tbuckley/cabot-search huggingface dataset:
1357. Intraperitoneal Therapy of Ovarian Cancer Using an Engineered Measles Virus
Authors: Kah-Whye Peng, Cynthia J TenEyck, Evanthia Galanis, Kimberly R Kalli, Lynn C Hartmann, Stephen J Russell
Journal: Molecular Therapy (2002)

The use of replicating viruses for cancer therapy (virotherapy) holds much promise. We reported previously that the live attenuated Edmonston B vaccine strain of measles virus (MV-Edm) had antineoplastic efficacy against hematological malignancies. In this study, we demonstrate that a recombinant MV-Edm, genetically engineered to express an inert soluble marker peptide (MV-hCEA), is potent against human epithelial ovarian cancer cells in vitro and in vivo. The virus was selectively oncolytic for ovarian tumor cells but caused minimal cytopathic damage on nontransformed ovarian surface epithelium and mesothelium. In contrast to nontransformed cells, the ovarian tumor cells expressed high levels of the measles virus receptor CD46. When injected directly into large established s.c. SKOV3ip.1 human epithelial ovarian xenografts in athymic mice, the virus induced complete regression of 80% of the tumors. i.p. administration of virus enhanced the median survival of mice with advanced i.p. SKOV3ip.1 tumors by >50 days. In addition, we could easily follow the kinetic profile of viral gene expression in the treated mice by determining serum levels of the virally encoded marker peptide (soluble human carcinoembryonic antigen). Trackable recombinant measles viruses warrant further investigation for therapy of ovarian cancer.
37 ACTIVATION OF INTESTINAL FGF15 SIGNALING BY INFLAMMATION LEADS TO CHANGES IN HEPATIC BILE ACID METABOLISM AND A TOXIC BILE PROFILE IN DSS TREATED MICE
Authors: M. Rau, J. Schmitt, B. Stieger, K. Leucht, A. Cee, J.J.G. Marin, M.J. Monte, B. Müllhaupt, G. Rogler, A. Geier
Journal: Journal of Hepatology (2012)
Functional Interaction between BubR1 and Securin in an Anaphase-Promoting Complex/CyclosomeCdc20–Independent Manner
Authors: Hyun-Soo Kim, Yoon-Kyung Jeon, Geun-Hyoung Ha, Hye-Young Park, Yu-Jin Kim, Hyun-Jin Shin, Chang Geun Lee, Doo-Hyun Chung, Chang-Woo Lee
Journal: Cancer Research (2008)

Abstract Activation of the mitotic checkpoint requires the precise timing and spatial organization of mitotic regulatory events, and ensures accurate chromosome segregation. Mitotic checkpoint proteins such as BubR1 and Mad2 bind to Cdc20, and inhibit anaphase-promoting complex/cyclosomeCdc20–mediated securin degradation and the onset of anaphase. BubR1 mediates the proper attachment of microtubules to kinetochores, and links the regulation of chromosome-spindle attachment to mitotic checkpoint signaling. Therefore, disruption of BubR1 activity results in a loss of the checkpoint control, chromosome instability, and/or early onset of malignancy. In this study, we show that BubR1 directly interacts with securin in vitro and in vivo. In addition, the BubR1 interaction contributes to the stability of securin, and there is a significant positive correlation between BubR1 and securin expressions in human cancer. Importantly, BubR1 competes with Cdc20 for binding to securin, and thereby the interaction between BubR1 and securin is greatly increased by the depletion of Cdc20. Our findings may identify a novel regulation of BubR1 that can generate an additional anaphase-inhibitory signal through the Cdc20-independent interaction of BubR1 with securin. [Cancer Res 2009;69(1):27–36]
Well-Being and Symptoms in Relation to Insulin Therapy in Type 2 Diabetes
Authors: Jeroen J J De Sonnaville, Frank J Snoek, Louisa P Colly, Walter Devillé, Dirk Wijkel, Robert J Heine
Journal: Diabetes Care (1998)

OBJECTIVE To determine the influence of insulin therapy on physical symptoms, emotional and general well-being, and treatment satisfaction in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A descriptive prospective 2-year cohort study was performed. The study population consisted of 272 eligible NIDDM patients of Dutch origin ≥ 40 years of age who had a known diabetes duration ≥ 3 months and who were treated with diet and/or oral hypoglycemic agents. Dependent variables in the logistic regression analysis were scores on the Type 2 Diabetes Symptom Checklist, the Profile of Mood States, and questions regarding general well-being and treatment satisfaction. Potential determinants under study were age, sex, known diabetes duration, insulin dose, duration of insulin therapy, comorbidity, baseline and change in metabolic parameters and cardiovascular risk factors. RESULTS A baseline and 2-year questionnaire were available for 157 patients (58%). During follow-up, 39 of them (24.8%) were treated with insulin. Initiation of insulin therapy was significantly associated with improved glycemic control (mean HbA1c 8.2 ± 1.4 [SD] to 7.4 ± 0.9%, P = 0.001) and weight gain (BMI 27.1 ± 3.9 to 28.6 ± 4.3 kg/m2 P = 0.000). Of all symptom and well-being scores, only feelings of emotional fatigue worsened significantly, although modestly (0.4–1.7 on a scale of 0.0–10.0, P = 0.02). Although diabetes management with insulin was experienced as more demanding (P = 0.04), treatment satisfaction scores were not adversely influenced (2.5–1.9, P = 0.39). High insulin doses were significantly and independently associated with high symptom scores (total score, hypoglycemic score) and with low mood (displeasure score, anger, tension, emotional fatigue) and perceived state of health. CONCLUSIONS Initiation of insulin therapy in type 2 diabetes improves glycemic control effectively, has little influence on physical and psychological well-being dimensions, and does not affect treatment satisfaction.
Cowden Syndrome-Related Mutations in <i>PTEN</i> Associate with Enhanced Proteasome Activity
Authors: Xin He, Nicholas Arrotta, Deepa Radhakrishnan, Yu Wang, Todd Romigh, Charis Eng
Journal: Cancer Research (2013)

Germline mutations in PTEN have been described in a spectrum of syndromes that are collectively known as PTEN hamartoma tumor syndrome (PHTS). In addition to being mutated in the germline in PHTS, somatic loss-of-function PTEN mutations are seen in a wide range of sporadic human tumors. Here, we show evidence of upregulated proteasome activity in PHTS-derived lymphoblasts, Pten knock-in mice and cell lines expressing missense and nonsense PTEN mutations. Notably, elevated nuclear proteasome activity occurred in cells expressing the nuclear mislocalized PTEN-K62R mutant, whereas elevated cytosolic proteasome activity was observed in cells expressing the cytosolic-predominant mutant PTEN (M3M4 and C136R). Treatment with proteasome inhibitor MG-132 was able to restore both nonsense and missense mutant PTEN protein levels in vitro. PHTS patients with destabilizing PTEN mutations and proteasome hyperactivity are more susceptible to develop neurologic symptoms such as mental retardation and autism than mutation-positive patients with normal proteasome activity. A detailed molecular and functional analysis shows that PTEN mutants most likely cause proteasome hyperactivity via 2 different mechanisms, namely, induction of proteotoxic stress and loss of protein phosphatase activity. These results provide novel insights into the cellular functions of PTEN and reveal molecular mechanisms whereby PTEN mutations increase proteasome activity and lead to neurologic phenotypes.
Predictors of Survival in Never-Smokers with Non–Small Cell Lung Cancer: A Large-Scale, Two-Phase Genetic Study
Authors: Xia Pu, Yuanqing Ye, Margaret R. Spitz, Liang Wang, Jian Gu, Scott M. Lippman, Michelle A.T. Hildebrandt, Waun Ki Hong, John D. Minna, Jack A. Roth, Ping Yang, Xifeng Wu
Journal: Clinical Cancer Research (2012)

Lung cancer in never-smokers (LCINS) is increasingly recognized as a distinct disease from that in ever-smokers owing to substantial differences in etiology, clinical characteristics, and prognosis. Therefore, we aimed to identify prognostic markers specific for LCINS.First, 11,930 single-nucleotide polymorphisms (SNP) in 904 inflammation-related genes were genotyped, and their associations with overall survival in 411 patients with LCINS at MD Anderson Cancer Center were analyzed. Next, validation of the top 27 SNPs in 311 patients with LCINS at Mayo Clinic was conducted.Three SNPs (IL17RA:rs879576, BMP8A:rs698141, and STY:rs290229) were validated (P < 0.05), and two SNPs (CD74:rs1056400 and CD38:rs10805347) reached borderline significance (P = 0.08) in the Mayo Clinic population. We validated a survival-tree created in the MD Anderson population exploring gene-gene interactions in the Mayo Clinic population. This survival-tree stratified patients into subsets with significantly different risks of death: patients with the rs1056400_GG/rs698141_GA + AA genotype had significantly higher risk of death in both MD Anderson (HR:2.32, 95%CI: 1.58-3.41) and Mayo (HR:1.97, 95%CI: 1.11-3.50) populations compared with those with the rs1056400_GG/rs698141_GG or rs1056400_GA + AA genotype. We evaluated these five SNPs in 996 ever-smokers from MD Anderson and found no significant associations.Our study provides strong evidence that inflammation-related genetic variations can affect clinical outcomes in LCINS, which may lead to significant biologic insight into these outcomes.
Effects of routine individual feedback over nine years on general practitioners' requests for tests
Authors: R. A G Winkens, P. Pop, R. P T M Grol, A. M A Bugter-Maessen, A. D M Kester, G. H M I Beusmans, J A. Knottnerus
Journal: BMJ (1996)

Feedback to general practitioners about the diagnostic tests they request reduces the number of requests.1 This effect disappears, however, soon after feedback is stopped.2 Most studies have been short, so data on the long term effects of feedback are lacking.3

The Diagnostic Coordinating Centre Maastricht has provided feedback continuously since 1985, resulting in a more rational use of tests and fewer requests.4 5 We report the effects of nine years of feedback. We also investigated its effects on requests for tests that were not advised but had a recommended alternative. We expected the effects to be greatest for such requests. We thought that if general practitioners had a choice of alternative tests they might be more willing to follow recommendations.

The diagnostic coordinating centre coordinates all requests from the 85 general practitioners in the Maastricht region. Written …
Fluoxetine Inhibits Multidrug Resistance Extrusion Pumps and Enhances Responses to Chemotherapy in Syngeneic and in Human Xenograft Mouse Tumor Models
Authors: Dan Peer, Yaron Dekel, Dina Melikhov, Rimona Margalit
Journal: Cancer Research (2004)

Abstract Multidrug resistance (MDR) operated by extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins, is a major reason for poor responses and failures in cancer chemotherapy. MDR modulators (chemosensitizers) were found among drugs approved for noncancer indications and their derivatives. Yet toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Among newly designed chemosensitizers, some still suffer from toxicity and adverse effects, whereas others progressed to clinical trials. Diversities among tumors and among MDR pumps indicate a need for several clinically approved MDR modulators. Here we report for the first time that fluoxetine (Prozac), the well-known antidepressant, is a highly effective chemosensitizer. In vitro, fluoxetine enhanced (10- to 100-fold) cytotoxicity of anticancer drugs (doxorubicin, mitomycin C, vinblastine, and paclitaxel) in drug-resistant but not in drug-sensitive cells (5 and 3 lines, respectively). Fluoxetine increased drug accumulation within MDR-cells and inhibited drug efflux from those cells. In vivo, fluoxetine enhanced doxorubicin accumulation within tumors (12-fold) with unaltered pharmacokinetics. In four resistant mouse tumor models of both syngeneic and human xenograft, combination treatment of fluoxetine and doxorubicin generated substantial (P &amp;lt; 0.001) improvements in tumor responses and in survivals (2- to 3-fold). Moreover, fluoxetine reversed MDR at doses that are well below its human safety limits, free of the severe dose-related toxicity, adverse effects, and poor solubility that are obstacles to other chemosensitizers. This low-dose range, together with the findings reported here, indicate that fluoxetine has a high potential to join the arsenal of MDR reversal agents that may reach the clinic.
The Mitochondrial Chaperone TRAP1 Promotes Neoplastic Growth by Inhibiting Succinate Dehydrogenase
Authors: Marco Sciacovelli, Giulia Guzzo, Virginia Morello, Christian Frezza, Liang Zheng, Nazarena Nannini, Fiorella Calabrese, Gabriella Laudiero, Franca Esposito, Matteo Landriscina, Paola Defilippi, Paolo Bernardi, Andrea Rasola
Journal: Cell Metabolism (2013)
Changes in peak flow, symptom score, and the use of medications during acute exacerbations of asthma.
Authors: M Chan-Yeung, J H Chang, J Manfreda, A Ferguson, A Becker
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Changes in symptom score and peak expiratory flow (PEF) and the use of medications during the first acute exacerbation of asthma were studied in 41 patients and matched controls who took part in a panel study. An acute exacerbation was defined as the presence of at least one of the following: any unscheduled physician visit, visit to an emergency room, or hospitalization for treatment of asthma; a decrease in PEF by 30% from the patient's best reading; an increase in asthma symptoms during the day and night for over 48 h and not responding to usual medications; and the commencement or doubling of the dose of oral or inhaled steroids for any of the foregoing reasons. Data from -9 to -7 d before the onset of an acute exacerbation were taken as the baseline data, with which the values of the subsequent 14 d were compared. Significant increases in symptoms occurred before a significant reduction in PEF. None of the patients had a decrease of more than 30% in PEF before the onset of symptoms. Daily variation in PEF was not significantly increased from the baseline. Our results suggest that PEF monitoring is not as sensitive as a symptom diary for revealing acute exacerbations of asthma, and that a 30% decrease in PEF is too stringent a criterion for defining an acute exacerbation.
TSLP: An Epithelial Cell Cytokine that Regulates T Cell Differentiation by Conditioning Dendritic Cell Maturation
Authors: Yong-Jun Liu, Vassili Soumelis, Norihiko Watanabe, Tomoki Ito, Yui-Hsi Wang, Rene de Waal Malefyt, Miyuki Omori, Baohua Zhou, Steven F. Ziegler
Journal: Annual Review of Immunology (2006)

Dendritic cells (DCs) are professional antigen-presenting cells that have the ability to sense infection and tissue stress, sample and present antigen to T lymphocytes, and induce different forms of immunity and tolerance. The functional versatility of DCs depends on their remarkable ability to translate collectively the information from both the invading microbes and their resident tissue microenvironments and then make an appropriate immune response. Recent progress in understanding TLR biology has illuminated the mechanisms by which DCs link innate and adaptive antimicrobial immune responses. However, how tissue microenvironments shape the function of DCs has remained elusive. Recent studies of TSLP (thymic stromal lymphopoietin), an epithelial cell-derived cytokine that strongly activates DCs, provide evidence at a molecular level that epithelial cells/tissue microenvironments directly communicate with DCs. We review recent progress on how TSLP expressed within thymus and peripheral lymphoid and nonlymphoid tissues regulates DC-mediated central tolerance, peripheral T cell homeostasis, and inflammatory Th2 responses.
Defining the Cooperative Genetic Changes That Temporally Drive Alveolar Rhabdomyosarcoma
Authors: Sarasija Naini, Katherine T. Etheridge, Stacey J. Adam, Stephen J. Qualman, Rex C. Bentley, Christopher M. Counter, Corinne M. Linardic
Journal: Cancer Research (2008)

Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence. Despite advances in therapy, patients with a histologic variant of RMS known as alveolar (aRMS) have a 5-year survival rate of &amp;lt;30%. aRMS tissues exhibit a number of genetic changes, including loss-of-function of the p53 and Rb tumor suppressor pathways, amplification of MYCN, stabilization of telomeres, and most characteristically, reciprocal translocation of loci involving the PAX and FKHR genes, generating the PAX7-FKHR or PAX3-FKHR fusion proteins. We previously showed that PAX3-FKHR expression in primary human myoblasts, cells that can give rise to RMS, cooperated with loss of p16INK4A to promote extended proliferation. To better understand the genetic events required for aRMS formation, we then stepwise converted these cells to their transformed counterpart. PAX3-FKHR, the catalytic unit of telomerase hTERT, and MycN, in cooperation with down-regulation of p16INK4A/p14ARF expression, were necessary and sufficient to convert normal human myoblasts into tumorigenic cells that gave rise to aRMS tumors. However, the order of expression of these transgenes was critical, as only those cells expressing PAX3-FKHR early could form tumors. We therefore suggest that the translocation of PAX3 to FKHR drives proliferation of myoblasts, and a selection for loss of p16INK4A/p14ARF. These early steps, coupled with MycN amplification and telomere stabilization, then drive the cells to a fully tumorigenic state. [Cancer Res 2008;68(23):9583–8]
Serological diagnosis of bullous pemphigoid (BP): comparison of the sensitivity of indirect immunofluorescence on salt-split to immunoblotting
Authors: P. MACHADO, HELENE MICHALAKI, PASCALE ROCHE, MARTINE GAUCHERAND, J. THIVOLET, J-F. NICOLAS
Journal: British Journal of Dermatology (1992)

Specialized immunological assays are required for the accurate diagnosis of bullous dermatoses such as bullous pemphigoid (BP), epidermolysis bullous acquisita and bullous lupus erythematosus. The aim of this study was to analyse and compare the sensitivity of indirect immunofluorescence (IF) on salt-split skin and immunoblotting for the detection of circulating autoantibodies in BP. Of the BP patients selected for the study, 74/79 (94%) had circulating autoantibodies detected by at least one of the two methods. Both methods had comparable sensitivity and detected BP-specific autoantibodies in 82–85% of the patients. Because 20% of the patients were found to be positive by only one of the methods, both methods should be used in the diagnosis of BP. Indirect IF on salt-split skin is easier to perform and is preferable in routine analysis, but Western blotting may be used as a complementary assay with sera showing no reactivity on salt-split skin.
Preoperative Bone Scans
Authors: N. David Charkes
Journal: JAMA (1975)

Strontium nitrate Sr 87m bone scans were made preoperatively in a group of women with suspected breast cancer, 35 of whom subsequently underwent radical mastectomy. In 3 of the 35 (9%), the scans were abnormal despite the absence of clinical or roentgenographic evidence of metastatic disease. All three patients had extensive axillary lymph node involvement by tumor, and went on to have additional bone metastases, from which one died. Roentgenograms failed to detect the metastases in all three. Occult bone metastases account in part for the failure of radical mastectomy to cure some patients with breast cancer. It is recommended that all candidates for radical mastectomy have a preoperative bone scan. (<i>JAMA</i>233:516-518, 1975)
Triple Therapy in Type 2 Diabetes
Authors: Julio Rosenstock, Danny Sugimoto, Poul Strange, John A. Stewart, Erika Soltes-Rak, George Dailey
Journal: Diabetes Care (2006)

OBJECTIVE—To evaluate the efficacy and safety of add-on insulin glargine versus rosiglitazone in insulin-naïve patients with type 2 diabetes inadequately controlled on dual oral therapy with sulfonylurea plus metformin. RESEARCH DESIGN AND METHODS—In this 24-week multicenter, randomized, open-label, parallel trial, 217 patients (HbA1c [A1C] 7.5–11%, BMI &amp;gt;25 kg/m2) on ≥50% of maximal-dose sulfonylurea and metformin received add-on insulin glargine 10 units/day or rosiglitazone 4 mg/day. Insulin glargine was forced-titrated to target fasting plasma glucose (FPG) ≤5.5–6.7 mmol/l (≤100–120 mg/dl), and rosiglitazone was increased to 8 mg/day any time after 6 weeks if FPG was &amp;gt;5.5 mmol/l. RESULTS—A1C improvements from baseline were similar in both groups (−1.7 vs. −1.5% for insulin glargine vs. rosiglitazone, respectively); however, when baseline A1C was &amp;gt;9.5%, the reduction of A1C with insulin glargine was greater than with rosiglitazone (P &amp;lt; 0.05). Insulin glargine yielded better FPG values than rosiglitazone (−3.6 ± 0.23 vs. −2.6 ± 0.22 mmol/l; P = 0.001). Insulin glargine final dose per day was 38 ± 26 IU vs. 7.1 ± 2 mg for rosiglitazone. Confirmed hypoglycemic events at plasma glucose &amp;lt;3.9 mmol/l (&amp;lt;70 mg/dl) were slightly greater for the insulin glargine group (n = 57) than for the rosiglitazone group (n = 47) (P = 0.0528). The calculated average rate per patient-year of a confirmed hypoglycemic event (&amp;lt;70 mg/dl), after adjusting for BMI, was 7.7 (95% CI 5.4–10.8) and 3.4 (2.3–5.0) for the insulin glargine and rosiglitazone groups, respectively (P = 0.0073). More patients in the insulin glargine group had confirmed nocturnal hypoglycemia of &amp;lt;3.9 mmol/l (P = 0.02) and &amp;lt;2.8 mmol/l (P &amp;lt; 0.05) than in the rosiglitazone group. Effects on total cholesterol, LDL cholesterol, and triglyceride levels from baseline to end point with insulin glargine (−4.4, −1.4, and −19.0%, respectively) contrasted with those of rosiglitazone (+10.1, +13.1, and +4.6%, respectively; P &amp;lt; 0.002). HDL cholesterol was unchanged with insulin glargine but increased with rosiglitazone by 4.4% (P &amp;lt; 0.05). Insulin glargine had less weight gain than rosiglitazone (1.6 ± 0.4 vs. 3.0 ± 0.4 kg; P = 0.02), fewer adverse events (7 vs. 29%; P = 0.0001), and no peripheral edema (0 vs. 12.5%). Insulin glargine saved $235/patient over 24 weeks compared with rosiglitazone. CONCLUSIONS—Low-dose insulin glargine combined with a sulfonylurea and metformin resulted in similar A1C improvements except for greater reductions in A1C when baseline was ≥9.5% compared with add-on maximum-dose rosiglitazone. Further, insulin glargine was associated with more hypoglycemia but less weight gain, no edema, and salutary lipid changes at a lower cost of therapy.
Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria
Authors: Yuki Kinjo, Petr Illarionov, José Luis Vela, Bo Pei, Enrico Girardi, Xiangming Li, Yali Li, Masakazu Imamura, Yukihiro Kaneko, Akiko Okawara, Yoshitsugu Miyazaki, Anaximandro Gómez-Velasco, Paul Rogers, Samira Dahesh, Satoshi Uchiyama, Archana Khurana, Kazuyoshi Kawahara, Hasan Yesilkaya, Peter W Andrew, Chi-Huey Wong, Kazuyoshi Kawakami, Victor Nizet, Gurdyal S Besra, Moriya Tsuji, Dirk M Zajonc, Mitchell Kronenberg
Journal: Nature Immunology (2011)
Specific IgE-binding of rHev b 12 is restricted to fruit-allergic patients*1
Authors: H.P. Rihs, F. Rueff, M. Lundberg, P. Rozynek, J. Garcia-Selles, D. Barber, S. Scheurer, R. Alonso, A. Cistero-Bahima, T. Bruning, M. Raulf-Heimsoth
Journal: Journal of Allergy and Clinical Immunology (2004)