tbuckley/cabot-search huggingface dataset:
Morphologic Characterization of Nerves in Whole-Mount Airway Biopsies
Authors: Peter W. West, Brendan J. Canning, Emilio Merlo-Pich, Ashley A. Woodcock, Jaclyn A. Smith
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Neuroplasticity of bronchopulmonary afferent neurons that respond to mechanical and chemical stimuli may sensitize the cough reflex. Afferent drive in cough is carried by the vagus nerve, and vagal afferent nerve terminals have been well defined in animals. Yet, both unmyelinated C fibers and particularly the morphologically distinct, myelinated, nodose-derived mechanoreceptors described in animals are poorly characterized in humans. To date there are no distinctive molecular markers or detailed morphologies available for human bronchopulmonary afferent nerves.Morphologic and neuromolecular characterization of the afferent nerves that are potentially involved in cough in humans.A whole-mount immunofluorescence approach, rarely used in human lung tissue, was used with antibodies specific to protein gene product 9.5 (PGP9.5) and, for the first time in human lung tissue, 200-kD neurofilament subunit.We have developed a robust technique to visualize fibers consistent with autonomic and C fibers and pulmonary neuroendocrine cells. A group of morphologically distinct, 200-kD neurofilament-immunopositive myelinated afferent fibers, a subpopulation of which did not express PGP9.5, was also identified.PGP9.5-immunonegative nerves are strikingly similar to myelinated airway afferents, the cough receptor, and smooth muscle-associated airway receptors described in rodents. These have never been described in humans. Full description of human airway nerves is critical to the translation of animal studies to the clinical setting.
IFN and IL-4 regulate the expression of CC-chemokines (RANTES, MCP-4, TARC) by TLR ligands stimulated nasal fibroblasts
Authors: M. Nonaka, N. Ogihara, R. Pawankar, A. Fukumoto, A. Sakanushi, T. Yagi
Journal: Journal of Allergy and Clinical Immunology (2005)
650m flagship UK research centre is a "bargain" for the UK taxpayer, MPs hear
Authors: A. O'Dowd
Journal: BMJ (2011)

The man who will head up the UK’s flagship medical research institute costing £650m (€772m; $1050m) has described the building as a “bargain” for the UK taxpayer.

Sir Paul Nurse, chief executive and director of the UK Centre for Medical Research and Innovation (UKCMRI), which is due to begin construction in May and open in 2015, was giving evidence to MPs on the parliamentary science and technology committee on 16 February as part of their inquiry into the centre.

The £650m interdisciplinary medical research institute employing 1500 staff and housed in a newly built centre at St Pancras in central London, is being funded by the Medical …
Adoptive Transfer of Autologous T Cells Improves T-cell Repertoire Diversity and Long-term B-cell Function in Pediatric Patients with Neuroblastoma
Authors: Stephan A. Grupp, Eline Luning Prak, Jean Boyer, Kenyetta R. McDonald, Suzanne Shusterman, Edward Thompson, Colleen Callahan, Abbas F. Jawad, Bruce L. Levine, Carl H. June, Kathleen E. Sullivan
Journal: Clinical Cancer Research (2012)

Children with high-risk neuroblastoma have a poor prognosis with chemotherapy alone, and hematopoietic stem cell transplantation offers improved survival. As a dose-escalation strategy, tandem transplants have been used, but are associated with persistent immunocompromise. This study evaluated the provision of an autologous costimulated, activated T-cell product to support immunologic function.Nineteen subjects with high-risk neuroblastoma were enrolled in a pilot phase and 23 subjects were entered in to the randomized study. Immunologic reconstitution was defined by flow cytometric and functional assays. Next-generation sequencing was conducted to identify changes to the T-cell repertoire. Twenty-two patients were vaccinated to define effects on antibody responses.Subjects who received their autologous costimulated T-cell product on day 2 had significantly superior T-cell counts and T-cell proliferation compared with those who received T cells on day 90. Early administration of autologous T cells suppressed oligoclonality and enhanced repertoire diversity. The subjects who received the day 2 T-cell product also had better responses to the pneumococcal vaccine.The infusion of activated T cells can improve immunologic function especially when given early after transplant. This study showed the benefit of providing cell therapies during periods of maximum lymphopenia.
Benign prostatic hyperplasia. Part 2—Management
Authors: Timothy J Wilt, James N’Dow
Journal: BMJ (2008)

Management of benign prostatic hyperplasia (BPH) is mainly directed at improving bothersome lower urinary tract symptoms.The vast majority of men with these symptoms initially present to primary care seeking information about the risks and benefits of available treatments.Few men require urgent referral to a specialist for additional diagnostic testing or management.This article provides evidence to guide primary care doctors in the treatment of men with lower urinary tract symptoms, with emphasis on BPH.A previous article discussed diagnosis.
Tissue Transglutaminase Regulates Focal Adhesion Kinase/AKT Activation by Modulating PTEN Expression in Pancreatic Cancer Cells
Authors: Amit Verma, Sushovan Guha, Huamin Wang, Jansina Y. Fok, Dimpy Koul, James Abbruzzese, Kapil Mehta
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) progresses rapidly and exhibits profound resistance to treatment. We recently reported that a great majority of PDAC tumors and tumor cell lines express elevated levels of tissue transglutaminase (TG2). Here, we provide first evidence that TG2 expression in PDAC cells results in constitutive activation of focal adhesion kinase/AKT by modulating the expression of the tumor suppressor phosphatase PTEN. Experimental Design: Using PDAC cell lines, we determined the effect of TG2 overexpression on PTEN stability and functions. We confirmed the correlation between TG2 expression and PTEN levels in a few (n = 51) PDAC tumor samples. Results: We observed that expression of TG2 is inversely correlated with PTEN expression in PDAC cells. Ectopic expression of TG2 inhibited PTEN phosphorylation and promoted its degradation by ubiquitin-proteasomal pathway. Conversely, down-regulation of TG2 by small interfering RNA up-regulated PTEN expression. Clinical relevance of these results was evident in an athymic nude mouse model where down-regulation of endogenous TG2 caused a significant retardation in PDAC xenograft growth. Importantly, the analysis of 51 tumor samples from patients with stage II PDAC revealed that overexpression of TG2 was associated with loss of PTEN expression (P = 0.023; odds ratio, 4.1). In multivariate analysis, TG2-mediated loss of PTEN was a prognostic factor for overall survival in patients with stage II pancreatic ductal carcinoma independent of tumor stage/lymph node status and tumor differentiation (P = 0.01). Conclusion: TG2 expression in PDAC promotes degradation of PTEN by ubiquitin-proteasomal pathway and results in constitutive activation of focal adhesion kinase/AKT cell survival signaling.
The role of the sodium pump in the control of vascular tone in the rat.
Authors: S Lang, M P Blaustein
Journal: Circulation Research (1980)

We studied the effects of factors that alter active Na extrusion on microvascular smooth muscle contraction.As an index of contraction, we measured arterial pressure in perfused isolated rat hindlimbs.The perfusate was oxygenated Krebs-Henseleit solution containing 0-5.9 mM K + , 4% dextran-40, and, in some instances, dog red cells (6-15% hematocrit).The reference solutions contained 5.9 mM K + .Lowering [K + ] o by 50%, or more, substantially increased perfusion pressure reversibly; pressure was inversely related to [K + ] o .Treatment with 10" 3 M ouabain, which should completely inhibit Na-K pumps, caused a greater pressure increase than did nominally K + -free media.These effects were observed in the hindumbs of reserpine-treated (catecholamine-depleted) as well as normal rats and, thus, cannot be explained by modulation of catecholamine release.Perfusion with solutions containing a constant concentration of norepinephrine increased the perfusion pressure with 5.9 HIM K present and augmented the responses to both reduced [K + ] o and ouabain.The data are discussed in terms of two mechanisms that may lead to a rise in cell Ca 2+ : (1) inhibition of electrogenic Na-K pumps may cause the smooth muscle fibers to depolarize slightly, thereby activating a Ca 2+ conductance increase or release of stored Ca 2+ , and/or (2) the rise in cell Na*, due to Na-K pump inhibition, may cause the fibers to gain Ca 2+ by means of Na-Ca exchange.Circ Res 46: 463-470, 1980 ISOLATED vascular smooth muscle contracts on exposure to potassium-free media or to media containing cardiac glycosides (Blaustein, 1977a).A reduction in the extracellular K + concentration, or treatment with cardiac glycosides, produces an increase in peripheral resistance in intact vascular beds (Haddy, 1975).Three mechanisms, all involving effects on active sodium transport, have been proposed to explain these effects:1. Inhibition of ATP-dependent, cardiac glycoside-sensitive Na-K exchange pumps in the plasmalemma of sympathetic nerve endings may promote the release of catecholamines (e.g., Bonaccorsi et al., 1977;Katsuragi et al., 1978) which will, in turn, induce contraction of vascular smooth muscle.2. Inhibition of the Na-K pumps in the sarcolemma of vascular smooth muscle fibers (Heidlage and Jones, 1978) should depolarize the fibers by a few millivolts because these pumps, like those in many other types of cells (De Weer, 1975), are
Effect of Short-Term Hormone Replacement Therapy on Breast Cancer Risk Reduction After Bilateral Prophylactic Oophorectomy in <i>BRCA1</i> and <i>BRCA2</i> Mutation Carriers: The PROSE Study Group
Authors: Timothy R. Rebbeck, Tara Friebel, Theresa Wagner, Henry T. Lynch, Judy E. Garber, Mary B. Daly, Claudine Isaacs, Olufunmilayo I. Olopade, Susan L. Neuhausen, Laura van ′t Veer, Rosalind Eeles, D. Gareth Evans, Gail Tomlinson, Ellen Matloff, Steven A. Narod, Andrea Eisen, Susan Domchek, Katrina Armstrong, Barbara L. Weber
Journal: Journal of Clinical Oncology (2005)

Purpose Bilateral prophylactic oophorectomy (BPO) is widely used for cancer risk reduction in women with BRCA1/2 mutations. Many premenopausal women choose to take hormone replacement therapy (HRT) after undergoing BPO to abrogate immediate symptoms of surgically-induced menopause. Thus, we evaluated whether the breast cancer risk reduction conferred by BPO in BRCA1/2 mutation carriers is altered by use of post-BPO HRT. Methods We identified a prospective cohort of 462 women with disease-associated germline BRCA1/2 mutations at 13 medical centers to evaluate breast cancer risk after BPO with and without HRT. We determined the incidence of breast cancer in 155 women who had undergone BPO and in 307 women who had not undergone BPO on whom we had complete information on HRT use. Postoperative follow-up was 3.6 years. Results Consistent with previous reports, BPO was significantly associated with breast cancer risk reduction overall (hazard ratio [HR] = 0.40; 95%CI, 0.18 to 0.92). Using mutation carriers without BPO or HRT as the referent group, HRT of any type after BPO did not significantly alter the reduction in breast cancer risk associated with BPO (HR = 0.37; 95% CI, 0.14 to 0.96). Conclusion Short-term HRT use does not negate the protective effect of BPO on subsequent breast cancer risk in BRCA1/2 mutation carriers.
Reporting Bias in Drug Trials Submitted to the Food and Drug Administration: Review of Publication and Presentation
Authors: Kristin Rising, Peter Bacchetti, Lisa Bero
Journal: PLoS Medicine (2008)

Background Previous studies of drug trials submitted to regulatory authorities have documented selective reporting of both entire trials and favorable results. The objective of this study is to determine the publication rate of efficacy trials submitted to the Food and Drug Administration (FDA) in approved New Drug Applications (NDAs) and to compare the trial characteristics as reported by the FDA with those reported in publications. Methods and Findings This is an observational study of all efficacy trials found in approved NDAs for New Molecular Entities (NMEs) from 2001 to 2002 inclusive and all published clinical trials corresponding to the trials within the NDAs. For each trial included in the NDA, we assessed its publication status, primary outcome(s) reported and their statistical significance, and conclusions. Seventy-eight percent (128/164) of efficacy trials contained in FDA reviews of NDAs were published. In a multivariate model, trials with favorable primary outcomes (OR = 4.7, 95% confidence interval [CI] 1.33–17.1, p = 0.018) and active controls (OR = 3.4, 95% CI 1.02–11.2, p = 0.047) were more likely to be published. Forty-one primary outcomes from the NDAs were omitted from the papers. Papers included 155 outcomes that were in the NDAs, 15 additional outcomes that favored the test drug, and two other neutral or unknown additional outcomes. Excluding outcomes with unknown significance, there were 43 outcomes in the NDAs that did not favor the NDA drug. Of these, 20 (47%) were not included in the papers. The statistical significance of five of the remaining 23 outcomes (22%) changed between the NDA and the paper, with four changing to favor the test drug in the paper (p = 0.38). Excluding unknowns, 99 conclusions were provided in both NDAs and papers, nine conclusions (9%) changed from the FDA review of the NDA to the paper, and all nine did so to favor the test drug (100%, 95% CI 72%–100%, p = 0.0039). Conclusions Many trials were still not published 5 y after FDA approval. Discrepancies between the trial information reviewed by the FDA and information found in published trials tended to lead to more favorable presentations of the NDA drugs in the publications. Thus, the information that is readily available in the scientific literature to health care professionals is incomplete and potentially biased.
Downregulation of human platelet reactivity by neutrophils. Participation of lipoxygenase derivatives and adhesive proteins.
Authors: J Valles, M T Santos, A J Marcus, L B Safier, M J Broekman, N Islam, H L Ullman, J Aznar
Journal: Journal of Clinical Investigation (1993)

Unstimulated neutrophils inhibited activation and recruitment of thrombin- or collagen-stimulated platelets in an agonist-specific manner. This occurred under conditions of close physical cell-cell contact, although biochemical adhesion between the cells as mediated by P-selectin was not required. Moreover, in the presence of monoclonal P-selectin antibodies that blocked biochemical platelet-neutrophil adhesion, thrombin-stimulated platelets were more efficiently downregulated by neutrophils. This suggested a prothrombotic role for P-selectin under these circumstances. The neutrophil downregulatory effect on thrombin-stimulated platelets was amplified by lipoxygenase inhibition with 5,8,11,14-eicosatetraynoic acid. In contrast, the neutrophil inhibitory effect on platelets was markedly reduced by platelet-derived 12S-hydroxy-5,8-cis, 10-trans, 14-cis-eicosatetraenoic acid (12S-HETE), as well as by the platelet-neutrophil transcellular product, 12S,20-dihydroxy-5,8,10,14-eicosatetraenoic acid (12S,20-DiHETE), but not by another comparable metabolite, 5S,12S-dihydroxy-6-trans, 8-cis, 10-trans, 14-cis-eicosatetraenoic acid (5S,12S-DiHETE), or the neutrophil-derived hydroxy acid leukotriene B4. The neutrophil downregulatory effect on thrombin-induced platelet reactivity was enhanced by aspirin treatment. This may represent a novel action of aspirin as an inhibitor of platelet function. These results provide in vitro biochemical and functional evidence for the thromboregulatory role of neutrophils and emphasize the multicellular aspect of hemostasis and thrombosis.
Nitric oxide influences neuronal activity in the nucleus tractus solitarius of rat brainstem slices.
Authors: T Tagawa, T Imaizumi, S Harada, T Endo, M Shiramoto, Y Hirooka, A Takeshita
Journal: Circulation Research (1994)

Nitric oxide (NO) is shown to be synthesized in the central nervous system as well as in vascular endothelial cells. However, the physiological role of NO in cardiovascular regulation in the central nervous system remains unclear. The present study examines whether NO plays a role in the regulation of neuronal activity in the nucleus tractus solitarius (NTS). Single-unit extracellular recordings were obtained from NTS neurons in slices (400 microns) of the rat brainstem, which had spontaneous discharges at a frequency of 0.5 to 3 spikes per second. Eighty-one neurons were tested for sensitivity to L-arginine, which is the physiological precursor of NO. L-Arginine (10(-7) to 10(-4) mol/L) increased neuronal activity dose dependently in 33 (40.7%) of 81 neurons tested, but D-arginine (10(-5) mol/L) did not. The neurons that responded to L-arginine responded to glutamate as well. NG-Monomethyl-L-arginine (10(-5) to 3 x 10(-5) mol/L), an inhibitor of the formation of NO, dose-dependently blocked increases in the neuronal activity evoked with L-arginine (10(-5) mol/L). Hemoglobin (1.5 mg/L), a trapper of NO, and methylene blue (10(-5) mol/L), an inhibitor of guanylate cyclase, also blocked increases in the neuronal activity evoked with L-arginine (10(-5) mol/L). Sodium nitroprusside (SNP, 10(-5) to 10(-4) mol/L), which spontaneously produces NO, increased the neuronal activity in the neurons that responded to L-arginine. SNP did not alter the neuronal activity of the neurons that did not respond to L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)
Human Papillomavirus Type 16 E7 Up-regulates AKT Activity through the Retinoblastoma Protein
Authors: Craig W. Menges, Laurel A. Baglia, Randi Lapoint, Dennis J. McCance
Journal: Cancer Research (2006)

Abstract Human papillomaviruses (HPV) are small DNA tumor viruses causally associated with cervical cancer. The early gene product E7 from high-risk HPV is considered the major transforming protein expressed by the virus. Although many functions have been described for E7 in disrupting normal cellular processes, we describe in this study a new cellular target in primary human foreskin keratinocytes (HFK), the serine/threonine kinase AKT. Expression of HPV type 16 E7 in HFK caused inhibition of differentiation, hyperproliferation, and up-regulation of AKT activity in organotypic raft cultures. The ability of E7 to up-regulate AKT activity is dependent on its ability to bind to and inactivate the retinoblastoma (Rb) gene product family of proteins. Furthermore, we show that knocking down Rb alone, with short hairpin RNAs, was sufficient to up-regulate AKT activity in differentiated keratinocytes. Up-regulation of AKT activity and loss of Rb was also observed in HPV-positive cervical high-grade squamous intraepithelial lesions when compared with normal cervical tissue. Together, these data provide evidence linking inactivation of Rb by E7 in the up-regulation of AKT activity during cervical cancer progression. (Cancer Res 2006; 66(11): 5555-9)
Nephrotic Syndrome Due to an Amyloidogenic Mutation in Fibrinogen A α Chain
Authors: Maria M. Picken, Reinhold P. Linke
Journal: Journal of the American Society of Nephrology (2008)

We identified amyloid derived from a mutant fibrinogen A alpha chain associated with one of the hereditary amyloidoses by kidney biopsy. The recognition of molecular and etiologic diversity among amyloidoses has revolutionized the management of systemic amyloidosis and necessitates precision in amyloid typing. Pitfalls and recommendations for the differential diagnosis of renal amyloid and current standards of amyloid typing are briefly discussed. Diagnosis of the amyloidosis type must be based on identification of the chemical composition of the amyloid protein in deposits and not on clinical suspicion, laboratory tests, or genetic testing. A clinical correlation is required to support but not make a diagnosis of amyloid type. If a hereditary form is detected by amyloid protein typing, then molecular studies are indicated. Conversely, in cases in which DNA sequence indicates a mutant amyloid precursor protein, protein analysis of the deposits must provide the definitive evidence. Negative or inconclusive results must be investigated further by a reference laboratory with the capability of applying more sophisticated methods.
The amylin analog pramlintide improves glycemic control and reduces postprandial glucagon concentrations in patients with type 1 diabetes mellitus
Authors: Birgit Nyholm, Lotte Ørskov, Karen Y. Hove, Claus H. Gravholt, Niels Møller, K. George, M.M. Alberti, Chris Moyses, Orville Kolterman, Ole Schmitz
Journal: Metabolism (1999)
A Role for Reactive Oxygen Species in Endothelial Cell Anoikis
Authors: Arthur E. Li, Hideaki Ito, Ilsa I. Rovira, Kyung-Soo Kim, Kazuyo Takeda, Zu-Yi Yu, Victor J. Ferrans, Toren Finkel
Journal: Circulation Research (1999)

Abstract —When adherent cells, such as epithelial or endothelial cells, are detached and continuously maintained in suspension, they undergo a form of programmed cell death termed anoikis. We demonstrate that coincident with endothelial cell detachment, there is a dramatic rise in the intracellular level of reactive oxygen species (ROS). Reattachment to a solid surface rapidly attenuates the level of ROS. The mitochondria appear to be the major source of the detachment-induced rise in ROS. The change in the intracellular redox state appears to contribute to endothelial anoikis, because treatment with either the cell-permeant antioxidant N -acetylcysteine or the flavin protein inhibitor diphenylene iodonium is demonstrated to reduce oxidant levels and protect against subsequent cell death. Similarly, the endogenous intracellular level of ROS is shown to correlate with the extent of cell death. Finally, we demonstrate that the activities of both caspases and of the c-Jun N-terminal kinases are modulated by the rise in intracellular ROS levels. These results suggest that oxidants serve as signaling molecules and regulators of anoikis.