tbuckley/cabot-search huggingface dataset:
Long-Term Results of Tamoxifen Prophylaxis for Breast Cancer--96-Month Follow-up of the Randomized IBIS-I Trial
Authors: J. Cuzick, J. F. Forbes, I. Sestak, S. Cawthorn, H. Hamed, K. Holli, A. Howell
Journal: JNCI Journal of the National Cancer Institute (2007)

Initial results from the first International Breast Cancer Intervention Study (IBIS-I) found that tamoxifen reduced the risk of invasive estrogen receptor (ER)–positive tumors by 31% in women at increased risk for breast cancer, but most of the follow-up at this time was during the active treatment phase. We report an updated analysis of IBIS-I that focuses on the period after active treatment was completed, a time for which little evidence from other trials is available. A total of 7145 women who were aged 35–70 years and at increased risk of breast cancer were randomly assigned to receive either tamoxifen (20 mg/day) or placebo for 5 years. The primary outcome measure was the incidence of breast cancer (including ductal carcinoma in situ), but side effects were also investigated. Relative risks were computed as the ratio of incidence rates. All statistical tests were two-sided. After a median follow-up of 96 months after randomization, 142 breast cancers were diagnosed in the 3579 women in the tamoxifen group and 195 in the 3575 women in the placebo group (4.97 versus 6.82 per 1000 woman-years, respectively; risk ratio [RR] = 0.73, 95% confidence interval [CI] = 0.58 to 0.91, P = .004). The prophylactic effect of tamoxifen was fairly constant for the entire follow-up period, and no diminution of benefit was observed for up to 10 years after randomization. However, side effects in the tamoxifen group were much lower after completion of the active treatment period than during active treatment. For example, deep-vein thrombosis and pulmonary embolism were statistically significantly higher in the tamoxifen arm than in the placebo arm during active treatment (52 versus 23 cases, RR = 2.26, 95% CI = 1.36 to 3.87) but not after tamoxifen was stopped (16 versus 14 cases, RR = 1.14, 95% CI = 0.52 to 2.53). The two arms did not differ in the risk of ER-negative invasive tumors (35 in each arm, RR = 1.00, 95% CI = 0.61 to 1.65) across the entire follow-up period, but the risk of ER-positive invasive breast cancer was 34% lower in the tamoxifen arm (87 versus 132 cases, RR = 0.66, 95% CI = 0.50 to 0.87). The risk-reducing effect of tamoxifen appears to persist for at least 10 years, but most side effects of tamoxifen do not continue after the 5-year treatment period.
TREM-1 Mediates Inflammatory Injury and Cardiac Remodeling Following Myocardial Infarction
Authors: Amir Boufenzer, Jérémie Lemarié, Tabassome Simon, Marc Derive, Youcef Bouazza, Nguyen Tran, Fatiha Maskali, Frédérique Groubatch, Philippe Bonnin, Claire Bastien, Patrick Bruneval, Pierre-Yves Marie, Raphael Cohen, Nicolas Danchin, Jean-Sébastien Silvestre, Hafid Ait-Oufella, Sébastien Gibot
Journal: Circulation Research (2015)

Rationale: Optimal outcome after myocardial infarction (MI) depends on a coordinated healing response in which both debris removal and repair of the myocardial extracellular matrix play a major role. However, adverse remodeling and excessive inflammation can promote heart failure, positioning leucocytes as central protagonists and potential therapeutic targets in tissue repair and wound healing after MI. Objective: In this study, we examined the role of triggering receptor expressed on myeloid cells-1(TREM-1) in orchestrating the inflammatory response that follows MI. TREM-1, expressed by neutrophils and mature monocytes, is an amplifier of the innate immune response. Methods and Results: After infarction, TREM-1 expression is upregulated in ischemic myocardium in mice and humans. Trem-1 genetic invalidation or pharmacological inhibition using a synthetic peptide (LR12) dampens myocardial inflammation, limits neutrophils recruitment and monocyte chemoattractant protein-1 production, thus reducing classical monocytes mobilization to the heart. It also improves left ventricular function and survival in mice (n=20–22 per group). During both permanent and transient myocardial ischemia, Trem-1 blockade also ameliorates cardiac function and limits ventricular remodeling as assessed by fluorodeoxyglucose-positron emission tomographic imaging and conductance catheter studies (n=9–18 per group). The soluble form of TREM-1 (sTREM-1), a marker of TREM-1 activation, is detectable in the plasma of patients having an acute MI (n=1015), and its concentration is an independent predictor of death. Conclusions: These data suggest that TREM-1 could constitute a new therapeutic target during acute MI.
The lpr gene causes an intrinsic T cell abnormality that is required for hyperproliferation.
Authors: T Katagiri, P L Cohen, R A Eisenberg
Journal: The Journal of Experimental Medicine (1988)

The lpr gene induces marked lymphoproliferation characterized by the massive accumulation of T cells of an unusual phenotype and concomitant autoimmune disease. To clarify the mechanism of the lpr effect, bone marrow cells from B6-lpr/lpr (Ly-1.2) and B6-+/+ (Ly-1.1) mice were transferred into lethally irradiated B6-lpr/lpr mice. As has been previously reported, recipients of the B6-lpr/lpr bone marrow showed the typical lpr phenotype with marked lymphadenopathy, splenomegaly and increased levels of autoantibodies; while the recipients of B6-+/+ bone marrow had normal sized lymph nodes and spleen and no autoantibodies. A third group of mice received an equal mixture of bone marrow cells from the B6-lpr/lpr and B6-+/+ donors. These mice showed both lymphadenopathy and autoantibody production comparable to that of recipients of the B6-lpr/lpr marrow alone. Immunofluorocytometric analysis of the lymphoid populations in these mixed bone marrow recipients established that the T cells from the lpr/lpr and +/+ donors were equivalently represented in the peripheral blood and thymus. In striking contrast, the T cells that accumulated in abnormally large numbers in the lymph nodes were almost entirely from the lpr donor. Their surface phenotype was Thy-1+(dull), Ly-1.2+(dull), Lyt-2-, L3T4-, 9F3+, and 3A1+, which is consistent with that found in intact lpr mice. These results indicate that the lpr gene causes an intrinsic defect directly within the T cells that accumulate in large numbers in lpr mice. In addition, the presence of the +/+ T cells cannot prevent the expression of the lpr abnormalities.
Phase II Clinical Trial of Multiple Peptide Vaccination for Advanced Head and Neck Cancer Patients Revealed Induction of Immune Responses and Improved OS
Authors: Yoshihiro Yoshitake, Daiki Fukuma, Akira Yuno, Masatoshi Hirayama, Hideki Nakayama, Takuya Tanaka, Masashi Nagata, Yasuo Takamune, Kenta Kawahara, Yoshihiro Nakagawa, Ryoji Yoshida, Akiyuki Hirosue, Hidenao Ogi, Akimitsu Hiraki, Hirofumi Jono, Akinobu Hamada, Koji Yoshida, Yasuharu Nishimura, Yusuke Nakamura, Masanori Shinohara
Journal: Clinical Cancer Research (2014)

The peptides derived from ideal cancer-testis antigens, including LY6K, CDCA1, and IMP3 (identified using genome-wide cDNA microarray analyses), were used in immunotherapy for head and neck squamous cell cancer (HNSCC). In this trial, we analyzed the immune response to and safety and efficacy of vaccine therapy.A total of 37 patients with advanced HNSCC were enrolled in this trial of peptide vaccine therapy, and the OS, PFS, and immunologic response were evaluated using enzyme-linked ImmunoSpot (ELISPOT) and pentamer assays. The peptides were subcutaneously administered weekly with IFA. The primary endpoints were evaluated on the basis of differences between HLA-A*2402-positive [A24(+)] patients treated with peptide vaccine therapy and -negative [A24(-)] patients treated without peptide vaccine therapy among those with advanced HNSCC.Our cancer vaccine therapy was well tolerated. The OS of the A24(+) vaccinated group (n = 37) was statistically significantly longer than that of the A24(-) group (n = 18) and median survival time (MST) was 4.9 versus 3.5 months, respectively; P < 0.05. One of the patients exhibited a complete response. In the A24(+) vaccinated group, the ELISPOT assay identified LY6K-, CDCA1-, and IMP3-specific CTL responses in 85.7%, 64.3%, and 42.9% of the patients, respectively. The patients showing LY6K- and CDCA1-specific CTL responses demonstrated a longer OS than those without CTL induction. Moreover, the patients exhibiting CTL induction for multiple peptides demonstrated better clinical responses.The immune response induced by this vaccine may improve the prognosis of patients with advanced HNSCC.
The Role of Parental and Grandparental Epigenetic Alterations in Familial Cancer Risk
Authors: Jessica L. Fleming, Tim H-M. Huang, Amanda Ewart Toland
Journal: Cancer Research (2008)

Epigenetic alterations of the genome such as DNA promoter methylation and chromatin remodeling play an important role in tumorigenesis. These modifications take place throughout development with subsequent events occurring later in adulthood. Recent studies, however, suggest that some epigenetic alterations that influence cancer risk are inherited through the germline from parent to child and are observed in multiple generations. Epigenetic changes may be inherited as Mendelian, non-Mendelian, or environmentally induced traits. Here, we will discuss Mendelian, non-Mendelian, and environmentally induced patterns of multigenerational epigenetic alterations as well as some possible mechanisms for how these events may be occurring.
Docetaxel plus oblimersen sodium (Bcl-2 antisense oligonucleotide): an EORTC multicenter, randomized phase II study in patients with castration-resistant prostate cancer
Authors: C.N. Sternberg, H. Dumez, H. Van Poppel, I. Skoneczna, A. Sella, G. Daugaard, T. Gil, J. Graham, P. Carpentier, F. Calabro, L. Collette, D. Lacombe
Journal: Annals of Oncology (2009)
Failure in generating hemopoietic stem cells is the primary cause of death from cytomegalovirus disease in the immunocompromised host.
Authors: W Mutter, M J Reddehase, F W Busch, H J Bühring, U H Koszinowski
Journal: The Journal of Experimental Medicine (1988)

We have shown in a murine model system for cytomegalovirus (CMV) disease in the immunocompromised host that CMV infection interferes with the earliest detectable step in hemopoiesis, the generation of the stem cell CFU-S-I, and thereby prevents the autoreconstitution of bone marrow after sublethal irradiation. The antihemopoietic effect could not be ascribed to a direct infection of stem cells. The failure in hemopoiesis was prevented by adoptive transfer of antiviral CD8+ T lymphocytes and could be overcome by syngeneic bone marrow transplantation. CD8+ T lymphocytes and bone marrow cells both mediated survival, although only CD8+ T lymphocytes were able to limit virus multiplication in host tissues. We concluded that not the cytopathic effect of virus replication in host tissues, but the failure in hemopoiesis, is the primary cause of death in murine CMV disease.
High and Rising Health Care Costs. Part 3: The Role of Health Care Providers
Authors: Thomas Bodenheimer
Journal: Annals of Internal Medicine (2005)

One commonly held explanation for high and rising health care costs in the United States points to the market power of health care providers. This third article of a 4-part series examines how the prices and quantities of health care services interact to influence health care expenditures. The article also reviews cost-containment strategies that are designed to reduce prices and quantities of services. One major difference between the costs of care in the United States and those in other developed nations is the price per unit of care—physician fees, payments per hospital day, and pharmaceutical prices. Greater quantities of high-priced innovative technologies in the United States also contribute to higher expenditures in the United States compared with other nations. During the 1990s, payers were partially successful in slowing cost growth by reducing the prices of physician and hospital payments, but more recently, hospitals increased their market power by consolidation and could demand higher prices. Quantities and costs of services for Medicare beneficiaries vary markedly among geographic regions, with research showing an association between health care costs and the supply of hospital beds and specialist physicians. These findings suggest that limiting the supply of resources may reduce the quantity, and thereby the costs, of health services. Shifting the financial risk of health care costs from insurers to providers, as has been done with the Medicare diagnosis-related-group payment and capitation reimbursement, can also be effective in containing costs.
Dietary factors and lung function in the general population: wine and resveratrol intake
Authors: M. Siedlinski, J.M.A. Boer, H.A. Smit, D.S. Postma, H.M. Boezen
Journal: European Respiratory Journal (2011)

Wine intake is associated with a better lung function in the general population, yet the source of this effect is unknown. Resveratrol, a polyphenol in wine, has anti-inflammatory properties in the lung, its effects being partially mediated via induction of Sirtuin (SIRT)1 activity. We assessed the impact of wine and resveratrol intake, and SIRT1 single-nucleotide polymorphisms (SNPs) on lung function in the general population. Effects of red and white wine and resveratrol intake on forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC) and FEV 1 /FVC were analysed in the population-based Doetinchem cohort (n=3,224). Associations of four tagging SIRT1 SNPs with lung function were analysed in the Doetinchem (n=1,152) and Vlagtwedde–Vlaardingen (n=1,390) cohorts. Resveratrol intake was associated with higher FVC levels, and white wine intake with higher FEV 1 levels and lower risk of airway obstruction. SIRT1 SNPs were not significantly associated with level or course of lung function, either directly or indirectly via wine or resveratrol intake. This study shows a positive association of resveratrol intake with lung function in the general population, confirms the previously reported positive association of white wine intake with higher levels of FEV 1 , and additionally shows an association with a higher FEV 1 /FVC ratio. These effects probably do not run via SNPs in SIRT1 .
The effect of breathing an ambient low-density, hyperoxic gas on the perceived effort of breathing and maximal performance of exercise in well-trained athletes
Authors: L Ansley, D Petersen, A Thomas, A St Clair Gibson, P Robson-Ansley, T D Noakes
Journal: British Journal of Sports Medicine (2006)

Background: The role of the perception of breathing effort in the regulation of performance of maximal exercise remains unclear. Aims: To determine whether the perceived effort of ventilation is altered through substituting a less dense gas for normal ambient air and whether this substitution affects performance of maximal incremental exercise in trained athletes. Methods: Eight highly trained cyclists (mean SD) maximal oxygen consumption (VO 2 max) = 69.9 (7.9) (mlO 2 /kg/min) performed two randomised maximal tests in a hyperbaric chamber breathing ambient air composed of either 35% O 2 /65% N 2 (nitrox) or 35% O 2 /65% He (heliox). A ramp protocol was used in which power output was incremented at 0.5 W/s. The trials were separated by at least 48 h. The perceived effort of breathing was obtained via Borg Category Ratio Scales at 3-min intervals and at fatigue. Oxygen consumption (VO 2 ) and minute ventilation (V E ) were monitored continuously. Results: Breathing heliox did not change the sensation of dyspnoea: there were no differences between trials for the Borg scales at any time point. Exercise performance was not different between the nitrox and heliox trials (peak power output = 451 (58) and 453 (56) W), nor was VO 2 max (4.96 (0.61) and 4.88 (0.65) l/min) or maximal V E (157 (24) and 163 (22) l/min). Between-trial variability in peak power output was less than either VO 2 max or maximal V E . Conclusion: Breathing a less dense gas does not improve maximal performance of exercise or reduce the perception of breathing effort in highly trained athletes, although an attenuated submaximal tidal volume and V E with a concomitant reduction in VO 2 suggests an improved gas exchange and reduced O 2 cost of ventilation when breathing heliox.
MYOCARDITIS AND DILATED CARDIOMYOPATHY
Authors: C Kawai, A Matsumori, H Fujiwara
Journal: Annual Review of Medicine (1987)

The recent developments in the study of myocarditis and dilated cardiomyopathy are reviewed here, with the primary emphasis on the issue of myocarditis as a precursor to dilated cardiomyopathy. Advances in immunologic approaches have expanded our knowledge of the course of myocarditis, experimentally as well as clinically. Although further investigations are necessary to prove the direct link between acute myocarditis and some cases of dilated cardiomyopathy, clinical trials of immunosuppressive agents, virus-specific vaccine, and antiviral agents such as ribavirin and interferon appear warranted, with the hope of potential benefits in the treatment of myocarditis and, therefore, in some forms of dilated cardiomyopathy.
Advances in embryo culture platforms: novel approaches to improve preimplantation embryo development through modifications of the microenvironment
Authors: J. E. Swain, G. D. Smith
Journal: Human Reproduction Update (2011)

The majority of research aimed at improving embryo development in vitro has focused on manipulation of the chemical environment, examining details such as energy substrate composition and impact of various growth factors or other supplements. In comparison, relatively little work has been done examining the physical requirements of preimplantation embryos and the role culture platforms or devices can play in influencing embryo development. Electronic searches were performed using keywords centered on embryo culture techniques using PUBMED through June 2010 and references were searched for additional research articles. Various approaches to in vitro embryo culture that involve manipulations of the physical culture environment are emerging. Novel culture platforms being developed examine issues such as media volume and embryo spacing. Furthermore, methods to permit dynamic embryo culture with fluid flow and embryo movement are now available, and novel culture surfaces are being tested. Although several factors remain to be studied to optimize efficiency, manipulations of the embryo culture microenvironment through novel culture devices may offer a means to improve embryo development in vitro. Reduced volume systems that reduce embryo spacing, such as the well-of-the-well approach, appear beneficial, although more work is needed to verify the source of their true benefit in human embryos. Emerging microfluidic technology appears to be a promising approach. However, along with the work on specialized culture surfaces, more information is required to determine the impact on human embryo development.
Formalizing an Integrative, Multidisciplinary Cancer Therapy Discovery Workflow
Authors: Mary F. McGuire, Heiko Enderling, Dorothy I. Wallace, Jaspreet Batra, Marie Jordan, Sushil Kumar, John C. Panetta, Eddy Pasquier
Journal: Cancer Research (2013)

Although many clinicians and researchers work to understand cancer, there has been limited success to effectively combine forces and collaborate over time, distance, data, and budget constraints. Here we present a workflow template for multidisciplinary cancer therapy that was developed during the 2nd Annual Workshop on Cancer Systems Biology sponsored by Tufts University, Boston, Massachusetts, in July 2012. The template was applied to the development of a metronomic therapy backbone for neuroblastoma. Three primary groups were identified: clinicians, biologists, and quantitative scientists (mathematicians, computer scientists, and engineers). The workflow described their integrative interactions; parallel or sequential processes; data sources and computational tools at different stages as well as the iterative nature of therapeutic development from clinical observations to in vitro, in vivo, and clinical trials. We found that theoreticians in dialog with experimentalists could develop calibrated and parameterized predictive models that inform and formalize sets of testable hypotheses, thus speeding up discovery and validation while reducing laboratory resources and costs. The developed template outlines an interdisciplinary collaboration workflow designed to systematically investigate the mechanistic underpinnings of a new therapy and validate that therapy to advance development and clinical acceptance.
International Union of Pharmacology. XXIX. Update on Endothelin Receptor Nomenclature
Authors: A. P. Davenport
Journal: Pharmacological Reviews (2002)

In mammals, the endothelin (ET) family comprises three endogenous isoforms, ET-1, ET-2, and ET-3. ET-1 is the principal isoform in the human cardiovascular system and remains the most potent and long-lasting constrictor of human vessels discovered. In humans, endothelins mediate their actions via only two receptor types that have been cloned and classified as the ET<sub>A</sub> and ET<sub>B</sub>receptors in the first NC-IUPHAR (International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification) report on nomenclature in 1994. This report was compiled before the discovery of the majority of endothelin receptor antagonists (particularly nonpeptides) currently used in the characterization of receptors and now updated in the present review. Endothelin receptors continue to be classified according to their rank order of potency for the three endogenous isoforms of endothelin. A selective ET<sub>A</sub> receptor agonist has not been discovered, but highly selective antagonists include peptides (BQ123, cyclo-[d-Asp-l-Pro-d-Val-l-Leu-d-Trp-]; FR139317, <i>N</i>- [(hexahydro-1-azepinyl)carbonyl]l-Leu(1-Me)d-Trp-3 (2-pyridyl)-d-Ala) and the generally more potent nonpeptides, such as PD156707, SB234551, L754142, A127722, and TBC11251. Sarafotoxin S6c, BQ3020 ([Ala<sup>11,15</sup>]Ac-ET-1<sub>(6–21)</sub>), and IRL1620 [Suc-(Glu<sup>9</sup>, Ala<sup>11,15</sup>)-ET-1<sub>(8–21)</sub>] are widely used synthetic ET<sub>B</sub> receptor agonists. A limited number of peptide (BQ788) and nonpeptide (A192621) ET<sub>B</sub> antagonists have also been developed. They are generally less potent than ET<sub>A</sub> antagonists and display lower selectivity (usually only 1 to 2 orders of magnitude) for the ET<sub>B</sub> receptor. Radioligands highly selective for either ET<sub>A</sub>(<sup>125</sup>I-PD151242, <sup>125</sup>I-PD164333, and<sup>3</sup>H-BQ123) or ET<sub>B</sub> receptors (<sup>125</sup>I-BQ3020 and <sup>125</sup>I-IRL1620) have further consolidated classification into only these two types, with no strong molecular or pharmacological evidence to support the existence of further receptors in mammals.
The molecular evolution of sperm bindin in six species of sea urchins (Echinoida: Strongylocentrotidae)
Authors: C. H. Biermann
Journal: Molecular Biology and Evolution (1998)

The acrosomal protein bindin attaches sperm to eggs during sea urchin fertilization. Complementary to ongoing functional biochemical studies, I take a comparative approach to explore the molecular evolution of bindin in a group of closely related free-spawning echinoid species. Two alleles of the mature bindin gene were sequenced for each of six species in the sea urchin family Strongylocentrotidae. The nucleotide sequences diverged by at least 1% per Myr at both silent and replacement sites. Two short sections flanking the conserved block show an excess of nonsynonymous substitutions. Each is homologous to a region that had been identified as a target of selection in other sea urchin comparisons. A large proportion of the bindin-coding sequence consists of a highly variable repeat region. Bindin sequences, even including the large intron, could not resolve the branching order among five of the species.