tbuckley/cabot-search huggingface dataset:
Calcipotriol inhibits the proliferation of hyperproliferative CD29 positive keratinocytes in psoriatic epidermis in the absence of an effect on the function and number of antigen-presenting cells
Authors: None Jensen, None BØrresen LladÓ, None Skov, None Hansen, None Larsen, None Baadsgaard
Journal: British Journal of Dermatology (1998)

The aim of this study was to elucidate some of the possible mechanisms of action of the vitamin D analogue calcipotriol in vivo. Calcipotriol is finding increasing use in the treatment of psoriasis, but the primary target cell in vivo has not yet been identified. We treated psoriatic patients and healthy volunteers with calcipotriol and placebo ointment for 4 and 7 days, and obtained epidermal cell suspensions from treated areas. Epidermal cells were cocultured with autologous T cells, isolated from peripheral blood, in the absence or the presence of a classical antigen or a superantigen. In both psoriatic and normal skin, calcipotriol treatment did not alter the capacity of epidermal antigen‐presenting cells to stimulate the proliferation of autologous T cells, either in the absence or in the presence of exogenous antigen. Epidermal cell suspensions were analysed further by staining for infiltrating leucocytes (CD45+) and Langerhans cells (CD1a+). Flow cytometric analyses showed that calcipotriol did not alter the number of CD45+ cells or Langerhans cells in psoriatic skin. These results indicate that calcipotriol does not alter either the number or the function of epidermal antigen‐presenting cells in psoriatic epidermis. In contrast, we found that calcipotriol significantly inhibited the proliferation of epidermal cells isolated from psoriatic skin after in vivo treatment, as determined by propidium iodide staining and flow cytometry. More specifically, we stained for CD29+ keratinocytes and found an even more significant reduction in proliferative capacity. This cell type contains the population of hyperproliferative keratinocytes in psoriatic epidermis. In conclusion, calcipotriol seems to act via an inhibitory effect on hyperproliferative basal keratinocytes of psoriatic epidermis, rather than via an effect on infiltrating leucocytes, including antigen‐presenting cells.
Effects of a Pediatric Weight Management Program With and Without Active Video Games
Authors: Stewart G. Trost, Deborah Sundal, Gary D. Foster, Michelle R. Lent, Deneen Vojta
Journal: JAMA Pediatrics (2014)

Active video games may offer an effective strategy to increase physical activity in overweight and obese children. However, the specific effects of active gaming when delivered within the context of a pediatric weight management program are unknown.To evaluate the effects of active video gaming on physical activity and weight loss in children participating in an evidence-based weight management program delivered in the community.Group-randomized clinical trial conducted during a 16-week period in YMCAs and schools located in Massachusetts, Rhode Island, and Texas. Seventy-five overweight or obese children (41 girls [55%], 34 whites [45%], 20 Hispanics [27%], and 17 blacks [23%]) enrolled in a community-based pediatric weight management program. Mean (SD) age of the participants was 10.0 (1.7) years; body mass index (BMI) z score, 2.15 (0.40); and percentage overweight from the median BMI for age and sex, 64.3% (19.9%).All participants received a comprehensive family-based pediatric weight management program (JOIN for ME). Participants in the program and active gaming group received hardware consisting of a game console and motion capture device and 1 active game at their second treatment session and a second game in week 9 of the program. Participants in the program-only group were given the hardware and 2 games at the completion of the 16-week program.Objectively measured daily moderate-to-vigorous and vigorous physical activity, percentage overweight, and BMI z score.Participants in the program and active gaming group exhibited significant increases in moderate-to-vigorous (mean [SD], 7.4 [2.7] min/d) and vigorous (2.8 [0.9] min/d) physical activity at week 16 (P < .05). In the program-only group, a decline or no change was observed in the moderate-to-vigorous (mean [SD] net difference, 8.0 [3.8] min/d; P = .04) and vigorous (3.1 [1.3] min/d; P = .02) physical activity. Participants in both groups exhibited significant reductions in percentage overweight and BMI z scores at week 16. However, the program and active gaming group exhibited significantly greater reductions in percentage overweight (mean [SD], -10.9%[1.6%] vs -5.5%[1.5%]; P = .02) and BMI z score (-0.25 [0.03] vs -0.11 [0.03]; P < .001). CONCLUSIONS AND RELEVANCE Incorporating active video gaming into an evidence-based pediatric weight management program has positive effects on physical activity and relative weight. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01757925.
Effects of Hypothermia on Norepinephrine Release and Effector Response in Isolated Perfused Cat Spleen
Authors: ÅKE WENNMALM, PER HEDQVIST, LENNART STJÄRNE
Journal: Circulation Research (1970)

The effects of hypothermia on the sympathetic neuroeffector junction were studied in the isolated perfused cat spleen. The experiments were aimed at determining the temperature dependence both of prejunctional events, i.e., efflux of norepinephrine from the sympathetic nerves in response to electrical stimulation or to indirectly acting sympathomimetic amines like tyramine or phenethylamine, and of postjunctional events, i.e., the contractile response of the smooth muscle to the norepinephrine liberated. Hypothermia was found to depress both the norepinephrine efflux in response to stimulation and the contractile response to the endogenous norepinephrine released, as well as to exogenous norepinephrine. However, these processes were found to respond differently to temperature change. Thus hypothermia depressed norepinephrine release as well as the pressor responses to tyramine and phenethylamine much more strongly than the corresponding responses to electrical nerve stimulation or the pressor response to exogenous norepinephrine. The results strongly support the concept that sympathomimetic amines release norepinephrine from sympathetic nerves by mechanisms which differ from those mediating norepinephrine release induced by depolarization.
Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma
Authors: Georgina V Long, Daniil Stroyakovskiy, Helen Gogas, Evgeny Levchenko, Filippo de Braud, James Larkin, Claus Garbe, Thomas Jouary, Axel Hauschild, Jean Jacques Grob, Vanna Chiarion Sileni, Celeste Lebbe, Mario Mandalà, Michael Millward, Ana Arance, Igor Bondarenko, John B A G Haanen, Johan Hansson, Jochen Utikal, Virginia Ferraresi, Nadezhda Kovalenko, Peter Mohr, Volodymyr Probachai, Dirk Schadendorf, Paul Nathan, Caroline Robert, Antoni Ribas, Douglas J DeMarini, Jhangir G Irani, Michelle Casey, Daniele Ouellet, Anne-Marie Martin, Ngocdiep Le, Kiran Patel, Keith Flaherty
Journal: New England Journal of Medicine (2014)

Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations.
Localized α4 Integrin Phosphorylation Directs Shear Stress–Induced Endothelial Cell Alignment
Authors: Lawrence E. Goldfinger, Eleni Tzima, Rebecca Stockton, William B. Kiosses, Kayoko Kinbara, Eugene Tkachenko, Edgar Gutierrez, Alex Groisman, Phu Nguyen, Shu Chien, Mark H. Ginsberg
Journal: Circulation Research (2008)

Vascular endothelial cells respond to laminar shear stress by aligning in the direction of flow, a process which may contribute to atheroprotection. Here we report that localized alpha4 integrin phosphorylation is a mechanism for establishing the directionality of shear stress-induced alignment in microvascular endothelial cells. Within 5 minutes of exposure to a physiological level of shear stress, endothelial alpha4 integrins became phosphorylated on Ser(988). In wounded monolayers, phosphorylation was enhanced at the downstream edges of cells relative to the source of flow. The shear-induced alpha4 integrin phosphorylation was blocked by inhibitors of cAMP-dependent protein kinase A (PKA), an enzyme involved in the alignment of endothelial cells under prolonged shear. Moreover, shear-induced localized activation of the small GTPase Rac1, which specifies the directionality of endothelial alignment, was similarly blocked by PKA inhibitors. Furthermore, endothelial cells bearing a nonphosphorylatable alpha4(S(988)A) mutation failed to align in response to shear stress, thus establishing alpha4 as a relevant PKA substrate. We thereby show that shear-induced PKA-dependent alpha4 integrin phosphorylation at the downstream edge of endothelial cells promotes localized Rac1 activation, which in turn directs cytoskeletal alignment in response to shear stress.
Genomic Analysis Reveals the Molecular Heterogeneity of Ovarian Clear Cell Carcinomas
Authors: David S.P. Tan, Marjan Iravani, W. Glenn McCluggage, Maryou B.K. Lambros, Fernanda Milanezi, Alan Mackay, Charles Gourley, Felipe C. Geyer, Radost Vatcheva, Joanne Millar, Karen Thomas, Rachael Natrajan, Kay Savage, Kerry Fenwick, Alistair Williams, Charles Jameson, Mona El-Bahrawy, Martin E. Gore, Hani Gabra, Stanley B. Kaye, Alan Ashworth, Jorge S. Reis-Filho
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Ovarian clear cell carcinomas (OCCC) are a drug-resistant and aggressive type of epithelial ovarian cancer. We analyzed the molecular genetic profiles of OCCCs to determine whether distinct genomic subgroups of OCCCs exist. Experimental design: Fifty pure primary OCCCs were subjected to high-resolution microarray-based comparative genomic hybridization (aCGH). Unsupervised hierarchical clustering using Ward's linkage analysis was performed to identify genomic subgroups of OCCCs. Survival analysis was performed using Kaplan–Meier method and log-rank test. Cox-regression analysis was used to identify independent predictors of outcome. Differentially amplified regions between genomic subgroups of OCCCs were identified using a multi-Fisher's exact test. Results: Hierarchical cluster analysis revealed two distinct clusters of OCCCs with different clinical outcomes. Patients from cluster-1 had a significantly shorter median progression-free survival (PFS) than those from cluster-2 (11 vs. 65 months, P = 0.009), although estimates for ovarian cancer–specific survival (OCS) did not reach statistical significance (P = 0.065). In multivariate analysis, suboptimal debulking surgery and genomic cluster were independently prognostic for PFS. Recurrently amplified genomic regions with a significantly higher prevalence in cluster-1 than cluster-2 OCCCs were identified and validated. HER2 gene amplification and protein overexpression was observed in 14% of OCCCs, suggesting that this may constitute a potential therapeutic target for a subgroup of these tumors. Conclusions: OCCCs constitute a heterogeneous disease at the genomic level despite having similar histological features. The pattern of genomic aberrations in subgroups of OCCCs is of clinical significance. We have identified recurrently amplified regions that may harbor potential therapeutic targets for subgroups of OCCCs. Clin Cancer Res; 17(6); 1521–34. ©2011 AACR.
Unilateral surgical treatment for patients with midportion Achilles tendinopathy may result in bilateral recovery
Authors: Håkan Alfredson, Christoph Spang, Sture Forsgren
Journal: British Journal of Sports Medicine (2012)

Background Bilateral midportion Achilles tendinopathy/tendinosis is not unusual, and treatment of both sides is often carried out. Experiments in animals suggest of the potential involvement of central neuronal mechanisms in Achilles tendinosis. Objectives To evaluate the outcome of surgery for Achilles tendinopathy. Methods This observational study included 13 patients (7 men and 6 women, mean age 53 years) with a long duration (6–120 months) of chronic painful bilateral midportion Achilles tendinopathy. The most painful side at the time for investigation was selected to be operated on first. Treatment was ultrasound-guided and Doppler-guided scraping procedure outside the ventral part of the tendon under local anaesthetic. The patients started walking on the first day after surgery. Follow-ups were conducted and the primary outcome was pain by visual analogue scale. In an additional part of the study, specimens from Achilles and plantaris tendons in three patients with bilateral Achilles tendinosis were examined. Results Short-term follow-ups showed postoperative improvement on the non-operated side as well as the operated side in 11 of 13 patients. Final follow-up after 37 (mean) months showed significant pain relief and patient satisfaction on both sides for these 11 patients. In 2 of 13 patients operation on the other, initially non-operated side, was instituted due to persisting pain. Morphologically, it was found that there were similar morphological effects, and immunohistochemical patterns of enzyme involved in signal substance production, bilaterally. Conclusion Unilateral treatment with a scraping operation can have benefits contralaterally; the clinical implication is that unilateral surgery may be a logical first treatment in cases of bilateral Achilles tendinopathy.
Neurilemmoma of the intrathoracic vagus nerve
Authors: CJ Davis, EG Butchart, AR Gibbs
Journal: European Respiratory Journal (1991)

A neurilemmoma (Schwannoma) of the left intrathoracic vagus nerve was discovered on a chest radiograph of a 28 yr old woman and was removed via a left thoracotomy. Although neurogenic tumours are the most common tumours of the mediastinum, they rarely involve the intrathoracic vagus nerve.
Multiple Biomarker Prediction of Type 2 Diabetes
Authors: James B. Meigs
Journal: Diabetes Care (2009)

Type 2 diabetes is predictable and preventable. Obesity, familial diabetes, and higher-than-normal blood glucose levels are well-known risk factors for development of type 2 diabetes by middle age; recent prediction models have incorporated these with other readily measurable features of metabolic syndrome (elevated blood pressure, low HDL cholesterol, and elevated triglycerides) to generate validated prediction rules (1–3). In clinical care, a patient of European descent with a family history of diabetes, obesity, and features of metabolic syndrome is at ∼25-fold increased risk to develop type 2 diabetes in the next few years relative to a patient without these characteristics (4). With regard to the public health of the population, these characteristics very reliably discriminate groups at relatively high risk from those at low risk (3). Once high-risk patients are identified, those adherent to a program of ∼30 min of moderate physical activity per day and weight loss of 5–10% of initial body weight can expect that risk for type 2 diabetes will be reduced by at least 50% relative to patients not following a therapeutic lifestyle program (5).

The relatively simple recognition of pre-diabetes and prevention of its transformation to diabetes may be well-known to the readers of Diabetes Care . However, some will raise concerns regarding practical problems obtaining fasting or oral glucose tolerance blood tests, the high intraindividual variability in blood glucose levels (6), the fact that fewer than 20% of white people with obesity will progress to diabetes over subsequent years (7), and the fact that the genetics that presumably underlie familial type 2 diabetes do not seem to add much to its predictability (8). Perhaps less well-known is the expanding understanding of pathophysiological axes beyond the classic triumvirate of β-cell, skeletal muscle, and liver (9) that contribute to the pre-diabetic state. Abnormal adipocyte …
Duplication and Functional Diversification of HAP3 Genes Leading to the Origin of the Seed-Developmental Regulatory Gene, LEAFY COTYLEDON1 (LEC1), in Nonseed Plant Genomes
Authors: Z. Xie, X. Li, B. J. Glover, S. Bai, G.-Y. Rao, J. Luo, J. Yang
Journal: Molecular Biology and Evolution (2008)

The HAP3 gene encodes a subunit of the CCAAT-box-binding factor (CBF), a highly conserved trimeric activator that recognizes and binds the ubiquitous CCAAT promoter element with high affinity. Two types of HAP3 gene have been identified in plant genomes. The LEAFY COTYLEDON1 (LEC1)–type HAP3 genes encode a functionally specialized subunit of CBF, which is expressed specifically in developing seeds. In contrast, most non–LEC1-type HAP3 genes are expressed in various tissues. It has been proposed that the LEC1-type HAP3 genes originated from the duplication and functional divergence of non–LEC1-type HAP3 genes. However, it is not yet known when this duplication event took place or whether the LEC1-type HAP3 genes appeared at the same time as the origin of seed plants. Here we describe a comprehensive comparison of the duplication patterns of HAP3 genes in different plant genomes. We recognize a major expansion of the HAP3 gene family accompanying the origin and early diversification of land plants and postulate that retrotransposition and other mechanisms of gene duplication have been involved in the expansion of the plant HAP3 gene family. We provide evidence that the LEC1-type HAP3 genes originated in nonseed vascular plant genomes and demonstrate that they are inductively expressed under drought stress in nonseed plants. These genes, however, were recruited to a novel regulatory network in the early stages of seed plant evolution and steadily expressed during seed development and maturation.
Pathologic Features of Prostate Cancer Found at Population-Based Screening With a Four-Year Interval
Authors: R. F. Hoedemaeker, T. H. van der Kwast, R. Boer, H. J. de Koning, M. Roobol, A. N. Vis, F. H. Schroder
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: The currently recommended frequency for prostate-specific antigen (PSA) screening tests for prostate cancer is 1 year, but the optimal screening interval is not known. Our goal was to determine if a longer interval would compromise the detection of curable prostate cancer. Methods: A cohort of 4491 men aged 55–75 years, all participants in the Rotterdam section of the European Randomized Study of (population-based) Screening for Prostate Cancer, were invited to participate in an initial PSA screening. Men who received that screening were invited for a second screen 4 years later. Pathology findings from needle biopsy cores were compared for men in both rounds. Statistical tests were two-sided. Results: A total of 4133 men were screened in the first round (the prevalence screen), and 2385 were screened in the second round. The median amount of cancer in needle biopsy sets was 7.0 mm (95% confidence interval [CI] = 5.4 mm to 8.6 mm) in the first round and 4.1 mm (95% CI = 2.6 mm to 5.6 mm) in the second round (P = .001). Thirty-six percent of the adenocarcinomas detected in the first round but only 16% of those detected in the second round had a Gleason score of 7 or higher (mean difference = 20% [95% CI = 10% to 30%]; P<.001). Whereas 25% of the adenocarcinomas detected in the first round had adverse prognostic features, only 6% of those detected in the second round did (mean difference = 19% [95% CI = 11% to 26%]; P<.001). Baseline PSA values were predictive for the amount of tumor in biopsies in men with cancer in the first round but not for that in the second round. Conclusion: Most large prostate cancers with high serum PSA levels were effectively detected in a prevalence screen. In this population, a screening interval of 4 years appears to be short enough to constrain the development of large tumors, although it is inconclusive whether this will result in a survival benefit.
Fcgamma receptor IIa, IIIa, and IIIb polymorphisms in German patients with systemic lupus erythematosus: association with clinical symptoms
Authors: K Manger
Journal: Annals of the Rheumatic Diseases (2002)

<b>Background:</b> Receptors for IgG play an important part in immune complex clearance. Several studies have identified polymorphisms of receptors for the Fc fragment of IgG (FcγR) as genetic factors influencing susceptibility to disease or disease course of systemic lupus erythematosus (SLE). <b>Objective:</b> To examine these possibilities by evaluating a panel of clinical parameters in a cohort of 140 German patients with SLE for correlations with the FcγRIIa, IIIa, and IIIb polymorphisms in an explorative study. <b>Methods:</b> 140 German patients with SLE according to American College of Rheumatology (ACR) criteria and 187 German controls were genotyped for the FcγRIIa, IIIa, and IIIb polymorphisms. Associations between FcγR genotypes, combined genotypes and clinical as well as laboratory features were analysed. <b>Results:</b> No significant skewing of any of the three FcγR polymorphisms was seen in the German SLE cohort studied. Various clinical and serological parameters were found more frequently and at younger age in homozygous patients with the genotypes IIA-R/R131 or IIIA-F/F158 than in patients with IIA-H/H131 or IIIA-V/V158. These effects were even more pronounced in patients with the low binding combined phenotypes of the FcγRIIa, IIIa (double negative phenotypes) and FcγRIIa, IIIa, and IIIb (triple negative phenotypes). In patients with the double negative IIA and IIIA genotypes significantly higher frequencies of nephritis (63% <i>v</i> 33%) and proteinuria according to ACR criteria (58% <i>v</i> 11%), anaemia (84% <i>v</i> 55%), and anticardiolipin antibodies (63% <i>v</i> 22%) were found than in patients with the double positive genotypes. Patients with the IIA-R/R131 genotype and the double negative homozygous genotype had an earlier incidence of clinical symptoms, haematological and immunological abnormalities. Accordingly, SLE is diagnosed earlier in these patients, the difference reaching statistical significance only in the double negative <i>v</i> the double positive genotype (26.3 <i>v</i> 39.5 years) and the IIIA-F/F158 genotype <i>v</i> the rest (26.7 <i>v</i> 32.0 years). Most relevant is the fact that a higher median disease activity (ECLAM score) was demonstrated, both in the IIA-R/R131 homozygous (3.3 <i>v</i> 2.7) and the double negative (3.4 <i>v</i> 2.3) patients, reaching statistical significance in the first group. <b>Conclusion:</b> The results of this explorative study support the view that the FcγRIIa/IIIa and IIIb polymorphisms constitute factors influencing clinical manifestations and the disease course of SLE but do not represent genetic risk factors for the occurrence of SLE. Higher frequencies of clinical symptoms, haematological and immunological abnormalities as well as an earlier onset of clinical symptoms, haematological and immunological markers of active disease were found in patients with the IIA-R/R131 genotype and the double negative and triple negative genotypes.