tbuckley/cabot-search huggingface dataset:
Risperidone in the treatment of schizophrenia
Authors: S R Marder, R C Meibach
Journal: American Journal of Psychiatry (1994)

The purpose of this study was to investigate the safety and efficacy of risperidone in the treatment of schizophrenic patients and determine its optimal dose.This double-blind study included 388 schizophrenic patients drawn from 20 sites in the United States. Patients were randomly assigned to 8 weeks' treatment with placebo, one of four doses of risperidone (2, 6, 10, or 16 mg), or 20 mg of haloperidol daily.Clinical improvement (20% reduction in total scores on the Positive and Negative Syndrome Scale for Schizophrenia) at the study end point was shown by 35% of the patients receiving 2 mg of risperidone, 57% receiving 6 mg, 40% receiving 10 mg, and 51% receiving 16 mg; and by 30% receiving haloperidol and 22% receiving placebo. Statistically significant differences in clinical improvement were found between 6 and 16 mg of risperidone versus placebo and versus haloperidol. Positive symptom scores were significantly lower after 6, 10, and 16 mg of risperidone and 20 mg of haloperidol than placebo; negative symptom scores, however, were reduced significantly, compared with placebo, only after 6 and 16 mg of risperidone. The incidence of extra-pyramidal side effects (measured by the Extrapyramidal Symptom Rating Scale) was significantly higher in patients treated with 16 mg of risperidone or 20 mg of haloperidol than placebo. The results indicate that the optimal daily dose of risperidone for most schizophrenic patients in this study was 6 mg; this dose was as effective as 16 mg, and the incidence of extrapyramidal symptoms in patients receiving 6 mg of risperidone was no higher than that in patients receiving placebo.Risperidone is a safe antipsychotic that is effective against both the positive and negative symptoms of schizophrenia.
Abstract 20091: Platelets Play Positive and Negative Roles in Abdominal Aortic Aneurysm Formation and Rupture
Authors: A. Phillip Owens, Yacine Boulaftali, Wolfgang Bergmeier, Nigel Mackman
Journal: Circulation (2014)

Objective: It is estimated that >90% of abdominal aortic aneurysm (AAA) patients are on anti-platelet regiments without documented benefit or clinical evaluation. Therefore, we examined the effects of pharmaceutical blockade of platelet activation in either early or late-stage angiotensin II (AngII)-induced AAA formation in a mouse model. Methods and Results: Temporal studies: Male Ldlr-/- mice (8 weeks) fed a saturated fat and cholesterol-enriched diet were infused with AngII (1,000 ng/kg/min) via mini-osmotic pumps for 1, 3, 5, 7, and 28 days. Utilizing in vivo platelet and macrophage labeling agents, it was determined that platelet accumulation (1 day) precedes macrophage accumulation (3 days) in the abdominal aorta. Further, platelet factor 4, a marker of platelet activation, increased time-dependently during the 28 day infusion. Early therapy during AAA formation: Aspirin (30 mg/L via drinking water [ASA]) or diet supplemented with the P2Y12 inhibitor clopidogrel (50 mg/kg/day [Plavix]) was administe...
Abstract 1633: Novel specific- and dual- tryptophan-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO) inhibitors for tumor immunotherapy
Authors: Mario R. Mautino, Richard A. Metz, Firoz Jaipuri, Jesse Waldo, Sanjeev Kumar, Agnieszka Marcinowicz-Flick, Hima Potturi, James T. Adams, Clarissa Van Allen, Nicholas N. Vahanian, Charles J. Link
Journal: Cancer Research (2014)

Abstract Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase is an central immune checkpoint mechanism that controls peripheral immune tolerance and tumor resistance to immune attack. The IDO pathway mediates immunosuppressive effects by expression of the IDO1 gene by tumor cells and/or host antigen presenting cells. Tryptophan depletion and generation of kynurenine generate downstream signals through GCN2, WARS, mTOR and AHR that ultimately lead to anergy of tumor-specific effector CD8+ T cells and activation of Tregs. High expression of IDO correlates negatively with clinical prognosis in patients with a variety of malignancies. Recently, it has been described that tumors can also achieve immunosuppressive effects mediated by tryptophan degradation through expression of TDO, an enzyme functionally and structurally related to IDO1. Therefore, development of small molecules that can prevent tryptophan degradation mediated by IDO1, TDO or both is a prime goal for immunotherapy of cancer. Here we report the discovery of a novel class of imidazoisoindole-based compounds that show potent and selective inhibition of TDO and IDO1, as well as compounds that show potent dual inhibition of both TDO and IDO1. We present structure-activity relationship studies that explore the molecular determinants of potency and specificity for TDO and IDO1. Compounds of these classes were tested for activity in in vitro assays using purified recombinant human and murine TDO and IDO1 as well as in cells expressing IDO1 or TDO. Many of these compounds are 10-200 fold more potent (IC50 &amp;lt; 50 nM) than previously published TDO-specific inhibitors. The pharmacokinetic properties of these compounds are being investigated and lead optimization efforts are in progress. Citation Format: Mario R. Mautino, Richard A. Metz, Firoz Jaipuri, Jesse Waldo, Sanjeev Kumar, Agnieszka Marcinowicz-Flick, Hima Potturi, James T. Adams, Clarissa Van Allen, Nicholas N. Vahanian, Charles J. Link. Novel specific- and dual- tryptophan-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO) inhibitors for tumor immunotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1633. doi:10.1158/1538-7445.AM2014-1633
High indoor microbial levels are associated with reduced Th1-cytokine secretion capacity in infancy
Authors: Juha Pekkanen, Mikko Lappalainen, Anne Hyvärinen, Helena Rintala, Harald Renz, Petra Pfefferle, Aino Nevalainen, Marjut Roponen, Maija-Riitta Hirvonen
Journal: European Respiratory Journal (2011)

Background: In the early stages of life exposure to microbes and their components may affect the maturation and functions of immune system.

Objective: To examine whether the house dust microbial content is associated with cytokine -producing capacity at birth and at age 1 year.

Methods: Production of TNF-α, IFN-γ, IL-5, IL-8 and IL-10 at birth (n=228) and at age 1 year (n=200) following 24h and 48h whole blood stimulation with Staphylococcal enterotoxin B (SEB), lipopolysaccharide and phorbol ester/ionomycin were measured using ELISA. Ergosterol (marker for fungal biomass), muramic acid (marker for Gram-positive bacteria) and 3-hydroxy fatty acids (C10:0-C14:0, marker for Gram-negative bacteria) were analyzed from floor dust. Five single microbial species or groups were determined using quantitative polymerase chain reaction method.

Results: A high total level of Gram-positive bacteria in general or Mycobacterium spp. in house dust was associated with decreased SEB-stimulated IFN-γ production, especially at age 1 year. Total level of analyzed indoor fungi (PenAsp group, Trichoderma viride group, Wallemia sebi) was also inversely associated with IFN-γ production at age 1 year, but this association lost significance after multivariate adjustment. Only few associations were found between microbial exposures and other measured cytokines.

Conclusions: High indoor microbial exposures may affect immune development in early life by reducing Th1 –cytokine secretion capacity. In the future, more attention should be paid especially to the immunomodulatory role of Gram-positive bacterial exposures.
Abstract 2544: Visually Guided Pulmonary Vein Isolation Using a Compliant Endoscopic Laser Balloon
Authors: Edward P Gerstenfeld, Joshua Moss, John Michele
Journal: Circulation (2009)

Introduction: We tested the efficacy and safety of an endoscopic laser balloon ablation system (ELBAS) for achieving persistent pulmonary vein isolation (PVI) in a swine model. Methods: PVI was per...
Effects of Cortisone in Tumor Transplantation<xref ref-type="fn" rid="FN1">2</xref>
Authors: George E. Moore, Tatsuhei Kondo, Robert J. Oliver
Journal: JNCI Journal of the National Cancer Institute (1960)

In these studies, the observations of earlier workers that pretreatment with cortisone effectively aids in the growth of transplanted Sarcoma 180, Krebs-2, and Ehrlich ascites tumor cells have been confirmed. In a series of experiments, we made the following observations: If a minimally effective dose of cortisone was used, it had to be given before cell inoculation. With the use of cortisone, single Ehrlich cells could be consistently grown in subcutaneous tissues. Pretreatment with cortisone reduced the number of intravenously injected tumor cells required for the establishment of comparable numbers of tumor implants from approximately 2 million to only 5,000. The predominant site of metastases shifted from the lung in normal mice to the liver in cortisone-treated animals.
Abstract 13352: Work Absenteeism, Short Term Disability and Related Indirect Costs Associated with Cardiovascular Events and Related Clinical Procedures
Authors: Xue Song, Ruben G Quek, Shravanthi R Gandra, Katherine Cappell, Robert Fowler, Ze Cong
Journal: Circulation (2014)

Objectives: To examine work absenteeism (WA) and short-term disability (STD) hours and related indirect costs associated with cardiovascular events and related procedures (CVERP): myocardial infarction (MI), ischemic stroke (IS), unstable angina (UA), heart failure (HF), transient ischemic attack (TIA), coronary artery bypass graft (CABG), and percutaneous coronary intervention (PCI). Methods: Full-time employees aged 18-64, with WA or STD benefits, hyperlipidemia or lipid-lowering therapy, and ≥1 CVERP in 2003-2011 were extracted from a large claims and productivity database. Index date was the date of the first CVERP. All patients had data for ≥1 year pre-index and ≥1 month post-index. Per patient per month (PPPM) WA and STD hours were measured during the acute 1 month and 1 year post-index periods. Indirect costs associated with these hours were calculated using the Bureau of Labor Statistics wage rates (in 2013 $). Results: A total of 5,803 patients were included in the WA analysis (mean age 53, 86% male, mean Charlson comorbidity index [CCI] 0.6) and 21,074 in the STD analysis (mean age 53, 82% male, mean CCI 0.7). Patients with CABG as the first CVERP type had the highest mean PPPM costs and hours during the acute 1 month and the 1 year post-index periods (Fig. 1), followed by MI (for WA acute 1 month and 1 year, for STD acute 1 month) and HF (for STD 1 year). Mean PPPM WA hours ranged between 31 - 61 (indirect cost: $998 - $1842) and STD hours between 31- 121 (indirect cost: $532 - $2154) during the acute 1 month post-index period. Compared with the mean PPPM hours lost from work in the pre-index period, mean PPPM WA hours went up by 22.5 hours (indirect cost by $647) in the acute 1 month post-index period, and STD went up by 53 hours ($916). Conclusions: CVERP were associated with substantial work loss and related indirect costs, especially in the acute first month period following CVERP. Prevention of CVERP could result in potential WA and STD related cost savings for employers.
Adolescent-parent disagreement on health-related quality of life of food-allergic adolescents: who makes the difference?
Authors: J. L. van der Velde, B. M. J. Flokstra-de Blok, A. Hamp, R. C. Knibb, E. J. Duiverman, A. E. J. Dubois
Journal: Allergy (2011)

To cite this article: van der Velde JL, Flokstra-de Blok BMJ, Hamp A, Knibb RC, Duiverman EJ, Dubois AEJ. Adolescent–parent disagreement on health-related quality of life of food-allergic adolescents: who makes the difference? Allergy 2011; 66: 1580–1581. Abstract Background: Food-allergic adolescents are at highest risk for food allergy fatalities, which may be partly due to compromised self-management behavior. Such behavior may be negatively influenced by conflictual situations caused by adolescent–parent disagreement on the adolescent's health-related quality of life (HRQL). Comparisons of adolescent-self-reported and parent-proxy-reported HRQL of food-allergic adolescents have never extensively been studied. The aims of this study were to investigate disagreement in adolescent-self-reports and parent-proxy-reports on the HRQL of food-allergic adolescents and to investigate the factors influencing adolescent–parent disagreement. Methods: Teenager Form (TF) and Parent Form (PFA) of the Food Allergy Quality of Life Questionnaire (FAQLQ), Food Allergy Independent Measure (FAIM), and Brief-Illness Perception Questionnaire (Brief-IPQ) were sent to food-allergic Dutch adolescents (13–17 years) and their parents. ICCs, t-tests, and Bland–Altman plots were used to investigate adolescent–parent disagreement. Participant characteristics, illness expectations, and illness perceptions influencing adolescent–parent disagreement were studied using regression analysis. Results: Seventy adolescent–parent pairs were included. There were a moderate correlation (ICC = 0.61, P < 0.001) and no significant difference (3.78 vs 3.56, P = 0.103) between adolescent-self-reported and parent-proxy-reported HRQL at group level. However, Bland–Altman plots showed relevant differences (exceeding the minimal important difference) for 63% of all adolescent–parent pairs. Adolescent's age (>15 years), poorer adolescent-reported illness comprehension (Brief-IPQ-TF, coherence), and higher adolescent-reported perceived disease severity (Food Allergy Independent Measure-Teenager Form & -Parent Form) were associated with adolescent–parent disagreement. Conclusions: Adolescent–parent disagreement on the adolescent's HRQL was mainly associated with adolescents' rather than parents' perceptions and characteristics. Illness comprehension of the adolescent may be an important target for intervention aimed at reducing adolescent–parent disagreement.
Management of the Patient with Cancer.
Authors: Thomas F. ed Nealon
Journal: Annals of Internal Medicine (1966)

Management of the Patient With Cancer. Edited by Thomas F. Nealon, Jr., MD. Price, $27.50. Pp 1,067, with illustrations. W. B. Saunders Company, 218 W Washington Sq, Philadelphia, Pa, 1965. Management of the Patient With Cancer is 1067 pages of contributions in 40 chapters devoted to a comprehensive goal of complete coverage of a vast field as of 1965. The contributors with one exception are from the United States. The editor is a professor of surgery in Philadelphia and therefore it is not surprising that 50 of 71 contributors are surgeons and 35 of these from the Philadelphia-New York-Boston axis. There are eight contributors in internal medicine, eight in pathology, and five in radiology. I have used this text in my office for the past six months and find that I refer most often to the chapters in Section 1 on subjects of radiation therapy, chemotherapy, diagnosis, cancer research, and rehabilitation. Section 2 of the text, with the exception of the chapter on leukemia and lymphoma, is devoted to specific surgical approach of various organs or tissues involved with can-
Localized expression of small RNA inhibitors in human cells
Authors: Cynthia P Paul, Paul D Good, Shirley X.L Li, Annette Kleihauer, John J Rossi, David R Engelke
Journal: Molecular Therapy (2003)

Several types of small RNAs have been proposed as gene expression repressors with great potential for use in gene therapy. RNA polymerase III (pol III) provides an ideal means of expressing small RNAs in cells because its normal products are small, highly structured RNAs that are found in a variety of subcellular compartments. We have designed cassettes that use human pol III promoters for the high-level expression of small RNAs in the cytoplasm, nucleoplasm, and nucleolus. The levels and subcellular destinations of the transcripts are compared for transcripts expressed using the U6 small nuclear RNA (snRNA), 5S ribosomal RNA (rRNA), and the 7SL RNA component of the signal recognition particle. The most effective location for a particular inhibitory RNA is not necessarily predictable; thus these cassettes allow testing of the same RNA insert in multiple subcellular locations. Several small interfering RNA (siRNA) inserts were tested for efficacy. An siRNA insert that reduces lamin expression when transcribed from the U6 snRNA promoter in the nucleus has no effect on lamin expression when transcribed from 5S rRNA and 7SL RNA-based cassettes and found in the nucleolus and cytoplasm. To test further the generality of U6-driven siRNA inhibitors, siRNAs targeting HIV were tested by co-transfection with provirus in cell culture. Although the degree of HIV-1 inhibition varied among inserts, results show that the U6 cassette provides a means of expressing an siRNA-like inhibitor of HIV gene expression.
Abstract 781: Efficacy of trifluridine for 5-fluorouracil-resistant human gastric cancer cell lines and their mechanisms
Authors: Kazuaki Matsuoka, Takashi Kobunai, Teiji Takechi
Journal: Cancer Research (2014)

Abstract Background: TAS-102 is a novel oral nucleoside antitumor agent consisting of trifluridine (FTD) and tipiracil hydrochloride (TPI). TAS-102 was found to significantly improve the overall survival of patients with metastatic colorectal cancer who were refractory to treatment with a fluoropyrimidine, irinotecan, and oxaliplatin in a double-blind randomized phase II study. Although significant survival benefits from 5-fluorouracil (5-FU)-based chemotherapy have also been reported in patients with gastric cancer, many patients experience recurrences after several courses of 5-FU-based chemotherapy. The resistance of gastric tumors to 5-FU therapy is thus a major clinical problem. In this study, the efficacy of FTD against 5-FU-resistant human gastric cancer cell lines was investigated. Method: 5-FU-resistant cell lines established by continuously exposing the parent cell lines (MKN-45, MKN-74, and KATOIII) to escalating concentrations (1-5 μM) of 5-FU over a 1-year period were used. The sensitivities of the cell lines to FTD were evaluated using a crystal violet staining assay. To elucidate the mechanism by which resistance is overcome, the mRNA levels of TK1, which converts FTD into an active monophosphate form, and hENT1, which is involved in the cellular uptake of FTD, were determined using RT-PCR. Results: The resistant cell lines KATOIII/5FU, MKN74/5FU, and MKN45/5FU exhibited a 2.0-fold, 4.8-fold, and 14.2-fold resistance to 5-FU, compared with their parent cell lines, respectively. MKN-45/5FU also showed a 3.7-fold resistance to FTD, whereas MKN-74/5FU (1.0-fold) and KATOIII/5FU (1.2-fold) showed no cross-resistance to FTD. The TK1 mRNA level was decreased by 40% in the MKN-45/5FU cells, compared with the parent cell line. Furthermore, this cell line showed a 60% decrease in the mRNA level for hENT1. In contrast, the hENT1 mRNA level increased by 1.6-fold in the KATOIII/5FU cells, with a 50% decrease in the TK1 mRNA level. The TK1 and hENT1 mRNA levels in MKN-74/5FU were increased by 1.9-fold and 1.7-fold, respectively. Conclusion: FTD was able to overcome the resistance to 5-FU in 2 out of 3 resistant cell lines in vitro, with MKN45/5FU exhibiting a partial cross-resistance to FTD. These results suggest that TAS-102 might be a promising chemotherapeutic agent for the treatment of gastric cancer relapses after 5-FU-based treatment. Furthermore, TK1 and hENT1 might be involved in FTD-related cytotoxicity. Citation Format: Kazuaki Matsuoka, Takashi Kobunai, Teiji Takechi. Efficacy of trifluridine for 5-fluorouracil-resistant human gastric cancer cell lines and their mechanisms. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 781. doi:10.1158/1538-7445.AM2014-781
Abstract 612: Endostatin is a novel inhibitor of androgen receptor function in prostate cancer
Authors: Joo Hyoung Lee, Tatyana Isayeva, Matthew Larson, Diptiman Chanda, Igor Chesnokov, Selvarangan Ponnazhagan
Journal: Cancer Research (2014)

Abstract Abnormalities in androgen-androgen receptor (AR) axis have long been recognized for their roles in promoting prostate tumor growth and metastasis. Conventional therapies targeting androgen ablation show transient tumor regression, however, when the tumor recurs during castration-refractory metastatic stage, the current treatment options are very limited. Although the precise mechanism by which prostate cancer (PCa) cells circumvent the androgen deprivation is unclear, recurring tumors have been shown to retain AR activity and upregulation of AR-target gene expression such as prostate specific antigen (PSA), suggesting that targeting AR remains a key component of developing novel therapeutic strategies. Here, we show a profound effect of endostatin, an endogenous angiogenesis inhibitor, on proliferation and invasion of AR-positive PCa cells by targeting AR function. The present study identified that intracellular trafficking of endostatin and direct interaction with AR disrupts AR nuclear translocation and the consequent transcriptional activation of PSA gene. In addition, our structural modeling and site-directed mutagenesis studies suggest that the binding mechanism may include the interaction of bulky side chains (F31 and F34) present in endostatin with the co-activator binding interface (AF-2) in AR ligand-binding domain (LBD). Regarding drug resistance to the second-generation androgen antagonists in patients with metastatic PCa, recent studies revealed that a missense mutation in AR LBD (F876L) and the consequential antagonist-to-agonist switch confers continued AR activity. In this context, our study suggests that endostatin can be recognized as an endogenous AR inhibitor where its molecular interaction with AR may prevent from agonistic switch of AR function by fully masking the AF-2 subdomain. Overall, the current finding provides new insights into endostatin whose anti-cancer activity is not only limited to inhibiting angiogenesis, but can also be expanded to suppressing AR-mediated PCa progression by disrupting AR transactivation. Citation Format: Joo Hyoung Lee, Tatyana Isayeva, Matthew Larson, Diptiman Chanda, Igor Chesnokov, Selvarangan Ponnazhagan. Endostatin is a novel inhibitor of androgen receptor function in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 612. doi:10.1158/1538-7445.AM2014-612