tbuckley/cabot-search huggingface dataset:
Regulatory idiotopes. Induction of idiotype-recognizing helper T cells by free light and heavy chains.
Authors: M McNamara, H Kohler
Journal: The Journal of Experimental Medicine (1984)

Previously, we have demonstrated the induction of T helper cells that recognize idiotype by antigen (19), idiotype (20), and antiidiotype (12). The T cell population has been characterized and found to recognize both the T15 and M167 myeloma proteins, which share PC binding specificity but differ in idiotypic specificities. In the present work, we used isolated heavy and light chains of T15 and M167 to generate T helper cells, and examined the response to trinitrophenyl (TNP)-T15 and TNP-M167. We found that the heavy chains induced a dose-dependent response to TNP-T15 and TNP-M167, while the light chain priming was ineffective. When isolated chains of a monoclonal anti-T15 antibody (F6-3) were used to induce idiotype-recognizing T cells, only the F6-3 light chains generated T cell help for TNP-T15 and TNP-M167. Evidently, the idiotypic determinant that is recognized by the T cells is not dependent upon the conformation of combined heavy and light chains. These data show that the Th2 helper cells for the T15/M167 idiotopes are induced by free heavy chains of T15 and M167; the Th1 T cells that interact with the Th2 population, of T15 and M167; the Th1 T cells that interact with the Th2 population, however, can be triggered by free light chains of an antiidiotypic hybridoma antibody. These provocative findings suggest a new model for the T helper cell network.
Acid Prohormone Sequence Determines Size, Shape, and Docking of Secretory Vesicles in Atrial Myocytes
Authors: Alex J. Baertschi, Dominique Monnier, Uta Schmidt, Edwin S. Levitan, Stanislas Fakan, Angela Roatti
Journal: Circulation Research (2001)

How vesicles are born in the trans -Golgi network and reach their docking sites at the plasma membrane is still largely unknown and is investigated in the present study on live, primary cultured atrial cardiomyocytes. Secretory vesicles (n=422) are visualized by expressing fusion proteins of proatrial natriuretic peptide (proANP) and green fluorescent protein. Myocytes expressing fusion proteins with intact proANP display two populations of fluorescent vesicles with apparent diameters of 120 and 175 nm, moving at a top velocity of 0.3 μm/s. The number of docked vesicles is significantly correlated with the number of mobile vesicles ( r =0.71, P &lt;0.0005). The deletion of the acidic N-terminal proANP[1-44] or point mutations (glu 23,24 →gln 23,24 ) change size and shape—but not velocity—of the vesicles, and, strikingly, abolish their docking at the plasma membrane. The shapes thus change from spheres to larger, irregular floppy bags or vesicle trains. Deletion of the C-terminal proANP[45-127], where the ANP and its disulfide bond reside, does not change size, shape, docking, or velocity of the mobile vesicles. The N-terminal acid calcium-binding sequence of proANP is known to cause protein aggregation at the high calcium concentration prevailing in the trans -Golgi network. Therefore, these results indicate that amino acid residues favoring cargo aggregation are critically important in shaping the secretory vesicles and determining their fate—docking or not docking—at the plasma membrane. The full text of this article is available at http://www.circresaha.org.
Time- and exercise-dependent gene regulation in human skeletal muscle
Authors: Alexander C Zambon, Erin L McDearmon, Nathan Salomonis, Karen M Vranizan, Kirsten L Johansen, Deborah Adey, Joseph S Takahashi, Morris Schambelan, Bruce R Conklin
Journal: Genome biology (2003)

Skeletal muscle remodeling is a critical component of an organism's response to environmental changes. Exercise causes structural changes in muscle and can induce phase shifts in circadian rhythms, fluctuations in physiology and behavior with a period of around 24 hours that are maintained by a core clock mechanism. Both exercise-induced remodeling and circadian rhythms rely on the transcriptional regulation of key genes.We used DNA microarrays to determine the effects of resistance exercise (RE) on gene regulation in biopsy samples of human quadriceps muscle obtained 6 and 18 hours after an acute bout of isotonic exercise with one leg. We also profiled diurnal gene regulation at the same time points (2000 and 0800 hours) in the non-exercised leg. Comparison of our results with published circadian gene profiles in mice identified 44 putative genes that were regulated in a circadian fashion. We then used quantitative PCR to validate the circadian expression of selected gene orthologs in mouse skeletal muscle.The coordinated regulation of the circadian clock genes Cry1, Per2, and Bmal1 6 hours after RE and diurnal genes 18 hours after RE in the exercised leg suggest that RE may directly modulate circadian rhythms in human skeletal muscle.
Low concordance with HIV testing guidelines in a retrospective review of intensive care practice
Authors: Mark Christopher Dodd, Paul J Collini, David H Dockrell
Journal: Thorax (2013)

Records were reviewed (n=1052) for patients admitted to a large general intensive care unit (GICU) and examined for HIV testing criteria published in UK national testing guidelines (UKNG). All actual tests sent from GICU were also examined for comparison. Strict application of the UKNG revealed 30% of patients met criteria for HIV testing on admission to GICU. With pragmatic application, 18% of admissions met criteria for testing. Less than 5% of admissions were actually tested when no testing guideline was adopted. Discussion: The UKNG can be adopted in a representative GICU to increase HIV testing rate by 4–6-fold.
Exogenous Granulocyte–Macrophage Colony-Stimulating Factor Administration for Pulmonary Alveolar Proteinosis
Authors: MANI S. KAVURU, EUGENE J. SULLIVAN, RITA PICCIN, MARY JANE THOMASSEN, JAMES K. STOLLER
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of lipoproteinaceous material within the alveoli. Recent data suggest that granulocyte–macrophage colony- stimulating factor (GM-CSF) may be involved in the pathogenesis of PAP. To extend this understanding and clarify whether GM-CSF replacement confers benefit, we report the preliminary results for the first four patients in an open-label study of GM-CSF treatment for moderate exacerbation of PAP. All four patients had idiopathic PAP confirmed by open lung biopsy. Subcutaneous GM-CSF was self-administered once daily for 12 wk (dose escalation from 3 to 9 μ g/kg/d). Response was assessed from symptom scores, arterial blood gas measurements, pulmonary function testing, and chest radiographs. Three of the four patients experienced symptomatic, physiologic, and radiographic improvement with GM-CSF. Responders experienced sufficient improvement in oxygenation as to eliminate the need for supplemental oxygen, and one patient was removed from the waiting list for lung transplantation. Improved oxygenation was not apparent until 8 to 12 wk after the start of therapy. Notably, expected increases in the peripheral white blood cell count did not occur, suggesting lack of a hematopoietic response to exogenous GM-CSF in PAP. We conclude that GM-CSF appears to benefit a subset of patients with adult PAP, and may represent an alternative to whole-lung lavage in treating the disease.
Multiple Familial Trichoepithelioma Caused by Mutations in the Cylindromatosis Tumor Suppressor Gene
Authors: Aicha Salhi, Dorothea Bornholdt, Frank Oeffner, Sajid Malik, Ernest Heid, Rudolf Happle, Karl-Heinz Grzeschik
Journal: Cancer Research (2004)

The recessive oncogene cylindromatosis (CYLD) mapping on 16q12-q13 is generally implicated in familial cylindromatosis, whereas a gene region for multiple familial trichoepithelioma has been assigned to 9p21. Markers from both chromosome intervals were subjected to linkage analysis in a large family with multiple hereditary trichoepithelioma (TE) from Algeria. Linkage to 9p21 was excluded, whereas CYLD remained as a candidate. Mutation analysis identified a single bp germ-line deletion expected to result in truncation or absence of the encoded protein, which segregated with the multiple TE phenotype. In individual tumors, loss of heterozygosity at 16q or a somatic point mutation in the CYLD gene was detected. Hence, mutations of the tumor suppressor gene CYLD at 16q12-q13 may give rise to familial TE indistinguishable from the phenotype assigned to 9p21.
Role of sympathoadrenergic mechanisms in arrhythmogenesis
Authors: X Du
Journal: Cardiovascular Research (1999)

See article by Guo et al. ([1], pages 930–938) in this issue. 

Ventricular arrhythmias occur frequently following acute myocardial infarction, during reperfusion and in heart failure. They are the likely major cause of sudden cardiac death in the majority of instances and as such represent a continuing and major cardiac health problem. The role of the sympathetic nervous system (SNS) in the genesis of arrhythmias under these conditions has been extensively studied for many years. Nevertheless, the importance of SNS activation in arrhythmogenesis remains controversial. This is again apparent in the current issue of Cardiovascular Research, where the findings from two papers with apparently contradictory interpretations are presented [1,2].

Numerous experimental approaches have been applied to manipulate the activity of the SNS, from dennervation and catecholamine depletion to cardiac sympathetic nerve stimulation or treatment with adrenergic agonists. These studies have been reviewed thoroughly [3–7]. Several lines of evidence have suggested an important or perhaps even pivotal role for SNS activation in initiating arrhythmias following myocardial infarction, reperfusion or heart failure. Thus both high levels of circulating catecholamines as well as increased cardiac noradrenaline (NA) spillover [8], increased sympathetic nerve firing rates and suppressed baroreflex sensitivity are all associated with increased incidences of arrhythmias and mortality [5]. β-blockers have been shown to be particularly beneficial in reducing cardiac mortality following myocardial infarction or heart failure, although evidence that their mechanism is by an anti-arrhythmic effect is less clear cut. There is strong evidence that ventricular fibrillation and sudden cardiac death may be triggered in some patients by psychologic stressors [9,10]. … 

* Corresponding author. Tel.: +61-3-9522-4399; fax: +61-3-9521-1362 xiaojun.du{at}baker.edu.au
Hematopoietic Stem Cell and Gene Therapy Corrects Primary Neuropathology and Behavior in Mucopolysaccharidosis IIIA Mice
Authors: Alexander Langford-Smith, Fiona L Wilkinson, Kia J Langford-Smith, Rebecca J Holley, Ana Sergijenko, Steven J Howe, William R Bennett, Simon A Jones, JE Wraith, Catherine LR Merry, Robert F Wynn, Brian W Bigger
Journal: Molecular Therapy (2012)

Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo disease) is a neurodegenerative disorder caused by a deficiency in the lysosomal enzyme sulfamidase (SGSH), catabolizing heparan sulfate (HS). Affected children present with severe behavioral abnormalities, sleep disturbances, and progressive neurodegeneration, leading to death in their second decade. MPS I, a similar neurodegenerative disease accumulating HS, is treated successfully with hematopoietic stem cell transplantation (HSCT) but this treatment is ineffectual for MPS IIIA. We compared HSCT in MPS IIIA mice using wild-type donor cells transduced ex vivo with lentiviral vector-expressing SGSH (LV-WT-HSCT) versus wild-type donor cell transplant (WT-HSCT) or lentiviral-SGSH transduced MPS IIIA cells (LV-IIIA-HSCT). LV-WT-HSCT results in 10% of normal brain enzyme activity, near normalization of brain HS and GM2 gangliosides, significant improvements in neuroinflammation and behavioral correction. Both WT-HSCT and LV-IIIA-HSCT mediated improvements in GM2 gangliosides and neuroinflammation but were less effective at reducing HS or in ameliorating abnormal HS sulfation and had no significant effect on behavior. This suggests that HS may have a more significant role in neuropathology than neuroinflammation or GM2 gangliosides. These data provide compelling evidence for the efficacy of gene therapy in conjunction with WT-HSCT for neurological correction of MPS IIIA where conventional transplant is ineffectual.
Remote Ischemic Preconditioning in Human Coronary Artery Bypass Surgery
Authors: Ishtiaq A. Rahman, Jorge G. Mascaro, Rick P. Steeds, Michael P. Frenneaux, Peter Nightingale, Peter Gosling, Peter Townsend, John N. Townend, David Green, Robert S. Bonser
Journal: Circulation (2010)

Background— We assessed whether remote ischemic preconditioning (RIPC) improves myocardial, renal, and lung protection after on-pump coronary surgery. Methods and Results— This was a single-center, prospective, randomized (1:1), placebo-controlled trial. Patients, investigators, anesthetists, surgeons, and critical care teams were blinded to group allocation. Subjects received RIPC (or placebo) stimuli (×3 upper limb (or dummy arm), 5-minute cycles of 200 mm Hg cuff inflation/deflation) before aortic clamping. Anesthesia, perfusion, cardioplegia, and surgical techniques were standardized. The primary end point was 48-hour area under the curve (AUC) troponin T (cTnT) release. Secondary end points were 6-hour and peak cTnT, ECG changes, cardiac index, inotrope and vasoconstrictor use, renal dysfunction, and lung injury. Hospital survival was 99.4%. Comparing placebo and RIPC, median (interquartile range) AUC 48-hour cTnT (ng/mL −1 /48 h −1 ); 28 (19, 39) versus 30 (22, 38), 6-hour cTnT (ng/mL −1 ); 0.93(0.59, 1.35) versus 1.01(0.72, 1.43), peak cTnT (ng/mL −1 ); 1.02 (0.74, 1.44) versus 1.04 (0.78, 1.51), de novo left bundle-branch block (4% versus 0%) and Q waves (5.3% versus 5.5%), serial cardiac indices, intraaortic balloon pump usage (8.5% versus 7.5%), inotrope (39% versus 50%) and vasoconstrictor usage (66% versus 64%) were not different. Dialysis requirement (1.2% versus 3.8%), peak creatinine (median [interquartile range], 1.2 mg/dL −1 (1.1, 1.4) versus 1.2 (1.0, 1.4)), and AUC urinary albumin-creatinine ratios 69 (40, 112) versus 58 (32, 85) were not different. Intubation times; median (interquartile range), 937 minutes(766, 1402) versus 895(675, 1180), 6-hour; 278 (210, 338) versus 270 (218, 323) and 12-hour pO 2 :FiO 2 ratios 255 (195, 323) versus 263 (210, 308) were similar. Conclusions— In contrast to prior smaller studies, RIPC did not reduce troponin release, improve hemodynamics, or enhance renal or lung protection. Clinical Trial Registration— URL: http://www.ukcrn.org.uk. Unique identifier: 4659.
Neoadjuvant Chemotherapy Is the Better Treatment Option in Some Patients With Stage IIIc to IV Ovarian Cancer
Authors: Ignace Vergote, Claes G. Tropé, Frédéric Amant, Tom Ehlen, Nick S. Reed, Antonio Casado
Journal: Journal of Clinical Oncology (2011)

Ignace Vergote, University Hospitals Leuven, Leuven, Belgium Claes G. Trope, Norwegian Radium Hospital, Oslo, Norway Frederic Amant, University Hospitals Leuven, Leuven, Belgium Tom Ehlen, University of British Columbia, Vancouver, British Columbia, Canada Nick S. Reed, Gartnavel General Hospital and Beatson Oncology Center, Glasgow, United Kingdom Antonio Casado, Hospital Universitario San Carlos, Madrid, Spain
Micaceous and keratotic pseudoepitheliomatous balanitis and rapidly fatal fibrosarcoma of the penis occurring in the same patient
Authors: Catriona Irvine, Janice R. Anderson, R.J. Pye
Journal: British Journal of Dermatology (1987)

A 55-year-old man had a rare, benign condition of the penis, micaceous and keratotic pseudoepitheliomatous balanitis, for 9 years before developing an aggressive soft tissue sarcoma of the glans. Five months after the appearance of this tumour, the patient died with widespread metastases. The sarcoma was small and superficial and the limited recorded experience suggested that local excision should offer a good prognosis. However, the histology showed poor differentiation and it would seem that this may be the important factor in the management and prognosis of penile sarcoma, as it is in sarcoma at other sites.
Increased Expression and Secretion of Interleukin-6 in Patients with Barrett’s Esophagus
Authors: Katerina Dvorakova, Claire M. Payne, Lois Ramsey, Hana Holubec, Richard Sampliner, Jessica Dominguez, Bohuslav Dvorak, Harris Bernstein, Carol Bernstein, Anil Prasad, Ronnie Fass, Haiyan Cui, Harinder Garewal
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Barrett’s esophagus (BE) is a common premalignant lesion of the distal part of the esophagus that arises as a consequence of chronic duodenogastroesophageal reflux. Interleukin (IL)-6 is a pleiotropic cytokine that regulates immune defense mechanisms and hematopoiesis. In addition, IL-6 may also be involved in malignant transformation and tumor progression. IL-6 has been shown to inhibit apoptosis. The major aim of this study was to evaluate expression of IL-6 in BE at the protein and mRNA levels. In addition, we tested whether proteins that are associated with IL-6 signaling, phosphorylated signal transducer and activator of transcription 3 and two antiapoptotic proteins, Bcl-xL and Mcl-1, are also expressed in the same tissues. Experimental Design: Biopsies of duodenum, BE, and squamous epithelium were evaluated by using a human cytokine protein array, ELISA, real-time PCR, and immunohistochemistry. Results: Increased IL-6 levels were found to be secreted from BE tissue compared with duodenum or squamous epithelium from sites adjacent or 5 cm away from the BE lesion. IL-6 mRNA was also elevated in BE compared with duodenum or squamous epithelium in five of seven patients. Immunohistochemical studies confirmed IL-6 expression in intestinal glandular epithelium in BE tissue. Activated signal transducer and activator of transcription 3, Mcl-1, and Bcl-xL are present at higher levels in BE glands, with lower levels being found in duodenum or squamous epithelium Conclusions: These data, taken together, suggest that elevated IL-6 levels in BE may contribute to the development of apoptosis resistance, thereby placing this epithelium at higher risk of developing malignancy.
Altered splicing of CEACAM1 in breast cancer: Identification of regulatory sequences that control splicing of CEACAM1 into long or short cytoplasmic domain isoforms
Authors: Shikha Gaur, John E Shively, Yun Yen, Rajesh K Gaur
Journal: Molecular Cancer (2008)

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a cell adhesion molecule expressed in a variety of cell types is a putative tumor suppressor gene. Alternative splicing of CEACAM1 generates 11 different splice variants, which include 1–4 ectodomains with either short or long cytoplasmic domain generated by the exclusion (CEACAM1-S) or inclusion (CEACAM1-L) of exon 7. Studies in rodents indicate that optimal ratios of CEACAM1 splice variants are required to inhibit colonic tumor cell growth. We show that CEACAM1 is expressed in a tissue specific manner with significant differences in the ratios of its short (CEACAM1-S) and long (CEACAM1-L) cytoplasmic domain splice variants. Importantly, we find dramatic differences between the ratios of S:L isoforms in normal breast tissues versus breast cancer specimens, suggesting that altered splicing of CEACAM1 may play an important role in tumorogenesis. Furthermore, we have identified two regulatory cis-acting elements required for the alternative splicing of CEACAM1. Replacement of these regulatory elements by human β-globin exon sequences resulted in exon 7-skipped mRNA as the predominant product. Interestingly, while insertion of exon 7 in a β-globin reporter gene resulted in its skipping, exon 7 along with the flanking intron sequences recapitulated the alternative splicing of CEACAM1. Our results indicate that a network of regulatory elements control the alternative splicing of CEACAM1. These findings may have important implications in therapeutic modalities of CEACAM1 linked human diseases.
Effect of five anti-inflammatory steroids on collagen and glycoaminoglycan synthessis in vitro
Authors: H. SAARNI, M. JALKANEN, V. K. HOPSU-HAVU
Journal: British Journal of Dermatology (1980)

The effect of five anti-inflammatory corticosteroids, i.e. hydrocortisone, hydrocortisone 17-butyrate, betamethasone 17-valerate, nicocortonide acetate and nicocortonide, on the synthesis of hyaluronic acid, sulphated glycosaminoglycans and collagen by cultured skin fibroblasts was studied. As inhibitors of all these parameters the steroids could be arranged in order hydrocortisone < hydrocortisone 17-butyrate < betamethasone 17-valerate, nicocortonide acetate and nicocortonide. The corticosteroid concentrations required for inhibition of hyaluronic acid were very low as compared to those required for inhibition of sulphated glycosaminoglycan and collagen synthesis.
Development of diabetes mellitus in aging transgenic mice following suppression of pancreatic homeoprotein IDX-1
Authors: Melissa K. Thomas, Octavia N. Devon, Jee H. Lee, Andreas Peter, David A. Schlosser, Matthew S. Tenser, Joel F. Habener
Journal: Journal of Clinical Investigation (2001)

Monogenic forms of diabetes can result from mutations in genes encoding transcription factors. Mutations in the homeodomain transcription factor IDX-1, a critical regulator of pancreas development and insulin gene transcription, confer a strong predisposition to the development of diabetes mellitus in humans. To investigate the role of IDX-1 expression in the pathogenesis of diabetes, we developed a model for the inducible impairment of IDX-1 expression in pancreatic β cells in vivo by engineering an antisense ribozyme specific for mouse IDX-1 mRNA under control of the reverse tetracycline transactivator (rtTA). Doxycycline-induced impairment of IDX-1 expression reduced activation of the Insulin promoter but activated the Idx-1 promoter, suggesting that pancreatic β cells regulate IDX-1 transcription to maintain IDX-1 levels within a narrow range. In transgenic mice that express both rtTA and the antisense ribozyme construct, impaired IDX-1 expression elevated glycated hemoglobin levels, diminished glucose tolerance, and decreased insulin/glucose ratios. Metabolic phenotypes induced by IDX-1 deficiency were observed predominantly in male mice over 18 months of age, suggesting that cellular mechanisms to protect IDX-1 levels in pancreatic β cells decline with aging. We propose that even in the absence of Idx-1 gene mutations, pathophysiological processes that decrease IDX-1 levels are likely to impair glucose tolerance. Therapeutic strategies to attain normal glucose homeostasis by restoring normal IDX-1 levels may be of particular importance for older individuals with diabetes mellitus.