tbuckley/cabot-search huggingface dataset:
Reversion of Human Glioblastoma Malignancy by U1 Small Nuclear RNA/Ribozyme Targeting of Scatter Factor/Hepatocyte Growth Factor and c-met Expression
Authors: R Abounader, S Ranganathan, B Lal, K Fielding, A Book, H Dietz, P Burger, J Laterra
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Expression of scatter factor (SF), also known as hepatocyte growth factor (HGF), and its receptor, c-met, is often associated with malignant progression of human tumors, including gliomas. Overexpression of SF/HGF in experimental gliomas enhances tumorigenicity and tumor-associated angiogenesis (i.e., growth of new blood vessels). However, the role of endogenous SF/HGF or c-met expression in the malignant progression of gliomas has not been examined directly. In this study, we tested the hypothesis that human glioblastomas can be SF/HGF–c-met dependent and that a reduction in endogenous SF/HGF or c-met expression can lead to inhibition of tumor growth and tumorigenicity. METHODS: Expression of the SF/HGF and c-met genes was inhibited by transfecting glioblastoma cells with chimeric transgenes consisting of U1 small nuclear RNA, a hammerhead ribozyme, and antisense sequences. The effects of reduced SF/HGF and c-met expression on 1) SF/HGF-dependent induction of immediate early genes (c-fos and c-jun), indicative of signal transduction; 2) anchorage-independent colony formation (clonogenicity), an in vitro correlate of solid tumor malignancy; and 3) intracranial tumor formation in immunodeficient mice were quantified. Statistical tests were two-sided. RESULTS: Introduction of the transgenes into glioblastoma cells reduced expression of the SF/HGF and c-met genes to as little as 2% of control cell levels. Reduction in c-met expression specifically inhibited SF/HGF-dependent signal transduction ( P <.01). Inhibition of SF/HGF or c-met expression in glioblastoma cells possessing an SF/HGF–c-met autocrine loop reduced tumor cell clonogenicity ( P = .005 for SF/HGF and P = .009 for c-met) and substantially inhibited tumorigenicity ( P <.0001) and tumor growth in vivo ( P <.0001). CONCLUSIONS: To our knowledge, this is the first successful inhibition of SF/HGF and c-met expression in a tumor model directly demonstrating a role for endogenous SF/HGF and c-met in human glioblastoma. Our results suggest that targeting the SF/HGF–c-met signaling pathway may be an important approach in controlling tumor progression.
The epidermal basement membrane in basal cell carcinoma: an immunohistochemical study
Authors: A. C. MARKEY, M. J. TIDMAN, L. J. CHURCHILL, J. D. APLIN, I. M. LEIGH, P. PURKIS, D. M. MACDONALD
Journal: British Journal of Dermatology (1991)

An immunohistochemical study of basal cell carcinomas of varying histological type, using a panel of antibodies to constituents of the epidermal basement membrane, showed marked deficiencies in the expression of the antigens identified by the antibodies LH7.2, GB3 and G71. There was no correlation between loss of immunoreactivity to these antibodies and the histological features of the tumour.
Religion's evolutionary landscape: Counterintuition, commitment, compassion, communion
Authors: Scott Atran, Ara Norenzayan
Journal: Behavioral and Brain Sciences (2004)

Religion is not an evolutionary adaptation per se, but a recurring cultural by-product of the complex evolutionary landscape that sets cognitive, emotional, and material conditions for ordinary human interactions. Religion exploits only ordinary cognitive processes to passionately display costly devotion to counterintuitive worlds governed by supernatural agents. The conceptual foundations of religion are intuitively given by task-specific panhuman cognitive domains, including folkmechanics, folkbiology, and folkpsychology. Core religious beliefs minimally violate ordinary notions about how the world is, with all of its inescapable problems, thus enabling people to imagine minimally impossible supernatural worlds that solve existential problems, including death and deception. Here the focus is on folkpsychology and agency. A key feature of the supernatural agent concepts common to all religions is the triggering of an “Innate Releasing Mechanism,” or “agency detector,” whose proper (naturally selected) domain encompasses animate objects relevant to hominid survival – such as predators, protectors, and prey – but which actually extends to moving dots on computer screens, voices in wind, and faces on clouds. Folkpsychology also crucially involves metarepresentation, which makes deception possible and threatens any social order. However, these same metacognitive capacities provide the hope and promise of open-ended solutions through representations of counterfactual supernatural worlds that cannot be logically or empirically verified or falsified. Because religious beliefs cannot be deductively or inductively validated, validation occurs only by ritually addressing the very emotions motivating religion. Cross-cultural experimental evidence encourages these claims.
Meaning-Centered Group Psychotherapy: An Effective Intervention for Improving Psychological Well-Being in Patients With Advanced Cancer
Authors: William Breitbart, Barry Rosenfeld, Hayley Pessin, Allison Applebaum, Julia Kulikowski, Wendy G. Lichtenthal
Journal: Journal of Clinical Oncology (2015)

To test the efficacy of meaning-centered group psychotherapy (MCGP) to reduce psychological distress and improve spiritual well-being in patients with advanced or terminal cancer.Patients with advanced cancer (N = 253) were randomly assigned to manualized eight-session interventions of either MCGP or supportive group psychotherapy (SGP). Patients were assessed before and after completing the treatment and 2 months after treatment. The primary outcome measures were spiritual well-being and overall quality of life, with secondary outcome measures assessing depression, hopelessness, desire for hastened death, anxiety, and physical symptom distress.Hierarchical linear models that included a priori covariates and only participants who attended ≥ three sessions indicated a significant group × time interaction for most outcome variables. Specifically, patients receiving MCGP showed significantly greater improvement in spiritual well-being and quality of life and significantly greater reductions in depression, hopelessness, desire for hastened death, and physical symptom distress compared with those receiving SGP. No group differences were observed for changes in anxiety. Analyses that included all patients, regardless of whether they attended any treatment sessions (ie, intent-to-treat analyses), and no covariates still showed significant treatment effects (ie, greater benefit for patients receiving MCGP v SGP) for quality of life, depression, and hopelessness but not for other outcome variables.This large randomized controlled study provides strong support for the efficacy of MCGP as a treatment for psychological and existential or spiritual distress in patients with advanced cancer.
Activating Fc Receptors Are Required for Antitumor Efficacy of the Antibodies Directed toward CD25 in a Murine Model of Adult T-Cell Leukemia
Authors: Meili Zhang, Zhuo Zhang, Kayhan Garmestani, Carolyn K. Goldman, Jeffrey V. Ravetch, Martin W. Brechbiel, Jorge A. Carrasquillo, Thomas A. Waldmann
Journal: Cancer Research (2004)

We previously showed therapeutic efficacy of humanized anti-Tac (HAT), murine anti-Tac (MAT), and 7G7/B6 monoclonal antibodies, which recognize CD25, for human adult T-cell leukemia (ATL) in a murine model. In this study, we investigated the mechanism underlying the tumor-killing action mediated by these antibodies on an ATL model in nonobese diabetic/severe combined immunodeficient (SCID/NOD) wild-type mice that lack effective T and natural killer (NK) cells and in SCID/NOD Fc receptor common gamma chain knockout (FcRgamma-/-) mice. The ATL model was established by i.p. injection of human ATL cells (MET-1) into SCID/NOD wild-type or SCID/NOD FcRgamma-/- mice. HAT, MAT, and 7G7/B6 were given to the leukemia-bearing mice at a dose of 100 microg weekly for 4 weeks. The three antibodies inhibited the leukemia growth significantly in SCID/NOD wild-type mice, as monitored by serum levels of human beta2-microglobulin (P < 0.01), and prolonged survival of the leukemia-bearing SCID/NOD wild-type mice (P < 0.01) as compared with the control group. However, none of the antibodies manifested efficacy on the leukemia growth and survival of the SCID/NOD FcRgamma-/- mice bearing MET-1 leukemia. In a pharmacokinetics study, the blood concentrations of the radiolabeled antibodies decreased with time similarly in SCID/NOD wild-type and SCID/NOD FcRgamma-/- mice. Although NK cells may play a role in humans, in this murine model FcRgamma receptors on non-NK cells, such as polymorphonuclear leukocytes or monocytes, are required for the tumor-killing action of the antibodies directed toward CD25.
Long-Term Outcomes of Dilated Cardiomyopathy Diagnosed During Childhood
Authors: Peta M.A. Alexander, Piers E.F. Daubeney, Alan W. Nugent, Katherine J. Lee, Christian Turner, Steven D. Colan, Terry Robertson, Andrew M. Davis, James Ramsay, Robert Justo, Gary F. Sholler, Ingrid King, Robert G. Weintraub
Journal: Circulation (2013)

Background— Existing studies of childhood dilated cardiomyopathy deal mainly with early survival. This population-based study examines long-term outcomes for children with dilated cardiomyopathy. Methods and Results— The diagnosis of dilated cardiomyopathy was based on clinical, echocardiographic, and pathological findings. The primary study end point included time to the combined outcome of death or cardiac transplantation. There were 175 patients 0 to &lt;10 years of age at the time of diagnosis. Survival free from death or transplantation was 74% (95% confidence interval, 67–80) 1 year after diagnosis, 62% (95% confidence interval, 55–69) at 10 years, and 56% (95% confidence interval, 46–65) at 20 years. In multivariable analysis, age at diagnosis &lt;4 weeks or &gt;5 years, familial cardiomyopathy, and lower baseline left ventricular fractional shortening Z score were associated with increased risk of death or transplantation, as was lower left ventricular fractional shortening Z score during follow-up. At 15 years after diagnosis, echocardiographic normalization had occurred in 69% of surviving study subjects. Normalization was related to higher baseline left ventricular fractional shortening Z score, higher left ventricular fractional shortening Z score during follow-up, and greater improvement in left ventricular fractional shortening Z score. Children with lymphocytic myocarditis had better survival and a higher rate of echocardiographic normalization. At the latest follow-up, 100 of 104 of survivors (96%) were free of cardiac symptoms, and 83 (80%) were no longer receiving pharmacotherapy. Conclusions— Death or transplantation occurred in 26% of patients with childhood dilated cardiomyopathy within 1 year of diagnosis and ~1% per year thereafter. Risk factors for death or transplantation include age at diagnosis, familial cardiomyopathy, and severity of left ventricular dysfunction. The majority of surviving subjects are well and free of cardiac medication.
Sustained Heterozygosity Across a Self-Incompatibility Locus in an Inbred Ascidian
Authors: Yutaka Satou, Kazuko Hirayama, Kaoru Mita, Manabu Fujie, Shota Chiba, Reiko Yoshida, Toshinori Endo, Yasunori Sasakura, Kazuo Inaba, Nori Satoh
Journal: Molecular Biology and Evolution (2014)

Because self-incompatibility loci are maintained heterozygous and recombination within self-incompatibility loci would be disadvantageous, self-incompatibility loci are thought to contribute to structural and functional differentiation of chromosomes. Although the hermaphrodite chordate, Ciona intestinalis, has two self-incompatibility genes, this incompatibility system is incomplete and self-fertilization occurs under laboratory conditions. Here, we established an inbred strain of C. intestinalis by repeated self-fertilization. Decoding genome sequences of sibling animals of this strain identified a 2.4-Mbheterozygous region on chromosome 7. A self-incompatibility gene, Themis-B, was encoded within this region. This observation implied that this self-incompatibility locus and the linkage disequilibrium of its flanking region contribute to the formation of the 2.4-Mb heterozygous region, probably through recombination suppression. We showed that different individuals in natural populations had different numbers and different combinations of Themis-B variants, and that the rate of self-fertilization varied among these animals. Our result explains why self-fertilization occurs under laboratory conditions. It also supports the concept that the Themis-B locus is preferentially retained heterozygous in the inbred line and contributes to the formation of the 2.4-Mb heterozygous region. High structural variations might suppress recombination, and this long heterozygous region might represent a preliminary stage of structural differentiation of chromosomes.
Effectiveness of Pneumococcal Polysaccharide Vaccine in Older Adults
Authors: Lisa A. Jackson, Kathleen M. Neuzil, Onchee Yu, Patti Benson, William E. Barlow, Annette L. Adams, Christi A. Hanson, Lisa D. Mahoney, David K. Shay, William W. Thompson
Journal: New England Journal of Medicine (2003)

Streptococcus pneumoniae is the chief cause of pneumonia in older adults, but it remains unclear whether use of the pneumococcal polysaccharide vaccine alters the overall risk of community-acquired pneumonia. In a large population of older adults, we assessed the effectiveness of the pneumococcal vaccine.
Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial.
Authors: D. Rachmilewitz
Journal: BMJ (1989)

To assess the safety and efficacy of a preparation of mesalazine (5-aminosalicylic acid) coated with a pH dependent resin (Eudragit L) as compared with sulphasalazine in patients with active mild to moderate ulcerative colitis.Eight week randomised double blind parallel group study.Forty six gastroenterology outpatient clinics in seven countries.Two hundred and twenty patients aged 18-70 who met the following criteria: clinical activity index greater than or equal to 6 and endoscopic index greater than or equal to 4; no concomitant treatment for ulcerative colitis; no hypersensitivity to salicylates or sulphonamides. Of the 164 patients eligible for efficacy analysis, 87 received the coated preparation of mesalazine and 77 sulphasalazine. Most of the remaining patients (28 in each group) were ineligible for the efficacy analysis because of treatment with steroid enemas. All pretrial characteristics were comparable in the two treatment groups.Coated mesalazine (Mesasal) 1.5 g daily or sulphasalazine 3.0 g daily for eight weeks. Compliance monitored by pill counts.Clinical and endoscopic remission.Clinical activity measured by daily diary cards, assessment by investigators, and laboratory findings. Endoscopic evaluation at week 8. After four weeks 50 of 70 patients (71%) taking coated mesalazine and 38 of 58 (66%) taking sulphasalazine had achieved remission of their disease by eight weeks remission rates were 74% (37/50 patients) and 81% (35/43) in the two treatment groups respectively. Endoscopic remission at eight weeks was recorded in 20 of 41 patients (49%) taking coated mesalazine and 18 of 38 (47%) taking sulphasalazine. There was a higher incidence of adverse events among patients taking sulphasalazine (25/105; 24%) than among those taking coated mesalazine (16/115; 14%).Mesalazine coated with Eudragit L is a safe, logical alternative to sulphasalazine.
Poly(ADP-Ribose) Polymerase-1 Could Facilitate the Religation of Topoisomerase I-linked DNA Inhibited by Camptothecin
Authors: Shin-Young Park, Yung-Chi Cheng
Journal: Cancer Research (2005)

Abstract Poly(ADP-ribose) polymerase-1 (PARP-1) is known to have an important role in camptothecin sensitivity and interacts with topoisomerase I. In the present study, the impact of PARP-1 on the topoisomerase I-DNA complex stabilized by camptothecin was assessed. It was shown that NH2 terminus–truncated topoisomerase I (amino acids 201-765) showed at least 4-fold less sensitivity to camptothecin than full-length topoisomerase I in the oligonucleotide religation assay. PARP-1 could prevent the action of camptothecin on the religation activity of full-length topoisomerase I, which is linked to DNA in a stoichiometrical manner. However, the religation activity of NH2 terminus–truncated topoisomerase I, which is linked to DNA, could not be enhanced by PARP-1 in the presence of camptothecin. Both full-length and NH2 terminus–truncated topoisomerase I interact with PARP-1. This data suggests that PARP-1 destabilizes the topoisomerase I-camptothecin-DNA complex with the participation of the NH2-terminal domain of topoisomerase I. Poly(ADP-ribosyl)ation of topoisomerase I by PARP-1 in the presence its substrate, NAD, could also promote the religation activity of full-length topoisomerase I as well as NH2 terminus–truncated topoisomerase I. PARP-1 inhibitors (3-aminobenzamide, PJ34) could inhibit this process. Therefore, PARP-1 could facilitate the religation activity of topoisomerase I by itself through topoisomerase I-PARP-1 interaction (PARP-1 action) or by the formation of poly(ADP-ribosyl)ation of topoisomerase I (PARP-1/NAD action). This study also implies that PARP-1 and PARP-1/NAD actions need to be highly regulated by cellular factors for camptothecin to exert its cytotoxicity inside the cells. We propose ATP to be one of the important regulatory factors.
Efficacy of a Device to Narrow the Coronary Sinus in Refractory Angina
Authors: Stefan Verheye, E. Marc Jolicœur, Miles W. Behan, Thomas Pettersson, Paul Sainsbury, Jonathan Hill, Mathias Vrolix, Pierfrancesco Agostoni, Thomas Engstrom, Marino Labinaz, Ranil de Silva, Marc Schwartz, Nathalie Meyten, Neal G. Uren, Serge Doucet, Jean-François Tanguay, Steven Lindsay, Timothy D. Henry, Christopher J. White, Elazer R. Edelman, Shmuel Banai
Journal: New England Journal of Medicine (2015)

Many patients with coronary artery disease who are not candidates for revascularization have refractory angina despite standard medical therapy. The balloon-expandable, stainless steel, hourglass-shaped, coronary-sinus reducing device creates a focal narrowing and increases pressure in the coronary sinus, thus redistributing blood into ischemic myocardium.
Molecular Basis of Cardiovascular Drug Metabolism
Authors: Darrell R. Abernethy, David A. Flockhart
Journal: Circulation (2000)

T he recent withdrawal of the calcium antagonist mibe- fradil from the market in the United States has refocused attention on drug interactions that involve cardiovascular drugs. 1 It is appropriate to ask whether pharmacokinetic drug interactions like this that pose substantial clinical risk can be predicted and/or prevented.We believe that if the appropriate information is obtained during drug development and effectively communicated to physicians, many episodes such as that involving mibefradil will be predicted and prevented.Many known pharmacokinetic drug interactions with the potential for either excessive drug exposure, effect, and toxicity or decreased drug exposure and loss of drug effect are associated with phase I drug biotransformations. 2In addition, the importance of P-glycoprotein-mediated drug transport is currently being appreciated.
Initial and 6-Month Results of Biodegradable Poly- <i>l</i> -Lactic Acid Coronary Stents in Humans
Authors: Hideo Tamai, Keiji Igaki, Eisho Kyo, Kunihiko Kosuga, Akiyoshi Kawashima, Shigeo Matsui, Hidenori Komori, Takafumi Tsuji, Seiichiro Motohara, Hiromu Uehata
Journal: Circulation (2000)

Although metallic stents are effective in preventing acute occlusion and reducing late restenosis after coronary angioplasty, many concerns still remain. Compared with metallic stents, poly-l-lactic acid (PLLA) stents are biodegradable and can deliver drugs locally. The aim of this study was to evaluate the feasibility, safety, and efficacy of the PLLA stent.Fifteen patients electively underwent PLLA Igaki-Tamai stent implantation for coronary artery stenoses. The Igaki-Tamai stent is made of a PLLA monopolymer, has a thickness of 0.17 mm, and has a zigzag helical coil pattern. A balloon-expandable covered sheath system was used, and the stent expanded by itself to its original size with an adequate temperature. A total of 25 stents were successfully implanted in 19 lesions in 15 patients, and angiographic success was achieved in all procedures. No stent thrombosis and no major cardiac event occurred within 30 days. Coronary angiography and intravascular ultrasound were serially performed 1 day, 3 months, and 6 months after the procedure. Angiographically, both the restenosis rate and target lesion revascularization rate per lesion were 10.5%; the rates per patient were 6.7% at 6 months. Intravascular ultrasound findings revealed no significant stent recoil at 1 day, and they revealed stent expansion at follow-up. No major cardiac event, except for repeat angioplasty, developed within 6 months.Our preliminary experience suggests that coronary PLLA biodegradable stents are feasible, safe, and effective in humans. Long-term follow-up with more patients will be required to validate the long-term efficacy of PLLA stents.
VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses
Authors: Li Wang, Rotem Rubinstein, Janet L. Lines, Anna Wasiuk, Cory Ahonen, Yanxia Guo, Li-Fan Lu, David Gondek, Yan Wang, Roy A. Fava, Andras Fiser, Steve Almo, Randolph J. Noelle
Journal: The Journal of Experimental Medicine (2011)

The immunoglobulin (Ig) superfamily consists of many critical immune regulators, including the B7 family ligands and receptors. In this study, we identify a novel and structurally distinct Ig superfamily inhibitory ligand, whose extracellular domain bears homology to the B7 family ligand PD-L1. This molecule is designated V-domain Ig suppressor of T cell activation (VISTA). VISTA is primarily expressed on hematopoietic cells, and VISTA expression is highly regulated on myeloid antigen-presenting cells (APCs) and T cells. A soluble VISTA-Ig fusion protein or VISTA expression on APCs inhibits T cell proliferation and cytokine production in vitro. A VISTA-specific monoclonal antibody interferes with VISTA-induced suppression of T cell responses by VISTA-expressing APCs in vitro. Furthermore, anti-VISTA treatment exacerbates the development of the T cell–mediated autoimmune disease experimental autoimmune encephalomyelitis in mice. Finally, VISTA overexpression on tumor cells interferes with protective antitumor immunity in vivo in mice. These findings show that VISTA, a novel immunoregulatory molecule, has functional activities that are nonredundant with other Ig superfamily members and may play a role in the development of autoimmunity and immune surveillance in cancer.