tbuckley/cabot-search huggingface dataset:
Successive Action of Meprin A and Neprilysin Catabolizes B-Type Natriuretic Peptide
Authors: Kristin Pankow, Yong Wang, Florian Gembardt, Eberhard Krause, Xiaoou Sun, Gerd Krause, Heinz-Peter Schultheiss, Wolf-Eberhard Siems, Thomas Walther
Journal: Circulation Research (2007)

Natriuretic peptides such as B-type natriuretic peptide (BNP) are important cardioprotective hormones with essential functions in sodium excretion, water balance and blood pressure regulation. Consequently, the catabolism of these peptides is in the focus of clinical research. In previous studies, we demonstrated that BNP, in contrast to the structurally related atrial and C-type natriuretic peptide, was not hydrolyzed by neprilysin (NEP). Because membrane preparations of several organs of NEP-knockout mice rapidly degrade BNP, the aim of this study was to identify BNP-catabolizing peptidases responsible for this fast clearance. Using kidney membranes of wild-type and NEP-knockout mice, as well as several peptidase inhibitors, we monitored the catabolism of BNP and analyzed its degradation products. We identified meprin A, a multimeric metalloprotease expressed in the brush borders of kidney proximal tubules, to initially truncate mouse BNP in the N terminus to mBNP7-32, a BNP metabolite with conserved biological activity. Consequently, in vivo experiments with the meprin inhibitor actinonin successfully elevated plasma BNP concentration in rats. We further demonstrated that the generation of mBNP7-32 is the prerequisite to catabolize BNP and identified NEP as the peptidase degrading the truncated BNP. Thus, the cooperative, successive action of the 2 transmembranal peptidases meprin A and NEP is crucial for rapid renal BNP inactivation. Therefore, the inhibition of meprin A could be a potent tool for increasing circulating BNP levels.
INFARCT HETEROGENEITY IS AN INDEPENDENT AND INCREMENTAL PREDICTOR OF MORTALITY IN PATIENTS WITH SEVERE ISCHEMIC CARDIOMYOPATHY
Authors: Lisa Asamoto, Rory Hachamovitch, Zoran Popovic, Randall Starling, Scott Flamm, Thomas Marwick, Deborah Kwon
Journal: Journal of the American College of Cardiology (2012)
Predicting relapse in patients with inflammatory bowel disease: what is the role of biomarkers?
Authors: D S Pardi, W J Sandborn
Journal: Gut (2005)

Faecal calprotectin seems to be a relatively sensitive and specific marker of the risk of relapse in ulcerative colitis, but not in Crohn’s disease

Various laboratory biomarkers have been studied in inflammatory bowel disease (IBD) as diagnostic aids, indicators of disease activity or severity, and to predict the risk of relapse in those patients in remission. These biomarkers have enormous potential implications for patient management. For example, therapeutic decisions could be directed more appropriately if a marker could reliably distinguish active IBD from other inflammatory or non-inflammatory causes of symptoms, or if one could distinguish Crohn’s disease from ulcerative colitis. In addition, a simple, inexpensive, sensitive, specific marker could help monitor response in the clinic and in clinical trials. Finally, the ability to reliably predict the risk of recurrence would help direct appropriate therapy to those who would most likely benefit from it and avoid the expense and potential toxicity of chronic maintenance therapy in those who have a low risk of recurrence. In the current issue of Gut , Costa and colleagues1 addressed the latter issue by studying the role of faecal calprotectin as a marker of risk of relapse in ulcerative colitis and Crohn’s disease (see page 364) . Calprotectin represents 50–60% of neutrophilic cytosolic protein, is stable in faeces for several days after excretion, and has a relatively easy to perform assay which is available commercially and correlates well with the more difficult and more expensive indium 111-labelled leucocyte excretion2

Costa and colleagues1 studied 38 patients with Crohn’s disease and 41 with ulcerative colitis in remission for a mean of five months. A baseline faecal calprotectin level greater than 150 μg/g had a sensitivity for predicting relapse within the next year of 89% in ulcerative colitis and 87% in Crohn’s disease. The specificity …
Multicystic Dysplastic Kidney and Variable Phenotype in a Family with a Novel Deletion Mutation of PAX2
Authors: Jeffery Fletcher, Min Hu, Yemima Berman, Felicity Collins, John Grigg, Margot McIver, Harald Ju[Combining Diaeresis]ppner, Stephen I. Alexander
Journal: Journal of the American Society of Nephrology (2005)

The renal coloboma syndrome (OMIM 120330) is caused by mutations in the PAX2 gene. Typical findings in these patients include renal hypoplasia, renal insufficiency, vesicoureteric reflux, and optic disc coloboma. A family with a novel heterozygous 10-bp deletion in exon 2 of the PAX2 gene leading to a truncating mutation and variable phenotype across three generations is reported. The first presentation of multicystic dysplastic kidney in this syndrome is reported. The possibility that abnormal PAX2 protein in this case may cause a dominant negative effect also is discussed. The finding of multicystic dysplastic kidney in renal coloboma syndrome could suggest that PAX2 may play a role in early ureteric obstruction and subsequent renal maldevelopment.
Dietary Choline and Betaine and the Risk of Distal Colorectal Adenoma in Women
Authors: E. Cho, W. C. Willett, G. A. Colditz, C. S. Fuchs, K. Wu, A. T. Chan, S. H. Zeisel, E. L. Giovannucci
Journal: JNCI Journal of the National Cancer Institute (2007)

BackgroundCholine and betaine are involved in methyl-group metabolism as methyl-group donors; thus, like folate, another methyl-group donor, they may be associated with a reduced risk of colorectal adenomas. No epidemiologic study has examined the association of intake of these nutrients and colorectal adenoma risk.
The effects of acetylstrophanthidin and ouabain on the sympathetic adrenergic neuroeffector junction in canine vascular smooth muscle.
Authors: R R Lorenz, D A Powis, P M Vanhoutte, J T Shepherd
Journal: Circulation Research (1980)

We performed experiments to determine the effects of acetylstrophanthidin (ACS) and ouabain on the adrenergic neuroeffector junction in dog saphenous veins. In quiescent strips incubated with 3H-norepinephrine (3H-NE), the drugs caused contraction and a progressive increase in overflow of 3H-NE and O-methylated metabolites; 3,4-dihydroxyphenylglycol (DOPEG) decreased. Tissue uptake of 3H-NE was partially inhibited. After surgical sympathectomy, both contraction and 3H-NE overflow were markedly attenuated. Following chemical sympathectomy with 6-hydroxydopamine, ouabain contractions were 11% of control, whereas the contractions due to exogenous norepinephrine were exaggerated. The initial overflow of 3H-NE was unaffected by tetrodotoxin, but the later and larger overflow with prolonged exposure was depressed. The former occurred in the absence of Ca2+, but the latter was Ca2+ dependent. Inhibition of the neuronal amine carrier by cocaine or desipramine and blockade of the neuronal alpha-adrenoceptors with phentolamine or phenoxybenzamine attenuated the release of 3H-NE evoked by ACS and ouabain. During electrical stimulation, ACS augmented the overflow of 3H-NE. This was attenuated by cocaine, desipramine, and the alpha-adrenolytic drugs. ACS, like pargyline, augmented the overflow of 3H-NE evoked by tyramine and depressed that of DOPEG. These experiments suggest that acetylstrophanthidin and ouabain (1) cause contraction of vascular smooth muscle by displacement of norepinephrine from neuronal stores, (2) reduce neuronal monoamine oxidase activity, (3) facilitate and may trigger Ca2+-dependent exocytotic release of norepinephrine, (4) partially inhibit the neuronal amine carrier mechanism but do not interfere with extraneuronal disposition of norepinephrine, and, finally (5) may have unexplained interactions with prejunctional alpha-adrenoceptors.
THE PATTERN OF TISSUE REACTIONS TO AUTOLOGOUS AND HOMOLOGOUS MUSCULOFASCIAL TRANSPLANTS
Authors: Richard H. Andresen, Clarence W. Monroe, George M. Hass
Journal: The Journal of Experimental Medicine (1952)

Simultaneous autologous and homologous musculofascial transplants were made in New Zealand white rabbits. The basic pattern of degeneration and granulation tissue organization of both types of transplant was essentially identical. The superposition of two reactions in the framework of organizing granulation tissue served to distinguish homologous from autologous transplants. One reaction to homologous transplants was predominantly characterized by lymphocytic infiltration and the other by angeitis. The principal locus of these reactions was in the musculofascial zone of the transplant, and from this zone the reactions spread to a variable degree through the fascia into the overlying pannus of granulation tissue. When single homologous transplants were made, the lymphocytic and mild angeitic forms of reaction predominated, becoming conspicuous at the end of 2 weeks. When multiple successive homologous transplants were made from the same donor to the same recipient, acute angeitis with thrombosis supervened and the lymphocytic reaction failed to develop or persist. Multiple successive autologous transplants, on the other hand, did not influence the type or degree of reaction to autologous transplants in the same animal. There was no evidence that autologous transplants had any influence upon the sequence of reactions to homologous transplants or that the presence of homologous transplants influenced the nature of the reaction to autologous transplants in the same animal. Until better methods are developed, methods of bio-assay of the type described, though lacking in quantitative precision, offer the best means for further analysis of factors which govern the incompatibility of tissues of one animal for those of another animal of the same species.
Trickle-up phonetics: A vocal role for the infant
Authors: John L. Locke
Journal: Behavioral and Brain Sciences (2004)

Falk claims that human language took a step forward when infants lost their ability to cling and were placed on the ground, increasing their fears, which mothers assuaged prosodically. This claim, which is unsupported by anthropological and psychological evidence, would have done little for the syllabic and segmental structure of language, and ignores infants' own contribution to the process.
Hair Bundles Are Specialized for ATP Delivery via Creatine Kinase
Authors: Jung-Bum Shin, Femke Streijger, Andy Beynon, Theo Peters, Laura Gadzala, Debra McMillen, Cory Bystrom, Catharina E.E.M. Van der Zee, Theo Wallimann, Peter G. Gillespie
Journal: Neuron (2007)
Use of sirolimus (rapamycin) to treat refractory Crohn's disease
Authors: D C O Massey, F Bredin, M Parkes
Journal: Gut (2008)

We present the case of a 37-year-old woman with severe refractory colonic and perianal Crohn's disease who had lost response to second-line, steroid-sparing treatments azathioprine, methotrexate and infliximab. For many such patients extensive surgery has often been considered the only option. New insights provided by the results of genome-wide association scanning in Crohn's disease highlight autophagy, a cellular process implicated in the clearance of intracellular bacteria, as a key process in Crohn's disease pathogeneses. Sirolimus (rapamycin) is a drug used to upregulate autophagy in cell culture in the laboratory, and in clinical practice to prevent rejection following organ transplantation due to independent immunosuppressive action. Our patient was treated with sirolimus for 6 months at a dose that maintained serum trough levels of 5 ng/ml. There was marked and sustained improvement in Crohn's disease symptoms with the Harvey–Bradshaw index falling from 13 to 3, in serum markers of inflammation (C-reactive protein fell from 79 to 2) and endoscopic appearance. This is the first reported case of the use of sirolimus to treat Crohn's disease.
Underestimation of Patient Breathlessness by Nurses and Physicians during a Spontaneous Breathing Trial
Authors: Hege S. Haugdahl, Sissel L. Storli, Barbro Meland, Knut Dybwik, Ulla Romild, Pål Klepstad
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Breathlessness is a prevalent and distressing symptom in intensive care unit patients. There is little evidence of the ability of healthcare workers to assess the patient's experiences of breathing. Patient perception of breathing is essential in symptom management, and patient perception during a spontaneous breathing trial (SBT) might be related to extubation success.To assess mechanically ventilated patients' experiences of breathlessness during SBT.This was a prospective observational multicenter study of 100 mechanically ventilated patients. We assessed the agreement between nurses, physicians, and patients' 11-point Numerical Rating Scales scores of breathlessness, perception of feeling secure, and improvement of respiratory function at the end of an SBT (most performed with some level of support). We also determined the association between breathlessness and demographic factors or respiratory observations.Sixty-two patients (62%) reported moderate or severe breathlessness (Numerical Rating Scales ≥ 4). The median intensity of breathlessness reported by patients was five compared with two by nurses and physicians (P < 0.001). Patients felt less secure and reported less improvement of respiratory function compared with nurses' and physicians' ratings. About half of the nurses and physicians underestimated breathlessness (difference score, ≤-2) compared with the patients' self-reports. Underestimation of breathlessness was not associated with professional competencies. There were no major differences in objective assessments of respiratory function in patients with moderate or severe breathlessness, and no apparent relationship between breathlessness during the SBT and extubation outcome.Patients reported higher breathlessness after SBT compared with nurses and physicians. Clinical trial registered with www.clinicaltrials.gov (NCT 01928277).
IDENTIFICATION OF TRACE ELEMENT–CONTAINING PROTEINS IN GENOMIC DATABASES
Authors: Vadim N. Gladyshev, Gregory V. Kryukov, Dmitri E. Fomenko, Dolph L. Hatfield
Journal: Annual Review of Nutrition (2004)

▪ Abstract Development of bioinformatics tools provided researchers with the ability to identify full sets of trace element–containing proteins in organisms for which complete genomic sequences are available. Recently, independent bioinformatics methods were used to identify all, or almost all, genes encoding selenocysteine-containing proteins in human, mouse, and Drosophila genomes, characterizing entire selenoproteomes in these organisms. It also should be possible to search for entire sets of other trace element–associated proteins, such as metal-containing proteins, although methods for their identification are still in development.
Cell-Mediated Immunity to Pityrosporum Orbiculare in Tinea Versicolor
Authors: Peter G. Sohnle, C. Collins Lech
Journal: Journal of Clinical Investigation (1978)

Pityrosporum orbiculare, the presumed etiologic agent of tinea versicolor, was cultured in vitro and antigenic extracts prepared from the cultured organisms. Studies with lymphocytes from human cord blood and peripheral blood of guinea pigs demonstrated that such extracts were not mitogenic. Further studies in guinea pigs indicated that the animals could be sensitized by the injection of P. orbiculare extract in Freund's complete adjuvant and that this extract could elicit lymphocyte transformation and delayed skin test responses in sensitized animals. A group of 12 tinea versicolor patients and 15 normal subjects were studied in vitro for cell-mediated immunity to P. orbiculare extract. The majority of the subjects tested in both groups demonstrated positive lymphocyte transformation responses to this extract, as well as to standard mitogens and common microbial antigens. However, lymphocytes from tinea versicolor patients produced significantly less leukocyte migration inhibitory factor activity when stimulated by Candida albicans and P. orbiculare extracts than did lymphocytes from normal subjects. This was also true if only subjects with positive lymphocyte transformation responses to these antigens were considered. Leukocyte migration inhibitory factor responses to streptokinase/streptodornase were not significantly different between the two groups. Therefore, it appears that although both normal subjects and tinea versicolor patients demonstrate prior sensitization to antigens of P. orbiculare, the effector function of lymphocytes from most tinea versicolor patients appears to be impaired in that they produce subnormal amounts of the mediator leukocyte migration inhibitory factor when stimulated with antigenic extracts of this organism.
Autoimmune pancreatitis results from loss of TGF signalling in S100A4-positive dendritic cells
Authors: C S Boomershine, A Chamberlain, P Kendall, A-R Afshar-Sharif, H Huang, M K Washington, W E Lawson, J W Thomas, T S Blackwell, N A Bhowmick
Journal: Gut (2009)

<h3>Background and aims:</h3> Autoimmune pancreatitis (AIP) is a poorly understood human disease affecting the exocrine pancreas. The goal of the present study was to elucidate the pathogenic mechanisms underlying pancreatic autoimmunity in a murine disease model. <h3>Methods:</h3> A transgenic mouse with an S100A4/fibroblast-specific protein 1 (FSP1) Cre-mediated conditional knockout of the transforming growth factor β (TGFβ) type II receptor, termed Tgfbr2<i><sup>fspKO</sup></i>, was used to determine the direct role of TGFβ in S100A4<sup>+</sup> cells. Immunohistochemical studies suggested that Tgfbr2<i><sup>fspKO</sup></i> mice develop mouse AIP (mAIP) characterised by interlobular ductal inflammatory infiltrates and pancreatic autoantibody production. Fluorescence-activated cell sorting (FACS)-isolated dendritic cells (DCs) from diseased pancreata were verified to have S100A4-Cre-mediated DNA recombination. <h3>Results:</h3> The Tgfbr2<i><sup>fspKO</sup></i> mice spontaneously developed mAIP by 6 weeks of age. DCs were confirmed to express S100A4, a previously reported protein expressed by fibroblasts. Adoptive transfer of bone marrow-derived DCs from Tgfbr2<i><sup>fspKO</sup></i> mice into 2-week-old syngenic wild-type C57BL/6 mice resulted in reproduction of pancreatitis within 6 weeks. Similar adoptive transfer of wild-type DCs had no effect on pancreas pathology of the host mice. The inability to induce pancreatitis by adoptive transfer of Tgfbr2<i><sup>fspKO</sup></i> DCs in adult mice suggested a developmental event in mAIP pathogenesis. Tgfbr2<i><sup>fspKO</sup></i> DCs undergo elevated maturation in response to antigen and increased activation of naïve CD4-positive T cells. <h3>Conclusion:</h3> The development of mAIP in the Tgfbr2<i><sup>fspKO</sup></i> mouse model illustrates the role of TGFβ in maintaining myeloid DC immune tolerance. The loss of immune tolerance in myeloid S100A4<sup>+</sup> DCs can mediate mAIP and may explain some aspects of AIP disease pathogenesis.
Sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST): Final results of a University of Chicago Phase II Consortium trial.
Authors: H. L. Kindler, N. P. Campbell, K. Wroblewski, R. G. Maki, D. R. D'Adamo, W. A. Chow, D. R. Gandara, C. Antonescu, W. M. Stadler, E. E. Vokes
Journal: Journal of Clinical Oncology (2011)

10009 Background: Treatment (tx) options are limited after GIST pts develop resistance to IM and SU. SOR inhibits KIT, VEGFR, PDGFR-β, and BRAF kinases. In preclinical GIST models, SOR inhibits many secondary resistance mutations, including IM-RES ATP-binding pocket and IM/SU-RES activation loop mutations (Heinrich, Proc ASCO 2009). Methods: We performed a multi-center, phase II trial of SOR in KIT-expressing GIST pts who had disease progression (PD) on IM by RECIST. After FDA approval of SU for GIST, the amended study required PD after both IM and SU. Pts received SOR 400 mg orally twice daily. Primary endpoint: objective response rate. A Simon minimax 2-stage design required 1 response in 18 pts for a 2nd stage, and 4 responses in 32 IM/SU RES pts for further study. Results: 38 pts (6 IM-RES, 32 IM/SU-RES) enrolled 1/06-9/09 at 6 centers. Pt characteristics: male 55%; median age 57 (range 42-85); PS 0/1/2: 47%/47%/5%; liver metastases 74%; primary drug resistance (PD ≤ 6 mo): IM 3%, SU 59%. Baseline mutations: exon 11 65%, exon 9 15%, PDGFR-α 4%. Median cycles: 4 (range 1-40); 42% received SOR ≥ 6 mo, 26% ≥ 1 year (yr). Dose reductions: 61%. Partial response (PR): 13% (1 IM-RES, 4 IM/SU-RES); stable disease (SD): 55% (3 IM-RES, 18 IM/SU-RES). Disease control rate (PR + SD): 68%. Survival: median progression-free: 5.2 mo (95% CI: 3.4, 7.4); median overall 11.6 mo (95% CI: 8.8, 14.3); 1-yr 50%; 2-yr 26%. 32% of pts with primary SU-RES had PR or SD ≥ 6 mo on SOR. Grade 3/4 toxicities (% pts): hand-foot syndrome 45%, hypertension 21%, diarrhea 8%, hypophosphatemia 8%, GI bleed 5%, thrombosis 3%, GI perforation 3%, intracranial hemorrhage 3%. Conclusions: SOR has definite activity in IM/SU-resistant GIST, with a disease control rate of 68%. Prolonged disease control is possible, even in pts with primary SU resistance. Though well-tolerated, dose reductions are often required. Further investigation of SOR in GIST is warranted. Supported by NCI grant N01-CM-62201.
miR-218 Suppresses Nasopharyngeal Cancer Progression through Downregulation of Survivin and the SLIT2-ROBO1 Pathway
Authors: Nehad M. Alajez, Michelle Lenarduzzi, Emma Ito, Angela B.Y. Hui, Wei Shi, Jeff Bruce, Shijun Yue, Shao H. Huang, Wei Xu, John Waldron, Brian O'Sullivan, Fei-Fei Liu
Journal: Cancer Research (2011)

Nasopharayngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia and Africa. Here we report frequent downregulation of the microRNA miR-218 in primary NPC tissues and cell lines where it plays a critical role in NPC progression. Suppression of miR-218 was associated with epigenetic silencing of SLIT2 and SLIT3, ligands of ROBO receptors that have been previously implicated in tumor angiogenesis. Exogenous expression of miR-218 caused significant toxicity in NPC cells in vitro and delayed tumor growth in vivo. We used an integrated trimodality approach to identify targets of miR-218 in NPC, cervical, and breast cell lines. Direct interaction between miR-218 and the 3'-untranslated regions (UTR) of mRNAs encoding ROBO1, survivin (BIRC5), and connexin43 (GJA1) was validated in a luciferase-based transcription reporter assay. Mechanistic investigations revealed a negative feedback loop wherein miR-218 regulates NPC cell migration via the SLIT-ROBO pathway. Pleotropic effects of miR-218 on NPC survival and migration were rescued by enforced expression of miR-218-resistant, engineered isoforms of survivin and ROBO1, respectively. In clinical specimens of NPC (n=71), ROBO1 overexpression was significantly associated with worse overall (P=0.04, HR=2.4) and nodal relapse-free survival (P=0.008, HR=6.0). Our findings define an integrative tumor suppressor function for miR-218 in NPC and further suggest that restoring miR-218 expression in NPC might be useful for its clinical management.