tbuckley/cabot-search huggingface dataset:
Purinergic Receptor Signaling at the Basolateral Membrane of Macula Densa Cells
Authors: Ruisheng Liu, P. Darwin Bell, Janos Peti-Peterdi, Gergly Kovacs, Alf Johansson, A. Erik G. Persson
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Purinergic receptors are important in the regulation of renal hemodynamics; therefore, this study sought to determine if such receptors influence macula densa cell function. Isolated glomeruli containing macula densa cells, with and without the cortical thick ascending limb, were loaded with the Ca 2+ sensitive indicators, Fura Red (confocal microscopy) or fura 2 (conventional video image analysis). Studies were performed on an inverted microscope in a chamber with a flow-through perfusion system. Changes in cytosolic calcium concentration ([Ca 2+ ] i ) from exposed macula densa plaques were assessed upon addition of adenosine, ATP, UTP, ADP, or 2-methylthio-ATP (2- MeS-ATP) for 2 min added to the bathing solution. There was no change in [Ca 2+ ] i with addition of adenosine (10 −7 to 10 −3 M). UTP and ATP (10 −4 M) caused [Ca 2+ ] i to increase by 268 ± 40 nM ( n = 21) and 295 ± 53 nM ( n = 21), respectively, whereas in response to 2MesATP and ADP, [Ca 2+ ] i increased by only 67 ± 13 nM ( n = 8) and 93 ± 36 nM ( n = 14), respectively. Dose response curve for ATP (10 −7 to 10 −3 M) added in bath showed an EC 50 of 15 μM. No effect on macula densa [Ca 2+ ] i was seen when ATP was added from the lumen. ATP caused similar increases in macula densa [Ca 2+ ] i in the presence or absence of bath Ca 2+ and addition of 5 mM ethyleneglycotetraacetic acid (EGTA). Suramin (an antagonist of P2X and P2Y receptors) completely inhibited ATP-induced [Ca 2+ ] i dynamics. Also, ATP-Ca 2+ responsiveness was prevented by the phospholipase C inhibitor, U-73122, but not by its inactive analog, U-73343. These results suggest that macula densa cells possess P2Y 2 purinergic receptors on basolateral but not apical membranes and that activation of these receptors results in the mobilization of Ca 2+ .
Case Reports of Heart Failure after Therapy with a Tumor Necrosis Factor Antagonist
Authors: Hyon J. Kwon, Timothy R. Cot, Michael S. Cuffe, Judith M. Kramer, M Miles Braun
Journal: Annals of Internal Medicine (2003)

Background: Etanercept and infliximab are U.S. Food and Drug Administrationapproved tumor necrosis factor (TNF) antagonists. Objective: To describe adverse event reports of heart failure after TNF antagonist therapy. Design: Case series. Setting: The U.S. Food and Drug Administration's MedWatch program. Patients: 47 patients who developed new or worsening heart failure during TNF antagonist therapy. Measurements: Clinical and laboratory reports. Results: After TNF antagonist therapy, 38 patients developed new-onset heart failure and 9 patients experienced heart failure exacerbation. Of the 38 patients with new-onset heart failure, 19 (50%) had no identifiable risk factors. Ten patients younger than 50 years of age developed new-onset heart failure after receiving TNF antagonists. After TNF antagonist therapy was discontinued and heart failure therapy was started in these 10 patients, 3 had complete resolution of heart failure, 6 improved, and 1 died. Conclusion: In a fraction of patients, TNF antagonists might induce new-onset heart failure or exacerbate existing disease.
Tissue-Specific Pathways for Estrogen Regulation of Ovarian Cancer Growth and Metastasis
Authors: Monique A. Spillman, Nicole G. Manning, Wendy W. Dye, Carol A. Sartorius, Miriam D. Post, Joshua Chuck Harrell, Britta M. Jacobsen, Kathryn B. Horwitz
Journal: Cancer Research (2010)

Menopausal estrogen (E2) replacement therapy increases the risk of estrogen receptor (ER)-positive epithelial ovarian cancers (EOC). Whether E2 is tumorigenic or promotes expansion of undiagnosed preexisting disease is unknown. To determine E2 effects on tumor promotion, we developed an intraperitoneal mouse xenograft model using ZsGreen fluorescent ER(-) 2008 and ER(+) PEO4 human EOC cells. Tumor growth was quantified by in vivo fluorescent imaging. In ER(+) tumors, E2 significantly increased size, induced progesterone receptors, and promoted lymph node metastasis, confirming that ERs are functional and foster aggressiveness. Laser-captured human EOC cells from ER(-) and ER(+) xenografted tumors were profiled for expression of E2-regulated genes. Three classes of E2-regulated EOC genes were defined, but <10% were shared with E2-regulated breast cancer genes. Because breast cancer selective ER modulators (SERM) are therapeutically ineffective in EOC, we suggest that our EOC-specific E2-regulated genes can assist pharmacologic discovery of ovarian-targeted SERM.
Utility of Eosinophil-derived Neurotoxin as a Biomarker in Eosinophilic Esophagitis: Results From a Randomized, Double-blind, Controlled Trial of Mepolizumab in Pediatric Patients
Authors: S. Gupta, H. Kita, M. Collins, T. Perschy, A. Heath, C. Jurgensen
Journal: Journal of Allergy and Clinical Immunology (2010)
Gene Signatures Associated with Mouse Postnatal Hindbrain Neural Stem Cells and Medulloblastoma Cancer Stem Cells Identify Novel Molecular Mediators and Predict Human Medulloblastoma Molecular Classification
Authors: Daniela Corno, Mauro Pala, Manuela Cominelli, Barbara Cipelletti, Ketty Leto, Laura Croci, Valeria Barili, Federico Brandalise, Raffaella Melzi, Alessandra Di Gregorio, Lucia Sergi Sergi, Letterio Salvatore Politi, Lorenzo Piemonti, Alessandro Bulfone, Paola Rossi, Ferdinando Rossi, Gian Giacomo Consalez, Pietro Luigi Poliani, Rossella Galli
Journal: Cancer Discovery (2012)

Medulloblastoma arises from mutations occurring in stem/progenitor cells located in restricted hindbrain territories. Here we report that the mouse postnatal ventricular zone lining the IV ventricle also harbors bona fide stem cells that, remarkably, share the same molecular profile with cerebellar white matter-derived neural stem cells (NSC). To identify novel molecular mediators involved in medulloblastomagenesis, we compared these distinct postnatal hindbrain-derived NSC populations, which are potentially tumor initiating, with murine compound Ptch/p53 mutant medulloblastoma cancer stem cells (CSC) that faithfully phenocopy the different variants of human medulloblastoma in vivo. Transcriptome analysis of both hindbrain NSCs and medulloblastoma CSCs resulted in the generation of well-defined gene signatures, each reminiscent of a specific human medulloblastoma molecular subclass. Most interestingly, medulloblastoma CSCs upregulated developmentally related genes, such as Ebfs, that were shown to be highly expressed in human medulloblastomas and play a pivotal role in experimental medullo-blastomagenesis. These data indicate that gene expression analysis of medulloblastoma CSCs holds great promise not only for understanding functional differences between distinct CSC populations but also for identifying meaningful signatures that might stratify medulloblastoma patients beyond histopathologic staging.
Identification of Genes for Childhood Heritable Diseases
Authors: Kym M. Boycott, David A. Dyment, Sarah L. Sawyer, Megan R. Vanstone, Chandree L. Beaulieu
Journal: Annual Review of Medicine (2014)

Genes causing rare heritable childhood diseases are being discovered at an accelerating pace driven by the decreasing cost and increasing accessibility of next-generation DNA sequencing combined with the maturation of strategies for successful gene identification. The findings are shedding light on the biological mechanisms of childhood disease and broadening the phenotypic spectrum of many clinical syndromes. Still, thousands of childhood disease genes remain to be identified, and given their increasing rarity, this will require large-scale collaboration that includes mechanisms for sharing phenotypic and genotypic data sets. Nonetheless, genomic technologies are poised for widespread translation to clinical practice for the benefit of children and families living with these rare diseases.
Interaction, function words, and the wider goals of speech perception
Authors: Richard Shillcock
Journal: Behavioral and Brain Sciences (2000)

We urge caution in generalising from content words to function words, in which lexical-to-phonemic feedback might be more likely. Speech perception involves more than word recognition; feedback might be outside the narrow logic of word identification but still be present for other purposes. Finally, we raise the issue of evidence from imaging studies of auditory hallucination.
Effects of Age, Diabetes, and Vascular Disease on Growth Differentiation Factor 11: First-in-Human Study
Authors: Gian Paolo Fadini, Lisa Menegazzo, Benedetta Maria Bonora, Marta Mazzucato, Sara Persano, Saula Vigili de Kreutzenberg, Angelo Avogaro
Journal: Diabetes Care (2015)

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β superfamily, has been recently described as a soluble rejuvenation factor for the heart, muscle, and brain. In fact, GDF11 declines in aged mice, while its replenishment improves vascular, brain, muscle, and cardiac function (1–3). As type 2 diabetes (T2D) increases with age and is characterized by accelerated aging (4), we cross-sectionally explored the effects of age, diabetes, and vascular disease on plasma GDF11 concentrations. The study was approved by the local ethics committee and conducted in accordance with the principles of the Declaration of Helsinki. Plasma GDF11 concentrations were measured by ELISA (MBS2502734, MyBioSource) in a previously described cohort of T2D patients and age- and sex-matched control subjects without diabetes (5). As the distribution of GDF11 concentrations was skewed, it was log-transformed before statistical analyses. On average, plasma GDF11 concentrations were higher in T2D patients than …
Vascular Endothelial Growth Factor Drives Autocrine Epithelial Cell Proliferation and Survival in Chronic Rhinosinusitis with Nasal Polyposis
Authors: Hyun Sil Lee, Allen Myers, Jean Kim
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

The pathogenesis of nasal polyps in chronic rhinosinusitis is poorly understood.These studies seek to implicate a functional role for vascular endothelial growth factor (VEGF) in perpetuating primary nasal epithelial cell overgrowth, a key feature of hyperplastic polyps.Comparison of VEGF and receptor expression was assessed by ELISA of nasal lavage, immunohistochemistry of sinus tissue, flow cytometry of nasal epithelial cells, and ELISA of supernatants. VEGF-dependent cell growth and apoptosis were assessed with blocking antibodies to VEGF, their receptors, or small interfering RNA knockdown of neuropilin-1 by cell proliferation assays and flow cytometric binding of annexin V.VEGF protein was sevenfold higher in nasal lavage from patients with polyposis compared with control subjects (P < 0.001). We also report elevated expression of VEGF (P < 0.012), receptors VEGFR2 and phospho-VEGFR2 (both P < 0.04), and identification of VEGF coreceptor neuropilin-1 in these tissues. Nasal epithelial cells from patients with polyps demonstrated faster growth rates (P < 0.005). Exposure of cells to blocking antibodies against VEGF resulted in inhibition of cell growth (P < 0.05). VEGF receptor blockade required blockade of neuropilin-1 (P < 0.05) and resulted in increased apoptosis (P < 0.001) and inhibition of autocrine epithelial VEGF production (P < 0.05).These data demonstrate that VEGF is a novel biomarker for chronic rhinosinusitis with hyperplastic sinonasal polyposis that functions in an autocrine feed-forward manner to promote nasal epithelial cell growth and to inhibit apoptosis. These findings implicate a previously unrecognized and novel role of VEGF functioning through neuropilin-1 on nonneoplastic primary human airway epithelial cells, to amplify cell growth, contributing to exuberant hyperplastic polyposis.
Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease
Authors: Clive Page, Mario Cazzola
Journal: European Respiratory Journal (2014)

Over the last decade, there has been a steady increase in the use of fixed-dose combinations of drugs for the treatment of a range of diseases, including hypertension, cancer, AIDS, tuberculosis and other infectious diseases. It is now evident that patients with asthma or chronic obstructive pulmonary disease (COPD) can also benefit from the use of fixed-dose combinations, including combinations of a long-acting β2-agonist and an inhaled corticosteroid, and combinations of long-acting β2-agonists and long-acting muscarinic receptor antagonists. In fact, there are now a number of "triple-inhaler" fixed-dose combinations under development, with the first such triple combination having been approved in India. This use of combinations containing drugs with complementary pharmacological actions in the treatment of patients with asthma or COPD has also led to the discovery and development of drugs having two different primary pharmacological actions in the same molecule, which we have called "bifunctional drugs". In this review, we discuss the state of the art of these new bifunctional drugs as novel treatments for asthma and COPD that can be categorised as bifunctional bronchodilators, bifunctional bronchodilator/anti-inflammatory drugs and bifunctional anti-inflammatory drugs.
Translating the Metastasis Paradigm from Scientific Theory to Clinical Oncology
Authors: Fei Dong, Anuradha S. Budhu, Xin Wei Wang
Journal: Clinical Cancer Research (2009)

Cancer metastasis contributes to significant morbidity and mortality. Patients with metastatic cancer, often considered incurable, are provided with either supportive care or aggressive management without curative intent. Despite decades of research toward unraveling cancer progression mechanisms, the current body of knowledge has not translated into effective antimetastasis therapies, but recent findings challenge the classic notion that metastases develop during the late stages of carcinogenesis. Here, we evaluate the scientific evidence in the context of the multistage metastasis model. The resolution of current controversies has implications on both the prognostic value of molecular technology and the future of targeted therapies for the clinical benefit of metastasis patients.
Dietary Intake of Lactose as a Strong Predictor for Secretor Status of Nipple Aspirate Fluid in Healthy Premenopausal Nonlactating Women
Authors: Yafei Huang, Karl E. Anderson, Manubai Nagamani, James J. Grady, Lee-Jane W. Lu
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Nipple aspirate fluid (NAF) is considered a potential source for discovering breast cancer biomarkers. However, the success rate of obtaining NAF was reported to vary from 48% to 77%, and mechanisms for its secretion are not fully understood. The purpose of this study was to investigate dietary, demographic, reproductive, hormonal, and anthropometric factors that are associated with the ability to obtain NAF by aspiration (secretor status) from premenopausal women. Study Design: NAF procedures were attempted for women who were 30 to 40 years old, not pregnant, not breast-feeding, and not taking contraceptive medications. Results: Compared with nonsecretors, secretors of NAF consumed significantly more dietary lactose (mainly from milk), were more likely to be parous, were older at first and last childbirth, breast-fed their babies for a longer period of time, and had an earlier menarche and lower plasma concentrations of 17β-estradiol (P &amp;lt; 0.05). Using multivariate logistic regression models, higher dietary intake of lactose [odds ratio (OR), 2.7; 95% confidence interval (95% CI), 1.5-4.8], earlier menarche (OR, 0.8; 95% CI, 0.7-1.0), being parous (OR, 2.3; 95% CI, 1.0-5.6), and being older at first childbirth (OR, 1.5; 95% CI, 1.0-2.1) were found to be independent and positive predictors for being a secretor of NAF. Conclusions: These findings suggest that dietary intake of lactose, a modifiable factor, may be used to change the NAF secretor status of women. This finding may facilitate the use of NAF as a diagnostic material for detecting breast diseases.
On Malgaigne's Hooks for Fractured Patella
Authors: C. De Morgan
Journal: BMJ (1862)

of the nerves arising therefrom.Lastly, Faradisation is useless in the general paralysis of the insane; injurious in myelitis until after recovery has taken place; and is the only remedy worthy of confidence in the fatty atrophy of muscles, and in the paralysee atrophique graisseuse de lenfance.As strikingly illustrative of the charming results sometimes obtained by its judicious employment, I will, in conclusion, quote the following case which I treated when in practice in Liverpool, and which wvas subsequently published in Mr. Lobb's work on galvanism.CASE. A. B., aged 18, a single gentleman, came under my care to be treated for an attack of paraplegia, on August 27th, 1859.He was a fresh looking well deve- loped young man of sanguine temperament.The vas- cular and respiratory organs appeared healthy, and the functions of the abdominal viscera were well performed.The pulse was 80, regular; the skin was cool; the tongue was furred, moist, and steadily protruded; there was no defect of articulation.For some time past, he had been complaining of gradually increasing debility of the lower limbs ; and latterly they had been utterly useless as organs of locomotion.He was quite unable to stand, and moved from one apartment to another by the aid of a pair of crutches.If he attempted to rise from a sitting posture by grasping a chair or table, he fell back quite helpless; if supported on one side, the legs doubled up, the knees knocking together; and, if not prevented, he would sink to the grounds He had no pain in the back, and no pain was felt on percussion along the spine.Sleep was natural, not troubled with dreams or involuntary startings; the senses and sensi- bility were normal.There was no evidence of saturnine poisoning, of worms, nor of rheumatic affection.The functions of the bladder and rectum were normal; and the superior extremities were unaffected.He had been taking eleven grains of sulphate of zinc daily, which was prescribed by the late Dr. Bright.Two sisters were afflicted much in the same way to a greater degree; one having being confined almost constantly in the recum- bent posture for eleven years.August 207th, 1850.A gentle to-and-fro galvanic cur- rent was passed from the lumbar region to the feet, and electricity localised in each of the affected muscles for one or two minutes.August 30th.He complained of lassitude after the last seance; but expressed himself now as slightly im- proved.The localised electricity was again applied.
Measurement properties of adult quality‐of‐life measurement instruments for eczema: a systematic review
Authors: D. Heinl, C. A. C. Prinsen, S. Deckert, J. R. Chalmers, A. M. Drucker, R. Ofenloch, R. Humphreys, T. Sach, S. L. Chamlin, J. Schmitt, C. Apfelbacher
Journal: Allergy (2015)

The Harmonising Outcome Measures for Eczema (HOME) initiative has identified quality of life (QoL) as a core outcome domain to be evaluated in every eczema trial. It is unclear which of the existing QoL instruments is most appropriate for this domain. Thus, the aim of this review was to systematically assess the measurement properties of existing measurement instruments developed and/or validated for the measurement of QoL in adult eczema.We conducted a systematic literature search in PubMed and Embase identifying studies on measurement properties of adult eczema QoL instruments. For all eligible studies, we assessed the adequacy of the measurement properties and the methodological quality with the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. A best evidence synthesis summarizing findings from different studies was the basis to assign four degrees of recommendation (A-D).A total of 15 articles reporting on 17 instruments were included. No instrument fulfilled the criteria for category A. Six instruments were placed in category B, meaning that they have the potential to be recommended depending on the results of further validation studies. Three instruments had poor adequacy in at least one required adequacy criterion and were therefore put in category C. The remaining eight instruments were minimally validated and were thus placed in category D.Currently, no QoL instrument can be recommended for use in adult eczema. The Quality of Life Index for Atopic Dermatitis (QoLIAD) and the Dermatology Life Quality Index (DLQI) are recommended for further validation research.
Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity
Authors: Kimihisa Ichikawa, Weimin Liu, Limin Zhao, Zheng Wang, Di Liu, Toshiaki Ohtsuka, Huangge Zhang, John D. Mountz, William J. Koopman, Robert P. Kimberly, Tong Zhou
Journal: Nature Medicine (2001)
Abstract A19: The histone acetyltransferase PCAF is required for Hedgehog-Gli-dependent transcription and proliferation
Authors: Martina Malatesta, Cornelia Steinhauer, Massimo Squatrito, Kristian Helin
Journal: Cancer Research (2013)

Abstract The Hedgehog (Hh) signaling pathway plays an important role in embryonic patterning and development of many tissues and organs as well as in maintaining and repairing mature tissues in adults. Uncontrolled activation of the Hh-Gli pathway has been implicated in developmental abnormalities as well as in several cancers, including brain tumors like medulloblastoma and glioblastoma. Inhibition of an aberrant Hh-Gli signaling has thus emerged as an attractive target for anticancer therapy, however the mechanisms that mediate Hh-Gli signaling in vertebrates remain still poorly understood. Here, we show that the histone acetyltransferase (HAT) PCAF/KAT2B is an important regulator of the Hh pathway. Specifically, we demonstrate that PCAF depletion leads to an impairment of Hh activity and reduced expression of Hh target genes. Consequently, downregulation of PCAF in medulloblastoma and glioblastoma cell lines leads to decreased cell proliferation and increased apoptosis. Furthermore, we show that PCAF interacts with GLI1, the downstream effector in the Hh-Gli pathway, and that PCAF or GLI1 loss reduces the levels of H3K9 acetylation on Hh target gene promoters. Our study identifies the acetyltransferase PCAF as a positive cofactor of the Hh-Gli signaling pathway, and we propose PCAF as a potential interesting novel therapeutic target for the treatment of patients with medulloblastoma and glioblastoma. Citation Format: Martina Malatesta, Cornelia Steinhauer, Massimo Squatrito, Kristian Helin. The histone acetyltransferase PCAF is required for Hedgehog-Gli-dependent transcription and proliferation. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A19.