tbuckley/cabot-search huggingface dataset:
New Strategies in Estrogen Receptor–Positive Breast Cancer
Authors: Stephen R.D. Johnston
Journal: Clinical Cancer Research (2010)

Endocrine therapy has led to a significant improvement in outcomes for women with estrogen receptor-positive (ER+) breast cancer. Current questions in the adjuvant setting include the optimal duration of endocrine therapy, and the accurate molecular prediction of endocrine responsiveness using gene array-based assays compared with ER expression itself. In advanced disease, novel selective estrogen receptor antagonists (SERM) have failed to make an impact, although the pure ER antagonist fulvestrant may have a role, albeit optimal dose and sequence remain unclear. Overcoming de novo or acquired endocrine resistance remains critical to enhancing further the benefit of existing endocrine therapies. Recent progress has been made in understanding the molecular biology associated with acquired endocrine resistance, including adaptive "cross-talk" between ER and peptide growth factor receptor pathways such as epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2). Future strategies that are being evaluated include combining endocrine therapy with inhibitors of growth factor receptors or downstream signaling pathways, to treat or prevent critical resistance pathways that become operative in ER+ tumors. Preclinical experiments have provided great promise for this approach, although clinical data remain mixed. Enriching trial recruitment by molecular profiling of different ER+ subtypes will become increasingly important to maximize additional benefit that new agents may bring to current endocrine therapies for breast cancer.
Regulation of murine B cells through surface immunoglobulin. I. Monoclonal anti-delta antibody that induces allotype-specific proliferation.
Authors: I M Zitron, B L Clevinger
Journal: The Journal of Experimental Medicine (1980)

We describe the identification of a monoclonal antibody that recognizes a determinant on the delta chain of mice of the Iga, allotype groups. The monoclonal Ig in soluble form induces allotype-specific proliferation by splenic B lymphocytes from normal animals of these haplotypes. Spleen cells from mice bearing the X-linked defect of CBA/N mice fail to respond, although they bear the determinant. Proliferation is independent of T lymphocytes. The data indicate a direct triggering function for sIgD.
Reversal of changes in myocardial beta-receptors and inotropic responsiveness with regression of cardiac hypertrophy in renal hypertensive rats (RHR).
Authors: M H Ayobe, R C Tarazi
Journal: Circulation Research (1984)

Our previous studies, in vivo and in vitro, have shown reduced inotropic responsiveness to isoproterenol of hypertrophied hearts in renovascular hypertensive rats. In the present study, we have investigated, in the same model, the effects of treatment either by nephrectomy or captopril on the inotropic responsiveness to isoproterenol and on the number and affinity of ventricular beta-receptors. Isoproterenol infusion of isolated hearts from renovascular hypertensive rats 12-18 weeks post-clipping produced lower inotropic responses (delta peak dP/dt) than age-matched sham-operated normotensive rats (P less than 0.001). Quantitative assessment of beta-adrenergic receptors in the same hearts showed a significant decrease in renovascular hypertensive rats ventricular receptor numbers, whether calculated per milligram membrane protein (22.3 +/- 2.66 fmol/mg vs. 37.9 +/- 4.34, P less than 0.005) or per gram wet ventricular weight (1.43 +/- 0.14 pmol/g vs. 2.2 +/- 0.21, P less than 0.005), with no significant change in Kd. Control of hypertension by either nephrectomy or captopril led to regression of hypertrophy 6 weeks after stabilization of blood pressure (12-18 weeks post-clipping) and returned both the ventricular receptor density and inotropic responsiveness toward normal. The improvement in inotropic responsiveness to isoproterenol in regressed hearts correlated with both the reduction in ventricular weight and the decrease of blood pressure. Regression of hypertrophy did not alter the relationship between inotropic response, receptor density, and ventricular weight. These results indicate that the increase in cardiac mass associated with renovascular hypertension may interfere with adrenergic support to the heart, and that proper control of hypertension and regression of hypertrophy could reverse that impairment and restore its responsiveness to adrenergic stimulation.
Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice
Authors: Taro Fukao, Taketo Yamada, Masanobu Tanabe, Yasuo Terauchi, Takayuki Ota, Tetsuro Takayama, Tomoichiro Asano, Tsutomu Takeuchi, Takashi Kadowaki, Jun-ichi Hata, Shigeo Koyasu
Journal: Nature Immunology (2002)
Prevalence and clinical characteristics of myelodysplastic syndrome with bone marrow eosinophilia or basophilia
Authors: Takafumi Matsushima, Hiroshi Handa, Akihiko Yokohama, Jun Nagasaki, Hiromi Koiso, Yoshitora Kin, Yoko Tanaka, Tohru Sakura, Norifumi Tsukamoto, Masamitsu Karasawa, Katsuhiko Itoh, Hisami Hirabayashi, Morio Sawamura, Shogo Shinonome, Shun-ichi Shimano, Shuichi Miyawaki, Yoshihisa Nojima, Hirokazu Murakami
Journal: Blood (2003)
The Continued Use of Retracted, Invalid Scientific Literature
Authors: M P Pfeifer, G L Snodgrass
Journal: JAMA (1990)

Little is known about the ultimate scientific fate of retracted, invalid literature. We identified 82 completely retracted articles by electronic and manual methods and measured their subsequent use in the scientific literature by performing citation analysis. After retraction, these studies were cited, for support of scientific concepts, 733 times. Comparison with a control group revealed that retraction reduces subsequent citation by approximately 35%. There was no evidence that small, obscure journals, non-US journals, or non-US authors were disproportionately responsible for these citations. Although, after retraction, US authors accounted for a smaller percentage of citations, they continued to be the single greatest source. Several possible reasons why invalid information continues to be used were identified. These included a dearth of available information on retracted works; inconsistency in retraction format, terminology, and indexing; and an apparent lack of sufficient attention to manuscripts by some authors and editors. (<i>JAMA</i>. 1990;263:1420-1423)
Tumour necrosis factors receptor associated signalling molecules and their role in activation of apoptosis, JNK and NF-kappa B
Authors: B. B Aggarwal
Journal: Annals of the Rheumatic Diseases (2000)

Tumour necrosis factor (TNF) is a pleiotropic cytokine that mediates apoptosis, cell proliferation, immunomodulation, inflammation, viral replication, allergy, arthritis, septic shock, insulin resistance, autoimmune diseases, and other pathological conditions. TNF transduces these cellular responses through two distinct receptors: type I, which are expressed on all cell types, and type II, which are expressed only on cells of the immune system and endothelial cells. At the cellular level, these receptors activate the pathways leading to the activation of transcription factors NF-κB and AP-1, apoptosis and proliferation, and mitogen activated protein kinases. None of these receptors exhibit any enzymatic activity but the signals are transmitted through the recruitment of more than a dozen different signalling proteins, which together form signalling cascades. Inhibitors of TNF signalling have therapeutic value as indicated by the approval of the soluble TNF receptors and anti-TNF antibodies for rheumatoid arthritis and for inflammatory bowl disease.
Efficient stimulation of HIV-1-specific T cells using dendritic cells electroporated with mRNA encoding autologous HIV-1 Gag and Env proteins
Authors: Er Vangulck, P. Ponsaerts, L. Heyndrickx, K. Vereecken, F. Moerman, A. Deroo, R. Colebunders, G. Vandenbosch, Dr Vanbockstaele, Vf Vantendeloo, S. Allard, B. Verrier, C. Maranon, G. Hoeffel, A. Hosmalin, Zn Berneman, G. Vanham
Journal: Blood (2005)
Temporal Trends in Cause of Death Among Swedish and US Men with Prostate Cancer
Authors: M. M. Epstein, G. Edgren, J. R. Rider, L. A. Mucci, H.-O. Adami
Journal: JNCI Journal of the National Cancer Institute (2012)

BackgroundA growing proportion of men diagnosed with localized prostate cancer detected through prostate-specific antigen testing are dying from causes other than prostate cancer. Temporal trends in specific causes of death among prostate cancer patients have not been well described.
One single dose of etomidate negatively influences adrenocortical performance for at least 24 h in children with meningococcal sepsis
Authors: Marieke den Brinker, Anita C. S. Hokken-Koelega, Jan A. Hazelzet, Frank H. de Jong, Wim C. J. Hop, Koen F. M. Joosten
Journal: Intensive Care Medicine (2007)

To investigate the effect of one single bolus of etomidate used for intubation on adrenal function in children with meningococcal sepsis. Retrospective study conducted between 1997 and 2004. University-affiliated paediatric intensive care unit (PICU). Sixty children admitted to the PICU with meningococcal sepsis, not treated with steroids. Adrenal hormone concentrations were determined as soon as possible after PICU admission, and after 12 h and 24 h. To assess disease severity, PRISM score and selected laboratory parameters were determined. On admission, before blood was drawn, 23 children had been intubated with etomidate, 8 without etomidate and 29 were not intubated. Children who were intubated had significantly higher disease severity parameters than those not intubated, whereas none of these parameters significantly differed between children intubated with or without etomidate. Children who received etomidate had significantly lower cortisol, higher ACTH and higher 11-deoxycortisol levels than those who did not receive etomidate. Arterial glucose levels were significantly lower in children who were intubated with etomidate than in non-intubated children. When children were intubated with etomidate, cortisol levels were 3.2 times lower for comparable 11-deoxycortisol levels. Eight children died, seven of whom had received etomidate. Within 24 h cortisol/ACTH and cortisol/11-deoxycortisol ratios increased significantly in children who received etomidate, but not in children who did not, resulting in comparable cortisol/ACTH ratios with still significantly lowered cortisol/11-deoxycortisol ratios 24 h after admission. Our data imply that even one single bolus of etomidate negatively influences adrenal function for at least 24 h. It might therefore increase risk of death.
Dietary Sodium Intake and Risk of Cardiovascular Disease
Authors: Zhihao Liu, Xiwen Zhang
Journal: JAMA Internal Medicine (2015)

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α-Adrenergic Coronary Vasoconstriction and Myocardial Ischemia in Humans
Authors: Gerd Heusch, Dietrich Baumgart, Paolo Camici, William Chilian, Luisa Gregorini, Otto Hess, Ciro Indolfi, Ornella Rimoldi
Journal: Circulation (2000)

Abstract —The use of quantitative coronary angiography, combined with Doppler and PET, has recently been directed at the study of α-adrenergic coronary vasomotion in humans. Confirming prior animal experiments, there is no evidence of α-adrenergic coronary constrictor tone at rest. Again confirming prior experiments, responses to α-adrenoceptor activation are augmented in the presence of coronary endothelial dysfunction and atherosclerosis, involving both α 1 - and α 2 -adrenoceptors in epicardial conduit arteries and microvessels. Such augmented α-adrenergic coronary constriction is observed during exercise and coronary interventions, and it is powerful enough to induce myocardial ischemia and limit myocardial function. Recent studies indicate a genetic determination of α 2 -adrenergic coronary constriction.
Silibinin Inhibits Inflammatory and Angiogenic Attributes in Photocarcinogenesis in SKH-1 Hairless Mice
Authors: Mallikarjuna Gu, Rana P. Singh, Sivanandhan Dhanalakshmi, Chapla Agarwal, Rajesh Agarwal
Journal: Cancer Research (2007)

Abstract Sunscreens partially filter UVB and, therefore, could partially prevent skin cancer; however, efficient approaches are desired to effectively prevent photocarcinogenesis. It is hypothesized that nontoxic pharmacologically active natural compounds can increase photoprotective effects. Our completed studies suggest that silibinin, a bioactive phytochemical, strongly prevents photocarcinogenesis; however, its mechanism is not fully understood. Herein, for the first time, we used a clinically relevant UVB dose (30 mJ/cm2/day) to examine the photoprotective effect and associated mechanisms of silibinin in SKH1 hairless mice. Topical or dietary silibinin treatment caused a strong protection against photocarcinogenesis in terms of delay in tumor appearance, multiplicity, and volume. Analyses of normal skin, uninvolved skin from tumor-bearing mice, and skin tumors showed a statistically significant decrease (P &amp;lt; 0.05–0.001) in inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) levels by silibinin. Concomitantly, phospho–signal transducers and activators of transcription 3 (Tyr705) and phospho-p65(Ser536) were also decreased by silibinin, which are potential up-stream regulators of iNOS and COX-2. Simultaneously, silibinin also decreased UVB-caused increase in cell proliferation and microvessel density. In tumors, hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor protein levels were decreased by silibinin. Further analysis showed that silibinin inhibited UVB-caused phosphorylation and nuclear translocation of STAT3 and p65, as well as nuclear factor κB (NF-κB) DNA binding activity. Together, these results suggest that silibinin causes a strong protective effect against photocarcinogenesis via down-regulation of inflammatory and angiogenic responses, involving HIF-1α, STAT3, and NF-κB transcription factors, as well as COX2 and iNOS. [Cancer Res 2007;67(7):3483–91]
Gene Transfer–Mediated Pre-mRNA Segmental<i>Trans</i>-splicing As a Strategy to Deliver Intracellular Toxins for Cancer Therapy
Authors: Katsutoshi Nakayama, Robert G. Pergolizzi, Ronald G. Crystal
Journal: Cancer Research (2005)

Abstract Virus-mediated transfer of genes coding for intracellular toxins holds promise for cancer therapy, but the inherent toxicity of such vectors make them a risk to normal tissues and a challenge to produce due to the intrinsic dilemma that expression of toxin molecules kills producer cells. We employed pre-mRNA segmental trans-splicing (STS), in which two engineered DNA fragments coding for 5′ “donor” and 3′ “acceptor” segments of a toxin gene, respectively, are expressed by viral vectors. When co-delivered to target cells, the two vectors generate two toxin pre-mRNA fragments which are spliced by the target cell machinery to produce functional mRNA and toxin. To test this approach, we used an enzymatic fragment of Shigatoxin1A1 (STX1A1) known to provoke apoptotic cell death. Two adenovirus vectors, Shigatoxin1A1 donor (AdStx1A1Do) and Shigatoxin1A1 acceptor (AdStx1A1Ac), respectively, were used to deliver the Stx1A1 gene fragments. HeLa, HEp2, and A549 cells transfected with AdStx1A1Do and AdStx1A1Ac had a dose-dependent reduction in viability and inhibition of protein synthesis. Intratumoral injection of AdStx1A1Do and AdStx1A1Ac into preexisting HeLa, Hep2, and A549 tumors in immunodeficient mice revealed significant inhibition of tumor growth. There was no evidence of liver damage, suggesting that there was no leakage of vector or toxin from the site of injection following intratumoral injection of AdStx1A1Do and AdStx1A1Ac. These results suggest that the obstacles preventing gene transfer of intracellular toxins for local cancer therapy could be overcome by pre-mRNA segmental trans-splicing.
African Haplogroup L mtDNA Sequences Show Violations of Clock-like Evolution
Authors: Neil Howell, Joanna L. Elson, D. M. Turnbull, Corinna Herrnstadt
Journal: Molecular Biology and Evolution (2004)

A set of 96 complete mtDNA sequences that belong to the three major African haplogroups (L1, L2, and L3) was analyzed to determine if mtDNA has evolved as a molecular clock. Likelihood ratio tests (LRTs) were carried out with each of the haplogroups and with combined haplogroup sequence sets. Evolution has not been clock-like, neither for the coding region nor for the control region, in combined sets of African haplogroup L mtDNA sequences. In tests of individual haplogroups, L2 mtDNAs showed violations of a molecular clock under all conditions and in both the control and coding regions. In contrast, haplogroup L1 and L3 sequences, both for the coding and control regions, show clock-like evolution. In clock tests of individual L2 subclades, the L2a sequences showed a marked violation of clock-like evolution within the coding region. In addition, the L2a and L2c branch lengths of both the coding and control regions were shorter relative to those of the L2b and L2d sequences, a result that indicates lower levels of sequence divergence. Reduced median network analyses of the L2a sequences indicated the occurrence of marked homoplasy at multiple sites in the control region. After exclusion of the L2a and L2c sequences, African mtDNA coding region evolution has not significantly departed from a molecular clock, despite the results of neutrality tests that indicate the mitochondrial coding region has evolved under nonneutral conditions. In contrast, control region evolution is clock-like only at the haplogroup level, and it thus appears to have evolved essentially independently from the coding region. The results of the clock tests, the network analyses, and the branch length comparisons all caution against the use of simple mtDNA clocks.
Positive Concepts of Privacy in Research
Authors: Ralph K. Schwitzgebel
Journal: New England Journal of Medicine (1967)

THE "invasion of privacy" through the use of new technologic devices has been the subject of much current publicity. The Special Subcommittee on Invasion of Privacy of the Committee on Government Operations, better known as the "Gallagher Committee," has pointed out some of the dangers in the establishment of a central data bank by the federal Government. The Committee has also studied the implications of psychologic testing by federal agencies of employees and of recipients of federal grants and contracts.1 As a result, the use of evaluation tests by federal agencies has been considerably reduced.At about the same time . . .
Inherited Dysfunction of Sarcoplasmic Reticulum Ca <sup>2+</sup> Handling and Arrhythmogenesis
Authors: Silvia G. Priori, S.R. Wayne Chen
Journal: Circulation Research (2011)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease occurring in patients with a structurally normal heart: the disease is characterized by life-threatening arrhythmias elicited by stress and emotion. In 2001, the ryanodine receptor was identified as the gene that is linked to CPVT; shortly thereafter, cardiac calsequestrin was implicated in the recessive form of the same disease. It became clear that abnormalities in intracellular Ca(2+) regulation could profoundly disrupt the electrophysiological properties of the heart. In this article, we discuss the molecular basis of the disease and the pathophysiological mechanisms that are impacting clinical diagnosis and management of affected individuals. As of today, the interaction between basic scientists and clinicians to understand CPVT and identify new therapeutic strategies is one of the most compelling examples of the importance of translational research in cardiology.
Aortic and Mitral Annular Calcifications Are Predictive of All-Cause and Cardiovascular Mortality in Patients With Type 2 Diabetes
Authors: Andrea Rossi, Giovanni Targher, Giacomo Zoppini, Mariantonietta Cicoira, Stefano Bonapace, Carlo Negri, Vincenzo Stoico, Pompilio Faggiano, Corrado Vassanelli, Enzo Bonora
Journal: Diabetes Care (2012)

To examine the association of aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) with all-cause and cardiovascular mortality in type 2 diabetic individuals.We retrospectively analyzed the data from 902 type 2 diabetic outpatients, who had undergone a transthoracic echocardiography for clinical reasons during the years 1992-2007. AVS and MAC were diagnosed by echocardiography, and a heart valve calcium (HVC) score was calculated by summing up the AVS and MAC variables. The study outcomes were all-cause and cardiovascular mortality.At baseline, 477 (52.9%) patients had no heart valves affected (HVC-0), 304 (33.7%) had one valve affected (HVC-1), and 121 (13.4%) had both valves affected (HVC-2). During a mean follow-up of 9 years, 137 (15.2%) patients died, 78 of them from cardiovascular causes. Compared with patients with HVC-0, those with HVC-2 had the highest risk of all-cause and cardiovascular mortality, whereas those with HVC-1 had an intermediate risk (P < 0.0001 by the log-rank test). After adjustment for sex, age, BMI, systolic blood pressure, diabetes duration, A1C, LDL cholesterol, estimated glomerular filtration rate, smoking, history of myocardial infarction, and use of antihypertensive and lipid-lowering drugs, the hazard ratio of all-cause mortality was 2.3 (95% CI 1.1-4.9; P < 0.01) for patients with HVC-1 and 9.3 (3.9-17.4; P < 0.001) for those with HVC-2. Similar results were found for cardiovascular mortality.Our findings indicate that AVS and MAC, singly or in combination, are independently associated with all-cause and cardiovascular mortality in type 2 diabetic patients.