tbuckley/cabot-search huggingface dataset:
Urokinase Receptor Promotes Skin Tumor Formation by Preventing Epithelial Cell Activation of Notch1
Authors: Roberta Mazzieri, Giovanni Pietrogrande, Laura Gerasi, Alessandro Gandelli, Piergiuseppe Colombo, Davide Moi, Chiara Brombin, Alessandro Ambrosi, Silvio Danese, Paolo Mignatti, Francesco Blasi, Silvia D'Alessio
Journal: Cancer Research (2015)

The urokinase-type plasminogen activator receptor (uPAR) has a well-established role in cancer progression, but it has been little studied at earlier stages of cancer initiation. Here, we show that uPAR deficiency in the mouse dramatically reduces susceptibility to the classical two-stage protocol of inflammatory skin carcinogenesis. uPAR genetic deficiency decreased papilloma formation and accelerated keratinocyte differentiation, effects mediated by Notch1 hyperactivation. Notably, Notch1 inhibition in uPAR-deficient mice rescued their susceptibility to skin carcinogenesis. Clinically, we found that human differentiated keratoacanthomas expressed low levels of uPAR and high levels of activated Notch1, with opposite effects in proliferating tumors, confirming the relevance of the observations in mice. Furthermore, we found that TACE-dependent activation of Notch1 in basal kerantinocytes was modulated by uPAR. Mechanistically, uPAR sequestered TACE within lipid rafts to prevent Notch1 activation, thereby promoting cell proliferation and tumor formation. Given that uPAR signaling is nonessential for normal epidermal homeostasis, our results argue that uPAR may present a promising disease-specific target for preventing skin cancer development.
Controversies in the modern management of hydrosalpinx
Authors: M. Aboulghar
Journal: Human Reproduction Update (1998)

The management of hydrosalpinx is a difficult clinical problem. Surgical treatment includes fimbrioplasty for patients with fimbrial obstruction and salpingostomy to fashion a stoma in the distal Fallopian tube in patients with a damaged fimbrial end. Surgery is only suitable for a small thin-walled hydrosalpinx with healthy mucosa. These operations can be performed via laparoscopy or open microsurgery. The proper selection of patients for surgical treatment and of the type of surgical technique are essential to achieve good results. The results of open microsurgery and laparoscopic surgery are summarized. In general, the prognosis of surgery is poor; however, in well selected cases, good results can be achieved by an experienced surgeon. In-vitro fertilization (IVF) is the main line of treatment for infertility caused by hydrosalpinx. In 1991, our group was the first to report on fluid accumulation in the uterine cavity before embryo transfer as a possible hindrance for implantation. Later, several publications reported an associated between patients with hydrosalpinx and a reduced pregnancy rate when treated by IVF. The cause of a low pregnancy rate could be due to mechanical, chemical or toxic effects of the tubal fluid on the endometrium preventing implantation. All these mechanisms are reviewed in detail. The literature is controversial concerning the effect of transvaginal aspiration of hydrosalpinx on the outcome of IVF. Several reports suggest that surgical correction of the hydrosalpinx may improve the outcome of IVF. Further studies are required to verify this assumption and to find out the most suitable surgical procedure and if there is a sub-group of patients who could benefit most from salpingectomy. Keywords:fimbrioplasty/hydrosalpinx/pregnancy rate/salpingectomy/salpingostomy
Activities and Accomplishments of the Cancer and Leukemia Group B Genitourinary Committee
Authors: Eric J. Small, Susan Halabi, Phillip Kantoff, Anthony D'Amico, Walter Stadler, W. Kevin Kelley, James Mohler, Dean Bajorin, Nicholas J. Vogelzang
Journal: Clinical Cancer Research (2006)

Abstract The Cancer and Leukemia Group B Genitourinary (GU) Committee has developed a multidisciplinary approach to treatment of GU cancer and has integrated correlative science research into the major research themes of the GU Committee. In localized prostate cancer, trials have evaluated novel approaches in radiation therapy. For patients with recurrence after local therapy, a trial evaluating local recurrence with salvage prostatectomy and a study of systemic therapy with “peripheral androgen blockade” were undertaken. Major contributions have been made in developing and testing therapeutics for advanced, androgen-independent prostate cancer (ketoconazole, suramin, estramustine/docetaxel, and docetaxel/bevacizumab), and in developing predictive markers and algorithms to assess prognosis in these patients. Contributions in kidney cancer have included the development of novel trial methodology, such as the randomized discontinuation trial design, and the testing of antiangiogenics. In addition to these areas, future work of the committee will include further development of therapy for earlier-stage prostate cancer patients and bladder cancer patients.
Waldenström's macroglobulinemia resulting from localized gastric lymphoplasmacytoid lymphoma
Authors: Jessica A. Rosenthal, Walter J. Curran, Stephen J. Schuster
Journal: American Journal of Hematology (1998)

A patient with a high level serum monoclonal IgM lambda paraprotein (3,850 mg/dL) was found to have a mass infiltrating the gastric mucosa. Gastric biopsy with immunohistochemical stains showed a B-cell lymphoplasmacytoid infiltrate expressing IgM lambda, consistent with Waldenström's macroglobulinemia. The patient's response to gastric radiation indicated that the primary source of the macroglobulinemia was the stomach. This is an extremely rare presentation, with only six other reported cases of this entity with gastric involvement.
Reversibility of <i>PRKAG2</i> Glycogen-Storage Cardiomyopathy and Electrophysiological Manifestations
Authors: Cordula M. Wolf, Michael Arad, Ferhaan Ahmad, Atsushi Sanbe, Scott A. Bernstein, Okan Toka, Tetsuo Konno, Gregory Morley, Jeffrey Robbins, J.G. Seidman, Christine E. Seidman, Charles I. Berul
Journal: Circulation (2007)

Background— PRKAG2 mutations cause glycogen-storage cardiomyopathy, ventricular preexcitation, and conduction system degeneration. A genetic approach that utilizes a binary inducible transgenic system was used to investigate the disease mechanism and to assess preventability and reversibility of disease features in a mouse model of glycogen-storage cardiomyopathy. Methods and Results— Transgenic (Tg) mice expressing a human N488I PRKAG2 cDNA under control of the tetracycline-repressible α-myosin heavy chain promoter underwent echocardiography, ECG, and in vivo electrophysiology studies. Transgene suppression by tetracycline administration caused a reduction in cardiac glycogen content and was initiated either prenatally (Tg OFF(E-8 weeks) ) or at different time points during life (Tg OFF(4–16 weeks) , Tg OFF(8–20 weeks) , and Tg OFF(&gt;20 weeks) ). One group never received tetracycline, expressing transgene throughout life (Tg ON ). Tg ON mice developed cardiac hypertrophy followed by dilatation, ventricular preexcitation involving multiple accessory pathways, and conduction system disease, including sinus and atrioventricular node dysfunction. Conclusions— Using an externally modifiable transgenic system, cardiomyopathy, cardiac dysfunction, and electrophysiological disorders were demonstrated to be reversible processes in PRKAG2 disease. Transgene suppression during early postnatal development prevented the development of accessory electrical pathways but not cardiomyopathy or conduction system degeneration. Taken together, these data provide insight into mechanisms of cardiac PRKAG2 disease and suggest that glycogen-storage cardiomyopathy can be modulated by lowering glycogen content in the heart.
Unique CD14+ intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis
Authors: Nobuhiko Kamada, Tadakazu Hisamatsu, Susumu Okamoto, Hiroshi Chinen, Taku Kobayashi, Toshiro Sato, Atsushi Sakuraba, Mina T. Kitazume, Akira Sugita, Kazutaka Koganei, Kiyoko S. Akagawa, Toshifumi Hibi
Journal: Journal of Clinical Investigation (2008)

Intestinal macrophages play a central role in regulation of immune responses against commensal bacteria. In general, intestinal macrophages lack the expression of innate-immune receptor CD14 and do not produce proinflammatory cytokines against commensal bacteria. In this study, we identified what we believe to be a unique macrophage subset in human intestine. This subset expressed both macrophage (CD14, CD33, CD68) and DC markers (CD205, CD209) and produced larger amounts of proinflammatory cytokines, such as IL-23, TNF-α, and IL-6, than typical intestinal resident macrophages (CD14–CD33+ macrophages). In patients with Crohn disease (CD), the number of these CD14+ macrophages were significantly increased compared with normal control subjects. In addition to increased numbers of cells, these cells also produced larger amounts of IL-23 and TNF-α compared with those in normal controls or patients with ulcerative colitis. In addition, the CD14+ macrophages contributed to IFN-γ production rather than IL-17 production by lamina propria mononuclear cells (LPMCs) dependent on IL-23 and TNF-α. Furthermore, the IFN-γ produced by LPMCs triggered further abnormal macrophage differentiation with an IL-23–hyperproducing phenotype. Collectively, these data suggest that this IL-23/IFN-γ–positive feedback loop induced by abnormal intestinal macrophages contributes to the pathogenesis of chronic intestinal inflammation in patients with CD.
Tissue distribution and anti-inflammatory activity of corticosteroids incorporated in lipid emulsion.
Authors: Y Mizushima, T Hamano, K Yokoyama
Journal: Annals of the Rheumatic Diseases (1982)

Dexamethasone palmitate was incorporated into a lipid emulsion (Intralipid, Intralipos) and was injected into rats, and its distribution in the organs and tissues and its anti-inflammatory effects were compared with those of free dexamethasone disodium phosphate. The distribution patterns of [3H] dexamethasone were markedly different between the 2 preparations in 3 hours after intravenous administration. Dexamethasone palmitate given as a lipid emulsion showed a much higher concentration in the blood, spleen, and inflamed tissues (carrageenan oedema), whereas dexamethasone sodium phosphate had a high concentration in the muscles. The anti-inflammatory activity of both preparations given intravenously was evaluated by using the preformed carrageenan granuloma pouch method. The anti-inflammatory activity of lipid emulsion dexamethasone was 5.6 times as potent as an equivalent amount of free dexamethasone. These results may indicate that corticosteroids which are incorporated in lipid emulsions are taken up by the reticuloendothelial system and some inflammatory cells much more than are free corticosteroids; thus they have a stronger anti-inflammatory activity. The clinical use of lipid emulsion corticosteroids for certain types of diseases is suggested.
Architecture and Activity-Mediated Refinement of Axonal Projections from a Mosaic of Genetically Identified Retinal Ganglion Cells
Authors: Andrew D. Huberman, Mihai Manu, Selina M. Koch, Michael W. Susman, Amanda Brosius Lutz, Erik M. Ullian, Stephen A. Baccus, Ben A. Barres
Journal: Neuron (2008)
Calcium-Dependent Action Potentials Produced by Catecholamines in Guinea Pig Atrial Muscle Fibers Depolarized by Potassium
Authors: ACHILLES J. PAPPANO
Journal: Circulation Research (1970)

Atrial muscle fibers of the guinea pig were depolarized and rendered inexcitable by elevation of [K + ] o to 22 m M . Isoproterenol, epinephrine, and norepinephrine restored propagated action potentials and contractions to atrial cells without changing the resting potential. The peak value of the intracellularly recorded action potentials varied 28 mv for a 10-fold change in [Ca 2+ ] o . Isoproterenol-induced restoration of action potentials was insensitive to large concentrations of tetrodotoxin (3 x 10 -6 M ) but antagonized by Mn 2+ (0.2 m M ). These data supported the proposal that the catecholamines restored excitability by increasing membrane conductance to Ca 2+ . In addition to the catecholamines, the divalent cations Ba 2+ , Sr 2+ , and Ca 2+ restored action potentials to atrial muscle fibers depolarized by elevated K + . The effectiveness of the divalent ions in allowing action potentials was inversely related to the estimated hydrated ionic radii. Like the action potentials observed in the presence of isoproterenol, those permitted by Ba 2+ , Sr 2+ , and Ca 2+ were prevented by Mn 2+ but insensitive to blockade by tetrodotoxin.
Early detection and intervention evaluation for people at risk of psychosis: multisite randomised controlled trial
Authors: A. P. Morrison, P. French, S. L. K. Stewart, M. Birchwood, D. Fowler, A. I. Gumley, P. B. Jones, R. P. Bentall, S. W. Lewis, G. K. Murray, P. Patterson, K. Brunet, J. Conroy, S. Parker, T. Reilly, R. Byrne, L. M. Davies, G. Dunn
Journal: BMJ (2012)

<b>Objective</b> To determine whether cognitive therapy is effective in preventing the worsening of emerging psychotic symptoms experienced by help seeking young people deemed to be at risk for serious conditions such as schizophrenia. <b>Design</b> Multisite single blind randomised controlled trial. <b>Setting</b> Diverse services at five UK sites. <b>Participants</b> 288 participants aged 14-35 years (mean 20.74, SD 4.34 years) at high risk of psychosis: 144 were assigned to cognitive therapy plus monitoring of mental state and 144 to monitoring of mental state only. Participants were followed-up for a minimum of 12 months and a maximum of 24 months. <b>Intervention</b> Cognitive therapy (up to 26 (mean 9.1) sessions over six months) plus monitoring of mental state compared with monitoring of mental state only. <b>Main outcome measures</b> Primary outcome was scores on the comprehensive assessment of at risk mental states (CAARMS), which provides a dichotomous transition to psychosis score and ordinal scores for severity of psychotic symptoms and distress. Secondary outcomes included emotional dysfunction and quality of life. <b>Results</b> Transition to psychosis based on intention to treat was analysed using discrete time survival models. Overall, the prevalence of transition was lower than expected (23/288; 8%), with no significant difference between the two groups (proportional odds ratio 0.73, 95% confidence interval 0.32 to 1.68). Changes in severity of symptoms and distress, as well as secondary outcomes, were analysed using random effects regression (analysis of covariance) adjusted for site and baseline symptoms. Distress from psychotic symptoms did not differ (estimated difference at 12 months −3.00, 95% confidence interval −6.95 to 0.94) but their severity was significantly reduced in the group assigned to cognitive therapy (estimated between group effect size at 12 months −3.67, −6.71 to −0.64, P=0.018). <b>Conclusions</b> Cognitive therapy plus monitoring did not significantly reduce transition to psychosis or symptom related distress but reduced the severity of psychotic symptoms in young people at high risk. Most participants in both groups improved over time. The results have important implications for the at risk mental state concept. <b>Trial registration</b> Current Controlled Trials ISRCTN56283883.
Molecular Basis of Colorectal Cancer
Authors: Sanford D. Markowitz, Monica M. Bertagnolli
Journal: New England Journal of Medicine (2009)

This review gives an account of recent advances in our knowledge of the molecular mechanisms in colorectal cancer. Genetic changes in the germ line, combined with somatic mutations, occur in familial syndromes of colorectal cancer, whereas somatic mutations are the outstanding feature of sporadic colorectal cancer. Genetic changes drive the progression from adenoma to carcinoma and probably influence individual susceptibility and response to treatment.
Dietary antioxidants and asthma in adults
Authors: B D Patel
Journal: Thorax (2006)

Several antioxidant nutrients have been reported to be inversely associated with asthma. A study was undertaken to assess the independent associations of these nutrients with asthma in adults.A nested case-control study was performed in 515 adults with physician diagnosed asthma and 515 matched controls using dietary data obtained from 7 day food diaries. The main outcome measures were physician diagnosed asthma and current symptomatic asthma (diagnosed asthma and self-reported wheeze within the previous 12 months).Cases were similar to controls in age, sex, social class, and daily energy intake but had a lower median intake of fruit (132.1 v 149.1 g/day, p< or =0.05). 51.5% of the population reported zero consumption of citrus fruit; relative to these individuals, people who consumed >46.3 g/day had a reduced risk of diagnosed and symptomatic asthma (OR adjusted for potential confounders 0.59 (95% CI 0.43 to 0.82) and 0.51 (95% CI 0.33 to 0.79), respectively). In nutrient analysis, dietary vitamin C and manganese were inversely and independently associated with symptomatic asthma (adjusted OR per quintile increase 0.88 (95% CI 0.77 to 1.00) for vitamin C and 0.85 (95% CI 0.74 to 0.98) for manganese), but only manganese was independently associated with diagnosed asthma (OR 0.86 (95% CI 0.77 to 0.95)). Adjusted plasma levels of vitamin C were significantly lower in symptomatic cases than in controls (54.3 v 58.2 micromol/l, p = 0.003).Symptomatic asthma in adults is associated with a low dietary intake of fruit, the antioxidant nutrients vitamin C and manganese, and low plasma vitamin C levels. These findings suggest that diet may be a potentially modifiable risk factor for the development of asthma.
Feeling rested predicts good health in subjects with and without chronic musculoskeletal pain
Authors: Susann Arvidsson, Barbro Arvidsson, Bengt Fridlund, Stefan Bergman
Journal: Annals of the Rheumatic Diseases (2008)

Background: Musculoskeletal pain is a public health problem and a common cause for people to seek health care. It has also been shown that people with musculoskeletal pain estimates their health-re ...
Induction of a virus-specific effector–memory CD4+ T cell response by attenuated SIV infection
Authors: Marie-Claire Gauduin, Yi Yu, Amy Barabasz, Angela Carville, Mike Piatak, Jeffrey D. Lifson, Ronald C. Desrosiers, R. Paul Johnson
Journal: The Journal of Experimental Medicine (2006)

We investigated simian immunodeficiency virus (SIV)-specific CD4+ T cell responses in rhesus macaques chronically infected with attenuated or pathogenic SIV strains. Analysis of SIVΔnef-infected animals revealed a relatively high frequency of SIV-specific CD4+ T cells representing 4–10% of all CD4+ T lymphocytes directed against multiple SIV proteins. Gag-specific CD4+ T cells in wild-type SIV-infected animals were 5–10-fold lower in frequency and inversely correlated with the level of plasma viremia. SIV-specific CD4+ cells from SIVΔnef animals were predominantly CD27−CD28−CD45RAlowCCR7−CCR5−, consistent with an effector–memory subset, and included a fully differentiated CD45RA+CCR7− subpopulation. In contrast, SIV-specific CD4+ T cells from SIV-infected animals were mostly CD27+CD28+CD45RA−CCR7+CCR5+, consistent with an early central memory phenotype. The CD45RA+CCR7−CD4+ subset from SIVΔnef animals was highly enriched for effector CD4+ T cells, as indicated by the perforin expression and up-regulation of the lysosomal membrane protein CD107a after SIV Gag stimulation. SIV-specific CD4+ T cells in attenuated SIV-infected animals were increased in frequency in bronchioalveolar lavage and decreased in lymph nodes, consistent with an effector–memory T cell population. The ability of SIVΔnef to induce a high frequency virus-specific CD4+ T cell response with direct effector function may play a key role in protective immunity produced by vaccination with attenuated SIV strains.
miRNA Expression Profiling Enables Risk Stratification in Archived and Fresh Neuroblastoma Tumor Samples
Authors: Katleen De Preter, Pieter Mestdagh, Joëlle Vermeulen, Fjoralba Zeka, Arlene Naranjo, Isabella Bray, Victoria Castel, Caifu Chen, Elzbieta Drozynska, Angelika Eggert, Michael D. Hogarty, Ewa Iżycka-Swieszewska, Wendy B. London, Rosa Noguera, Marta Piqueras, Kenneth Bryan, Benjamin Schowe, Peter van Sluis, Jan J. Molenaar, Alexander Schramm, Johannes H. Schulte, Raymond L. Stallings, Rogier Versteeg, Geneviève Laureys, Nadine Van Roy, Frank Speleman, Jo Vandesompele
Journal: Clinical Cancer Research (2011)

More accurate assessment of prognosis is important to further improve the choice of risk-related therapy in neuroblastoma (NB) patients. In this study, we aimed to establish and validate a prognostic miRNA signature for children with NB and tested it in both fresh frozen and archived formalin-fixed paraffin-embedded (FFPE) samples.Four hundred-thirty human mature miRNAs were profiled in two patient subgroups with maximally divergent clinical courses. Univariate logistic regression analysis was used to select miRNAs correlating with NB patient survival. A 25-miRNA gene signature was built using 51 training samples, tested on 179 test samples, and validated on an independent set of 304 fresh frozen tumor samples and 75 archived FFPE samples.The 25-miRNA signature significantly discriminates the test patients with respect to progression-free and overall survival (P < 0.0001), both in the overall population and in the cohort of high-risk patients. Multivariate analysis indicates that the miRNA signature is an independent predictor of patient survival after controlling for current risk factors. The results were confirmed in an external validation set. In contrast to a previously published mRNA classifier, the 25-miRNA signature was found to be predictive for patient survival in a set of 75 FFPE neuroblastoma samples.In this study, we present the largest NB miRNA expression study so far, including more than 500 NB patients. We established and validated a robust miRNA classifier, able to identify a cohort of high-risk NB patients at greater risk for adverse outcome using both fresh frozen and archived material.
Role of Health-Related Quality of Life in Palliative Chemotherapy Treatment Decisions
Authors: S. B. Detmar, M. J. Muller, J. H. Schornagel, L. D.V. Wever, N. K. Aaronson
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To determine the frequency with which health-related quality-of-life (HRQL) considerations lead to modification or discontinuation of palliative chemotherapy, and the association between physicians' ratings of patients' HRQL and such treatment decisions. METHODS: Four consecutive medical consultations of 203 patients receiving outpatient palliative chemotherapy were tape-recorded and the content was analyzed to determine the frequency of and reasons for treatment alterations. Physicians rated their patients' HRQL by using the COOP/WONCA health assessment charts. Data on tumor response and treatment toxicity were obtained from the audiotapes and, when necessary, were confirmed by medical chart audits. RESULTS: Treatment was modified in 54 cases (26%) and discontinued in 40 (20%). The primary reasons for modifying treatment were toxicity (n = 22), HRQL considerations (n = 18), and tumor progression (n = 14). The primary reasons for discontinuation of treatment were tumor progression (n = 23), HRQL considerations (n = 6), and toxicity (n = 3). For eight patients, a combination of tumor progression and HRQL issues resulted in discontinuation of treatment. Treatment decisions were associated significantly with physicians' global ratings of patients' HRQL but not with more specific HRQL domains. In the presence of tumor progression or serious toxicity, HRQL considerations played little or no role in treatment decisions. Furthermore, approximately 70% of patients without evidence of tumor progression or toxicity, but with seriously impaired HRQL, continued to receive their treatment as planned. CONCLUSION: Contrary to previous findings based on physicians' self-report data, HRQL considerations seem to play a relatively minor role in decisions regarding modification or discontinuation of palliative chemotherapy.