tbuckley/cabot-search huggingface dataset:
Soluble factors secreted by glioblastoma cell lines facilitate recruitment, survival, and expansion of regulatory T cells: implications for immunotherapy
Authors: C. A. Crane, B. J. Ahn, S. J. Han, A. T. Parsa
Journal: Neuro-Oncology (2012)

In patients with glioma, the tumor microenvironment can significantly impact pro-inflammatory immune cell functions. However, the mechanisms by which this occurs are poorly defined. Because immunosuppressive regulatory T cells (Treg) are over represented in the tumor microenvironment compared with peripheral blood, we hypothesized that the tumor may have an effect on Treg survival, migration, expansion, and/or induction of a regulatory phenotype from non-Treg conventional CD4+ T cells. We defined the impact of soluble factors produced by tumor cells on Treg from healthy patients in vitro to determine mechanisms by which gliomas influence T cell populations. We found that tumor-derived soluble factors allowed for preferential proliferation and increased chemotaxis of Treg, compared with conventional T cells, indicating that these mechanisms may contribute to the increased Treg in the tumor microenvironment. Conventional T cells also exhibited a significantly increased expression of pro-apoptotic transcripts in the presence of tumor-derived factors, indicating that survival of Treg in the tumor site is driven by exposure to soluble factors produced by the tumor. Together, these data suggest that tumor burden may induce increased Treg infiltration, proliferation, and survival, negating productive anti-tumor immune responses in patients treated with immunotherapies. Collectively, our data indicate that several mechanisms of Treg recruitment and retention in the tumor microenvironment exist and may need to be addressed to improve the specificity of immunotherapies seeking to eliminate Treg in patients with glioma.
Sweet Time Unafflicted
Authors: Daniel Rayson
Journal: Journal of Clinical Oncology (2002)

Article Tools THE ART OF ONCOLOGY: WHEN THE TUMOR IS NOT THE TARGET Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.23.4603 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12454122 Sweet Time Unafflicted Daniel RaysonxDaniel RaysonSearch for articles by this author Show More From the Division of Medical Oncology, Dalhousie University, Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada. https://doi.org/10.1200/JCO.2002.20.23.4603 Full Text PDF Figures and Tables "Sweet Time Unafflicted." Journal of Clinical Oncology, 20(23), pp. 4603–4604© 2002 by American Society of Clinical Oncology
Activation of Protein Kinase G Up-regulates Expression of 15-Lipoxygenase-1 in Human Colon Cancer Cells
Authors: Atsuko Deguchi, Steven W. Xing, Imad Shureiqi, Peiying Yang, Robert A. Newman, Scott M. Lippman, Steven J. Feinmark, Bert Oehlen, I. Bernard Weinstein
Journal: Cancer Research (2005)

Abstract Recent studies indicate that the induction of apoptosis in human colon cancer cells by certain nonsteroidal antiinflammatory drugs involves increased expression of 15-LOX-1 and synthesis of its major product 13-S-hydroxyoctadecadienoic acid (13-S-HODE). Evidence was obtained that this occurs via a cyclooxygenase-2 (COX-2)–independent mechanism, but the actual mechanism of induction of 15-LOX-1 by these compounds is not known. There is extensive evidence that treatment of SW480 human colon cancer cells with sulindac sulfone (Exisulind, Aptosyn) or the related derivative OSI-461, both of which inhibit cyclic GMP (cGMP)-phosphodiesterases but lack COX-2 inhibitory activity, causes an increase in intracellular levels of cGMP, thus activating protein kinase G (PKG), which then activates pathways that lead to apoptosis. Therefore, in the present study, we examined the effects of various agents that cause increased cellular levels of cGMP on the expression of 15-LOX-1 in SW480 human colon cancer cells. Treatment of the cells with Exisulind, sulindac sulfide, OSI-461, the guanylyl cyclase activator YC-1, or the cell-permeable cGMP compound 8-para-chlorophenylthio-cGMP (8-pCPT-cGMP) caused an increase in cellular levels of 15-LOX-1. Exisulind, OSI-461, and 8-pCPT-cGMP also increased mRNA levels of 15-LOX-1, suggesting that the effects were at the level of transcription. The cGMP-phosphodiesterase inhibitors and YC-1 increased the production of 13-S-HODE, which is the linoleic acid metabolite of 15-LOX-1. Treatment of SW480 cells with the PKG inhibitor Rp-8-pCPT-cGMP blocked Exisulind-induced 15-LOX-1 expression. Furthermore, derivatives of SW480 cells that were engineered to stably overexpress wild-type PKG Iβ displayed increased cellular levels of 15-LOX-1 when compared with vector control cells. Taken together, these results provide evidence that the cGMP/PKG pathway can play an important role in the induction of 15-LOX-1 expression by nonsteroidal antiinflammatory drugs and related agents.
2007 Homer W. Smith Award
Authors: Qais Al-Awqati
Journal: Journal of the American Society of Nephrology (2008)

The intercalated cell of the cortical collecting tubule exists in two functional and morphologic forms: α cells secrete acid, while β cells secrete HCO<sub>3</sub>. It was found that β cells convert to α type when the animal ingests an acid diet or when isolated perfused tubules are exposed to acid. This conversion of cell phenotype requires the induction of new genes, accompanied by a change in cell shape, development of microvilli, and apical endocytosis. All of these changes are reminiscent of terminal differentiation in epithelial cells. Using a β intercalated cell line, the cause of this phenotypic change was identified as a new extracellular matrix protein, which was termed hensin. When the action of hensin is blocked, the conversion of β to α intercalated cells is prevented and the animals develop distal renal tubular acidosis. Hensin is expressed in most epithelia, and global knockout of hensin results in embryonic lethality at the time of development of the first columnar epithelium, the visceral endoderm. Furthermore, hensin also seems to be involved in the differentiation of transitional and perhaps stratified epithelia as well. A large number of human carcinomas have deletions in the human ortholog of hensin (DMBT1). Collectively, these studies demonstrate that hensin is a mediator of terminal differentiation in many epithelia.
Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial
Authors: Albert M Maguire, Katherine A High, Alberto Auricchio, J Fraser Wright, Eric A Pierce, Francesco Testa, Federico Mingozzi, Jeannette L Bennicelli, Gui-shuang Ying, Settimio Rossi, Ann Fulton, Kathleen A Marshall, Sandro Banfi, Daniel C Chung, Jessica IW Morgan, Bernd Hauck, Olga Zelenaia, Xiaosong Zhu, Leslie Raffini, Frauke Coppieters, Elfride De Baere, Kenneth S Shindler, Nicholas J Volpe, Enrico M Surace, Carmela Acerra, Arkady Lyubarsky, T Michael Redmond, Edwin Stone, Junwei Sun, Jennifer Wellman McDonnell, Bart P Leroy, Francesca Simonelli, Jean Bennett
Journal: The Lancet (2009)
Epigenetics of discordant monozygotic twins: implications for disease
Authors: Juan E Castillo-Fernandez, Tim D Spector, Jordana T Bell
Journal: Genome Medicine (2014)

Monozygotic (MZ) twins share nearly all of their genetic variants and many similar environments before and after birth. However, they can also show phenotypic discordance for a wide range of traits. Differences at the epigenetic level may account for such discordances. It is well established that epigenetic states can contribute to phenotypic variation, including disease. Epigenetic states are dynamic and potentially reversible marks involved in gene regulation, which can be influenced by genetics, environment, and stochastic events. Here, we review advances in epigenetic studies of discordant MZ twins, focusing on disease. The study of epigenetics and disease using discordant MZ twins offers the opportunity to control for many potential confounders encountered in general population studies, such as differences in genetic background, early-life environmental exposure, age, gender, and cohort effects. Recently, analysis of disease-discordant MZ twins has been successfully used to study epigenetic mechanisms in aging, cancer, autoimmune disease, psychiatric, neurological, and multiple other traits. Epigenetic aberrations have been found in a range of phenotypes, and challenges have been identified, including sampling time, tissue specificity, validation, and replication. The results have relevance for personalized medicine approaches, including the identification of prognostic, diagnostic, and therapeutic targets. The findings also help to identify epigenetic markers of environmental risk and molecular mechanisms involved in disease and disease progression, which have implications both for understanding disease and for future medical research.
Immunohistochemical Analysis of Phosphotyrosine Signal Transducer and Activator of Transcription 3 and Epidermal Growth Factor Receptor Autocrine Signaling Pathways in Head and Neck Cancers and Metastatic Lymph Nodes
Authors: Raja R. Seethala, William E. Gooding, Phoebe N. Handler, Bobby Collins, Qing Zhang, Jill M. Siegfried, Jennifer R. Grandis
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To determine the effect of tyrosine-phosphorylated signal transducer and activator of transcription 3 (pSTAT3) immunoexpression on survival in two independent cohorts of patients with squamous cell carcinoma of the head and neck (SCCHN) and to evaluate pSTAT3, transforming growth factor-α (TGF-α), epidermal growth factor receptor (EGFR), and gastrin-releasing peptide receptor (GRPR) expression in matched tumor and lymph node metastases in one of these cohorts. Experimental Technique: Immunostaining for pSTAT3, TGF-α, EGFR, and GRPR was done in two SCCHN cohorts (cohort 1, 61 tumors; cohort 2, 69 paired primary tumors and lymph node metastases). Semiquantitative scores derived from the product of staining intensity (scale 0-3) score and percentage of positive tumor cells were correlated with clinical outcome. Results: Immunoexpression of pSTAT3 did not correlate with clinical outcome in either cohort (cohort 1, P = 0.914; cohort 2, P = 0.312). In cohort 2, TGF-α and EGFR expression in the primary tumors showed some association with decreased disease-free survival (P = 0.0306 and P = 0.0985, respectively). Both pSTAT3 and EGFR showed a correlation of expression between tumor and matched lymph node metastasis (P &amp;lt; 0.0001 and P = 0.0046, respectively). In addition, the expression of EGFR and GRPR in the primary tumors correlated with TGF-α expression in paired nodal metastases (P = 0.0043 and P = 0.0268, respectively). In the nodal metastases, TGF-α expression correlated with EGFR expression (P = 0.0069). In primary tumors, GRPR expression correlated with TGF-α and EGFR expression (P = 0.0378 and P = 0.0026, respectively). Conclusions: These findings support an autocrine signaling pathway involving TGF-α, EGFR, and pSTAT3 in metastatic SCCHN as well as transactivation of EGFR by GRPR via TGF-α, but fails to identify an independent prognostic role for pSTAT3 immunoexpression.
Auto-servoventilation in heart failure with sleep apnoea: a randomised controlled trial
Authors: Michael Arzt, Stephan Schroll, Frederic Series, Keir Lewis, Amit Benjamin, Pierre Escourrou, Ruth Luigart, Victoria Kehl, Michael Pfeifer
Journal: European Respiratory Journal (2012)

We tested the hypotheses that in patients with congestive heart failure (CHF) and sleep disordered breathing (SDB) auto-servoventilation (ASV) improves cardiac function and quality of life. Between March 2007 and September 2009, patients with stable CHF (left ventricular ejection fraction (LVEF) ≤40%) and SDB (apnoea/hypopnoea index ≥20 events·h −1 ) were randomised to receive either ASV (BiPAP ASV (Philips Respironics, Murrysville, PA, USA), n=37) and optimal medical management, or optimal medical management alone (n=35). Outcomes were assessed at baseline and 12 weeks. The apnoea/hypopnoea index assessed with polysomnography scored in one core laboratory was significantly more reduced in the ASV group (-39±16 versus -1±13 events·h −1 ; p&lt;0.001) with an average use of 4.5±3.0 h·day −1 . Both groups showed similar improvements of the primary end-point LVEF (+3.4±5 versus +3.5±6%; p=0.915) assessed with echocardiography. In the ASV group, reduction of N-terminal pro-brain natriuretic peptide (NT-proBNP) was significantly greater (-360±569 versus +135±625 ng·mL −1 ; p=0.010). No differences were observed between the groups in subjective quality of life. In patients with CHF and SDB, ASV reduced NT-proBNP levels, but improvement of LVEF or quality of life was not greater than in the control group. The data support that such patients can be randomised in large-scale, long-term trials of positive airway pressure therapy versus control to determine effects on cardiovascular outcome.
Prospective Study of Factors Predicting Adherence to Surveillance Mammography in Women Treated for Breast Cancer
Authors: Rebecca A. Shelby, Cindy D. Scipio, Tamara J. Somers, Mary Scott Soo, Kevin P. Weinfurt, Francis J. Keefe
Journal: Journal of Clinical Oncology (2012)

Purpose This prospective study examined the factors that predicted sustained adherence to surveillance mammography in women treated for breast cancer. Methods Breast cancer survivors (N = 204) who were undergoing surveillance mammography completed questionnaires assessing mammography-related anticipatory anxiety, persistent breast pain, mammography pain, and catastrophic thoughts about mammography pain. Adherence to mammography in the following year was assessed. Results In the year after study entry, 84.8% of women (n = 173) returned for a subsequent mammogram. Unadjusted associations showed that younger age, shorter period of time since surgery, and having upper extremity lymphedema were associated with lower mammography adherence. Forty percent of women reported moderate to high levels of mammography pain (score of ≥ 5 on a 0 to 10 scale). Although mammography pain was not associated with adherence, higher levels of mammography-related anxiety and pain catastrophizing were associated with not returning for a mammogram (P &lt; .05). The impact of anxiety on mammography use was mediated by pain catastrophizing (indirect effect, P &lt; .05). Conclusion Findings suggest that women who are younger, closer to the time of surgery, or have upper extremity lymphedema may be less likely to undergo repeated mammograms. It may be important for health professionals to remind selected patients directly that some women avoid repeat mammography and to re-emphasize the value of mammography for women with a history of breast cancer. Teaching women behavioral techniques (eg, redirecting attention) or providing medication for reducing anxiety could be considered for women with high levels of anxiety or catastrophic thoughts related to mammography.
Mozart--portrait and myth
Authors: J. Jenkins
Journal: Journal of the Royal Society of Medicine (2006)

On 27 January 2006 we celebrated the 250th anniversary of the birth of Wolfgang Amadeus Mozart, considered by many to be the greatest musical genius that the world has ever known. His life has been chronicled in more detail than any other musician and there are extant about 1200 letters in the Mozart family correspondence that give first-hand information about much of the composer's life. Paradoxically, however, in spite of this wealth of material which is repeatedly being re-assessed, the circumstances of his health and death continue to abound in myth.

The main reason for this anomaly lies in the failure of many authors to take cognizance of the primary sources of information, such as the family letters; instead, they cite the numerous secondary sources, which have accumulated over the years to which are added speculative opinions masquerading as fact. Soon after his death stories began to circulate that he had succumbed to poison administered by his rival Salieri or, according to some, the Freemasons. The poisoning tales have now been laid to rest but many other fables grew up particularly those concerned with his medical history and death some of which show remarkable persistence.
Sequence of excitation as a factor in sympathetic-parasympathetic interactions in the heart.
Authors: T Yang, M N Levy
Journal: Circulation Research (1992)

We determined the influence of differences in the time of initiation of sympathetic and vagal stimulation (both at 10 Hz) on the cardiac autonomic interactions in 16 open-chest anesthetized dogs. We always ended the concurrent sympathetic and vagal stimulations simultaneously. Sympathetic stimulation alone for 1 minute increased heart rate by 90 +/- 7 (mean +/- SEM) beats per minute, and vagal stimulation alone for 1 minute decreased heart rate by 67 +/- 5 beats per minute; i.e., the algebraic sum of these responses was an increase of 23 beats per minute. However, combined sympathetic and vagal stimulation for 1 minute actually decreased heart rate by 35 beats per minute; i.e., the vagal effects predominated. When vagal stimulation was initiated first, the chronotropic responses to combined stimulation were not significantly affected by the duration of antecedent vagal stimulation. However, when sympathetic stimulation was initiated first, the vagal predominance (disparity between the summated individual responses and the combined response) progressively diminished as we increased the duration of antecedent sympathetic stimulation. The vagal predominance diminished from a value of 67 +/- 21 beats per minute when the stimulations were initiated simultaneously to a value of 37 +/- 21 beats per minute when the duration of antecedent sympathetic stimulation was 10 minutes. Sympathetic stimulation releases not only norepinephrine but also neuropeptide Y, and this neuropeptide inhibits vagal neurotransmission. Our data suggest, therefore, that the longer the antecedent sympathetic stimulation, the greater the inhibition of vagal neurotransmission (presumably by the neuropeptide Y) and, therefore, the less pronounced the vagal predominance.
PRIMARY SARCOMA OF THE SKIN*
Authors: H. MacCORMAC
Journal: British Journal of Dermatology (1929)

Journal Article PRIMARY SARCOMA OF THE SKIN Get access H. MacCORMAC, C.B.E., M.D., F.R.C.P. H. MacCORMAC, C.B.E., M.D., F.R.C.P. Physician, Skin Department, Middlesex Hospital Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology and Syphilis, Volume 41, Issue 11, 1 November 1929, Pages 403–407, https://doi.org/10.1111/j.1365-2133.1929.tb09293.x Published: 01 November 1929
Nailfold capillary density is associated with the presence and severity of pulmonary arterial hypertension in systemic sclerosis
Authors: H M A Hofstee, A Vonk Noordegraaf, A E Voskuyl, B A C Dijkmans, P E Postmus, Y M Smulders, E H Serné
Journal: Annals of the Rheumatic Diseases (2008)

The aim of this study was to investigate whether there are differences in capillary nailfold changes in patients with systemic sclerosis (SSc) with and without pulmonary arterial hypertension (PAH), and whether these changes are associated with PAH severity and disease specificity.Capillary density and loop dimensions were studied in 21 healthy controls, 20 patients with idiopathic PAH (IPAH) and 40 patients with SSc. Of the 40 patients with SSc, 19 had no PAH (SSc-nonPAH) and 21 had PAH (SSc-PAH), of whom eight had PAH during exercise.Capillary density was lower in SSc-PAH compared with patients who had SSc-nonPAH (4.33/mm vs 6.56/mm respectively, p = 0.001), but loop dimensions were equal. In comparison with IPAH, patients with SSc-PAH had reduced capillary density (4.33/mm vs 7.86/mm, p<0.001) and larger loop dimensions (total width 101.05 microm vs 44.43 microm, p<0.001). Capillary density in healthy controls (9.87/mm) was significantly higher when compared with SSc-nonPAH (6.56/mm), SSc-PAH (4.33/mm) and with IPAH (7.86/mm). No differences in capillary dimensions were present between healthy controls and IPAH. Capillary density correlated with mean pulmonary arterial pressure (PAP) at rest in SSc-PAH at rest (r = -0.58, p = 0.039) and IPAH (r = -0.67, p = 0.001).Reduction of nailfold capillary density, but not capillary loop dimensions is associated with PAH, and correlates with the severity of PAH in both SSc and IPAH. This suggests that either systemic microvascular changes play a part in the development of PAH, or that PAH itself contributes to systemic microvascular changes.
Pathogenesis of human parvovirus B19 in rheumatic disease
Authors: J. R Kerr
Journal: Annals of the Rheumatic Diseases (2000)

Human parvovirus B19, discovered in 19751 and first linked with human disease in 1981,2 is a small single stranded DNA virus classified within the family Parvoviridae, and the genus Erythrovirus , having tropism primarily for erythroid precursors. B19 is the only parvovirus which has been clearly linked with disease in humans. It replicates only in human cells and is autonomous, not requiring the presence of a helper virus.

Acute B19 virus infection is classically associated with the childhood rash illness, erythema infectiosum (EI), arthralgia, fetal death, and transient aplastic crisis (TAC) in those with shortened red cell survival. However, it has been assumed that in those with a normal immune system, the virus has a relatively simple pathogenesis and that after the acute phase the virus is cleared by a specific humoral immune response. However, increasingly B19 virus and B19 infection have been reported in association with quite atypical and unpredictable findings based on previous assumptions. For example, persistence of the virus in various tissues after acute infection in apparently normal subjects and the association of B19 infection with various connective tissue and autoimmune diseases. This paper will therefore summarise present knowledge of the virus, its known and potential pathogenetic mechanisms, and its associations with human disease, with an emphasis on rheumatic disease.

The B19 genome consists of a single stranded linear molecule of 5596 nucleotides, which is composed of an internal coding sequence of 4830 nucleotides flanked by terminal repeat sequences of 383 nucleotides each.3 These terminal repeat sequences are imperfect palindromes and fold back on themselves to form hairpin loops.4 Viral replication is thus self primed by the 3′ terminus,5 and in minute virus of mice, a related parvovirus, has recently been shown to require the host cell transcriptional modulator, …
NHS staff readied to deal with Ebola cases in hospitals and general practices
Authors: A. O'Dowd
Journal: BMJ (2014)

Preparations are being made for NHS staff to know how to deal with possible cases of people coming into hospital or general practices in England infected with the Ebola virus, MPs have been told.

NHS England has asked managers to confirm that steps are being taken to ensure that isolation rooms are available and that their staff know what to do should a person with the virus come into the hospital or practice, but staff are also expected to make sure they are well informed.

These reassurances were given by England’s chief medical officer, Sally Davies, during an evidence session of the House of Commons Health Committee for its inquiry into the Ebola virus on 22 October.

Figures …