on the incidence of cardiac arrhythmias, we generated a transgenic mouse expressing HERG specifically in the heart.ECG recordings at baseline showed no obvious difference between transgenic and wild-type (WT) mice with the exception of the T wave, which was more negative in transgenic mice than in WT mice. E4031 (20 mg/kg) prolonged the QTc interval and flattened the T wave in transgenic mice, but not in WT mice. Injection of BaCl(2) (25 mg/kg) induced short runs of ventricular tachycardia in 9/10 WT mice, but not in transgenic animals. Atrial pacing reproducibly induced atrial tachyarrhythmias in 11/15 WT mice. In contrast, atrial arrhythmia was inducible in only 2/11 transgenic mice. When pretreated with dofetilide (10 mg/kg), transgenic mice were as sensitive to experimental arrhythmias as WT mice. Microelectrode studies showed that atrial action potentials have a steeper slope of duration-rate adaptation in WT than in transgenic mice. Transgenic mice were also characterized by a post-repolarization refractoriness, which could result from the substantial amount of I(Kr) subsisting after repolarization as assessed with action potential-clamp experiments and simulations with a model of the transgenic mouse action potential.HERG expression in the mouse heart can protect against experimental induction of arrhythmias. This is the first report of such a protective effect of HERG in vivo.
Thalidomide: dermatological indications, mechanisms of action and side-effects
Authors: J.J. Wu, D.B. Huang, K.R. Pang, S. Hsu, S.K. Tyring
Journal: British Journal of Dermatology (2005)

Thalidomide was first introduced in the 1950s as a sedative but was quickly removed from the market after it was linked to cases of severe birth defects. However, it has since made a remarkable comeback for the U.S. Food and Drug Administration-approved use in the treatment of erythema nodosum leprosum. Further, it has shown its effectiveness in unresponsive dermatological conditions such as actinic prurigo, adult Langerhans cell histiocytosis, aphthous stomatitis, Behçet's syndrome, graft-versus-host disease, cutaneous sarcoidosis, erythema multiforme, Jessner-Kanof lymphocytic infiltration of the skin, Kaposi sarcoma, lichen planus, lupus erythematosus, melanoma, prurigo nodularis, pyoderma gangrenosum and uraemic pruritus. This article reviews the history, pharmacology, mechanism of action, clinical uses and adverse effects of thalidomide.
THE HIGH-AFFINITY I<scp>g</scp>E RECEPTOR (FcεRI): From Physiology to Pathology
Authors: Jean-Pierre Kinet
Journal: Annual Review of Immunology (1999)

▪ Abstract The high affinity receptor for immunoglobulin E (designated FcεRI) is the member of the antigen (Ag) receptor superfamily responsible for linking pathogen- or allergen-specific IgEs with cellular immunologic effector functions. This review provides background information on FcεRI function combined with more detailed summaries of recent progress in understanding specific aspects of FcεRI biology and biochemistry. Topics covered include the coordination and function of the large multiprotein signaling complexes that are assembled when FcεRI and other Ag receptors are engaged, new information on human receptor structures and tissue distribution, and the role of the FcRβ chain in signaling and its potential contribution to atopic phenotypes.
Seizures after alendronate
Authors: R. J Maclsaac, E. Seeman, G. Jerums
Journal: Journal of the Royal Society of Medicine (2002)

Alendronate and other bisphosphonates are effective in the prevention and treatment of osteoporosis by inhibiting bone resorption. In normal circumstances a small initial fall in serum calcium has no clinical consequences because it is corrected by an increase in parathyroid hormone (PTH) secretion1.
Enhanced levels of Hsulf-1 interfere with heparin-binding growth factor signaling in pancreatic cancer
Authors: Junsheng Li, Jörg Kleeff, Ivane Abiatari, Hany Kayed, Nathalia A Giese, Klaus Felix, Thomas Giese, Markus W Büchler, Helmut Friess
Journal: Molecular Cancer (2005)

Abstract Hsulf-1 is a newly identified enzyme, which has the ability to decrease the growth of hepatocellular, ovarian, and head and neck squamous cell carcinoma cells by interfering with heparin-binding growth factor signaling. Since pancreatic cancers over-express a number of heparin-binding growth factors and their receptors, the expression and function of this enzyme in pancreatic cancer was analyzed. Results Pancreatic cancer samples expressed significantly (22.5-fold) increased Hsulf-1 mRNA levels compared to normal controls, and Hsulf-1 mRNA was localized in the cancer cells themselves as well as in peritumoral fibroblasts. 4 out of 8 examined pancreatic cancer cell lines expressed Hsulf-1, whereas its expression was below the level of detection in the other cell lines. Stable transfection of the Hsulf-1 negative Panc-1 pancreatic cancer cell line with a full length Hsulf-1 expression vector resulted in increased sulfatase activity and decreased cell-surface heparan-sulfate proteoglycan (HSPG) sulfation. Hsulf-1 expression reduced both anchorage-dependent and -independent cell growth and decreased FGF-2 mediated cell growth and invasion in this cell line. Conclusion High expression of Hsulf-1 occurs in the stromal elements as well as in the tumor cells in pancreatic cancer and interferes with heparin-binding growth factor signaling.
The beauty of models for developmental disorders
Authors: J. Briscoe
Journal: Behavioral and Brain Sciences (2002)

Cognitive frameworks provide important means for uniting concepts of specificity, cognition, and dynamic change in development. Two points are challenged by evidence from special populations: (1) that boundary constraints such as Residual Normality and a cognitive “endstate” compromise the use of cognitive models; and (2) the developmental process itself automatically rejects either Residual Normality or residual deviance from typical development.
Incidental Meniscal Findings on Knee MRI in Middle-Aged and Elderly Persons
Authors: Martin Englund, Ali Guermazi, Daniel Gale, David J. Hunter, Piran Aliabadi, Margaret Clancy, David T. Felson
Journal: New England Journal of Medicine (2008)

Magnetic resonance imaging (MRI) of the knee is often performed in patients who have knee symptoms of unclear cause. When meniscal tears are found, it is commonly assumed that the symptoms are attributable to them. However, there is a paucity of data regarding the prevalence of meniscal damage in the general population and the association of meniscal tears with knee symptoms and with radiographic evidence of osteoarthritis.
Identification of the multiple beta-thalassemia mutations by denaturing gradient gel electrophoresis.
Authors: S P Cai, Y W Kan
Journal: Journal of Clinical Investigation (1990)

We used denaturing gradient gel electrophoresis to detect the beta-thalassemia mutations in the Chinese population. By amplifying the beta-globin gene in four separate fragments and electrophoresing the amplified DNA in two gels, we were able to distinguish all the 12 known mutations on the basis of the mobility of the homoduplexes and heteroduplexes. We conclude that denaturing gradient gel electrophoresis offers a nonradioactive means of detecting multiple mutations in genetic disorders.
A heterozygous moth genome provides insights into herbivory and detoxification
Authors: Minsheng You, Zhen Yue, Weiyi He, Xinhua Yang, Guang Yang, Miao Xie, Dongliang Zhan, Simon W Baxter, Liette Vasseur, Geoff M Gurr, Carl J Douglas, Jianlin Bai, Ping Wang, Kai Cui, Shiguo Huang, Xianchun Li, Qing Zhou, Zhangyan Wu, Qilin Chen, Chunhui Liu, Bo Wang, Xiaojing Li, Xiufeng Xu, Changxin Lu, Min Hu, John W Davey, Sandy M Smith, Mingshun Chen, Xiaofeng Xia, Weiqi Tang, Fushi Ke, Dandan Zheng, Yulan Hu, Fengqin Song, Yanchun You, Xiaoli Ma, Lu Peng, Yunkai Zheng, Yong Liang, Yaqiong Chen, Liying Yu, Younan Zhang, Yuanyuan Liu, Guoqing Li, Lin Fang, Jingxiang Li, Xin Zhou, Yadan Luo, Caiyun Gou, Junyi Wang, Jian Wang, Huanming Yang, Jun Wang
Journal: Nature Genetics (2013)

Minsheng You and colleagues report the whole-genome sequence of the diamondback moth, Plutella xylostella. Their transcriptome analysis from different life stages, together with comparative genomic and phylogenetic analysis, provides insights into herbivore evolution and insect adaptation to plant feeding and detoxification. How an insect evolves to become a successful herbivore is of profound biological and practical importance. Herbivores are often adapted to feed on a specific group of evolutionarily and biochemically related host plants1, but the genetic and molecular bases for adaptation to plant defense compounds remain poorly understood2. We report the first whole-genome sequence of a basal lepidopteran species, Plutella xylostella, which contains 18,071 protein-coding and 1,412 unique genes with an expansion of gene families associated with perception and the detoxification of plant defense compounds. A recent expansion of retrotransposons near detoxification-related genes and a wider system used in the metabolism of plant defense compounds are shown to also be involved in the development of insecticide resistance. This work shows the genetic and molecular bases for the evolutionary success of this worldwide herbivore and offers wider insights into insect adaptation to plant feeding, as well as opening avenues for more sustainable pest management.
Reactivation of Suppressed RhoB is a Critical Step for the Inhibition of Anaplastic Thyroid Cancer Growth
Authors: Laura A. Marlow, Lisa A. Reynolds, Alan S. Cleland, Simon J. Cooper, Michelle L. Gumz, Shinichi Kurakata, Kosaku Fujiwara, Ying Zhang, Thomas Sebo, Clive Grant, Bryan McIver, J. Trad Wadsworth, Derek C. Radisky, Robert C. Smallridge, John A. Copland
Journal: Cancer Research (2009)

Anaplastic thyroid carcinoma (ATC) is a highly aggressive form of the disease for which new therapeutic options are desperately needed. Previously, we showed that the high-affinity peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, RS5444, inhibits cell proliferation of ATC cells via induction of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21). We show here that up-regulation of RhoB is a critical step in PPARgamma-mediated activation of p21-induced cell stasis. Using multiple independently derived ATC cell lines, we found that treatment with RS5444 leads to the up-regulation of RhoB and subsequent activation of p21, and that silencing of RhoB by RNAi blocks the ability of RS5444 to induce p21 and to inhibit cell proliferation. Our results show that transcriptional regulation of RhoB by the nuclear transcription factor PPARgamma is responsible for the induction of p21 mRNA and protein. We further implicate RhoB as a key signaling effector for the growth inhibition of ATC, as treatment with a histone deacetylase inhibitor shown to increase RhoB expression in lung cancer cells caused the up-regulation of RhoB in ATC cells accompanied by increased expression of p21 and inhibition of cell proliferation; this effect occurred even in ATC cells that were unresponsive to RS5444 due to a lack of expression of PPARgamma. Our results implicate RhoB as a novel intermediate in critical signaling pathways and as an additional target for therapeutic intervention in ATC.
The Biological Role of the Low-Affinity p75 Neurotrophin Receptor in Esophageal Squamous Cell Carcinoma
Authors: Tomoyuki Okumura, Shigeru Tsunoda, Yukiko Mori, Tetsuo Ito, Keiji Kikuchi, Timothy Cragin Wang, Shigeru Yasumoto, Yutaka Shimada
Journal: Clinical Cancer Research (2006)

Abstract In this study, we investigated the clinicopathologic significance of the low-affinity p75 neurotrophin receptor (p75NTR; which is expressed in the stem/progenitor cell fraction of normal esophageal epithelial cells) in 187 resected esophageal squamous cell carcinoma (ESCC) specimens and found that ∼50% of ESCC expressed p75NTR. Our investigation using ESCC cell lines showed that p75NTR was intensely expressed in the cells with high colony-forming capacity but they were sensitive to cell death on inhibition of p75NTR expression with transient transfection of small interfering RNA (siRNA). These findings suggest that p75NTR is necessary for survival and maintenance of ESCC tumors, providing us with a potential target for novel therapies. Purpose: p75NTR is expressed in a stem/progenitor cell fraction of human normal esophageal epithelial cells. In this study, we investigated the expression and biological role of p75NTR in ESCC. Experimental Design: The expression of p75NTR in 187 resected ESCC specimens was immunohistochemically investigated. The expression of p75NTR in 30 ESCC cell lines (KYSEs) was assessed by reverse transcription-PCR, immunocytochemistry, and flow cytometry. The p75NTR-bright and p75NTR-dim/negative cells were isolated from KYSE150 by magnetic beads and colony formation was investigated. The role of p75NTR in KYSEs was assessed by transient transfection of siRNA. Results: p75NTR was expressed in 92 of 187 (49.2%) tumors. In well-differentiated tumors, positive staining was apparent in the first one to two layers from infiltrative margin of the tumors where most of the cells were actively proliferating. In moderately differentiated tumors, p75NTR was expressed in wider range from the margin of the tumors whereas p75NTR was diffusely distributed in poorly differentiated tumors. p75NTR was expressed in all examined KYSEs and the mean proportion of the p75NTR-bright fraction was 30.1%. The size of p75NTR-positive colonies was larger than that of p75NTR-negative colonies derived from KYSE150 (P &amp;lt; 0.0001). The purified p75NTR-bright cells formed p75NTR-positive large colonies more frequently than the p75NTR-dim/negative cells (P &amp;lt; 0.0001). Down-regulation of p75NTR expression by siRNA resulted in marked growth inhibition with induction of apoptosis. Conclusions: Our findings suggest that p75NTR is necessary for survival and maintenance of ESCC tumors, providing us with a potential target for novel therapies.
Development, Maturation, and Transdifferentiation of Cardiac Sympathetic Nerves
Authors: Kensuke Kimura, Masaki Ieda, Keiichi Fukuda
Journal: Circulation Research (2012)

The heart is electrically and mechanically controlled as a syncytium by the autonomic nervous system. The cardiac nervous system comprises the sympathetic, parasympathetic, and sensory nervous systems that together regulate heart function on demand. Sympathetic electric activation was initially considered the main regulator of cardiac function; however, modern molecular biotechnological approaches have provided a new dimension to our understanding of the mechanisms controlling the cardiac nervous system. The heart is extensively innervated, although the innervation density is not uniform within the heart, being high in the subepicardium and the special conduction system. We and others showed previously that the balance between neural chemoattractants and chemorepellents determine cardiac nervous development, with both factors expressed in heart. Nerve growth factor is a potent chemoattractant synthesized by cardiomyocytes, whereas Sema3a is a neural chemorepellent expressed specifically in the subendocardium. Disruption of this well-organized molecular balance and innervation density can induce sudden cardiac death due to lethal arrhythmias. In diseased hearts, various causes and mechanisms underlie cardiac sympathetic abnormalities, although their detailed pathology and significance remain contentious. We reported that cardiac sympathetic rejuvenation occurs in cardiac hypertrophy and, moreover, interleukin-6 cytokines secreted from the failing myocardium induce cholinergic transdifferentiation of the cardiac sympathetic system via a gp130 signaling pathway, affecting cardiac performance and prognosis. In this review, we summarize the molecular mechanisms involved in sympathetic development, maturation, and transdifferentiation, and propose their investigation as new therapeutic targets for heart disease.
Clinicopathologic Correlations of Genomic Gains and Losses in Follicular Lymphoma
Authors: Andreas Viardot, Peter Möller, Josef Högel, Kirsten Werner, Gunhild Mechtersheimer, Anthony D. Ho, German Ott, Thomas F.E. Barth, Reiner Siebert, Stefan Gesk, Brigitte Schlegelberger, Hartmut Döhner, Martin Bentz
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To evaluate the clinical relevance of genomic aberrations in follicular lymphomas (FLs). PATIENTS AND METHODS: In this study, we analyzed 124 biopsy samples of patients with FL using comparative genomic hybridization. RESULTS: In 87 cases (70%), genomic imbalances were detectable. The most frequent aberrations were gains of chromosome arms 7p (21 patients), 7q (21 patients), Xp (16 patients), 12q (15 patients), and 18q (14 patients) as well as losses on 6q (21 patients). Grades 2 and 3 according to the World Health Organization classification correlated with a more complex karyotype (P &lt; .0001). In a subset of 82 patients, a comprehensive clinical data set was available. In a multivariate analysis including all clinical risk factors of the International Prognostic Index as well as genomic aberrations, the loss of material on chromosomal bands 6q25q27 was the strongest predictor of a shorter survival (P = .0001; hazard ratio, 6.5), followed by elevated serum lactate dehydrogenase level (P = .0009; hazard ratio, 4.9), the presence of more than one extranodal manifestation (P = .017; hazard ratio, 4.2), and age greater than 60 years (P = .022; hazard ratio, 2.6). CONCLUSION: These data indicate that genomic aberrations may contribute significantly to risk assessment in patients with FL, the majority of whom are included in low-risk groups using established clinical prognostic scores.
Prevalence and Characteristics of <i>MUTYH</i>-Associated Polyposis in Patients with Multiple Adenomatous and Serrated Polyps
Authors: Carla Guarinos, Miriam Juárez, Cecilia Egoavil, María Rodríguez-Soler, Lucía Pérez-Carbonell, Ramón Salas, Joaquín Cubiella, Francisco Rodríguez-Moranta, Luisa de-Castro, Luis Bujanda, Anna Serradesanferm, David Nicolás-Pérez, Maite Herráiz, Fernando Fernández-Bañares, Alberto Herreros-de-Tejada, Elena Aguirre, Judith Balmaña, María-Luisa Rincón, Angeles Pizarro, Francisco Polo-Ortiz, Adela Castillejo, Cristina Alenda, Artemio Payá, José-Luis Soto, Rodrigo Jover
Journal: Clinical Cancer Research (2014)

The present study aimed to determine the prevalence of MUTYH mutations in patients with multiple colonic polyps and to explore the best strategy for diagnosing MUTYH-associated polyposis (MAP) in these patients.This study included 405 patients with at least 10 colonic polyps each. All cases were genetically tested for the three most frequent MUTYH mutations. Whole-gene analysis was performed in heterozygous patients and in 216 patients lacking the three most frequent mutations. Polyps from 56 patients were analyzed for the KRAS-Gly12Cys and BRAF V600E somatic mutations.Twenty-seven (6.7%) patients were diagnosed with MAP, of which 40.8% showed serrated polyps. The sensitivity of studying only the three common variants was 74.1%. Of 216 patients without any monoallelic mutation in common variants, whole-gene analysis revealed biallelic pathogenic mutation in only one. G396D mutation was associated with serrated lesions and older age at diagnosis. There was a strong association between germinal MUTYH mutation and KRAS Gly12Cys somatic mutation in polyps. BRAF V600E mutation was found in 74% of serrated polyps in MUTYH-negative patients and in none of the polyps of MAP patients.We observed a low frequency of MUTYH mutations among patients with multiple adenomatous and serrated polyps. The MAP phenotype frequently included patients with serrated polyps, especially when G396D mutation was involved. Our results show that somatic molecular markers of polyps can be useful in identifying MAP cases and support the need for the complete MUTYH gene analysis only in patients heterozygous for recurrent variants.