tbuckley/cabot-search huggingface dataset:
Genetics and Breast Cancer Risk Prediction—Are We There Yet?
Authors: Nancy R. Cook, Nina P. Paynter
Journal: JNCI Journal of the National Cancer Institute (2010)

Whether information on genetic variants can be used for better prediction of disease risk is of current clinical interest. Previous studies have shown that mutations in the BRCA1 and BRCA2 genes are associated with high risk of breast cancer (1). Theoretical considerations suggest that further work will lead to the discovery of more genes that are involved in breast carcinogenesis (2). However, it requires more than proof of association to assess improvement in risk prediction by including genetic information. In this issue of the Journal, Mealiffe et al. (3) use data from the Women’s Health Initiative Clinical Trial to provide additional support for including genetic information in risk prediction models for breast cancer. This study finds that adding a small number of single-nucleotide polymorphisms to the well-known and established Gail model can improve the prediction of breast cancer. The authors (3) indicate that previous studies that added single-nucleotide polymorphisms to the Gail model for breast cancer risk prediction suffer from methodological limitations or are merely theoretical in nature. What statistical methods are appropriate to use in comparing risk prediction models has been subject to much recent debate. Standard analyses comparing receiver operating characteristic curves have been criticized as being insensitive to meaningful changes in predicted risk and not well suited to prospective data (4,5). Mealiffe et al. (3) use newer methods based on reclassification, or changes in risk strata, which have become relatively widespread in the clinical literature. A reclassification table sorts the predicted probabilities from each risk prediction model into clinically relevant risk categories and tabulates one against the other. The extent and accuracy of any reclassification, or change in risk category, indicate whether a model can generate improvements in risk stratification, and ultimately, decisions regarding therapies. The authors compute the net reclassification improvement (NRI), which compares the proportion of case patients appropriately moving up vs down a risk category with
The HELLP syndrome in the antiphospholipid syndrome: retrospective study of 16 cases in 15 women
Authors: D Le Thi Thuong, N Tieulié, N Costedoat, M-R Andreu, B Wechsler, D Vauthier-Brouzes, O Aumaître, J-C Piette
Journal: Annals of the Rheumatic Diseases (2005)

To study the characteristics of the haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome in the antiphospholipid syndrome (APS) and its influence on the subsequent pregnancies. This was a retrospective analysis of 16 episodes of HELLP complicating APS in 15 women. HELLP was complete in 10 cases and partial in six. It occurred during the second trimester in seven cases (the earliest at 18 weeks' gestation), the third trimester in seven cases, and the day following delivery in two cases. Pre-eclampsia was present in six cases and eclampsia in five. Outcome of pregnancies was: live birth (n = 8), stillbirth (n = 2) and fetal death (n = 6). APS was primary in nine women and secondary to systemic lupus erythematosus (SLE) in six. HELLP revealed primary APS in six cases. Seven women were not treated. Low dose aspirin was empirically prescribed in one woman whose APS had been undiagnosed despite a history of two fetal deaths. In the other women, therapy consisted of aspirin (n = 8), low molecular weight heparin with a dose varying between 3000 and 12 000 U daily (n = 5), and high dose immunoglobulin every 4 weeks (n = 2), hydroxychloroquine (n = 4), and prednisone (n = 6). Six women had seven subsequent pregnancies, 3-6 years after the complicated pregnancy. HELLP recurred at 33 weeks' gestation in one woman with SLE treated with prednisone, hydroxychloroquine, aspirin, and enoxaparin, and pregnancy ended in live birth. One woman became pregnant after in vitro fertilisation and embryo transfer, but pregnancy ended in fetal death despite prednisone, hydroxychloroquine, and enoxaparin. Four women had five uneventful pregnancies with 100 mg daily aspirin and heparin. APS may be revealed by HELLP. In APS, HELLP is associated with pre-eclampsia/eclampsia in most cases and seems to occur earlier than in the general population. Heparin plus aspirin may prevent obstetric complications in the subsequent pregnancies.
Selective Histocompatibility Leukocyte Antigen (Hla)-A2 Loss Caused by Aberrant Pre-mRNA Splicing in 624mel28 Melanoma Cells
Authors: Zhigang Wang, Francesco M. Marincola, Licia Rivoltini, Giorgio Parmiani, Soldano Ferrone
Journal: The Journal of Experimental Medicine (1999)

Histocompatibility leukocyte antigen (HLA)-A2 is used as a restricting element to present several melanoma-associated antigen (MAA)-derived peptides to cytotoxic T lymphocytes (CTLs). HLA-A2 antigen is selectively lost in primary melanoma lesions and more frequently in metastases. Only scanty information is available about the molecular mechanisms underlying this abnormality, in spite of its potentially negative impact on the clinical course of the disease and on the outcome of T cell–based immunotherapy. Therefore, in this study we have shown that the selective HLA-A2 antigen loss in melanoma cells 624MEL28 is caused by a splicing defect of HLA-A2 pre-mRNA because of a base substitution at the 5′ splice donor site of intron 2 of the HLA-A2 gene. As a result, HLA-A2 transcripts are spliced to two aberrant forms, one with exon 2 skipping and the other with intron 2 retention. The latter is not translated because of an early premature stop codon in the retained intron. In contrast, the transcript with exon 2 skipping is translated to a truncated HLA-A2 heavy chain without the α1 domain. Such a polypeptide is synthesized in vitro but is not detectable in cells, probably because of the low steady state level of the corresponding mRNA and the low translation efficiency. These results indicate that a single mutational event in an HLA class I gene is sufficient for loss of the corresponding allele. This may account, at least in part, for the high frequency of selective HLA class I allele loss in melanoma cells. Our conclusion emphasizes the need to implement active specific immunotherapy with a combination of peptides presented by various HLA class I alleles. This strategy may counteract the ability of melanoma cells with selective HLA class I allele loss to escape from immune recognition.
Diffuse Proliferative Lupus Glomerulonephritis
Authors: W. Scott Moore
Journal: JAMA (1980)

A patient with systemic lupus erythematosus, diffuse proliferative lupus glomerulonephritis, and deteriorating renal function was treated with immunosuppression. During the subsequent eight weeks of hemodialysis and immunosuppression, substantial recovery of renal function occurred, allowing for cessation of dialysis. In the following year, the endogenous creatinine clearance increased to 30 mL/min. A therapeutic trial of prednisone is indicated for patients with abrupt, severe deterioration in renal function in association with clinical, histological, or serological evidence of activity of lupus nephritis in the absence of other causes of renal failure. (<i>JAMA</i>244:63-65, 1980)
Breaking Free of Sample Size Dogma to Perform Innovative Translational Research
Authors: Peter Bacchetti, Steven G. Deeks, Joseph M. McCune
Journal: Science Translational Medicine (2011)

Innovative clinical and translational research is often delayed or prevented by reviewers' expectations that any study performed in humans must be shown in advance to have high statistical power. This supposed requirement is not justifiable and is contradicted by the reality that increasing sample size produces diminishing marginal returns. Studies of new ideas often must start small (sometimes even with an n of 1) because of cost and feasibility concerns, and recent statistical work shows that small sample sizes for such research can produce more projected scientific value per dollar spent than larger sample sizes. Renouncing false dogma about sample size would remove a serious barrier to innovation and translation.
Relationship Between Testosterone Levels, Insulin Sensitivity, and Mitochondrial Function in Men
Authors: Nelly Pitteloud, Vamsi K. Mootha, Andrew A. Dwyer, Megan Hardin, Hang Lee, Karl-Fredrik Eriksson, Devjit Tripathy, Maria Yialamas, Leif Groop, Dariush Elahi, Frances J. Hayes
Journal: Diabetes Care (2005)

OBJECTIVE— The goal of this study was to examine the relationship between serum testosterone levels and insulin sensitivity and mitochondrial function in men. RESEARCH DESIGN AND METHODS—A total of 60 men (mean age 60.5 ± 1.2 years) had a detailed hormonal and metabolic evaluation. Insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Mitochondrial function was assessed by measuring maximal aerobic capacity (Vo2max) and expression of oxidative phosphorylation genes in skeletal muscle. RESULTS—A total of 45% of subjects had normal glucose tolerance, 20% had impaired glucose tolerance, and 35% had type 2 diabetes. Testosterone levels were positively correlated with insulin sensitivity (r = 0.4, P &amp;lt; 0.005). Subjects with hypogonadal testosterone levels (n = 10) had a BMI &amp;gt;25 kg/m2 and a threefold higher prevalence of the metabolic syndrome than their eugonadal counterparts (n = 50); this relationship held true after adjusting for age and sex hormone–binding globulin but not BMI. Testosterone levels also correlated with Vo2max (r = 0.43, P &amp;lt; 0.05) and oxidative phosphorylation gene expression (r = 0.57, P &amp;lt; 0.0001). CONCLUSIONS—These data indicate that low serum testosterone levels are associated with an adverse metabolic profile and suggest a novel unifying mechanism for the previously independent observations that low testosterone levels and impaired mitochondrial function promote insulin resistance in men.
THE ROLE OF RECEPTOR KINASES AND ARRESTINS IN G PROTEIN–COUPLED RECEPTOR REGULATION
Authors: Jason G. Krupnick, Jeffrey L. Benovic
Journal: The Annual Review of Pharmacology and Toxicology (1998)

▪ Abstract G protein–coupled receptors (GPRs) play a key role in controlling hormonal regulation of numerous second-messenger pathways. However, following agonist activation, most GPRs rapidly lose their ability to respond to hormone. For many GPRs, this process, commonly referred to as desensitization, appears to be primarily mediated by two protein families: G protein–coupled receptor kinases (GRKs) and arrestins. GRKs specifically bind to the agonist-occupied receptor, thereby promoting receptor phosphorylation, which in turn leads to arrestin binding. Arrestin binding precludes receptor/G protein interaction leading to functional desensitization. Many GPRs are then removed from the plasma membrane via clathrin-mediated endocytosis. Recent studies have implicated endocytosis in the resensitization of GPRs and have linked both GRKs and arrestins to this process. In this review, we discuss the role of GRKs and arrestins in regulating agonist-specific signaling and trafficking of GPRs.
FACTORS ASSOCIATED TO PATELLAR TENDINOSIS IN ATHLETES: PROVIDING A BASE FOR INJURY MECHANISM AND PREVENTION
Authors: L Mendonça, S Fonseca, N Bittencourt, J Ocarino, G Gonçalves, E Verhagen
Journal: British Journal of Sports Medicine (2014)

Background Patellar tendon abnormalities (PTA) are frequent in volleyball and basketball athletes. Tendon degeneration happens through chronic process, related to the amount of stress applied in musculoskeletal system. An appropriated mechanical behaviour of lower limb may be key factor to properly distribute forces in patellar tendon during landing. Identify biomechanical factors associated to patellar tendinosis process could guide preventive attitudes to athletes in risk of chronic dysfunction and/or tendon rupture. Objective To investigate the association of lower limb biomechanical factors to patellar tendon morphological abnormalities at ultrasound. Design Cross-sectional. Setting Institutional clinical care and sports facility. Participants 35 basketball and volleyball athletes participating on preseason assessment with mean age of 24.0±5.7 years, body mass of 88.9±13.3 kg and height of 1.9±0.1 m. Risk factor assessment Ankle dorsiflexion range (ADR), shank-forefoot alignment (SFA), iliotibial band flexibility (IBF), hip lateral rotators and abductors isometric strength, hip passive medial rotation range, patellar rotation and knee alignment in the frontal plane were measured during preseason assessment. Ultrasonographic evaluation was performed in both patellar tendons in longitudinal and transverse planes. Main outcome measurements Patellar tendon hypoechoic areas and thickness at ultrasound. Results The results showed that low ADR, high IBF and high SFA were associated to PTA. These three variables presented significant areas under ROC curve (P=.008; P=.011; P=.012, respectively). Based on ROC curve sensitivity and specificity values, cut-off points were determined. SFA presented the highest OR; 13.1 (2.1–296); with a cut-off point of 20 o . ADR (cut-off point=36 o ) presented an OR of 4.10 (1.3–13.5) and IBF (cut-off point=-0.04 o ) presented an OR of 4.53 (1.2–21.6). Conclusions High shank-forefoot varus alignment, ankle dorsiflexion restriction and iliotibial band flexible were associated to PTA. These results show that biomechanical factors could participate on patellar tendon mechanical overload in athletes.
Simian immunodeficiency virus needlestick accident in a laboratory worker
Authors: R.F. Khabbaz, T. Rowe, W.M. Heneine, J.E. Kaplan, T.M. Folks, C.A. Schable, J.R. George, C. Pau, B.S. Parekh, J.W. Curran, G. Schochetman, M.D. Lairmore, M. Murphey-Corb
Journal: The Lancet (1992)
Long-Term Effects of Intensive Glucose Lowering on Cardiovascular Outcomes
Authors: Hertzel C. Gerstein, Michael E. Miller, Saul Genuth, Faramarz Ismail-Beigi, John B. Buse, David C. Goff, Jeffrey L. Probstfield, William C. Cushman, Henry N. Ginsberg, J. Thomas Bigger, Richard H. Grimm, Robert P. Byington, Yves D. Rosenberg, William T. Friedewald
Journal: New England Journal of Medicine (2011)

Intensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease. This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events.
Brief Communication: An Attenuated Mouse Leukemia Virus. I. Origin and Immunization2
Authors: W. H. Kirsten, E. Stefanski, S. Panem
Journal: JNCI Journal of the National Cancer Institute (1974)

An attenuated Kirsten murine leukemia virus was isolated from the culture fluids of a chronically infected C3Hf/Gs mouse embryo cell line. The attenuated virus failed to induce erythroblastosis or lymphomas in mice after 16–18 months. Inoculation of 3-week-old C3Hf/Gs mice with attenuated leukemia virus prevented induction of erythroblastosis or lymphomas by virulent virus given 1 month later. A similar protective effect was observed when 3-week-old Wistar/Furth rats were inoculated with attenuated virus and challenged 1 month later with a lethal dose of rat-adapted leukemia virus.
Reversal of nzb/nzw disease with total lymphoid irradiation.
Authors: B L Kotzin, S Strober
Journal: The Journal of Experimental Medicine (1979)

NZB/NZW mice spontaneously exhibit autoimmune disease similar to that seen in human systemic lupus erythematosus (SLE). We demonstrated that total lymphoid irradiation (TLI) reversed well expressed disease in 6-mo-old NZB/NZW females with a prolongation in survival, decrease in proteinuria, and decrease in anti-DNA antibodies as compared to control animals. Few side effects were observed in the treated group. TLI also prolonged survival in animals with advanced renal disease. These findings suggest that TLI may have application to the treatment of human SLE.
The Effect of Glucocorticoids on the Relative Distribution of Aspartate Aminotransferase Isozymes of Morris Hepatoma 5123B
Authors: Theodore T. Otani, Harold P. Morris
Journal: Cancer Research (1968)

Summary  The effect of adrenal glucocorticoids on the activity and on the relative isozyme distribution of aspartate aminotransferase from normal liver and from Hepatoma 5123B (Morris) under a defined set of conditions was studied.  Although no marked effect was observed on the specific activities and on the relative isozyme distribution of the aspartate aminotransferase from normal female rat liver after adrenalectomy, hydrocortisone treatment, or both, there appeared to be some responsiveness by aspartate aminotransferase of Hepatoma 5123B to these treatments. Adrenalectomy effected a decrease in specific activity of the aspartate aminotransferase from Hepatoma 5123B, while hydrocortisone caused a slight increase in specific activity, as well as a change in the isozyme distribution in favor of the cationic or mitochondrial component. A combination of adrenalectomy and hydrocortisone treatment caused a normalization of the two effects on the specific activity and an alteration of the isozyme distribution favoring the cationic component.  Under the conditions of these experiments, the specific activity of the aspartate aminotransferase from normal male rat liver remained essentially unchanged upon administration of cortisone. However, adrenalectomy of the tumor-bearing male animal caused a decrease, and cortisone administration, a slight increase in specific activity of the tumor aspartate aminotransferase. Cortisone or hydrocortisone administration to adrenalectomized male tumor-bearing rats neither normalized the decrease in tumor aspartate aminotransferase activity caused by the adrenalectomy nor caused an alteration in the isozyme profile.
Outcome markers for clinical trials in cerebral amyloid angiopathy
Authors: Steven M Greenberg, Rustam Al-Shahi Salman, Geert Jan Biessels, Mark van Buchem, Charlotte Cordonnier, Jin-Moo Lee, Joan Montaner, Julie A Schneider, Eric E Smith, Meike Vernooij, David J Werring
Journal: The Lancet Neurology (2014)
MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B
Authors: Jennifa Gosling, Sarah Slaymaker, Long Gu, Susan Tseng, Constance H. Zlot, Stephen G. Young, Barrett J. Rollins, Israel F. Charo
Journal: Journal of Clinical Investigation (1999)

The earliest recognizable atherosclerotic lesions are fatty streaks composed of lipid-laden macrophages (foam cells). Circulating monocytes are the precursors of these foam cells, but the molecular mechanisms that govern macrophage trafficking through the vessel wall are poorly understood. Monocyte chemoattractant protein-1 (MCP-1), a member of the chemokine (chemotactic cytokine) family, is a potent monocyte agonist that is upregulated by oxidized lipids. Recent studies in hypercholesterolemic mice lacking apo E or the low-density lipoprotein receptor have suggested a role for MCP-1 in monocyte recruitment to early atherosclerotic lesions. To determine if MCP-1 is critically involved in atherogenesis in the setting of elevated physiological plasma cholesterol levels, we deleted the MCP-1 gene in transgenic mice expressing human apo B. Here we report that the absence of MCP-1 provides dramatic protection from macrophage recruitment and atherosclerotic lesion formation in apo B transgenic mice, without altering lipoprotein metabolism. Taken together with the results of earlier studies, these data provide compelling evidence that MCP-1 plays a critical role in the initiation of atherosclerosis.
Voltage-gated potassium channels are required for human T lymphocyte activation.
Authors: K G Chandy, T E DeCoursey, M D Cahalan, C McLaughlin, S Gupta
Journal: The Journal of Experimental Medicine (1984)

The calcium channel blockers, verapamil and diltiazem, inhibit phytohemagglutinin (PHA)-induced mitogenesis at concentrations that block the T lymphocyte K channel currents. K channel blockers also inhibit the allogeneic mixed lymphocyte response in a dose-dependent manner with the same potency sequence as for block of K currents. K channel blockers inhibit PHA-stimulated mitogenesis only if added during the first 20-30 h after PHA addition, but not later, indicating a requirement for functional K channels during this period. We investigated the effect of K channel blockers on various aspects of protein synthesis for two reasons: first, protein synthesis appears to be necessary for the events leading to DNA synthesis, and second, the increase in the protein synthetic rate commences during the first 24-48 h after PHA addition. PHA-induced total protein synthesis was reduced to the level in unstimulated T lymphocytes by K channel blockers in a dose-dependent manner with the same potency sequence as for the block of K currents and inhibition of [3H]thymidine incorporation. Two-dimensional gel electrophoresis demonstrated that although the synthesis of the majority of proteins was reduced by K channel blockers to the level in unstimulated T cells, some proteins continued to be synthesized at an enhanced rate compared with resting cells. Two proteins, S and T, detected by two-dimensional gel electrophoresis in unstimulated T lymphocytes, appeared to be reduced in intensity in gels of PHA-treated T lymphocytes, in contrast to the increased synthesis of the remaining proteins. 4-Aminopyridine (4-AP), at concentrations that inhibit protein synthesis, prevented the apparent PHA-induced reduction of proteins S and T. These proteins may play a role in maintaining the T lymphocyte in a resting state and may be related to the translation inhibitory factors reported to be present at a higher specific activity in quiescent T lymphocytes than in PHA-activated T cells. The expression of the IL-2 receptor (Tac) during T lymphocyte activation was not altered by K channel blockers, whereas the production of interleukin 2 (IL-2) was reduced to the level in unstimulated T lymphocytes. Exogenous IL-2 partially relieved the inhibition of mitogenesis by low, but not by high, concentrations of 4-AP. These experiments clarify the role of K channels in T lymphocyte activation and suggest that functional K channels are required either for protein synthesis or for events leading to protein synthesis.
A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia
Authors: Ruben A. Mesa, David P. Steensma, Animesh Pardanani, Chin-Yang Li, Michelle Elliott, Scott H. Kaufmann, Gregory Wiseman, Leigh A. Gray, Georgene Schroeder, Terra Reeder, Jerome B. Zeldis, Ayalew Tefferi
Journal: Blood (2003)