tbuckley/cabot-search huggingface dataset:
Modulation of Exaggerated-IgE Allergic Responses by Gene Transfer-mediated Antagonism of IL-13 and IL-17e
Authors: Christian Mueller, Allison Keeler, Sofia Braag, Timothy Menz, Qiushi Tang, Terence R Flotte
Journal: Molecular Therapy (2009)

Asthma and allergic rhinitis are almost invariable accompanied by elevated levels of immunoglobin E (IgE), and more importantly a genetic link between IgE levels and airway hyper-responsiveness has been established. We hypothesized that expression of soluble receptors directed against interleukin (IL)-13 and IL-17e would prevent the cytokines from engaging the cell-bound receptors and therefore help to attenuate allergic responses in a Cftr(-/-)-dependent mouse model of exaggerated-IgE responses. Cftr(-/-) mice were injected with recombinant adeno-associated virus 1 (rAAV1) intramuscularly expressing soluble receptors to IL-17e (IL-17Rh1fc) or IL-13 (IL-13Ralpha2Fc). Total IgE levels, in mice receiving the IL-17Rh1fc and IL-13Ralpha2Fc therapy, were lower than in the control group. Interestingly Aspergillus fumigatus (Af)-specific IgE levels were undetectable in both the mice receiving the IL-17Rh1fc and IL-13Ralpha2Fc therapies. Further flow cytometry analysis of intracellular gene expression suggests that blocking IL-17e may be interfering with signaling upstream of CD4+ and CD11b+ cells and reducing IgE levels by affecting signaling on these cell populations. In contrast it appears that IL-13 blockade acts downstream to reduce IgE levels probably by directly affecting B-cell maturation. These studies demonstrate the feasibility of targeting T helper 2 (Th2) cytokines with rAAV-delivered fusion proteins as a means to treat aberrant immune responses.
Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study
Authors: Peter Schmid, Yutaka Nagai, Roshan Agarwal, Barry Hancock, Philip M Savage, Neil J Sebire, Iain Lindsay, Michael Wells, Rosemary A Fisher, Delia Short, Edward S Newlands, Manfred B Wischnewsky, Michael J Seckl
Journal: The Lancet (2009)
2012 highlights in translational 'omics
Authors: Charles Auffray, Timothy Caulfield, Muin J Khoury, James R Lupski, Matthias Schwab, Timothy Veenstra
Journal: Genome Medicine (2013)

�is annual editorial from Genome Medicine’s Section Editors highlights the most exciting research from the past year and the potential of these advances for medicine. Last year, we noted that medical ‘omics continued its inexorable move towards the clinic; in 2012 it has truly arrived. DNA capture technologies and sequencing continue to lead the way, with implications for human genomics, personalized medicine, pharmacogenomics and drug labeling, public health screening, and public policy already apparent. �ere have also been technological advances in proteomics and other ‘omic approaches, and in the integration of these approaches to provide more informative molecular signatures of health and suscep tibility to disease. De novo mutations: from complexity to the clinic
Ovarian Suppression for Breast Cancer: An Effective Treatment in Search of a Home
Authors: Ian E. Krop, Eric P. Winer
Journal: Journal of Clinical Oncology (2005)

Adjuvant endocrine therapy is the most important systemic treatment for the majority of women with hormone receptor–positive breast cancer. Our understanding of the role of endocrine therapy in premenopausal women has lagged considerably in comparison with our knowledge of its role in postmenopausal women. Tamoxifen, for example, was initially shown to be beneficial in postmenopausal women; only after many years were similar benefits demonstrated in premenopausal women. 1 In the last few years, adjuvant endocrine therapy for postmenopausal women has taken another step forward with the incorporation of the aromatase inhibitors into the treatment armamentarium. 2 The benefits seen with aromatase inhibitors, which arise as a consequence of estrogen deprivation, have contributed to continued interest in the use of ovarian suppression in premenopausal women. Why do we know so much less about endocrine therapy in premenopausal than in postmenopausal women? There are at least three reasons. First, breast cancer, and specifically hormone receptor–positive breast cancer, is much less common in premenopausal women than in postmenopausal women. However, receptor-positive breast cancer in premenopausal women is hardly a rare disease. There are approximately 47,000 cases of breast cancer in women younger than 50 years diagnosed in the United States each year; of these, 11,500 cases are in women younger than 40 years. 3 More than half of all premenopausal women with breast cancer have receptor-positive disease, resulting in more than 25,000 cases of receptorpositive disease among premenopausal women. Taking a more global perspective, there are hundreds of thousands of premenopausal women diagnosed each year with hormone receptor–positive disease. Second, there has been a longstanding conviction that chemotherapy was the more important treatment for younger women, and, consequently, trials of endocrine agents have been viewed as second-tier. There has been increasing reason to question this view, but translating hypotheses into practice-changing clinical trials can take many years. Finally, our understanding of endocrine therapy in premenopausal women has been clouded by the indirect endocrine effect of chemotherapy. At least some, if not most, of the benefit of chemotherapy in many premenopausal women with receptor-positive disease probably arises from suppression of ovarian function. There are several reasons to investigate new and im
Effect of Bisphosphonate Use on Risk of Postmenopausal Breast Cancer
Authors: Trisha F. Hue, Steven R. Cummings, Jane A. Cauley, Douglas C. Bauer, Kristine E. Ensrud, Elizabeth Barrett-Connor, Dennis M. Black
Journal: JAMA Internal Medicine (2014)

<h3>Importance</h3> Studies have shown that bisphosphonates may have antitumor and antimetastatic properties. Recently, observational studies have suggested a possible protective effect of bisphosphonates on breast cancer, but the effect of bisphosphonate use on risk of breast cancer has not been tested in randomized trials. <h3>Objective</h3> To assess the relationship of postmenopausal breast cancer incidence and bisphosphonate use using data from 2 randomized (1:1), double-blind, placebo-controlled trials. <h3>Design, Setting, and Participants</h3> The Fracture Intervention Trial (FIT) randomly assigned 6459 women aged 55 to 81 years to alendronate or placebo for a mean follow-up of 3.8 years. The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT) randomly assigned 7765 women aged 65 to 89 years to annual intravenous zoledronic acid or placebo for a mean follow-up of 2.8 years. Data were collected at clinical centers in the United States (FIT and HORIZON-PFT) and in Asia and the Pacific, Europe, North America, and South America (HORIZON-PFT). Women, in either study, with recurrent breast cancer or who reported a history of breast cancer were excluded from analyses. In each trial, a blinded review was conducted of each cancer adverse event report to verify incident invasive breast cancer cases. The primary analysis compared events in the active vs placebo group using a log-rank test. <h3>Intervention</h3> Alendronate vs placebo (FIT) or zoledronic acid vs placebo (HORIZON-PFT). <h3>Main Outcomes and Measures</h3> Hazard ratio for incident breast cancer in the bisphosphonate treatment group compared to the placebo group. <h3>Results</h3> There was no significant difference in the rate of breast cancer in FIT: 1.5% (n = 46) in the placebo group and 1.8% (n = 57) in the alendronate group (hazard ratio [HR], 1.24 [95% CI, 0.84-1.83]). In HORIZON-PFT, there was also no significant difference: 0.8% (n = 29) in the placebo group and 0.9% (n = 33) in the zoledronic acid group (HR, 1.15 [95% CI, 0.70-1.89]). There was also no significant difference when the data from FIT and HORIZON-PFT were pooled (HR, 1.20 [95% CI, 0.89-1.63]). <h3>Conclusions and Relevance</h3> These 2 randomized clinical trials do not support the findings from observational research. Contrary to the results from observational studies, we found that 3 to 4 years of bisphosphonate treatment did not decrease the risk of invasive postmenopausal breast cancer. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00049829(HORIZON-PFT).
Race, Nutritional Status, and Survival From Breast Cancer
Authors: R. J. Coates, W. S. Clark, J. W. Eley, R. S. Greenberg, C. M. Huguly, R. L. Brown
Journal: JNCI Journal of the National Cancer Institute (1990)

The effects of nutritional status on differences in the survival of black and white women with breast cancer were studied in a cohort of 1,960 Georgia women diagnosed during 1975-1979. After data were adjusted for stage of disease, socioeconomic status, and other prognostic factors, poorer survival rates were shown in black women. Within each stage classification, lower levels of serum albumin and hemoglobin and higher relative body weight were more common among blacks and were independently associated with poorer survival. Among women with stage 3 disease, adjustment for these variables substantially reduced the excess mortality rate among blacks, suggesting that racial differences in survival may be partly explained by differences in nutritional status or extent of disease within stage.
An audit of cyclosporin for systemic lupus erythematosus and related overlap syndromes: limitations of its use
Authors: S J Morton
Journal: Annals of the Rheumatic Diseases (2000)

To establish the usefulness of cyclosporin for systemic lupus erythematosus (SLE) in a routine clinical setting.Patients who had received cyclosporin for SLE, mixed connective tissue disease, and other overlap syndromes were identified. Data relating to treatment with cyclosporin, including dosage, concurrent steroid use, response to treatment, side effects, and reasons for withdrawal, were extracted from medical notes.A total of 43 patients had been treated with cyclosporin between 1995 and 1998. Cyclosporin, average dose 4 mg/kg/d, was started in patients whose disease was active despite previous use of alternative second line agents. On every occasion when cyclosporin was used for thrombocytopenia the response was good, but when arthritis was the indication, the response was good in 14/26. The success rates for symptoms of arthralgia, myalgia, and fatigue were lower. Side effects occurred in 28/43 (65%) cases, and on 39/47 (83%) occasions cyclosporin was withdrawn owing to either side effects or failure to control disease activity, after a median duration of treatment of only four months.The response to cyclosporin is mixed and usually short lived.
Autologous mixed lymphocyte culture reactions and generation of cytotoxic T cells.
Authors: R A Vande Stouwe, H G Kunkel, J P Halper, M E Weksler
Journal: The Journal of Experimental Medicine (1977)

Autologous mixed lymphocyte culture (MLC) reactions were studied utilizing autologous purified B cells and autologous established B lymphoid cell lines as stimulating cells. Similar results were obtained although somewhat greater stimulation of lymphocyte proliferation was found with the autologous lymphoid cell lines. Cytotoxic T cells were not generated against the stimulating cells in either case when peripheral blood cells were used as targets. A low cytotoxicity was detected when lymphoid cell lines were used both as stimulators and target cells. However this was nonspecific and was always greater for heterologous lines than for the stimulator line. Third-party cell experiments demonstrated that the autologous reaction could serve as a proliferative stimulus for specific cytotoxic lymphocyte generation. Heat-treated allogeneic lymphocytes that alone do not stimulate proliferation ro cytotoxic T-cell generation in MLC reactions when added to the autologous system produced specific cytotoxic cells. The separation of the proliferative phase from the cytotoxic cell generation was especially striking in these experiments. Possible uses of this system for the generation of specific cytotoxic cells to other nonstimulatory cells are discussed.
Fine-Needle Aspiration Biopsies for Gene Expression Ratio-Based Diagnostic and Prognostic Tests in Malignant Pleural Mesothelioma
Authors: Assunta De Rienzo, Lingsheng Dong, Beow Y. Yeap, Roderick V. Jensen, William G. Richards, Gavin J. Gordon, David J. Sugarbaker, Raphael Bueno
Journal: Clinical Cancer Research (2010)

Malignant pleural mesothelioma (MPM) is an aggressive disease associated with median survival between 9 and 12 months. The correct diagnosis of MPM is sometimes challenging and usually requires solid tissue biopsies rather than fine-needle aspiration biopsies (FNA). We postulated that the accuracy of FNA-based diagnosis might be improved by the addition of molecular tests using a gene expression ratio-based algorithm and that prognostic tests could be similarly performed.Two MPM and 2 lung cancer cell lines were used to establish the minimal quantity of RNA required to perform the gene ratio test. On the basis of these results, 276 ex vivo FNA biopsies from 63 MPM patients and 250 ex vivo FNA samples from 92 lung cancer patients were analyzed using previously described diagnostic and prognostic tests based on gene expression ratios.We found that the sensitivity of the diagnostic test for MPM was 100% [95% confidence interval (CI): 95%-100%] and the specificity in primary lung adenocarcinoma was 90% (95% CI: 81%-95%). The FNA-based prognostic classification was concordant among 76% (95% CI: 65%-87%) of patients with the risk assignment in a subset of the matched surgical specimens previously analyzed by the prognostic test.Sufficient RNA can be extracted from most FNA biopsies to perform gene expression molecular tests. In particular, we show that the gene expression ratio algorithms performed well when applied to diagnosis and prognosis in MPM. This study provides support for the development of additional RNA molecular tests that may enhance the utility of FNA in the management of other solid cancers.
Aging, Habitual Exercise, and Dynamic Arterial Compliance
Authors: Hirofumi Tanaka, Frank A. Dinenno, Kevin D. Monahan, Christopher M. Clevenger, Christopher A. DeSouza, Douglas R. Seals
Journal: Circulation (2000)

Background —A reduction in compliance of the large-sized cardiothoracic (central) arteries is an independent risk factor for the development of cardiovascular disease with advancing age. Methods and Results —We determined the role of habitual exercise on the age-related decrease in central arterial compliance by using both cross-sectional and interventional approaches. First, we studied 151 healthy men aged 18 to 77 years: 54 were sedentary, 45 were recreationally active, and 53 were endurance exercise–trained. Central arterial compliance (simultaneous B-mode ultrasound and arterial applanation tonometry on the common carotid artery) was lower ( P &lt;0.05) in middle-aged and older men than in young men in all 3 groups. There were no significant differences between sedentary and recreationally active men at any age. However, arterial compliance in the endurance-trained middle-aged and older men was 20% to 35% higher than in the 2 less active groups ( P &lt;0.01). As such, age-related differences in central arterial compliance were smaller in the endurance-trained men than in the sedentary and recreationally active men. Second, we studied 20 middle-aged and older (53±2 years) sedentary healthy men before and after a 3-month aerobic exercise intervention (primarily walking). Regular exercise increased central arterial compliance ( P &lt;0.01) to levels similar to those of the middle-aged and older endurance-trained men. These effects were independent of changes in body mass, adiposity, arterial blood pressure, or maximal oxygen consumption. Conclusions —Regular aerobic-endurance exercise attenuates age-related reductions in central arterial compliance and restores levels in previously sedentary healthy middle-aged and older men. This may be one mechanism by which habitual exercise lowers the risk of cardiovascular disease in this population.
Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial
Authors: R. Rosell, U. Gatzemeier, D.C. Betticher, U. Keppler, H.N. Macha, R. Pirker, P. Berthet, J.L. Breau, P. Lianes, M. Nicholson, A. Ardizzoni, A. Chemaissani, J. Bogaerts, G. Gallant
Journal: Annals of Oncology (2002)
SNPs in the coding region of the metastasis-inducing gene MACC1 and clinical outcome in colorectal cancer
Authors: Felicitas Schmid, Susen Burock, Konrad Klockmeier, Peter M Schlag, Ulrike Stein
Journal: Molecular Cancer (2012)

Colorectal cancer is one of the main cancers in the Western world. About 90% of the deaths arise from formation of distant metastasis. The expression of the newly identified gene metastasis associated in colon cancer 1 (MACC1) is a prognostic indicator for colon cancer metastasis. Here, we analyzed for the first time the impact of single nucleotide polymorphisms (SNPs) in the coding region of MACC1 for clinical outcome of colorectal cancer patients. Additionally, we screened met proto-oncogene (Met), the transcriptional target gene of MACC1, for mutations.We sequenced the coding exons of MACC1 in 154 colorectal tumors (stages I, II and III) and the crucial exons of Met in 60 colorectal tumors (stages I, II and III). We analyzed the association of MACC1 polymorphisms with clinical data, including metachronous metastasis, UICC stages, tumor invasion, lymph node metastasis and patients' survival (n = 154, stages I, II and III). Furthermore, we performed biological assays in order to evaluate the functional impact of MACC1 SNPs on the motility of colorectal cancer cells.We genotyped three MACC1 SNPs in the coding region. Thirteen % of the tumors had the genotype cg (rs4721888, L31V), 48% a ct genotype (rs975263, S515L) and 84% a gc or cc genotype (rs3735615, R804T). We found no association of these SNPs with clinicopathological parameters or with patients' survival, when analyzing the entire patients' cohort. An increased risk for a shorter metastasis-free survival of patients with a ct genotype (rs975263) was observed in younger colon cancer patients with stage I or II (P = 0.041, n = 18). In cell culture, MACC1 SNPs did not affect MACC1-induced cell motility and proliferation.In summary, the identification of coding MACC1 SNPs in primary colorectal tumors does not improve the prediction for metastasis formation or for patients' survival compared to MACC1 expression analysis alone. The ct genotype (rs975263) might be associated with a reduced survival for younger colon cancer patients in early stages. However, further studies with larger sample sizes are needed.
Targeting hepatocyte growth factor receptor (Met) positive tumor cells using internalizing nanobody-decorated albumin nanoparticles
Authors: Raimond Heukers, Isil Altintas, Smiriti Raghoenath, Erica De Zan, Richard Pepermans, Rob C. Roovers, Rob Haselberg, Wim E. Hennink, Raymond M. Schiffelers, Robbert J. Kok, Paul M.P. van Bergen en Henegouwen
Journal: Biomaterials (2013)
Occludin is regulated by epidermal growth factor receptor activation in brain endothelial cells and brains of mice with acute liver failure
Authors: Feng Chen, Tomohide Hori, Norifumi Ohashi, Ann-Marie Baine, Christopher B. Eckman, Justin H. Nguyen
Journal: Hepatology (2011)

Mechanisms of brain edema in acute liver failure (ALF) are not completely understood. We recently demonstrated that matrix metalloproteinase 9 (MMP-9) induces significant alterations to occludin in brain endothelial cells in vitro and in brains of mice with experimental ALF (Hepatology 2009;50:1914). In this study we show that MMP-9-induced transactivation of epidermal growth factor receptor (EGFR) and p38 MAPK/NFκB (mitogen-activated protein kinase/nuclear factor-kappa B) signals participate in regulating brain endothelial occludin level. Mouse brain endothelial bEnd3 cells were exposed to MMP-9 or p38 MAPK up-regulation in the presence and absence of EGFR inhibitor, p38 MAPK inhibitor, NFκB inhibitor, and/or appropriate small interfering RNA. Reverse-transcription polymerase chain reaction (RT-PCR) and western blotting were used for messenger RNA and protein expression analyses. Immunohistochemical staining and confocal microscopy were used to demonstrate cellular EGFR activation. Intraperitoneal azoxymethane was use to induce ALF in mice. Brains of comatose ALF mice were processed for histological and biochemical analyses. When bEnd3 cells were exposed to MMP-9, EGFR was significantly transactivated, followed by p38 MAPK activation, I-kappa B alpha (IκBα) degradation, NFκB activation, and suppression of occludin synthesis and expression. Similar EGFR activation and p38 MAPK/NFκB activation were found in the brains of ALF mice, and these changes were attenuated with GM6001 treatment. Conclusion: EGFR activation with p38 MAPK/NFκB signaling contributes to the regulation of tight junction integrity in ALF. EGFR activation may thus play an important role in vasogenic brain edema in ALF. (HEPATOLOGY 2011;)
Evidence-Based Assessment
Authors: John Hunsley, Eric J. Mash
Journal: Annual Review of Clinical Psychology (2007)

Evidence-based assessment (EBA) emphasizes the use of research and theory to inform the selection of assessment targets, the methods and measures used in the assessment, and the assessment process itself. Our review focuses on efforts to develop and promote EBA within clinical psychology. We begin by highlighting some weaknesses in current assessment practices and then present recent efforts to develop EBA guidelines for commonly encountered clinical conditions. Next, we address the need to attend to several critical factors in developing such guidelines, including defining psychometric adequacy, ensuring appropriate attention is paid to the influence of comorbidity and diversity, and disseminating accurate and up-to-date information on EBAs. Examples are provided of how data on incremental validity and clinical utility can inform EBA. Given the central role that assessment should play in evidence-based practice, there is a pressing need for clinically relevant research that can inform EBAs.
Effect of low-dose oral contraceptives on lipoproteins and lipolytic enzymes: Differences between two commonly used preparations
Authors: J.A. Gevers Leuven, L. Havekes, H.A. van der Kooij-Pontier, R.J.H. Starmans, H. Jansen, M.L. Bouwhuis-Hoogerwerf, H.A.Th. de Pagter, L.W. Hessel
Journal: Metabolism (1984)
Monitoring of Natural Killer Cell Immunotherapy Using Noninvasive Imaging Modalities
Authors: Priyanka Jha, Daniel Golovko, Sukhmine Bains, Daniel Hostetter, Reinhard Meier, Michael F. Wendland, Heike E. Daldrup-Link
Journal: Cancer Research (2010)

Cancer immunotherapies can be guided by cellular imaging techniques, which can identify the presence or absence of immune cell accumulation in the tumor tissue in vivo and in real time. This review summarizes various new and evolving imaging techniques employed for tracking and monitoring of adoptive natural killer cell immunotherapies.
Women's health : Life span: conception to adolescence
Authors: N. Craft
Journal: BMJ (1997)

The fragile X syndrome is a cause of mental disability in both males (1/4000 births) and females (1/8000 births). 1 Diagnosis is often delayed into mid-childhood or beyond, and in some families it is never made.The inheritance pattern is X linked, which means that members of the extended family are at risk of being carriers.These individuals have a right to information and counselling in making their own choices about reproduction.In New South Wales a programme of active case finding has been in place for 10 years. 2 We describe this programme and look at the outcome and possible future directions.