tbuckley/cabot-search huggingface dataset:
Brain metastases in melanoma: Roles of neurotrophins
Authors: Yvonne Denkins, Jane Reiland, Madhuchhanda Roy, Neeta D. Sinnappah-Kang, Jennifer Galjour, Brian P. Murry, Jason Blust, Rebecca Aucoin, Dario Marchetti
Journal: Neuro-Oncology (2004)

Brain metastasis, which occurs in 20% to 40% of all cancer patients, is an important cause of neoplastic morbidity and mortality. Successful invasion into the brain by tumor cells must include attachment to microvessel endothelial cells, penetration through the blood-brain barrier, and, of relevance, a response to brain survival and growth factors. Neurotrophins (NTs) are important in brain-invasive steps. Human melanoma cell lines express low-affinity NT receptor p75NTR in relation to their brain-metastatic propensity with their invasive properties being regulated by NGF, or nerve growth factor, the prototypic NT. They also express functional TrkC, the putative receptor for the invasion-promoting NT-3. In brain-metastatic melanoma cells, NTs promote invasion by enhancing the production of extracellular matrix (ECM)-degradative enzymes such as heparanase, an enzyme capable of locally destroying both ECM and the basement membrane of the blood-brain barrier. Heparanase is an endo-beta-d-glucuronidase that cleaves heparan sulfate (HS) chains of ECM HS proteoglycans, and it is a unique metastatic determinant because it is the dominant mammalian HS degradative enzyme. Brain-metastatic melanoma cells also produce autocrine/paracrine factors that influence their growth, invasion, and survival in the brain. Synthesis of these factors may serve to regulate NT production by brain cells adjacent to the neoplastic invasion front, such as astrocytes. Increased NT levels have been observed in tumor-adjacent tissues at the invasion front of human brain melanoma. Additionally, astrocytes may contribute to the brain-metastatic specificity of melanoma cells by producing NT-regulated heparanase. Trophic, autocrine, and paracrine growth factors may therefore determine whether metastatic cells can successfully invade, colonize, and grow in the CNS.
Interactions of the allogeneic effector leukemic T cell line, TALL-104, with human malignant brain tumors
Authors: German G. Gomez, Susana B. Read, Lazaro E. Gerschenson, Daniela Santoli, Adam Zweifach, Carol A. Kruse
Journal: Neuro-Oncology (2004)

TALL-104 is a human leukemic T cell line that expresses markers characteristic of both cytotoxic T lymphocytes and natural killer cells. TALL-104 cells are potent tumor killers, and the use of lethally irradiated TALL-104 as cellular therapy for a variety of tumors has been explored. We investigated the interactions of TALL-104 cells with human brain tumor cells. TALL-104 cells mediated increased lysis of a panel of brain tumor cells at low effector-to-target ratios over time. We obtained evidence that TALL-104 cells injured glioma cells by both apoptotic and necrotic pathways. A 7-amino actinomycin D flow cytometry assay revealed that the percentages of both apoptotic and necrotic glioma cells increased after TALL-104 cell/glioma cell coincubations. Fluorescent microscopy studies and a quantitative morphologic assay confirmed that TALL-104 cell/glioma cell interactions resulted in tumor cell apoptosis. Cytokines are secreted when TALL-104 cells are coincubated with brain tumor cells; however, morphologic analysis assays revealed that the soluble factors contained within clarified supernates obtained from 4 h coincubates added back to brain tumor cell cultures did not trigger the glioma apoptosis. TALL-104 cells do not express Fas ligand, even upon coincubation with glioma targets, which suggests that the Fas/Fas ligand apoptotic pathway is not likely responsible for the cell injury observed. We obtained evidence that cell injury is calcium dependent and that lytic granule exocytosis is triggered by contact of TALL-104 cells with human glioma cells, suggesting that this pathway mediates glioma cell apoptosis and necrosis.
P242 Pirfenidone As A Bridge To Lung Transplantation In Patients With Progressive Ipf
Authors: P. Riddell, P. Minnis, P. Ging, J. Egan
Journal: Thorax (2014)

<h3>Introduction and objectives</h3> Lung transplantation provides a significant survival benefit to patients with advanced idiopathic pulmonary fibrosis (IPF). However, at this time, the transplant community is unable to meet the requirements on it services due to donor organ shortages. This results in an increased length of time spent on the waiting list and an increased risk of death prior to transplantation. Pirfenidone has been reported to reduce the rate of disease progression in patients with IPF. It may therefore prolong the length of time that patients are able to spend on the transplant waiting list. We report the outcomes of three patients with progressive IPF who were successfully bridged to transplantation with Pirfenidone. <h3>Methods</h3> We retrospectively reviewed the medical records of all patients who had undergone lung transplantation for IPF from 2012–14 at our institution. Three patients who had been prescribed Pirfenidone prior to transplantation were identified. Each patient continued Pirfenidone until the day of transplantation. Patient demographics, lung function and post transplant data were collated. <h3>Results</h3> Prior to the commencement of Pirfenidone the mean decline in forced vital capacity (FVC) was 52.2ml per month. Following Pirfenidone therapy, the mean decline in FVC was 29.2ml per month. The mean length of time from commencing Pirfenidone to transplantation was 419 days (range 190–768 days). The mean length of time spent on the transplant waiting list was 144 days (range 35–271 days). With a mean follow up of 1.45 years, no episodes of acute or chronic rejection have occurred. Post-transplant survival is 100%. No adjustment in immunosuppressant induction or post-transplant therapy was necessitated. In the post-transplant period, Pirfenidone therapy was not linked to any adverse events. <h3>Conclusion</h3> Pirfenidone has been reported to reduce disease progression in IPF. However, despite this, lung transplantation remains necessary in the management of this condition. For patients with IPF, in whom the transplant window is short, Pirfenidone may allow for valuable added time on the lung transplant waiting list.
Isolated Ambulatory Hypertension Predicts Cardiovascular Morbidity in Elderly Men
Authors: Kristina Björklund, Lars Lind, Björn Zethelius, Bertil Andrén, Hans Lithell
Journal: Circulation (2003)

Background— Little is known about isolated ambulatory hypertension, a state with elevated ambulatory but normal office blood pressure (BP). This study aimed to investigate the prognostic significance of isolated ambulatory hypertension for cardiovascular morbidity in a population of elderly men. Methods and Results— At baseline, 24-hour ambulatory BP and metabolic and cardiac risk profiles were evaluated in 578 untreated 70-year-old men, participants of a population-based cohort. Subjects with isolated ambulatory hypertension (office BP &lt;140/90 and daytime BP ≥135/85) and sustained hypertension (office BP ≥140/90 and daytime BP ≥135/85) had increased plasma glucose, body mass index, and echocardiographically determined left ventricular relative wall thickness compared with normotensive subjects (office BP &lt;140/90 and daytime BP &lt;135/85). Seventy-two cardiovascular morbid events (2.37 per 100 person-years at risk) occurred over 8.4 years of follow-up. The prognostic value of isolated ambulatory and sustained hypertension was assessed with Cox proportional hazard regression. Multivariate models adjusting for serum cholesterol, smoking, and diabetes demonstrated that both isolated ambulatory hypertension (hazard ratio [HR], 2.77; 95% CI, 1.15 to 6.68) and sustained hypertension (HR, 2.94; 95% CI, 1.49 to 5.82) were independent predictors of cardiovascular morbidity. In a multivariate model with continuous BP variables, ambulatory daytime systolic BP (HR for 1 SD increase, 1.47; 95% CI, 1.09 to 1.97) was associated with an adverse outcome independently of office systolic BP. Conclusions— In the present study, isolated ambulatory hypertension as well as sustained hypertension predicted cardiovascular morbidity. The findings suggest that 24-hour ambulatory BP monitoring may disclose important prognostic information also in subjects characterized as normotensive according to office BP.
Performance of the UK Prospective Diabetes Study Risk Engine and the Framingham Risk Equations in Estimating Cardiovascular Disease in the EPIC- Norfolk Cohort
Authors: Rebecca K. Simmons, Ruth L. Coleman, Hermione C. Price, Rury R. Holman, Kay-Tee Khaw, Nicholas J. Wareham, Simon J. Griffin
Journal: Diabetes Care (2008)

OBJECTIVE The purpose of this study was to examine the performance of the UK Prospective Diabetes Study (UKPDS) Risk Engine (version 3) and the Framingham risk equations (2008) in estimating cardiovascular disease (CVD) incidence in three populations: 1) individuals with known diabetes; 2) individuals with nondiabetic hyperglycemia, defined as A1C ≥6.0%; and 3) individuals with normoglycemia defined as A1C &amp;lt;6.0%. RESEARCH DESIGN AND METHODS This was a population-based prospective cohort (European Prospective Investigation of Cancer-Norfolk). Participants aged 40–79 years recruited from U.K. general practices attended a health examination (1993–1998) and were followed for CVD events/death until April 2007. CVD risk estimates were calculated for 10,137 individuals. RESULTS Over 10.1 years, there were 69 CVD events in the diabetes group (25.4%), 160 in the hyperglycemia group (17.7%), and 732 in the normoglycemia group (8.2%). Estimated CVD 10-year risk in the diabetes group was 33 and 37% using the UKPDS and Framingham equations, respectively. In the hyperglycemia group, estimated CVD risks were 31 and 22%, respectively, and for the normoglycemia group risks were 20 and 14%, respectively. There were no significant differences in the ability of the risk equations to discriminate between individuals at different risk of CVD events in each subgroup; both equations overestimated CVD risk. The Framingham equations performed better in the hyperglycemia and normoglycemia groups as they did not overestimate risk as much as the UKPDS Risk Engine, and they classified more participants correctly. CONCLUSIONS Both the UKPDS Risk Engine and Framingham risk equations were moderately effective at ranking individuals and are therefore suitable for resource prioritization. However, both overestimated true risk, which is important when one is using scores to communicate prognostic information to individuals.
The role of the ERK1/2 pathway as an alternative to the aging-diminished cyclic AMP pathway in calcitonin-mediated chondrogenesis in human nucleus pulposus
Authors: Wei-Hong Chen, Rong Zeng, Wen-Cheng Lo, Szu-Yu Tina Chen, Tung-Yuan Lai, David F. Williams, Win-Ping Deng
Journal: Biomaterials (2012)
Contrasting roles for all-trans retinoic acid in TGF-β–mediated induction of <i>Foxp3</i> and <i>Il10</i> genes in developing regulatory T cells
Authors: Craig L. Maynard, Robin D. Hatton, Whitney S. Helms, James R. Oliver, Charles B. Stephensen, Casey T. Weaver
Journal: The Journal of Experimental Medicine (2009)

Extrathymic induction of regulatory T (T reg) cells is essential to the regulation of effector T cell responses in the periphery. In addition to Foxp3, T reg cell expression of suppressive cytokines, such as IL-10, is essential for peripheral tolerance, particularly in the intestines. TGF-β has been shown to induce expression of Foxp3 as well as IL10 and the vitamin A metabolite; all-trans retinoic acid (RA [at-RA]) has been found to enhance the former. We report that in contrast to its enhancement of TGF-β–mediated Foxp3 induction, at-RA potently inhibits the TGF-β–mediated induction of Il10 in naive CD4 T cells. Thus, mucosal DC subsets that are active producers of at-RA inhibit induction of Il10 in naive CD4 T cells while promoting induction of Foxp3. Accordingly, mice with vitamin A deficiency have increased numbers of IL-10–competent T reg cells. Activation of DCs by certain Toll-like receptors (TLRs), particularly TLR9, suppresses T cell induction of Foxp3 and enables induction of Il10. Collectively, our data indicate that at-RA has reciprocal effects on the induction of Foxp3 and Il10 in developing CD4+ T reg cells and suggest that TLR9-dependent inhibition of at-RA production by antigen-presenting cells might represent one mechanism to promote the development of IL-10–expressing T cells.
Geometric Distortions of the Mitral Valvular-Ventricular Complex in Chronic Ischemic Mitral Regurgitation
Authors: Frederick A. Tibayan, Filiberto Rodriguez, Mary K. Zasio, Lynn Bailey, David Liang, George T. Daughters, Frank Langer, Neil B. Ingels, D. Craig Miller
Journal: Circulation (2003)

Background— Better understanding of the precise 3-dimensional geometric changes of the mitral valvular-ventricular complex in chronic ischemic mitral regurgitation (CIMR) is needed in order to devise better surgical repair techniques. We hypothesized that changes after inferior myocardial infarction would be different in hearts that developed CIMR compared with those that did not. Methods and Results— Twenty-four sheep underwent coronary snare and marker placement (annulus, papillary muscles, and anterior and posterior leaflets). After 8 days, cinefluoroscopy provided 3-dimensional marker data, and snare occlusion of obtuse marginal branches created inferior myocardial infarction, including the posterior papillary muscle. After 7 weeks, the 16 surviving animals were studied again and grouped by mitral regurgitation grade (≥ 2+, n=10 versus ≤ 1+, n=6). End-systolic mitral annulus dimensions, components of papillary muscle and leaflet displacement, were calculated. After inferior myocardial infarction, total displacement of the posterior papillary muscle from the midseptal annulus (“saddle horn”) was greater in CIMR(+) animals: 6.5±3.2 versus 3.1±2.7 ( P =0.02), with the posterior papillary muscle moving more laterally (6.8±3.4 versus 2.5±3.5 mm, P =0.01). Increase in mitral annular septal-lateral diameter was greater in animals with CIMR (4.9±2.7 versus 2.3±2.0, P =0.02), and apical displacement of the posterior leaflet (PL) margin was also greater in the CIMR(+) group (1.7±1.0 versus 0.3±0.5, P =0.01). Conclusions— The CIMR(+) group had greater septal-lateral annular dilatation, lateral posterior papillary muscle displacement, and apical PL restriction, indicating that these associated geometric alterations may be important in the pathogenesis of CIMR. Treatment of CIMR should address both annular septal-lateral dilatation and lateral displacement of the posterior papillary muscle.
Screening for interstitial lung disease in systemic sclerosis: the diagnostic accuracy of HRCT image series with high increment and reduced number of slices
Authors: Anna Winklehner, Nicole Berger, Britta Maurer, Oliver Distler, Hatem Alkadhi, Thomas Frauenfelder
Journal: Annals of the Rheumatic Diseases (2011)

The objective of this study is to assess diagnostic accuracy for the detection of interstitial lung disease (ILD) in image series with high increment and reduced number of slices in patients with systemic sclerosis (SSc).45 patients with SSc underwent high-resolution CT (HRCT). Three series of secondary captures were reconstructed as follows: series 1, series with 10 mm increment and 1 mm slices; series 2, seven axial images with baso-apical gradient; series 3, three axial images were obtained at the apical, at the level of the carina and basal. The presence and extent of ILD, and the degree of diagnostic confidence were recorded. The effective dose for each image series was estimated. Standard HRCT was the standard of reference.The prevalence of ILD was 55% (25/45). Diagnostic sensitivity and accuracy of series 1, series 2 and series 3 were 100% and 94.4%, 94% and 97.8%, 92% and 97.8%, respectively. The extent of ILD was underestimated in series 3 (p<0.05) and was comparable to the standard HRCT in series 1 and 2 (p>0.05). Estimated dose reduction was more than 90% in all image series.HRCT image series with low sampling rate allow an accurate detection of ILD with very-low-radiation dose, making this approach potentially valuable for screening in patients with SSc.
Idiopathic pulmonary fibrosis: a treatable disease?
Authors: U. Costabel
Journal: European Respiratory Journal (2003)

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterised by fibroblast proliferation and extracellular matrix remodelling. The usual treatment strategy is anti-inflammatory, but this is unsuccessful in preventing thefatal outcome in most patients. The disorder is largely unresponsive to corticosteroids and immunosuppressants. Several papers have recently highlighted the prognostic importance of the new histological classification of the idiopathic interstitial pneumonia, which limits the definition of IPF to the histopathological pattern of usual interstitial pneumonia (UIP) and discriminates several other subgroups with a better prognosis 1–3. IPF is the most common and most aggressive variant of the chronic idiopathic interstitial pneumonias. One of the hallmarks of IPF/UIP is the formation of multiple patchy fibroblastic foci that evolve to fibrosis, in contrast with all the other entities of the idiopathic interstitial pneumonia.

For decades, the leading hypothesis with regards to the pathogenesis of IPF was that the initial event is an inflammatory process (alveolitis characterised by infiltration of inflammatory cells such as macrophages, lymphocytes and neutrophils). Inflammation would lead to recruitment of fibroblast/myofibroblasts and finally to collagen formation and irreversible fibrosis. The new concept is that IPF is a primary epithelial/fibroblastic disease, and inflammation is nowadays considered to be the secondary and not the primary event 4. This new hypothesis is the basis for understanding the disappointing results with an isolated anti-inflammatory treatment. New strategies are targeted at developing …
Glatiramer acetate (Copaxone®) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis
Authors: Petra W. Duda, Mascha C. Schmied, Sandra L. Cook, Jeffrey I. Krieger, David A. Hafler
Journal: Journal of Clinical Investigation (2000)

We examined the effect of glatiramer acetate, a random copolymer of alanine, lysine, glutamic acid, and tyrosine, on antigen-specific T-cell responses in patients with multiple sclerosis (MS). Glatiramer acetate (Copaxone) functioned as a universal antigen, inducing proliferation, independent of any prior exposure to the polymer, in T-cell lines prepared from MS or healthy subjects. However, for most patients, daily injections of glatiramer acetate abolished this T-cell response and promoted the secretion of IL-5 and IL-13, which are characteristic of Th2 cells. The surviving glatiramer acetate–reactive T cells exhibited a greater degree of degeneracy as measured by cross-reactive responses to combinatorial peptide libraries. Thus, it appears that, in some individuals, in vivo administration of glatiramer acetate induces highly cross-reactive T cells that secrete Th2 cytokines. To our knowledge, glatiramer acetate is the first agent that suppresses human autoimmune disease and alters immune function by engaging the T-cell receptor. This compound may be useful in a variety of autoimmune disorders in which immune deviation to a Th2 type of response is desirable.
Enhanced T cell recovery in HIV-1–infected adults through IL-7 treatment
Authors: Yves Levy, Christine Lacabaratz, Laurence Weiss, Jean-Paul Viard, Cecile Goujard, Jean-Daniel Lelièvre, François Boué, Jean-Michel Molina, Christine Rouzioux, Véronique Avettand-Fénoêl, Thérèse Croughs, Stéphanie Beq, Rodolphe Thiébaut, Geneviève Chêne, Michel Morre, Jean-François Delfraissy
Journal: Journal of Clinical Investigation (2009)

HIV infection results in CD4+ T cell deficiency, but efficient combination antiretroviral therapy (c-ART) restores T cells and decreases morbidity and mortality. However, immune restoration by c-ART remains variable, and prolonged T cell deficiency remains in a substantial proportion of patients. In a prospective open-label phase I/IIa trial, we evaluated the safety and efficacy of administration of the T cell regulator IL-7. The trial included 13 c-ART–treated HIV-infected patients whose CD4+ cell counts were between 100 and 400 cells/μl and plasma HIV RNA levels were less than 50 copies/ml. Patients received a total of 8 subcutaneous injections of 2 different doses of recombinant human IL-7 (rhIL-7; 3 or 10 μg/kg) 3 times per week over a 16-day period. rhIL-7 was well tolerated and induced a sustained increase of naive and central memory CD4+ and CD8+ T cells. In the highest dose group, 4 patients experienced transient increases in viral replication. However, functional assays showed that the expanded T cells responded to HIV antigen by producing IFN-γ and/or IL-2. In conclusion, in lymphopenic HIV-infected patients, rhIL-7 therapy induced substantial functional and quantitative changes in T cells for 48 weeks. Therefore, patients may benefit from intermittent therapy with IL-7 in combination with c-ART.
Impact of brodalumab treatment on psoriasis symptoms and health‐related quality of life: use of a novel patient‐reported outcome measure, the Psoriasis Symptom Inventory
Authors: K.B. Gordon, A.B. Kimball, D. Chau, H.N. Viswanathan, J. Li, D.A. Revicki, G. Kricorian, B.G. Ortmeier
Journal: British Journal of Dermatology (2013)

Psoriasis symptoms have a significant negative impact on health-related quality of life, impairing physical functioning and well-being.To evaluate the impact of brodalumab, a human anti-interleukin-17R monoclonal antibody, on psoriasis symptom severity as measured by a novel patient-reported outcome measure, the Psoriasis Symptom Inventory, and dermatology-specific health-related quality of life as measured by the Dermatology Life Quality Index (DLQI).This was a secondary analysis of a phase II, randomized, double-blind, placebo-controlled clinical study of patients with moderate-to-severe psoriasis (n = 198) treated with brodalumab or placebo. This analysis assessed Psoriasis Symptom Inventory scores and DLQI scores over time. Analyses were conducted on all patients who were randomized and received one or more injections of the study drug according to intention to treat using last observation carried forward to impute missing data.At week 12, subjects in the brodalumab groups had significant improvements in mean Psoriasis Symptom Inventory total scores [8.5 (70 mg), 15.8 (140 mg), 16.2 (210 mg) and 12.7 (280 mg)] compared with placebo (4.8). Mean improvements in DLQI were clinically meaningful (≥ 5.7) in the brodalumab groups (6.2, 9.1, 9.6 and 7.1, respectively) and significantly greater than placebo (3.1). Improvements in Psoriasis Symptom Inventory were observed as early as week 2 and in DLQI by week 4. All eight Psoriasis Symptom Inventory item scores improved significantly among the brodalumab groups by week 12.Results were from a single randomized clinical trial and may not generalize to broader patient populations. However, treatment with brodalumab provided significant improvement in psoriasis symptoms in patients with moderate-to-severe psoriasis.