tbuckley/cabot-search huggingface dataset:
Mother-to-Child Transmitted WT1 Splice-Site Mutation Is Responsible for Distinct Glomerular Diseases
Authors: ERICK DENAMUR, NATHALIE BOCQUET, BEATRICE MOUGENOT, FRANCIS DA SILVA, LAURENCE MARTINAT, CHANTAL LOIRAT, JACQUES ELION, ALBERT BENSMAN, PIERRE M. RONCO
Journal: Journal of the American Society of Nephrology (1999)

Mutations in the Wilms' tumor suppressor gene (WT1) are linked with Denys-Drash syndrome (DDS), a rare childhood disease characterized by diffuse mesangial sclerosis and renal failure of early onset, XY pseudohermaphroditism, and high risk of Wilms' tumor. KTS (lysine-threonine-serine) splice site mutations in WT1 intron 9 have been described in patients with Frasier syndrome, another rare syndrome defined by focal and segmental glomerulosclerosis (FSGS), XY pseudohermaphroditism, and frequent occurrence of gonadoblastoma. Cases of Frasier syndrome raise the question whether splice site mutations may also be found in XX females with isolated FSGS. A girl (index case) presented with the nephrotic syndrome at 9 mo of age. The diagnosis of DDS was based on the finding of diffuse mesangial sclerosis in the kidney biopsy and of a XY karyotype. The index case's mother had had proteinuria since she was 6 years of age. A renal biopsy was performed when she was 28 and disclosed FSGS. The same splice site mutation in intron 9 (WT1 1228+5 G-->A) involving one allele was found in the child and in her mother, but not in other members of the kindred (including the parents, the two brothers, and the two sisters of the index case's mother) who were free of renal symptoms. Quantification of WT1 +KTS/-KTS isoforms in the index case's father and one index case's maternal uncle showed a normal +KTS/-KTS ratio of 1.50. In contrast, the index case and her mother had a low ratio (0.40 and 0.34, respectively), within the range reported in Frasier syndrome. In conclusion, this study shows that the KTS splice site mutation is not specific for Frasier syndrome, but that it can also be found in DDS and in a normal female (XX) with FSGS, a woman who achieved normal pregnancy. It is suggested that WT1 splice site mutations should be sought in phenotypically normal females who present with FSGS or with related glomerulopathies of early onset.
A Proposal Regarding Reporting of <i>In Vitro</i> Testing Results
Authors: Malcolm A. Smith, Peter Houghton
Journal: Clinical Cancer Research (2013)

Abstract The high rate of negative clinical trials and failed drug development programs calls into question the use of preclinical testing as currently practiced. An important issue for the in vitro testing of agents that have advanced into the clinic is the use of clinically irrelevant concentrations in reports making claims for anticancer activity, as illustrated by publications for sorafenib, vorinostat, and metformin. For sorafenib, high protein binding leads to a dichotomy between concentrations active in the 10% serum conditions commonly used for in vitro testing and concentrations active in plasma. Failure to recognize this distinction leads to inappropriate claims of activity for sorafenib based on the micromolar concentrations commonly used for in vitro testing in low serum conditions. For vorinostat and metformin, results using in vitro concentrations higher than those achievable in patients are reported despite the availability of publications describing human pharmacokinetic data for each agent. We encourage journal editors and reviewers to pay greater attention to clinically relevant concentrations when considering reports that include in vitro testing of agents for which human pharmacokinetic data are available. Steps taken to more carefully scrutinize activity claims based on in vitro results can help direct researchers away from clinically irrelevant lines of research and toward lines of research that are more likely to lead to positive clinical trials and to improved treatments for patients with cancer. Clin Cancer Res; 19(11); 2828–33. ©2013 AACR.
Immunohistochemical demonstration of human cardiac innervation before and after transplantation.
Authors: J Wharton, J M Polak, L Gordon, N R Banner, D R Springall, M Rose, A Khagani, J Wallwork, M H Yacoub
Journal: Circulation Research (1990)

Knowledge about the distribution and origins of peptide-containing nerves in the innervated and transplanted heart is lacking. Immunohistochemical and histochemical techniques were used to visualize human cardiac innervation before and after transplantation. In the recipient heart cardiac nerve fibers and fascicles displayed immunoreactivity for general neural (protein gene product 9.5 and synaptophysin) and Schwann cell markers (S-100). A major proportion of cardiac nerves displayed neuropeptide tyrosine and tyrosine hydroxylase immunofluorescence staining. Subpopulations of nerves contained somatostatin, vasoactive intestinal polypeptide, calcitonin gene-related peptide, substance P- or neurokinin-like immunoreactivity, and acetylcholinesterase activity. Tissues from cardiac allografts (5 weeks to 63 months after transplantation) contained nerves and ganglion cells that were acetylcholinesterase positive and immunoreactive for the general neural markers. These nerves were less numerous than in recipient hearts and rarely displayed neuropeptide immunostaining. Atrial natriuretic peptide immunoreactivity was localized to myocardial cells in transplanted hearts as well as explanted recipient and postmortem hearts. While most human cardiac allografts remain functionally extrinsically denervated, they appear to contain viable intrinsic nerves, and myocardial cells retain the capacity to produce atrial natriuretic peptide.
Microfungal contamination of damp buildings--examples of risk constructions and risk materials.
Authors: S Gravesen, P A Nielsen, R Iversen, K F Nielsen
Journal: Environmental Health Perspectives (1999)

To elucidate problems with microfungal infestation in indoor environments, a multidisciplinary collaborative pilot study, supported by a grant from the Danish Ministry of Housing and Urban Affairs, was performed on 72 mold-infected building materials from 23 buildings. Water leakage through roofs, rising damp, and defective plumbing installations were the main reasons for water damage with subsequent infestation of molds. From a score system assessing the bioavailability of the building materials, products most vulnerable to mold attacks were water damaged, aged organic materials containing cellulose, such as wooden materials, jute, wallpaper, and cardboard. The microfungal genera most frequently encountered were Penicillium (68%), Aspergillus (56%), Chaetomium (22%), Ulocladium, (21%), Stachybotrys (19%) and Cladosporium (15%). Penicillium chrysogenum, Aspergillus versicolor, and Stachybotrys chartarum were the most frequently occurring species. Under field conditions, several trichothecenes were detected in each of three commonly used building materials, heavily contaminated with S. chartarum. Under experimental conditions, four out of five isolates of S. chartarum produced satratoxin H and G when growing on new and old, very humid gypsum boards. A. versicolor produced the carcinogenic mycotoxin sterigmatocystin and 5-methoxysterigmatocystin under the same conditions.
Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead
Authors: V. W.M. van Hinsbergh, P. Koolwijk
Journal: Cardiovascular Research (2007)

Sprouting angiogenesis is an invasive process that involves proteolytic activities required for the degradation of the endothelial basement membrane, cell migration with removal of obstructing matrix proteins, and generation of space in the matrix to allow endothelial cells to form a proper lumen. In the last decade it has become clear that besides these matrix-degrading properties, proteases exert additional, more subtle functions that play a key role in angiogenesis. These functions are discussed with specific emphasis on membrane type-1 matrix metalloproteinase (MT1-MMP), other MMPs, and the related ADAMs (a disintegrin and metalloproteinase domain). Proteases modulate the balance between pro- and anti-angiogenic factors by activation and modification of growth factors and chemokines, ectodomain shedding with accompanied receptor activation, shedding of cytokines from membrane-bound precursors, and generation of (matrix) protein fragments that inhibit or activate angiogenesis. Furthermore, they participate in the recruitment of leukocytes and progenitor cells, which contribute to the onset and progression of angiogenesis. Proteases facilitate the mobilization of progenitor cells in the bone marrow as well as the entry of these cells and leukocytes into the angiogenic area. The interaction between pericytes and the newly formed endothelial tubes is accompanied by silencing of MMP activities. Better understanding of the various activities of proteases may be helpful in developing more specific inhibitors that could result in tailor-made modification of proteolytic activities in disease.
MPs ask about conflict between aims of Public Health England and government policy
Authors: A. O'Dowd
Journal: BMJ (2013)

The leaders of England’s public health agency seem to be opposed to the government’s current reluctance to take specific steps on cutting smoking and alcohol consumption.

Standardised packaging of tobacco products could be the “next important step” in reducing the prevalence of smoking, the head of Public Health England told MPs on the parliamentary health select committee during an evidence session on 19 November.

However, the Department of Health announced in July that it wanted to wait for more evidence on the effects of such packaging on tobacco consumption before deciding whether to adopt the policy.1

MPs on the Health Committee were quizzing top officials of Public Health …
Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in partially platinum-sensitive ovarian cancer patients: results from a subset analysis of the CALYPSO phase III trial
Authors: L. Gladieff, A. Ferrero, G. De Rauglaudre, C. Brown, P. Vasey, A. Reinthaller, E. Pujade-Lauraine, N. Reed, D. Lorusso, S. Siena, H. Helland, L. Elit, S. Mahner
Journal: Annals of Oncology (2011)

To perform a subset analysis of patients with partially platinum-sensitive recurrent ovarian cancer (ROC) who received either CD [carboplatin-pegylated liposomal doxorubicin (PLD)] or CP (carboplatin-paclitaxel) in the CALYPSO trial.
Outcomes of a Randomized Trial of Hyperfractionated Cranial Radiation Therapy for Treatment of High-Risk Acute Lymphoblastic Leukemia: Therapeutic Efficacy and Neurotoxicity
Authors: Deborah P. Waber, Lewis B. Silverman, Lori Catania, William Mautz, Montse Rue, Richard D. Gelber, Donna E. Levy, Meredith A. Goldwasser, Heather Adams, Annie Dufresne, Victoria Metzger, Ivonne Romero, Nancy J. Tarbell, Virginia Kimball Dalton, Stephen E. Sallan
Journal: Journal of Clinical Oncology (2004)

We evaluated 8-year survival and late neuropsychologic toxicity in children with acute lymphoblastic leukemia treated in a randomized clinical trial to test whether hyperfractionated (twice daily) cranial radiation therapy (CRT) can reduce incidence and severity of late toxicities associated with 18 Gy of CRT.Between 1987 and 1995, 369 children treated on two consecutive Dana-Farber Cancer Institute Consortium protocols for high-risk acute lymphoblastic leukemia were randomly assigned to conventionally fractionated CRT (CFX) or hyperfractionated CRT (HFX) to a total dose of 18 Gy. Neuropsychologic testing was completed for 125 of 287 children in continuous complete remission. Event-free and overall survival, as well as neuropsychologic function, were compared for the two arms of the protocol.Eight-year event-free survival (+/- SE) was 80% +/- 3% for children randomly assigned to CFX and 72% +/- 3% for HFX (P =.06). Overall survival was 85% +/- 3% for CFX and 78% +/- 3% for HFX (P =.06). CNS relapses occurred in 2.8% of patients receiving CFX and 2.7% receiving HFX (P =.99). Cognitive function for both groups was solidly in the average range, with no group differences in intelligence, academic achievement, visuospatial reasoning, or verbal learning. Children on the HFX arm exhibited a modest advantage for visual memory (P <.05).HFX provides no benefit in terms of cognitive late effects and may compromise antileukemic efficacy. HFX should not be substituted for conventionally dosed CRT in children who require radiation therapy for treatment of acute lymphoblastic leukemia.
Altered cardiac collagen and associated changes in diastolic function of infarcted rat hearts
Authors: R Van Kerckhoven
Journal: Cardiovascular Research (2000)

Objective: Anti-inflammatory drugs have been shown to modulate collagen deposition during myocardial infarction (MI) induced remodeling. Chronic effects of methylprednisolone (5 mg/kg/day) and low-dose aspirin (25 mg/kg/day) on cardiac collagen and left ventricular diastolic function were studied in rat hearts, 21 days after MI. Methods: Left ventricular function was assessed at baseline and after β-adrenergic stimulation with isoproterenol in isolated perfused hearts, using an intraventricular balloon. After diastolic arrest, left ventricular pressure—volume curves were obtained. Left ventricular dilation was defined as the corresponding left ventricular volume at 20 mmHg left ventricular diastolic pressure. In histological sections, perivascular and interstitial collagen content were quantified morphometrically as the Sirius Red positive area in the non-infarcted interventricular septum. Results: Impaired baseline left ventricular function of MI-hearts was improved by methylprednisolone but not by low-dose aspirin. Isoprotenerol significantly enhanced systolic function in all hearts, whereas it augmented the decrease in left ventricular diastolic pressure only in methylprednisolone-treated MI-hearts. The rightward shift of the pressure—volume curve after MI was aggravated by methylprednisolone but not with low-dose aspirin treatment. Low-dose aspirin reduced perivascular but not interstitial collagen whereas methylprednisolone decreased both perivascular and interstitial collagen. Conclusions: Our findings indicate that MI-induced collagen deposition in the spared myocardium can be affected by chronic therapy with low-dose aspirin or methylprednisolone. The effects on interstitial collagen seemed reflected in an altered left ventricular diastolic function.
Interleukin (Il)-18 Promotes the Development of Chronic Gastrointestinal Helminth Infection by Downregulating IL-13
Authors: Helena Helmby, Kiyoshi Takeda, Shizuo Akira, Richard K. Grencis
Journal: The Journal of Experimental Medicine (2001)

Expulsion of the gastrointestinal nematode Trichuris muris is mediated by a T helper (Th) 2 type response involving interleukin (IL)-4 and IL-13. Here we show that Th1 response–associated susceptibility involves prior activation of IL-18 and caspase-1 followed by IL-12 and interferon (IFN)-γ in the intestine. IL-18–deficient mice are highly resistant to chronic T. muris infection and in vivo treatment of normal mice with recombinant (r)IL-18 suppresses IL-13 and IL-4 secretion but does not affect IFN-γ. In vivo treatment of T. muris–infected IFN-γ–deficient mice with rIL-18 demonstrated that the inhibitory effect of IL-18 on IL-13 secretion is independent of IFN-γ. Hence, IL-18 does not function as an IFN-γ–inducing cytokine during chronic T. muris infection but rather as a direct regulator of Th2 cytokines. These results provide the first demonstration of the critical role of IL-18 in regulating Th cell responses during gastrointestinal nematode infection.
Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for disease activity states and improvement scores
Authors: P. Machado, R. Landewe, E. Lie, T. K. Kvien, J. Braun, D. Baker, D. van der Heijde
Journal: Annals of the Rheumatic Diseases (2010)

The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a new composite index to assess disease activity in ankylosing spondylitis (AS). It fulfils important aspects of truth, feasibility and discrimination. Criteria for disease activity states and improvement scores are important for use in clinical practice, observational studies and clinical trials and so far have not been developed for the ASDAS.To determine clinically relevant cut-off values for disease activity states and improvement scores using the ASDAS.For the selection of cut-offs data from the Norwegian disease modifying antirheumatic drug (NOR-DMARD) registry, a cohort of patients with AS starting conventional or biological DMARDs, were used. Receiver operating characteristic analysis against several external criteria was performed and several approaches to determine the optimal cut-offs used. The final choice was made on clinical and statistical grounds, after debate and voting by Assessment of SpondyloArthritis international Society members. Crossvalidation was performed in NOR-DMARD and in Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy, a database of patients with AS participating in a randomised placebo-controlled trial with a tumour necrosis factor blocker.Four disease activity states were chosen by consensus: inactive disease, moderate, high and very high disease activity. The three cut-offs selected to separate these states were: 1.3, 2.1 and 3.5 units. Selected cut-offs for improvement were: change ≥1.1 units for clinically important improvement and change ≥2.0 units for major improvement. Results of the crossvalidation strongly supported the cut-offs.Cut-off values for disease activity states and improvement using the ASDAS have been developed. They proved to have external validity and a good performance compared to existing criteria.
The Arachidonic Acid Metabolome Serves as a Conserved Regulator of Cholesterol Metabolism
Authors: Egon Demetz, Andrea Schroll, Kristina Auer, Christiane Heim, Josef R. Patsch, Philipp Eller, Markus Theurl, Igor Theurl, Milan Theurl, Markus Seifert, Daniela Lener, Ursula Stanzl, David Haschka, Malte Asshoff, Stefanie Dichtl, Manfred Nairz, Eva Huber, Martin Stadlinger, Alexander R. Moschen, Xiaorong Li, Petra Pallweber, Hubert Scharnagl, Tatjana Stojakovic, Winfried März, Marcus E. Kleber, Katia Garlaschelli, Patrizia Uboldi, Alberico L. Catapano, Frans Stellaard, Mats Rudling, Keiji Kuba, Yumiko Imai, Makoto Arita, John D. Schuetz, Peter P. Pramstaller, Uwe J.F. Tietge, Michael Trauner, Giuseppe D. Norata, Thierry Claudel, Andrew A. Hicks, Guenter Weiss, Ivan Tancevski
Journal: Cell Metabolism (2014)
Force-time integral decreases with ejection despite constant oxygen consumption and pressure-volume area in dog left ventricle.
Authors: H Suga, Y Goto, T Nozawa, Y Yasumura, S Futaki, N Tanaka
Journal: Circulation Research (1987)

We have shown that systolic pressure-volume area (PVA), which is equivalent to the total mechanical energy generated by ventricular contraction, correlates linearly with myocardial oxygen consumption, VO2, in canine left ventricle. Systolic force-time integral, FTI, also correlates with VO2. In this study, stroke volume was increased from 0 (isovolumic) in isolated cross-circulated canine left ventricle in a stable contractile state while keeping PVA constant with a servo pump. Ventricular total force was calculated from ventricular pressure and volume by the force-equilibrium equation and was integrated from the end of diastole to the end of systole as identified with the time of Emax to yield FTI. Under the conditions of constant PVA, FTI significantly (p less than 0.001) decreased by 10 +/- 7% and 25 +/- 8% with increases in stroke volume from 0 to 8 +/- 4 ml and 17 +/- 3 ml and in ejection fraction from 0 to 0.24 +/- 0.10 and 0.61 +/- 0.05, respectively, while VO2 and Emax remained constant. Therefore, we conclude that in a stable contractile state, it is possible to keep PVA constant even when stroke volume and ejection fraction are varied and that under such conditions, FTI no longer predicts VO2. PVA remains a reliable predictor of VO2 regardless of ventricular loading conditions.
Gastric extremely well-differentiated intestinal-type adenocarcinoma: a challenging lesion to achieve complete endoscopic resection
Authors: K. Kang, K.-M. Kim, J. Kim, P.-L. Rhee, J. Lee, B.-H. Min, J. Rhee, R. Kushima, G. Lauwers
Journal: Endoscopy (2012)

Extremely well-differentiated tubular adenocarcinomas (EWDAs) of the stomach are characterized by surface maturation and their mimicking of intestinal metaplasia. Endoscopically, intramucosal EWDAs are frequently ill defined with indistinct borders due to the pallor of the neoplastic mucosa and the lack of contrast against the background atrophic and metaplastic mucosa. We evaluated the effectiveness of endoscopic resection for EWDAs after endoscopic submucosal dissection (ESD). Among 872 patients with early gastric cancer, 17 EWDAs were identified (1.9 %). Endoscopically, the flat or depressed type was significantly more common among EWDAs (88.2 %) than among early gastric cancers of other histologies (37.8 %; P < 0.01). The discrepancy between endoscopically estimated tumor size and tumor size as confirmed in pathology reports was significantly greater among EWDAs (18.4 ± 22.0 mm) than among others (5.8 ± 7.5 mm). Involvement of the lateral resection margin was more common (29.4 % vs. 2.5 %; P < 0.05), and complete resection was achieved less often in EWDAs (47.1 % vs. 80.4 %; P = 0.01) compared to the others. EWDAs are associated with higher rates of incomplete resection after ESD, especially along the lateral margins. Pathologists should alert endoscopists when this diagnosis is made, with its associated risks; and endoscopists should pay particular attention to the extent of these tumors during resection.
Isolated human follicular dendritic cells display a unique antigenic phenotype.
Authors: F Schriever, A S Freedman, G Freeman, E Messner, G Lee, J Daley, L M Nadler
Journal: The Journal of Experimental Medicine (1989)

In the present study, follicular dendritic cells (FDCs) were purified to homogeneity in order to define the lineage and function of these cells. FDCs were identified by their characteristic morphology and by their expression of receptors for the third complement component, the myeloid-restricted antigen CD14, and the FDC antigen DRC-1. Unclustered FDCs displayed a unique antigenic phenotype since they expressed several B- and myeloid lineage-restricted antigens, but lacked T and NK cell antigens as well as the leukocyte common antigen. FDCs expressed adhesion molecules, including most of the VLA proteins, intercellular adhesion molecule 1 (ICAM-1), and CD11b. FDCs could be isolated to homogeneity by their intense staining with anti-CD14 using flow cytometric cell sorting. These highly purified FDCs expressed CD14 and CD21 but lacked CD20. This antigen pattern and characteristic morphology confirmed that these cells were, in fact, homogeneous FDC preparations. Analysis of polymerase chain reaction-amplified cDNA from highly purified FDCs showed no transcripts for IL-6. The isolation of homogeneous FDC populations will be important for the analysis of the functional role of FDCs within the lymphoid follicle.