tbuckley/cabot-search huggingface dataset:
Left atrial enlargement is not rare in PAH- RA/LA ratio is significantly lower in PH due to left heart disease
Authors: Matthias Held, Maximilian Römmelt, Gudrun Huebner, Berthold Jany
Journal: European Respiratory Journal (2013)

Patients with pulmonary hypertension (PH) and a left ventricular dysfunction frequently show a pathological mitral valve inflow pattern, tissue doppler abnormalities and a left atrial enlargement. However, it is questionable, if left atrial enlargement exclusively indicates pulmonary venous hypertension.  We studied a cohort of 168 patients with PH of our PH center and 67 controls and analysed left and right atrial area as well as the RA/LA-ratio. PH had been diagnosed according to the guidelines including right heart catheterization in all patients.  The cohort comprised patients with PH of group 1 PAH (n=82) ,2 PH due to left heart disease(n= 13), 3 PH due to lung disease (n=39), 4 CTEPH (n= 27) and 5 miscellaneuos PH (n=7).  Left atrial and right atrial enlargement respectively was found as follows: PAH (46 %/62%),PH 2 (77%/77%), PH3 (41 %/66%), CTEPH (22 %/64%), PH 5 (50 %/60%). Controls (30 %/16%).  Right/left atrial area-ratio was different from controls: PAH: 1.15,  p  p =0.92; PH 3: 1.31,  p  p=0.001  and PH 5: 2.44,  p = 0.30. Right/left area ratio of patients with PAH (p  In patients with PH not related to left heart disease atrial fibrillation seems to be predictive for left atrial enlargement.  Conclusion: Even in patients with PAH left atrial enlargement is not a rare finding. Due to an even more dilated right atrium in PAH, PH 3, CTEPH than in PH due to left heart disease, the RA/LA-area-ratio is significantly lower in patients with PH due to left heart disease and might be a more helpful non invasive tool.
Mechanisms of epithelial translocation of the 2-gliadin-33mer in coeliac sprue
Authors: M Schumann, J F Richter, I Wedell, V Moos, M Zimmermann-Kordmann, T Schneider, S Daum, M Zeitz, M Fromm, J D Schulzke
Journal: Gut (2008)

<h3>Background and aims:</h3> The α<sub>2</sub>-gliadin-33mer has been shown to be important in the pathogenesis of coeliac disease. We aimed to study mechanisms of its epithelial translocation and processing in respect to transcytotic and paracellular pathways. <h3>Methods:</h3> Transepithelial passage of a fluorescence-labelled α<sub>2</sub>-gliadin-33mer was studied in Caco-2 cells by using reverse-phase high-performance liquid chromatography, mass spectrometry, confocal laser scanning microscopy (LSM) and fluorescence activated cell sorting (FACS). Endocytosis mechanisms were characterised with rab-GFP constructs transiently transfected into Caco-2 cells and in human duodenal biopsy specimens. <h3>Results:</h3> The α<sub>2</sub>-gliadin-33mer dose-dependently crossed the epithelial barrier in the apical-to-basal direction. Degradation analysis revealed translocation of the 33mer polypeptide in the uncleaved as well as in the degraded form. Transcellular passage was identified by confocal LSM, inhibitor experiments and FACS. Rab5 but not rab4 or rab7 vesicles were shown to be part of the transcytotic pathway. After pre-incubation with interferon-γ, translocation of the 33mer was increased by 40%. In mucosal biopsies of the duodenum, epithelial 33mer uptake was significantly higher in untreated coeliac disease patients than in healthy controls or coeliac disease patients on a gluten-free diet. <h3>Conclusion:</h3> Epithelial translocation of the α<sub>2</sub>-gliadin-33mer occurs by transcytosis after partial degradation through a rab5 endocytosis compartment and is regulated by interferon-γ. Uptake of the 33mer is higher in untreated coeliac disease than in controls and coeliac disease patients on a gluten-free diet.
Asymmetric septal hypertrophy in heterozygous cMyBP-C null mice
Authors: L CARRIER
Journal: Cardiovascular Research (2004)

Objective: Cardiac myosin-binding protein C (cMyBP-C) gene mutations are involved in familial hypertrophic cardiomyopathy (FHC). Many of these mutations produce truncated proteins, which are unstable in the cardiac tissue of patients, suggesting that haploinsufficiency could account for the development of the phenotype. However, existing mouse models of cMyBP-C gene mutations have represented hypomorphic alleles without evidence of asymmetric septal hypertrophy, a key FHC phenotypic feature. In the present study, we generated a new model of cMyBP-C null mice and characterized the phenotype in both homozygotes and heterozygotes at different ages. Methods: The mouse model was based upon the targeted deletion of exons 1 and 2, which contain the transcription initiation site, and the phenotype was determined by molecular, functional and morphological analyses. Results: Herein, we demonstrate that inactivation of one or two mouse cMyBP-C alleles leads to different cardiac disorders at different post-natal time windows. The homozygous cMyBP-C null mice do not express the cMyBP-C gene, develop eccentric left ventricular hypertrophy with decreased fractional shortening at 3–4 months of age and a markedly impaired relaxation after 9 months. This is associated with myocardial disarray and an increase of interstitial fibrosis. The heterozygous cMyBP-C null mice present a slight but significant decrease of cMyBP-C amount and develop asymmetric septal hypertrophy associated with fibrosis at 10–11 months of age. Conclusion: These data provide evidence that heterozygous cMyBP-C null mice represent the first model with a key feature of human FHC that is asymmetric septal hypertrophy.
Matrix metalloproteinase-12 (MMP-12) SNP affects MMP activity, lung macrophage infiltration and protects against emphysema in COPD
Authors: I. Haq, G. E. Lowrey, N. Kalsheker, S. R. Johnson
Journal: Thorax (2011)

<h3>Background</h3> Recent genetic and animal studies have implicated matrix metalloproteinase-12 (MMP-12) in the pathogenesis of chronic obstructive pulmonary disease (COPD). It has previously been shown that individuals homozygous for the A/A allele of rs652438 in MMP-12 are over-represented among patients with severe COPD (n=1517). A study was undertaken to examine the functional basis of these findings. <h3>Methods</h3> rs652438 A and G variants were generated by site-directed mutagenesis and transfected into COS7 cells where they were expressed. Casein zymography and a specific FRET activity assay were used to compare MMP-12 activity between alleles. Cell migration was examined using a transwell assay. Patients from two COPD cohorts were genotyped for rs652438 and associated with inflammatory cell number in bronchoalveolar lavage fluid (n=10) and induced sputum (n=262); the emphysema score (n=1428) was assessed by CT scanning. <h3>Results</h3> Mean MMP activity was 2.95-fold higher by zymography (p=0.0049) and 3.45-fold higher by FRET assay (p=0.0001) for the A allele than the G allele. Mean migration of COS7 cells expressing the A allele was 2.31-fold greater than for those expressing the G allele (p=0.0001). Macrophage numbers were greater in bronchoalveolar lavage fluid (1.28-fold increase, p=0.033) and induced sputum (1.58-fold increase, p=0.083) of A/A individuals compared with A/G heterozygotes. The presence of the A allele was dose-dependently associated with increased emphysema (p=0.016). <h3>Conclusions</h3> The rs652438 SNP alters MMP-12 activity with the A allele being more active, which is associated with increased macrophage infiltration and emphysema in the lungs of patients with COPD. These findings further implicate MMP-12 and this SNP in COPD.
Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes
Authors: E. J. Verspohl
Journal: Pharmacological Reviews (2012)

The huge increase in type 2 diabetes is a burden worldwide. Many marketed compounds do not address relevant aspects of the disease; they may already compensate for defects in insulin secretion and insulin action, but loss of secreting cells (β-cell destruction), hyperglucagonemia, gastric emptying, enzyme activation/inhibition in insulin-sensitive cells, substitution or antagonizing of physiological hormones and pathways, finally leading to secondary complications of diabetes, are not sufficiently addressed. In addition, side effects for established therapies such as hypoglycemias and weight gain have to be diminished. At present, nearly 1000 compounds have been described, and approximately 180 of these are going to be developed (already in clinical studies), some of them directly influencing enzyme activity, influencing pathophysiological pathways, and some using G-protein-coupled receptors. In addition, immunological approaches and antisense strategies are going to be developed. Many compounds are derived from physiological compounds (hormones) aiming at improving their kinetics and selectivity, and others are chemical compounds that were obtained by screening for a newly identified target in the physiological or pathophysiological machinery. In some areas, great progress is observed (e.g., incretin area); in others, no great progress is obvious (e.g., glucokinase activators), and other areas are not recommended for further research. For all scientific areas, conclusions with respect to their impact on diabetes are given. Potential targets for which no chemical compound has yet been identified as a ligand (agonist or antagonist) are also described.
The Use of Khat<i>(Catha edulis)</i>in Yemen
Authors: WIJDAN LUQMAN
Journal: Annals of Internal Medicine (1976)

Catha edulis, or khat, a plant indigenous to Yemen, Ethiopia, and East Africa, has sympathomimetic and euphoriant effects. Its role in the economic, social, and political lives of people in North and South Yemen and certain clinical and psychiatric aspects are discussed.
Chronic Lymphocytic Leukemia After Chronic Myeloid Leukemia in the Same Patient: Two Different Genomic Events and a Common Treatment?
Authors: Giovanni D'Arena, Marica Gemei, Luigiana Luciano, Fiorella D'Auria, Silvia Deaglio, Teodora Statuto, Gabriella Bianchino, Vitina Grieco, Giovanna Mansueto, Roberto Guariglia, Giuseppe Pietrantuono, Maria Carmen Martorelli, Oreste Villani, Luigi Del Vecchio, Pellegrino Musto
Journal: Journal of Clinical Oncology (2012)
Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4
Authors: Mickaël M Ménager, Gaël Ménasché, Maryse Romao, Perrine Knapnougel, Chen-Hsuan Ho, Mériem Garfa, Graça Raposo, Jérôme Feldmann, Alain Fischer, Geneviève de Saint Basile
Journal: Nature Immunology (2007)
Lymph Node Dissection at the Time of Radical Nephrectomy for High-Risk Clear Cell Renal Cell Carcinoma: Indications and Recommendations for Surgical Templates
Authors: Paul L. Crispen, Rodney H. Breau, Cristine Allmer, Christine M. Lohse, John C. Cheville, Bradley C. Leibovich, Michael L. Blute
Journal: European Urology (2010)
KERATIN AND WATER
Authors: C. F. H. Vickers.
Journal: British Journal of Dermatology (1968)

Journal Article KERATIN AND WATER Get access C. F. H. Vickers. C. F. H. Vickers. Department of Dermatology, University of Liverpool Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 80, Issue 7, 1 July 1968, Pages 469–471, https://doi.org/10.1111/j.1365-2133.1968.tb11983.x Published: 01 July 1968
Proteasome Inhibition Activates Epidermal Growth Factor Receptor (EGFR) and EGFR-Independent Mitogenic Kinase Signaling Pathways in Pancreatic Cancer Cells
Authors: Callum M. Sloss, Fang Wang, Rong Liu, Lijun Xia, Michael Houston, David Ljungman, Michael A. Palladino, James C. Cusack
Journal: Clinical Cancer Research (2008)

Abstract Purpose: In the current study, we investigate the activation of antiapoptotic signaling pathways in response to proteasome inhibitor treatment in pancreatic cancer and evaluate the use of concomitant inhibition of these pathways to augment proteasome inhibitor treatment responses. Experimental Design: Pancreatic cancer cell lines and mouse flank xenografts were treated with proteasome inhibitor alone or in combination with chemotherapeutic compounds (gemcitabine, erlotinib, and bevacizumab), induction of apoptosis and effects on tumor growth were assessed. The effect of bortezomib (a first-generation proteasome inhibitor) and NPI-0052 (a second-generation proteasome inhibitor) treatment on key pancreatic mitogenic and antiapoptotic pathways [epidermal growth factor receptor, extracellular signal-regulated kinase, and phosphoinositide-3-kinase (PI3K)/AKT] was determined and the ability of inhibitors of these pathways to enhance the effects of proteasome inhibition was assessed in vitro and in vivo. Results: Our data showed that proteasome inhibitor treatment activates antiapoptotic and mitogenic signaling pathways (epidermal growth factor receptor, extracellular signal-regulated kinase, c-Jun-NH2-kinase, and PI3K/AKT) in pancreatic cancer. Additionally, we found that activation of these pathways impairs tumor response to proteasome inhibitor treatment and inhibition of the c-Jun-NH2-kinase and PI3K/AKT pathways increases the antitumor effects of proteasome inhibitor treatment. Conclusion: These preclinical studies suggest that targeting proteasome inhibitor–induced antiapoptotic signaling pathways in combination with proteasome inhibition may augment treatment response in highly resistant solid organ malignancies. Further evaluation of these novel treatment combinations in clinical trials is warranted.
Brain death-induced impairment of cardiac contractile performance can be reversed by explantation and may not preclude the use of hearts for transplantation.
Authors: M Galiñanes, D J Hearse
Journal: Circulation Research (1992)

The shortage of suitable donor hearts for cardiac transplantation is exacerbated by the exclusion of those that exhibit contractile malfunction during the period after brain death but before excision. We have replicated the phenomenon of brain death-induced hemodynamic deterioration in the rat in vivo. After 60 minutes of brain death (defined as the absence of electrical activity in the brain), a variety of indicators of cardiac contractile function fell by approximately 50% (thus cardiac index fell from 21 +/- 2 to 11 +/- 1 ml/min per 100 g body weight). However, once excised and perfused ex vivo, the hearts recovered a level of cardiac function that was identical to that from control animals that had not been subjected to brain death. Similarly, when hearts were excised, stored (6 hours at 4 degrees C), and reperfused ex vivo with blood, they also recovered a functional capability identical to that of normal hearts from animals that had not been subjected to brain death. Our results question whether hemodynamic instability in brain-dead individuals is necessarily an irreversible detrimental cardiac phenomenon and whether these hearts should be excluded from transplantation.
Fetal Hydantoin Syndrome, Neuroblastoma, and Hemorrhagic Disease in a Neonate
Authors: Robert W. Allen
Journal: JAMA (1980)

This is the first patient report of maternal ingestion of anticonvulsants associated with the triad of fetal hydantoin syndrome, neuroblastoma, and hemorrhagic disease. The neuroblastoma, a neural crest tumor, is the fourth of such origin reported after in utero exposure to phenytoin, suggesting that phenytoin is a transplacental carcinogen. Infants of epileptic mothers receiving anticonvulsants should be closely examined at birth for the fetal hydantoin syndrome and monitored for hemorrhagic problems. The neural crest tumor may be found at birth or later in childhood. (<i>JAMA</i>244:1464-1465, 1980)
Oral treatment with a <i>Brachystemma calycinum D don</i> plant extract reduces disease symptoms and the development of cartilage lesions in experimental dog osteoarthritis: inhibition of protease-activated receptor 2
Authors: Christelle Boileau, Johanne Martel-Pelletier, Judith Caron, Frédéric Paré, Eric Troncy, Maxim Moreau, Jean-Pierre Pelletier
Journal: Annals of the Rheumatic Diseases (2009)

Objective The aims of this study were to evaluate the effect of oral treatment with a whole plant extract of Brachystemma calycinum D don (BCD) on the development of osteoarthritic lesions and symptoms in the experimental dog anterior cruciate ligament (ACL) transection model and to document its mechanism of action. Methods Osteoarthritis was induced by sectioning the ACL of the right knee in crossbred dogs. There were two experimental groups (n=6–7 dogs/group): placebo and BCD extract (200 mg/kg per day) given orally for 8 weeks. Macroscopic and histopathological evaluation of cartilage lesions and immunohistochemical analysis of cartilage to assess levels of inducible nitric oxide synthase (iNOS), matrix metalloprotease 13 (MMP-13) and protease activated receptor 2 (PAR-2) were done. A gait analysis of dogs was performed. Results Treatment with BCD reduced the severity (depth) (p=0.04) and histopathological score (p&lt;0.02) of osteoarthritis cartilage lesions. BCD treatment also significantly reduced the osteoarthritis chondrocyte level of key inflammatory and catabolic factors (iNOS, p=0.009 and MMP-13, p=0.003) as well as the level of PAR-2 (p=0.03). Dogs treated with BCD showed a significant improvement in peak vertical force measured at 8 weeks (p&lt;0.05). Conclusions Treatment with BCD extract exerts a positive effect on the prevention of cartilage lesions induced by joint instability, and improves joint function. This effect was associated with the inhibition of major catabolic and inflammatory mediators. This study is the first to demonstrate that a therapeutic intervention that can inhibit PAR-2 is associated with a disease-modifying osteoarthritis effect.
Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial
Authors: S W Schalm
Journal: Gut (2000)

<h3>BACKGROUND, AIM, AND METHODS</h3> Alpha interferon is the generally approved therapy for HBe antigen positive patients with chronic hepatitis B, but its efficacy is limited. Lamivudine is a new oral nucleoside analogue which potently inhibits hepatitis B virus (HBV) DNA replication. To investigate the possibility of an additive effect of interferon-lamivudine combination therapy compared with interferon or lamivudine monotherapy, we conducted a randomised controlled trial in 230 predominantly Caucasian patients with hepatitis B e antigen (HBeAg) and HBV DNA positive chronic hepatitis B. Previously untreated patients were randomised to receive: combination therapy of lamivudine 100 mg daily with alpha interferon 10 million units three times weekly for 16 weeks after pretreatment with lamivudine for eight weeks (n=75); alpha interferon 10 million units three times weekly for 16 weeks (n=69); or lamivudine 100 mg daily for 52 weeks (n=82). The primary efficacy end point was the HBeAg seroconversion rate at week 52 (loss of HBeAg, development of antibodies to HBeAg and undetectable HBV DNA). <h3>RESULTS</h3> The HBeAg seroconversion rate at week 52 was 29% for the combination therapy, 19% for interferon monotherapy, and 18% for lamivudine monotherapy (p=0.12 and p=0.10, respectively, for comparison of the combination therapy with interferon or lamivudine monotherapy). The HBeAg seroconversion rates at week 52 for the combination therapy and lamivudine monotherapy were significantly different in the per protocol analysis (36% (20/56) <i>v</i> 19% (13/70), respectively; p=0.02). The effect of combining lamivudine and interferon appeared to be most useful in patients with moderately elevated alanine aminotransferase levels at baseline. Adverse events with the combination therapy were similar to interferon monotherapy; patients receiving lamivudine monotherapy had significantly fewer adverse events. <h3>CONCLUSIONS</h3> HBeAg seroconversion rates at one year were similar for lamivudine monotherapy (52 weeks) and standard alpha interferon therapy (16 weeks). The combination of lamivudine and interferon appeared to increase the HBeAg seroconversion rate, particularly in patients with moderately elevated baseline aminotransferase levels. The potential benefit of combining lamivudine and interferon should be investigated further in studies with different regimens of combination therapy.
The genome sequence of the most widely cultivated cacao type and its use to identify candidate genes regulating pod color
Authors: Juan C Motamayor, Keithanne Mockaitis, Jeremy Schmutz, Niina Haiminen, Donald Livingstone III, Omar Cornejo, Seth D Findley, Ping Zheng, Filippo Utro, Stefan Royaert, Christopher Saski, Jerry Jenkins, Ram Podicheti, Meixia Zhao, Brian E Scheffler, Joseph C Stack, Frank A Feltus, Guiliana M Mustiga, Freddy Amores, Wilbert Phillips, Jean Philippe Marelli, Gregory D May, Howard Shapiro, Jianxin Ma, Carlos D Bustamante, Raymond J Schnell, Dorrie Main, Don Gilbert, Laxmi Parida, David N Kuhn
Journal: Genome biology (2013)

Abstract Background Theobroma cacao L. cultivar Matina 1-6 belongs to the most cultivated cacao type. The availability of its genome sequence and methods for identifying genes responsible for important cacao traits will aid cacao researchers and breeders. Results We describe the sequencing and assembly of the genome of Theobroma cacao L. cultivar Matina 1-6. The genome of the Matina 1-6 cultivar is 445 Mbp, which is significantly larger than a sequenced Criollo cultivar, and more typical of other cultivars. The chromosome-scale assembly, version 1.1, contains 711 scaffolds covering 346.0 Mbp, with a contig N50 of 84.4 kbp, a scaffold N50 of 34.4 Mbp, and an evidence-based gene set of 29,408 loci. Version 1.1 has 10x the scaffold N50 and 4x the contig N50 as Criollo, and includes 111 Mb more anchored sequence. The version 1.1 assembly has 4.4% gap sequence, while Criollo has 10.9%. Through a combination of haplotype, association mapping and gene expression analyses, we leverage this robust reference genome to identify a promising candidate gene responsible for pod color variation. We demonstrate that green/red pod color in cacao is likely regulated by the R2R3 MYB transcription factor TcMYB113 , homologs of which determine pigmentation in Rosaceae, Solanaceae, and Brassicaceae. One SNP within the target site for a highly conserved trans -acting siRNA in dicots, found within TcMYB113 , seems to affect transcript levels of this gene and therefore pod color variation. Conclusions We report a high-quality sequence and annotation of Theobroma cacao L. and demonstrate its utility in identifying candidate genes regulating traits.
Transcription-controlled gene therapy against tumor angiogenesis
Authors: Shoshana Greenberger, Aviv Shaish, Nira Varda-Bloom, Keren Levanon, Eyal Breitbart, Iris Goldberg, Iris Barshack, Israel Hodish, Niva Yaacov, Livnat Bangio, Tanya Goncharov, David Wallach, Dror Harats
Journal: Journal of Clinical Investigation (2004)

A major drawback of current approaches to antiangiogenic gene therapy is the lack of tissue-specific targeting. The aim of this work was to trigger endothelial cell–specific apoptosis, using adenoviral vector–mediated delivery of a chimeric death receptor derived from the modified endothelium-specific pre-proendothelin-1 (PPE-1) promoter. In the present study, we constructed an adenovirus-based vector that targets tumor angiogenesis. Transcriptional control was achieved by use of a modified endothelium-specific promoter. Expression of a chimeric death receptor, composed of Fas and TNF receptor 1, resulted in specific apoptosis of endothelial cells in vitro and sensitization of cells to the proapoptotic effect of TNF-α. The antitumoral activity of the vectors was assayed in two mouse models. In the model of B16 melanoma, a single systemic injection of virus to the tail vein caused growth retardation of tumor and reduction of tumor mass with central tumor necrosis. When the Lewis lung carcinoma lung-metastasis model was applied, i.v. injection of vector resulted in reduction of lung-metastasis mass, via an antiangiogenic mechanism. Moreover, by application of the PPE-1–based transcriptional control, a humoral immune response against the transgene was avoided. Collectively, these data provide evidence that transcriptionally controlled, angiogenesis-targeted gene therapy is feasible.