tbuckley/cabot-search huggingface dataset:
Crk gets hijacked
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

The ulcer-inducing bacterium Helicobacter pylori busts through the cells that line the stomach by hijacking a host protein, suggest Suzuki and colleagues on page 1235. The co-opted protein turns on multiple signaling pathways in gastric cells that cause the normally adhesive cells to pull apart from their neighbors.






Figure 

The H. pylori CagA protein disrupts cell–cell contacts among normally adherent epithelial cells.




Roughly half of all people worldwide have H. pylori living in their stomachs. Most people host the infection without consequence but, in some, H. pylori infection triggers peptic ulcers and gastric cancer. H. pylori encodes a set of proteins that allows it to adhere to and thrive in the stomach and to avoid immune attack. One of these proteins—CagA (cytotoxin-associated antigen-A)—helps ward off immune cells but also disrupts the epithelial cells that line the stomach.

Many studies have investigated how CagA, which is injected into gastric epithelial cells through a specialized bacterial secretion system, helps breach the epithelial lining of the stomach. Once inside the cells, CagA binds to a variety of intracellular signaling proteins. But it was not clear which of these proteins is required for CagA-induced cell scattering.

Suzuki and colleagues now identify a new target of CagA: the Crk family of adaptor proteins. CagA–Crk binding in infected epithelial cells triggered the activation of downstream signaling pathways, including the Ras–Raf and Rac1–WAVE pathways, which are normally induced during routine cell turnover. These signals prompted the expulsion of adhesive proteins β-catenin and E-cadherin from the adherens junctions that hold the cells together.

The liberation of β-catenin from adherens junctions not only compromises cell contacts, but likely also induces aberrant proliferation of the cells, as nuclear β-catenin drives the expression of cell cycle–promoting genes such as cyclin D1. Both cell scattering and proliferation compromise the integrity of the stomach lining, thus contributing to the development of H. pylori–induced gastric disease.
The relationship between cardiovascular risk factors and trait anxiety of Iranian referees and assistant referees in Premier League Soccer
Authors: Effat Bambaeichi, Ahmad Reza Movahedi, Misam Abedini
Journal: British Journal of Sports Medicine (2010)

The aim of this investigation was to explore the relationship between trait anxiety and cardiovascular disease risk factors of Iranian soccer referees and assistant referees. Twenty-five referees and 43 assistant referees (mean±SD, age: 36.7±3.8 years, height: 1.79±4.8 m, weight: 74.7±6 kg) with international (22% of all subjects) and national (78% of all subjects) degrees participated in this study. All referees were judging Premier League Soccer Competitions (2007–2008 season) under the supervision of Soccer Federation Referees committee. Trait anxiety was assessed by Zung Self-Rating Anxiety Scale and data regarding cardiovascular disease risk factors were obtained by cardiovascular disease risk factors (RISKO) questionnaire structured by Cardiovascular University of Michigan State in the USA. Blood pressure, heart rate and concentration of the cholesterol in blood serum were also measured. No significant difference was observed in trait anxiety score between soccer referees (34.4±4.9) and assistant referees (32.2±4.7) (p&gt;0.05). There was no significant difference in RISKO score between soccer referees (16.8±2.5) and assistant referees (16.8±2.5). A significant relationship was not observed between trait anxiety and RISKO score in both referees (r=0.26, p&gt;0.05) and assistant referees (r=0.11). Trait anxiety did not show significant relationship with age (r=0.07), physical activity (r=0.0), cholesterol (r=−0.00) and blood pressure (r=0.11) (p&gt;0.05). A significant relationship was found between trait anxiety with weight (r=0.20, p&lt;0.05) and heredity of cardiovascular disease (r=0.20, p&lt;0.05). It can be concluded that Iranian referees and assistant referees in Premier League Soccer had normal trait anxiety. In addition, their cardiovascular disease risk factors scores were in the low and intermediate risk range.
Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs
Authors: Michael D. Cahalan, Ian Parker
Journal: Annual Review of Immunology (2008)

The immune system is the most diffuse cellular system in the body. Accordingly, long-range migration of cells and short-range communication by local chemical signaling and by cell-cell contacts are vital to the control of an immune response. Cellular homing and migration within lymphoid organs, antigen recognition, and cell signaling and activation are clearly vital during an immune response, but these events had not been directly observed in vivo until recently. Introduced to the field of immunology in 2002, two-photon microscopy is the method of choice for visualizing living cells deep within native tissue environments, and it is now revealing an elegant cellular choreography that underlies the adaptive immune response to antigen challenge. We review cellular dynamics and molecular factors that contribute to basal motility of lymphocytes in the lymph node and cellular interactions leading to antigen capture and recognition, T cell activation, B cell activation, cytolytic effector function, and antibody production.
Immunotherapy targeting esophageal cancer stem cells
Authors: Dongli Yue, Hongzheng Ren, Lan Huang, Yi Zhang
Journal: Journal for ImmunoTherapy of Cancer (2013)

Meeting abstracts Esophageal cancer is one of most common malignancies. Cancer stem cells (CSC) are considered to be resistant to chemotherapy and radiotherapy, which might be associated with the recurrence of the tumor after treatment. To find the therapeutic procedures targeting CSCs, the
Inflammatory Monocyte Mobilization Decreases Patient Survival in Pancreatic Cancer: A Role for Targeting the CCL2/CCR2 Axis
Authors: Dominic E. Sanford, Brian A. Belt, Roheena Z. Panni, Allese Mayer, Anjali D. Deshpande, Danielle Carpenter, Jonathan B. Mitchem, Stacey M. Plambeck-Suess, Lori A. Worley, Brian D. Goetz, Andrea Wang-Gillam, Timothy J. Eberlein, David G. Denardo, Simon Peter Goedegebuure, David C. Linehan
Journal: Clinical Cancer Research (2013)

To determine the role of the CCL2/CCR2 axis and inflammatory monocytes (CCR2(+)/CD14(+)) as immunotherapeutic targets in the treatment of pancreatic cancer.Survival analysis was conducted to determine if the prevalence of preoperative blood monocytes correlates with survival in patients with pancreatic cancer following tumor resection. Inflammatory monocyte prevalence in the blood and bone marrow of patients with pancreatic cancer and controls was compared. The immunosuppressive properties of inflammatory monocytes and macrophages in the blood and tumors, respectively, of patients with pancreatic cancer were assessed. CCL2 expression by human pancreatic cancer tumors was compared with normal pancreas. A novel CCR2 inhibitor (PF-04136309) was tested in an orthotopic model of murine pancreatic cancer.Monocyte prevalence in the peripheral blood correlates inversely with survival, and low monocyte prevalence is an independent predictor of increased survival in patients with pancreatic cancer with resected tumors. Inflammatory monocytes are increased in the blood and decreased in the bone marrow of patients with pancreatic cancer compared with controls. An increased ratio of inflammatory monocytes in the blood versus the bone marrow is a novel predictor of decreased patient survival following tumor resection. Human pancreatic cancer produces CCL2, and immunosuppressive CCR2(+) macrophages infiltrate these tumors. Patients with tumors that exhibit high CCL2 expression/low CD8 T-cell infiltrate have significantly decreased survival. In mice, CCR2 blockade depletes inflammatory monocytes and macrophages from the primary tumor and premetastatic liver resulting in enhanced antitumor immunity, decreased tumor growth, and reduced metastasis.Inflammatory monocyte recruitment is critical to pancreatic cancer progression, and targeting CCR2 may be an effective immunotherapeutic strategy in this disease.
Continuing Outcomes Relevant to Evista: Breast Cancer Incidence in Postmenopausal Osteoporotic Women in a Randomized Trial of Raloxifene
Authors: Silvana Martino, Jane A Cauley, Elizabeth Barrett-Connor, Trevor J Powles, John Mershon, Damon Disch, Roberta J Secrest, Steven R Cummings
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: The randomized, double-blind Multiple Outcomes of Raloxifene Evaluation (MORE) trial found that 4 years of raloxifene therapy decreased the incidence of invasive breast cancer among postmenopausal women with osteoporosis by 72% compared with placebo. We conducted the Continuing Outcomes Relevant to Evista (CORE) trial to examine the effect of 4 additional years of raloxifene therapy on the incidence of invasive breast cancer in women in MORE who agreed to continue in CORE. Methods: Women who had been randomly assigned to receive raloxifene (either 60 or 120 mg/day) in MORE were assigned to receive raloxifene (60 mg/day) in CORE (n = 3510), and women who had been assigned to receive placebo in MORE continued on placebo in CORE (n = 1703). Breast cancer incidence was analyzed by a log-rank test, and a Cox proportional hazards model was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results: During the CORE trial, the 4-year incidences of invasive breast cancer and estrogen receptor (ER)-positive invasive breast cancer were reduced by 59% (HR = 0.41; 95% CI = 0.24 to 0.71) and 66% (HR = 0.34; 95% CI = 0.18 to 0.66), respectively, in the raloxifene group compared with the placebo group. There was no difference between the two groups in incidence of ER-negative invasive breast cancer during CORE ( P = .86). Over the 8 years of both trials, the incidences of invasive breast cancer and ER-positive invasive breast cancer were reduced by 66% (HR = 0.34; 95% CI = 0.22 to 0.50) and 76% (HR = 0.24; 95% CI = 0.15 to 0.40), respectively, in the raloxifene group compared with the placebo group. During the CORE trial, the relative risk of thromboembolism in the raloxifene group compared with that in the placebo group was 2.17 (95% CI = 0.83 to 5.70). This increased risk, also observed in the MORE trial, persisted over the 8 years of both trials. Conclusions: The reduction in invasive breast cancer incidence continues beyond 4 years of raloxifene treatment in postmenopausal women with osteoporosis. No new safety concerns related to raloxifene therapy were identified during CORE.
Molecular Imaging of Temporal Dynamics and Spatial Heterogeneity of Hypoxia-Inducible Factor-1 Signal Transduction Activity in Tumors in Living Mice
Authors: Inna Serganova, Michael Doubrovin, Jelena Vider, Vladimir Ponomarev, Suren Soghomonyan, Tatiana Beresten, Ludmila Ageyeva, Alexander Serganov, Shangde Cai, Julius Balatoni, Ronald Blasberg, Juri Gelovani
Journal: Cancer Research (2004)

Tumor hypoxia is a spatially and temporally heterogeneous phenomenon, which results from several tumor and host tissue-specific processes. To study the dynamics and spatial heterogeneity of hypoxia-inducible factor-1 (HIF-1)-specific transcriptional activity in tumors, we used repetitive noninvasive positron emission tomography (PET) imaging of hypoxia-induced HIF-1 transcriptional activity in tumors in living mice. This approach uses a novel retroviral vector bearing a HIF-1-inducible "sensor" reporter gene (HSV1-tk/GFP fusion) and a constitutively expressed "beacon" reporter gene (DsRed2/XPRT). C6 glioma cells transduced with this multireporter system revealed dose-dependent patterns in temporal dynamics of HIF-1 transcriptional activity induced by either CoCl2 or decreased atmospheric oxygen concentration. Multicellular spheroids of C6 reporter cells developed a hypoxic core when >350 microm in diameter. 18F-2'-fluoro-2'deoxy-1beta-D-arabionofuranosyl-5-ethyl-uracil (FEAU) PET revealed spatial heterogeneity of HIF-1 transcriptional activity in reporter xenografts in mice as a function of size or ischemia-reperfusion injury. With increasing tumor diameter (>3 mm), a marked increase in HIF-1 transcriptional activity was observed in the core regions of tumors. Even a moderate ischemia-reperfusion injury in small C6 tumors caused a rapid induction of HIF-1 transcriptional activity, which persisted for a long time because of the inability of C6 tumors to rapidly compensate acute changes in tumor microcirculation.
Basic Fibroblast Growth Factor (FGF-2) Overexpression Is a Risk Factor for Esophageal Cancer Recurrence and Reduced Survival, which Is Ameliorated by Coexpression of the FGF-2 Antisense Gene
Authors: Christie Barclay, Audrey W. Li, Laurette Geldenhuys, Mark Baguma-Nibasheka, Geoffrey A. Porter, Paul J. Veugelers, Paul R. Murphy, Alan G. Casson
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The basic fibroblast growth factor (FGF-2) gene is bidirectionally transcribed to generate overlapping sense and antisense (FGF-AS) mRNAs. FGF-AS has been implicated in the post-transcriptional regulation of FGF-2 expression. The aim of this study was to characterize FGF-2 and FGF-AS in esophageal cancer and to correlate their expression with clinicopathologic findings and outcome. Experimental Design: Reverse transcription-PCR was used to study FGF-2 and FGF-AS mRNA expression (normalized to glyceraldehyde-3-phosphate dehydrogenase) in 48 esophageal cancers relative to matched histologically normal esophageal epithelia (internal control). We used Cox proportional hazards analysis to calculate hazard ratios for recurrence and survival of patients with underexpression relative to the overexpression of FGF-2 and/or FGF-AS. Results: Overexpression of FGF-2 mRNA, by comparison with tumors underexpressing FGF-2, was associated with significantly increased risk for tumor recurrence (hazard ratio, 3.80; 95% confidence interval, 1.64-8.76) and reduced overall survival (hazard ratio, 2.11; 95% confidence interval, 1.0-4.58). When the effects of FGF-2 and FGF-AS were considered simultaneously, the association of FGF-2 mRNA overexpression with recurrence and mortality was even more pronounced, whereas FGF-AS mRNA overexpression was associated with reduced risk for recurrence and improved survival. Conclusions: Overexpression of FGF-2 mRNA is associated with tumor recurrence and reduced survival after surgical resection of esophageal cancer and that these risks are reduced in tumors coexpressing the FGF-AS mRNA. These data support the hypothesis that FGF-AS is a novel tumor suppressor that modulates the effect of FGF-2 expression and may have potential clinical application to the development of novel therapeutic strategies.
Proteasome Inhibitors in Cancer Therapy: Lessons from the First Decade
Authors: Robert Z. Orlowski, Deborah J. Kuhn
Journal: Clinical Cancer Research (2008)

Abstract The ubiquitin-proteasome pathway is involved in intracellular protein turnover, and its function is crucial to cellular homeostasis. First synthesized as probes of proteolytic processes, proteasome inhibitors began to be thought of as potential drug candidates when they were found to induce programmed cell death preferentially in transformed cells. They made their first leap into the clinic to be tested as therapeutic agents 10 years ago, and since then, great strides have been made in defining their mechanisms of action, their clinical efficacy and toxicity, and some of their limitations in the form of resistance pathways. Validation of the ubiquitin-proteasome pathway as a target for cancer therapy has come in the form of approvals of the first such inhibitor, bortezomib, for relapsed/refractory multiple myeloma and mantle cell lymphoma, for which this agent has become a standard of care. Lessons learned from this first-in-class agent are now being applied to the development of a new generation of proteasome inhibitors that hold the promise of efficacy in bortezomib-resistant disease and possibly in a broader spectrum of diseases. This saga provides a salient example of the promise of translational medicine and a paradigm by which other agents may be successfully brought from the bench to the bedside.
Human Demographic Processes and Genetic Variation as Revealed by mtDNA Simulations
Authors: A. T. Miro-Herrans, C. J. Mulligan
Journal: Molecular Biology and Evolution (2012)

Humans’ ability for rapid dispersal and adaptation has allowed us to colonize diverse geographic and climatic regions of the planet, creating a complex evolutionary history. This complexity can be understood, at least partially, by modeling the underlying demographic parameters in the evolutionary process. In this study, we analyze a model of human evolution in which population size, gene flow (GF), and time are varied. Specifically, we simulate mitochondrial DNA for 42 demographic scenarios, represented by 42 parameter combinations, to describe the initial dispersal of modern humans out of Africa. The analyses include three values for colonization size (CS; 1%, 10%, and 30% of the African population), seven values for rate of GF (10−6–0.5), and two values for time of colonization (50,000 and 100,000 years ago). We then estimate summary statistics for the simulated data sets to calculate the percent of explained variation by each parameter and to identify which parameter combinations generate distinct differences in genetic variation, that is, which demographic scenarios can be distinguished from each other. On the basis of these results, we make recommendations about which summary statistics to use according to the parameter of interest. Our results show that CS, GF, and their interaction have the largest effect on genetic variation under our model of human evolution. Comparison with empirical data suggests that 1% of the existing African mitochondrial genetic variation left and colonized the rest of the world (i.e., CS = 1%) and bidirectional GF continued at a level of ∼10 individuals per generation (i.e., GF = 10−3) after the initial colonization. Our study serves as a model to bridge the gap between the use of simulations for theoretical population genetics and empirical data analysis such as approximate Bayesian computation approaches and is, thus, applicable to the study of molecular evolution in any organism.
Effect of CPAP on Blood Pressure in Patients With Obstructive Sleep Apnea and Resistant Hypertension
Authors: Miguel-Angel Martínez-García, Francisco Capote, Francisco Campos-Rodríguez, Patricia Lloberes, María Josefa Díaz de Atauri, María Somoza, Juan F. Masa, Mónica González, Lirios Sacristán, Ferrán Barbé, Joaquín Durán-Cantolla, Felipe Aizpuru, Eva Mañas, Bienvenido Barreiro, Mar Mosteiro, Juan J. Cebrián, Mónica de la Peña, Francisco García-Río, Andrés Maimó, Jordi Zapater, Concepción Hernández, Nuria Grau SanMarti, Josep María Montserrat
Journal: JAMA (2013)

for the Spanish
IL-23–responsive innate lymphoid cells are increased in inflammatory bowel disease
Authors: Alessandra Geremia, Carolina V. Arancibia-Cárcamo, Myles P.P. Fleming, Nigel Rust, Baljit Singh, Neil J. Mortensen, Simon P.L. Travis, Fiona Powrie
Journal: The Journal of Experimental Medicine (2011)

Results of experimental and genetic studies have highlighted the role of the IL-23/IL-17 axis in the pathogenesis of inflammatory bowel disease (IBD). IL-23-driven inflammation has been primarily linked to Th17 cells; however, we have recently identified a novel population of innate lymphoid cells (ILCs) in mice that produces IL-17, IL-22, and IFN-γ in response to IL-23 and mediates innate colitis. The relevance of ILC populations in human health and disease is currently poorly understood. In this study, we have analyzed the role of IL-23-responsive ILCs in the human intestine in control and IBD patients. Our results show increased expression of the Th17-associated cytokine genes IL17A and IL17F among intestinal CD3⁻ cells in IBD. IL17A and IL17F expression is restricted to CD56⁻ ILCs, whereas IL-23 induces IL22 and IL26 in the CD56⁺ ILC compartment. Furthermore, we observed a significant and selective increase in CD127⁺CD56⁻ ILCs in the inflamed intestine in Crohn's disease (CD) patients but not in ulcerative colitis patients. These results indicate that IL-23-responsive ILCs are present in the human intestine and that intestinal inflammation in CD is associated with the selective accumulation of a phenotypically distinct ILC population characterized by inflammatory cytokine expression. ILCs may contribute to intestinal inflammation through cytokine production, lymphocyte recruitment, and organization of the inflammatory tissue and may represent a novel tissue-specific target for subtypes of IBD.
HISTOENZYMOLOGICAL STUDY OF DERMAL VESSELS IN NORMAL AND PATHOLOGICAL SKIN
Authors: J. HEWITT, M. GUIGON
Journal: British Journal of Dermatology (1970)

Journal Article HISTOENZYMOLOGICAL STUDY OF DERMAL VESSELS IN NORMAL AND PATHOLOGICAL SKIN Get access J. HÉWITT, J. HÉWITT Laboratoire de Recherches Dermatologique, Hôpital Broca, Paris, Rrance† Search for other works by this author on: Oxford Academic Google Scholar M. GUIGON M. GUIGON Laboratoire de Recherches Dermatologique, Hôpital Broca, Paris, Rrance† Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 82, Issue 4, 1 April 1970, Pages 364–370, https://doi.org/10.1111/j.1365-2133.1970.tb06834.x Published: 01 April 1970 Article history Accepted: 08 September 1969 Published: 01 April 1970
Flying and hypoxaemia at altitude: Cabine altitude should have been recorded
Authors: F Anstein, A O Johnson, R L Page, D J Sapsford, J G Jones
Journal: BMJ (1994)

Experience in our intensive care unit has also shown a considerable increase in the number of patients admitted after an overdose or self harm over the past three years, with the largest rise during 1993.Nine, 15, and 22 patients were admitted in 1990, 1991, and 1992, respectively.In the first 11 months of 1993, 51 patients required treatment, an increase of 566% in under three years.Using the therapeutic intervention scoring system4 and a cost of £30 per point on this score,5 we estimate that an average of £ 1638 range £150-16 620) was spent on each patient during his or her stay in the unit.The additional emergency work- load generated by such admissions has a consider- able impact on elective major surgery requiring support from the unit and often necessitates the transfer of other emergency patients to intensive care units in other districts.This worrying trend in the local rate of attempted suicide has important cost implications for purchasers and cannot be controlled by the internal market.Social and economic issues must be addressed before the government's targets can be achieved.