tbuckley/cabot-search huggingface dataset:
Ectopic pancreas formation in Hes1-knockout mice reveals plasticity of endodermal progenitors of the gut, bile duct, and pancreas
Authors: A. Fukuda
Journal: Journal of Clinical Investigation (2006)

Ectopic pancreas is a developmental anomaly occasionally found in humans. Hes1, a main effector of Notch signaling, regulates the fate and differentiation of many cell types during development. To gain insights into the role of the Notch pathway in pancreatic fate determination, we combined the use of Hes1-knockout mice and lineage tracing employing the Cre/loxP system to specifically mark pancreatic precursor cells and their progeny in Ptf1a-cre and Rosa26 reporter mice. We show that inactivation of Hes1 induces misexpression of Ptf1a in discrete regions of the primitive stomach and duodenum and throughout the common bile duct. All ectopic Ptf1a-expressing cells were reprogrammed, or transcommitted, to multipotent pancreatic progenitor status and subsequently differentiated into mature pancreatic exocrine, endocrine, and duct cells. This process recapitulated normal pancreatogenesis in terms of morphological and genetic features. Furthermore, analysis of Hes1/Ptf1a double mutants revealed that ectopic Ptf1a-cre lineage-labeled cells adopted the fate of region-appropriate gut epithelium or endocrine cells similarly to Ptf1a-inactivated cells in the native pancreatic buds. Our data demonstrate that the Hes1-mediated Notch pathway is required for region-appropriate specification of pancreas in the developing foregut endoderm through regulation of Ptf1a expression, providing novel insight into the pathogenesis of ectopic pancreas development in a mouse model.
Novel and recurrent mutations in the 1B domain of keratin 1 in palmoplantar keratoderma with tonotubules
Authors: G. Grimberg, I. Hausser, F.B. Müller, K. Wodecki, C. Schaffrath, T. Krieg, V. Oji, H. Traupe, M.J. Arin
Journal: British Journal of Dermatology (2008)

Conflicts of interest: none declared. Palmoplantar keratodermas (PPKs) are a large group of disorders characterized by hyperkeratosis of palms and soles. They can be classified by their mode of inheritance, the morphology and distribution of the hyperkeratosis (diffuse, focal or punctate), the involvement of other ectodermal structures, the presence or absence of associated nonectodermal features and the morphological findings at light and electron microscopic levels.1 Mutations in a variety of proteins are associated with different types of PPK. These proteins include keratins, proteins of the cornified cell envelope (loricrin), and molecules for cohesion (desmoglein, desmoplakin), intercellular communication (connexins) and transmembrane transduction (cathepsin C). PKK of Voerner is the most frequently inherited PPK.2 It is transmitted in an autosomal dominant mode and starts within the first year of life. It is characterized by a diffuse, yellowish or erythematous hyperkeratosis, sometimes covering bullous lesions, that is sharply demarcated with an erythematous margin; typically there is no progression to the dorsal aspects of hands and feet. Additional features frequently seen are knuckle pad‐like keratoses over the flexural areas of the finger joints, clubbing of the nails, and hyperhidrosis.3 Mutations in the keratin 9 gene (KRT9) have been identified in this PPK.3
Inhibitory Effect of Hippocampal 5-HT<sub>1A</sub>Receptors on Human Explicit Memory
Authors: Fumihiko Yasuno, Tetsuya Suhara, Takashi Nakayama, Tetsuya Ichimiya, Yoshiro Okubo, Akihiro Takano, Tomomichi Ando, Makoto Inoue, Jun Maeda, Kazutoshi Suzuki
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Recent studies have indicated that the serotonergic (5-HT) system plays important roles in memory function. However, the specific relationship between 5-HT1A receptors and memory function is not clear in the human brain. To clarify this relationship, the authors determined the availability of 5-HT1A receptors in the human brain and the relationship between regional receptor binding and memory function. METHOD: Using positron emission tomography (PET) with [11C]WAY-100635, the authors examined 5-HT1A receptors and assessed their relationship with memory function. The 5-HT1A agonist tandospirone was then administered to investigate the effect of 5-HT1A receptor stimulation on cognitive function and neuroendocrinological response. RESULTS: There was a significant negative correlation between explicit memory function and 5-HT1A receptor binding localized in the bilateral hippocampus where the postsynaptic 5-HT1A receptors are enriched. Furthermore, the administration of tandospirone dose-dependently impaired explicit verbal memory, while other cognitive functions showed no significant changes. The change in memory function paralleled those of body temperature and secretion of growth hormone, which were reported to be induced by the stimulation of postsynaptic 5-HT1A receptors. CONCLUSIONS: Postsynaptic 5-HT1A receptors localized in the hippocampal formation have a negative influence on explicit memory function, which raises the possibility that the antagonistic effect of postsynaptic 5-HT1A receptors in the hippocampus leads to improvement of human memory function. Drugs that work as antagonists on postsynaptic 5-HT1A receptors may be favorable for improved control of memory impairment.
Clevudine is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B with durable off-therapy viral suppression
Authors: Byung Chul Yoo, Ju Hyun Kim, Tae-Hun Kim, Kwang Cheol Koh, Soon-Ho Um, Young Soo Kim, Kwan Sik Lee, Byung Hoon Han, Chae Yoon Chon, Joon-Yeol Han, Soo Hyung Ryu, Haak Cheoul Kim, Kwan Soo Byun, Seong Gyu Hwang, Byung-Ik Kim, Mong Cho, Kwon Yoo, Heon-Ju Lee, Jae Seok Hwang, Yun Soo Kim, Young-Suk Lee, Sung-Kyu Choi, Youn-Jae Lee, Jin-Mo Yang, Joong-Won Park, Myung-Seok Lee, Dae-Ghon Kim, Young-Hwa Chung, Se-Hyun Cho, Jong-Young Choi, Young-Oh Kweon, Heon Young Lee, Sook-Hyang Jeong, Hee-Won Yoo, Hyo-Suk Lee
Journal: Hepatology (2007)

Clevudine is a pyrimidine analog with potent and sustained antiviral activity against HBV. In the present study, we evaluated the safety and efficacy of clevudine 30 mg daily for 24 weeks and assessed the durability of antiviral response for 24 weeks after cessation of dosing in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (e-CHB). We randomized a total of 86 patients (3:1) to receive clevudine 30 mg (n = 63) or placebo (n = 23) daily for 24 weeks. We followed patients for an additional 24 weeks after withdrawal of treatment. The median changes in HBV DNA from baseline were -4.25 and -0.48 log(10) copies/mL at week 24 in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained after withdrawal of therapy, with 3.11 log(10) reduction at week 48. At week 24 and week 48, 92.1% and 16.4% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (<300 copies/mL). The proportion of patients who achieved ALT normalization was 74.6% and 33.3% in the clevudine and placebo groups at week 24, respectively (P = 0.0006). ALT normalization in the clevudine group was well-maintained during the post-treatment follow-up period. The incidence of adverse events was similar in the 2 groups. No resistance to clevudine was detected during treatment.A 24-week clevudine therapy was well-tolerated and showed potent and sustained antiviral effect without evidence of viral resistance in e-CHB patients. However, treatment for longer than 24 weeks would be needed to achieve durable remission.
Optimal Management of Malignant Pleural Effusions (Results of CALGB 30102)
Authors: Todd L Demmy, Lin Gu, Jack E Burkhalter, Eric M Toloza, Thomas A D'Amico, Susan Sutherland, Xiaofei Wang, Laura Archer, Linda J Veit, Leslie Kohman
Journal: Journal of the National Comprehensive Cancer Network (2012)

The optimal strategy to achieve palliation of malignant pleural effusions (MPEs) is unknown. This multi-institutional, prospective, randomized trial compares 2 established methods for controlling symptomatic unilateral MPEs. Patients with unilateral MPEs were randomized to either daily tunneled catheter drainage (TCD) or bedside talc pleurodesis (TP). This trial is patterned after a previous randomized trial that showed that bedside TP was equivalent to thoracoscopic TP (CALGB 9334). The primary end point of the current study was combined success: consistent/reliable drainage/pleurodesis, lung expansion, and 30-day survival. A secondary end point, survival with effusion control, was added retrospectively. This trial randomized 57 patients who were similar in terms of age (62 years), active chemotherapy (28%), and histologic diagnosis (lung, 63%; breast, 12%; other/unknown cancers, 25%) to either bedside TP or TCD. Combined success was higher with TCD (62%) than with TP (46%; odds ratio, 5.0; P = .064). Multivariate regression analysis revealed that patients treated with TCD had better 30-day activity without dyspnea scores (8.7 vs. 5.9; P = .036), especially in the subgroup with impaired expansion (9.1 vs. 4.6; P = .042). Patients who underwent TCD had better survival with effusion control at 30 days compared with those who underwent TP (82% vs. 52%, respectively; P = .024). In this prospective randomized trial, TCD achieved superior palliation of unilateral MPEs than TP, particularly in patients with trapped lungs.
Insulin-like growth factor I gene promoter polymorphism, collagen type II 1 (COL2A1) gene, and the prevalence of radiographic osteoarthritis: the Rotterdam Study
Authors: G Zhai
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objective:</b> To examine the role of an IGF-I gene promoter polymorphism in the prevalence of radiographic osteoarthritis (ROA), and study its interaction with the COL2A1 gene. <b>Methods:</b> Individuals genotyped for IGF-I (n = 1546) and COL2A1 gene polymorphisms (n = 808) were selected from a random sample (n = 1583) derived from the Rotterdam study. The presence of ROA was defined as a Kellgren score of 2 or more in at least one of four joints (knee, hip, hand, and spine). Genotype specific odds ratios (OR) were adjusted for age, sex, body mass index, and bone mineral density using logistic regression. Interaction with the COL2A1 genotype was tested. <b>Results:</b> Overall, no association was found between the IGF-I polymorphism and ROA. In subjects aged 65 years or younger (n = 971), the prevalence of ROA increased with the absence of the 192 base pair (bp) allele (p for trend = 0.03). Compared with homozygotes for the 192 bp allele, the prevalence of ROA was 1.4 times higher in heterozygotes (95% confidence interval, 1.0 to 1.8) and 1.9 times higher in non-carriers (1.1 to 3.3). There was evidence of interaction between the IGF-I and COL2A1 genes. Individuals with the risk genotype of both genes had an increased prevalence of ROA (OR 3.4 (1.1 to 10.7)). No effect was observed in subjects older than 65 years. <b>Conclusions:</b> Subjects with genetically determined low IGF-I expression (non-carriers of the 192 bp allele) may be at increased risk of ROA before the age of 65 years. Furthermore, an interaction between the IGF-I and COL2A1 genes is suggested.
A study with cumulative doses of formoterol and salbutamol in children with asthma
Authors: T Foucard, G Lonnerholm
Journal: European Respiratory Journal (1991)

In a double-blind, cross-over study, 9 children (7-13 yrs old) with stable, moderate asthma inhaled formoterol (6, 18 and 54 micrograms) and salbutamol (100, 300 and 900 micrograms) at hourly intervals, in order to compare the peak effect of cumulative doses of the two drugs. One hour after the last dose, 1 mg salbutamol was inhaled to ensure that maximum bronchodilatation was obtained. The forced expiratory volume in one second (FEV1), peak expiratory flow rate (PEFR), forced vital capacity (FVC), pulse rate, blood pressure and tremor were measured regularly after each dose and the PEFR 5, 7, 9 and 20 h after the last dose. The first dose of each drug improved the FEV1, PEFR and FVC substantially while the following doses only gave minor improvement. The final addition of 1 mg salbutamol produced no further improvement. No statistically significant difference in bronchodilating effect was seen between the two drugs at any point in time. Side-effects were minimal. Our data indicate that doses of 6-24 micrograms formoterol can be recommended for school children. For most patients with mild to moderate bronchial asthma higher doses will not add much to the bronchodilating effect.
Recent Expansion of a New Ingi-Related Clade of Vingi non-LTR Retrotransposons in Hedgehogs
Authors: K. K. Kojima, V. V. Kapitonov, J. Jurka
Journal: Molecular Biology and Evolution (2010)

Autonomous non-long terminal repeat (non-LTR) retrotransposons and their repetitive remnants are ubiquitous components of mammalian genomes. Recently, we identified non-LTR retrotransposon families, Ingi-1_AAl and Ingi-1_EE, in two hedgehog genomes. Here we rename them to Vingi-1_AAl and Vingi-1_EE and report a new clade “Vingi,” which is a sister clade of Ingi that lacks the ribonuclease H domain. In the European hedgehog genome, there are 11 non-autonomous families of elements derived from Vingi-1_EE by internal deletions. No retrotransposons related to Vingi elements were found in any of the remaining 33 mammalian genomes nearly completely sequenced to date, but we identified several new families of Vingi and Ingi retrotransposons outside mammals. Our data suggest the horizontal transfer of Vingi elements to hedgehog, although the vertical transfer cannot be ruled out. The compact structure and trans-mobilization of nonautonomous derivatives of Vingi can make them useful for in vivo retrotransposition assay system.
Zebrafish as a model to study cardiac development and human cardiac disease
Authors: J. Bakkers
Journal: Cardiovascular Research (2011)

Over the last decade, the zebrafish has entered the field of cardiovascular research as a new model organism. This is largely due to a number of highly successful small- and large-scale forward genetic screens, which have led to the identification of zebrafish mutants with cardiovascular defects. Genetic mapping and identification of the affected genes have resulted in novel insights into the molecular regulation of vertebrate cardiac development. More recently, the zebrafish has become an attractive model to study the effect of genetic variations identified in patients with cardiovascular defects by candidate gene or whole-genome-association studies. Thanks to an almost entirely sequenced genome and high conservation of gene function compared with humans, the zebrafish has proved highly informative to express and study human disease-related gene variants, providing novel insights into human cardiovascular disease mechanisms, and highlighting the suitability of the zebrafish as an excellent model to study human cardiovascular diseases. In this review, I discuss recent discoveries in the field of cardiac development and specific cases in which the zebrafish has been used to model human congenital and acquired cardiac diseases.
T cell regulation of natural killer cells
Authors: Yann Kerdiles, Sophie Ugolini, Eric Vivier
Journal: The Journal of Experimental Medicine (2013)

In light of their role in the immune response against tumors and viruses, natural killer (NK) cells represent a promising target for immunotherapy. Before this target is reached, the various mechanisms that control NK cell activity must first be identified and understood. In the past decades, studies have identified two critical processes that prevent spontaneous NK cell-mediated autoimmune activation while maximizing the efficiency of these cells during an immune response. First is the education process, whereby NK cells adapt to their environment by sensing ligands for inhibitory and activating receptors. Second is the priming phase of NK cell activation, which arms NK cells with appropriate cytotoxic molecules during inflammation. New studies now indicate that NK cell proliferation, accumulation, and activation are also under the control of regulatory T cells that restrict availability of IL-2 released by activated CD4(+) T cells. Together with other recent studies, these data highlight the importance of the adaptive immune system in the regulation of NK cell activity.
Role of Phospholipid Oxidation Products in Atherosclerosis
Authors: Sangderk Lee, Konstantin G. Birukov, Casey E. Romanoski, James R. Springstead, Aldons J. Lusis, Judith A. Berliner
Journal: Circulation Research (2012)

There is increasing clinical evidence that phospholipid oxidation products (Ox-PL) play a role in atherosclerosis. This review focuses on the mechanisms by which Ox-PL interact with endothelial cells, monocyte/macrophages, platelets, smooth muscle cells, and HDL to promote atherogenesis. In the past few years major progress has been made in identifying these mechanisms. It has been recognized that Ox-PL promote phenotypic changes in these cell types that have long-term consequences for the vessel wall. Individual Ox-PL responsible for specific cellular effects have been identified. A model of the configuration of bioactive truncated Ox-PL within membranes has been developed that demonstrates that the oxidized fatty acid moiety protrudes into the aqueous phase, rendering it accessible for receptor recognition. Receptors and signaling pathways for individual Ox-PL species are now determined and receptor independent signaling pathways identified. The effects of Ox-PL are mediated both by gene regulation and transcription independent processes. It has now become apparent that Ox-PL affects multiple genes and pathways, some of which are proatherogenic and some are protective. However, at concentrations that are likely present in the vessel wall in atherosclerotic lesions, the effects promote atherogenesis. There have also been new insights on enzymes that metabolize Ox-PL and the significance of these enzymes for atherosclerosis. With the knowledge we now have of the regulation and effects of Ox-PL in different vascular cell types, it should be possible to design experiments to test the role of specific Ox-PL on the development of atherosclerosis.
Casein Kinase II Alpha Subunit and C1-Inhibitor Are Independent Predictors of Outcome in Patients with Squamous Cell Carcinoma of the Lung
Authors: Pornchai O-charoenrat, Valerie Rusch, Simon G. Talbot, Inderpal Sarkaria, Agnes Viale, Nicholas Socci, Ivan Ngai, Pulivarthi Rao, Bhuvanesh Singh
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Gene expression profiling has been shown to be a valuable tool for prognostication and identification of cancer-associated genes in human malignancies. We aimed to identify potential prognostic marker(s) in non-small cell lung cancers using global gene expression profiles. Experimental Design: Twenty-one previously untreated patients with non-small cell lung cancer were analyzed using the Affymetrix GeneChip high-density oligonucleotide array and comparative genomic hybridization. Identified candidate genes were validated in an independent cohort of 45 patients using quantitative real-time reverse transcription-PCR and Western blot analyses. Follow-up data for these patients was collected and used to assess outcome correlations. Results: Hierarchical clustering analysis yielded three distinct subgroups based on gene expression profiling. Cluster I consisted of 4 patients with adenocarcinoma and 1 with squamous cell carcinoma (squamous cell carcinoma); clusters II and III consisted of 6 and 10 patients with squamous cell carcinoma, respectively. Outcome analysis was performed on the cluster groups containing solely squamous cell carcinoma, revealing significant differences in disease-specific survival rates. Moreover, patients having a combination of advanced Tumor-Node-Metastasis stage and assigned to the poor prognosis cluster group (cluster II) had significantly poorer outcomes. Comparative genomic hybridization analysis showed recurrent chromosomal losses at 1p, 3p, 17, 19, and 22 and gains/amplifications at 3q, 5p, and 8q, which did not vary significantly between the cluster groups. We internally and externally validated a subset of 11 cluster II (poor prognosis)-specific genes having corresponding chromosomal aberrations identified by comparative genomic hybridization as prognostic markers in an independent cohort of patients with lung squamous cell carcinoma identifying CSNK2A1 and C1-Inh as independent predictors of outcome. Conclusion: CSNK2A1 and C1-Inh are independent predictors of survival in lung squamous cell carcinoma patients and may be useful as prognostic markers.
Trunk Versus Extremity Adiposity and Cardiometabolic Risk Factors in White and African American Adults
Authors: Gang Hu, Claude Bouchard, George A. Bray, Frank L. Greenway, William D. Johnson, Robert L. Newton, Eric Ravussin, Donna H. Ryan, Peter T. Katzmarzyk
Journal: Diabetes Care (2011)

OBJECTIVE To determine contributions of trunk and extremity adiposity to cardiometabolic risk factors (blood pressure, fasting blood glucose, HDL cholesterol, and triglycerides) among white and African American adults. RESEARCH DESIGN AND METHODS The sample consisted of 1,129 white women, 779 African American women, 1,012 white men, and 300 African American men. RESULTS Higher trunk adiposity was significantly associated with an increased risk of having two or more cardiometabolic risk factors among African American and white men and women. After adjustment for trunk and arm adiposity, higher leg adiposity was significantly associated with a decreased risk of having two or more cardiometabolic risk factors among white men and women and African American women. CONCLUSIONS In contrast with adverse risk with high trunk adiposity, high leg adiposity is associated with a decreased risk of having two or more cardiometabolic risk factors in both African American and white adults.
The Blood-Brain Barrier/Neurovascular Unit in Health and Disease
Authors: Brian T. Hawkins, Thomas P. Davis
Journal: Pharmacological Reviews (2005)

The blood-brain barrier (BBB) is the regulated interface between the peripheral circulation and the central nervous system (CNS). Although originally observed by Paul Ehrlich in 1885, the nature of the BBB was debated well into the 20th century. The anatomical substrate of the BBB is the cerebral microvascular endothelium, which, together with astrocytes, pericytes, neurons, and the extracellular matrix, constitute a "neurovascular unit" that is essential for the health and function of the CNS. Tight junctions (TJ) between endothelial cells of the BBB restrict paracellular diffusion of water-soluble substances from blood to brain. The TJ is an intricate complex of transmembrane (junctional adhesion molecule-1, occludin, and claudins) and cytoplasmic (zonula occludens-1 and -2, cingulin, AF-6, and 7H6) proteins linked to the actin cytoskeleton. The expression and subcellular localization of TJ proteins are modulated by several intrinsic signaling pathways, including those involving calcium, phosphorylation, and G-proteins. Disruption of BBB TJ by disease or drugs can lead to impaired BBB function and thus compromise the CNS. Therefore, understanding how BBB TJ might be affected by various factors holds significant promise for the prevention and treatment of neurological diseases.