tbuckley/cabot-search huggingface dataset:
Detection of Redundant Fusion Transcripts as Biomarkers or Disease-Specific Therapeutic Targets in Breast Cancer
Authors: Yan W. Asmann, Brian M. Necela, Krishna R. Kalari, Asif Hossain, Tiffany R. Baker, Jennifer M. Carr, Caroline Davis, Julie E. Getz, Galen Hostetter, Xing Li, Sarah A. McLaughlin, Derek C. Radisky, Gary P. Schroth, Heather E. Cunliffe, Edith A. Perez, E. Aubrey Thompson
Journal: Cancer Research (2012)

Fusion genes and fusion gene products are widely employed as biomarkers and therapeutic targets in hematopoietic cancers, but their applications have yet to be appreciated in solid tumors. Here, we report the use of SnowShoes-FTD, a powerful new analytic pipeline that can identify fusion transcripts and assess their redundancy and tumor subtype-specific distribution in primary tumors. In a study of primary breast tumors, SnowShoes-FTD was used to analyze paired-end mRNA-Seq data from a panel of estrogen receptor (ER)(+), HER2(+), and triple-negative primary breast tumors, identifying tumor-specific fusion transcripts by comparison with mRNA-Seq data from nontransformed human mammary epithelial cell cultures plus the Illumina Body Map data from normal tissues. We found that every primary breast tumor that was analyzed expressed one or more fusion transcripts. Of the 131 tumor-specific fusion transcripts identified, 86 were "private" (restricted to a single tumor) and 45 were "redundant" (distributed among multiple tumors). Among the redundant fusion transcripts, 7 were unique to ER(+) tumors and 8 were unique to triple-negative tumors. In contrast, none of the redundant fusion transcripts were unique to HER2(+) tumors. Both private and redundant fusion transcripts were widely expressed in primary breast tumors, with many mapping to genomic loci implicated in breast carcinogenesis and/or risk. Our finding that some fusion transcripts are tumor subtype-specific suggests that these entities may be critical determinants in the etiology of breast cancer subtypes, useful as biomarkers for tumor stratification, or exploitable as cancer-specific therapeutic targets.
Exercise, Hypogonadism, and Osteopenia
Authors: B. Lawrence Riggs
Journal: JAMA (1986)

Bone mass increases in response to exercise but decreases in hypogonadism. Thus, it is increased in woman athletes who have normal menses but is decreased in those with amenorrhea.1-3This decrease in bone mass is associated with increased frequency of stress fractures of a lower extremity.2,3  Exercise-induced menstrual irregularity is common. Between 25% and 40% of highly trained endurance athletes report fewer than three menses per year.4Menstrual irregularities are more likely if training is begun at the time of, or shortly after, the menarche, before complete maturation of the hypothalamic-pituitary-ovarian axis.2,4  Why is there an association between amenorrhea and decreased bone mass? The decrease could be due to delayed skeletal maturation, increased rate of bone loss, or both. Most of the women studied so far have been in the age range of 18 to 29 years. Although linear growth ceases with closure of the epiphyses,
Protein phosphatase 2A contributes to the cardiac dysfunction induced by endotoxemia
Authors: M. Marshall, N. Anilkumar, J. Layland, S. J. Walker, J. C. Kentish, A. M. Shah, A. C. Cave
Journal: Cardiovascular Research (2009)

Sepsis-associated cardiac dysfunction represents an intrinsic impairment of cardiomyocyte function due in part to a decrease in myofilament Ca2+ sensitivity associated with a sustained increase in cardiac troponin I (cTnI) phosphorylation at Ser23/24. Dephosphorylation of cTnI is under regulatory control. Thus, muscarinic and adenosine A1-receptor agonists antagonize β-adrenergic stimulation via activation of protein phosphatase 2A (PP2A). The aim of this study was to determine whether modulation of PP2A and thus cTnI phosphorylation could improve sepsis-induced contractile dysfunction. Cardiomyocytes were isolated from control or septic mice 16–18 h after an injection of vehicle or lipopolysaccharide (LPS; 9 mg/kg ip) respectively. Protein expression and phosphatase activity were determined in homogenates of control and septic hearts. Our data showed that LPS significantly increased cTnI phosphorylation at Ser23/24 in cardiomyocytes and reduced contraction amplitude without affecting Ca2+-transients. Treatment of cardiomyocytes with the A1 agonist cyclopentyladenosine (CPA) or the protein kinase A inhibitor H89 significantly attenuated the LPS-induced contractile dysfunction without effect on Ca2+-transients. Co-treatment with CPA and H89 completely reversed the contractile dysfunction. Increased cTnI phosphorylation in septic hearts was associated with a significant reduction in the protein expression of both the catalytic and regulatory subunits (B56α) of PP2A and a decrease in PP2A activity. CPA treatment of septic hearts increased PP2A activity. An increase in the protein expression of demethylated PP2A and a decrease in the PP2A-methyltransferase (PPMT; the methyltransferase that catalyses this reaction) were also observed. These data support the hypothesis that sustained cTnI phosphorylation underlies the contractile dysfunction seen in sepsis.
Th17 Cells Promote Autoimmune Anti-Myeloperoxidase Glomerulonephritis
Authors: Poh-Yi Gan, Oliver M. Steinmetz, Diana S.Y. Tan, Kim M. O'Sullivan, Joshua D. Ooi, Yoichiro Iwakura, A. Richard Kitching, Stephen R. Holdsworth
Journal: Journal of the American Society of Nephrology (2010)

A major target autoantigen in anti-neutrophil cytoplasmic antibody-associated vasculitis is myeloperoxidase (MPO). Although MPO-specific CD4+ Th cells seem to orchestrate renal injury, the role of the Th17 subset is unknown. We hypothesized that Th17 cells direct injurious anti-MPO autoimmunity in experimental murine anti-MPO-induced glomerulonephritis (GN). We immunized mice with MPO to establish autoimmunity, resulting in systemic IL-17A production with MPO-specific dermal delayed-type hypersensitivity. We triggered disease using antibodies to the glomerular basement membrane to induce glomerular deposition of MPO by neutrophils. Wild-type mice developed necrotizing GN with an influx of glomerular leukocytes and albuminuria. In contrast, mice deficient in the key Th17 effector cytokine IL-17A were nearly completely protected. The protective effects resulted partly from reduced neutrophil recruitment, which led to less disposition of glomerular MPO. To test whether IL-17A also drives autoimmune delayed-type hypersensitivity in the kidney, we injected MPO into the kidneys of MPO-sensitized mice. IL-17A deficiency reduced accumulation of renal macrophages and renal CCL5 mRNA expression. In conclusion, IL-17A contributes to the pathophysiology of autoimmune anti-MPO GN, suggesting that it may be a viable therapeutic target for this disease.
Relationship Between Health Locus of Control, Health Value, and Social Support and Compliance of Persons with Diabetes Mellitus
Authors: Elizabeth A Schlenk, Laura K Hart
Journal: Diabetes Care (1984)

Thirty insulin-dependent outpatients were interviewed during one of their diabetes clinic visits. Questionnaires were used to measure the independent variables of health locus of control, health value, and perceived social support. Self-report and direct observation were used to measure the dependent variable, compliance with insulin administration, diet, exercise, hypoglycemia management, self-monitoring of blood glucose (SMBG), and foot care prescriptions. All patients complied with at least 70% of the points measured; half the group complied with at least 80% of the regimen. However, no one complied with all the behaviors deemed essential for good control. The group was most compliant with SMBG, hypoglycemia management, and insulin administration and least compliant with foot care and exercise. A statistically significant relationship was found between compliance and social support (P &amp;lt; 0.001), powerful others health locus of control (PHLC) (P &amp;lt; 0.01), and internal health locus of control (IHLC) (P &amp;lt; 0.05). A multiple regression analysis found that social support and PHLC accounted for at least 50% of the variance in compliance scores. The multiple-R of the independent variables with compliance reached a significance level of P &amp;lt; 0.005. However, only the two variables of social support and PHLC added significantly (P &amp;lt; 0.05) to prediction accuracy. The multiple-R of these two variables used as a set reached the significance level of P &amp;lt; 0.001.
Host humoral and cellular immune mechanisms in the continued suppression of Friend erythroleukemia metastases after interferon alpha/beta treatment in mice.
Authors: I Gresser, C Carnaud, C Maury, A Sala, P Eid, D Woodrow, M T Maunoury, F Belardelli
Journal: The Journal of Experimental Medicine (1991)

DBA/2 mice were injected intravenously with 2 x 10(6) 3C18 Friend erythroleukemia cells (FLC), a cell line resistant to interferon alpha/beta (IFN-alpha/beta). Although daily administration of mouse IFN-alpha/beta markedly increased the mean survival time, most IFN-treated mice continued to harbor FLC in different organs. To investigate the mechanisms responsible for this persistent suppression of FLC growth in IFN-treated mice, we undertook a series of adoptive transfer experiments with sera and spleen cells. Sera from FLC-injected, IFN-treated mice were very effective in conferring protection on DBA/2 mice even when injected systemically (intravenously) 18-24 h before intravenous challenge with FLC. These sera also exhibited antitumor activity when injected subcutaneously or intraperitoneally together with FLC. The protective factor in serum was shown to be an immunoglobulin. FLC-injected, IFN-treated mice developed antibodies to FLC demonstrable by radioimmunoassay and complement-dependent cytotoxicity. Sera from these mice recognized a specific 65-kD FLC membrane antigen(s) not detectable on membrane extracts from RBL-5 or ESb tumor cells, or on normal spleen cells. FLC-injected, IFN-treated mice also developed a specific cellular response demonstrable by transfer of protection with spleen cells injected intravenously or subcutaneously. Analysis of the responsible spleen cell populations indicated that the effector cells were neither T nor B cells. These results demonstrating the importance of host humoral and cellular immune mechanisms in the persistent suppression of FLC in IFN-treated mice may be relevant to the use of IFN-alpha/beta in patients in whom tumors may regress and tumor cells may then remain latent for extended periods of time.
2-[11C]Thymidine Positron Emission Tomography Reproducibility in Humans
Authors: Paula Wells, Roger N. Gunn, Colin Steel, Alex S. Ranicar, Frank Brady, Safiye Osman, Terry Jones, Pat Price
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To evaluate the reproducibility of 2-[11C]thymidine positron emission tomography (PET) scanning in patients with advanced intra-abdominal malignancies. Patients and Methods: The reproducibility of 2-[11C]thymidine PET was studied by comparing interpatient and intrapatient variability (coefficient of variability, COV) of both blood and tissue data. Arterial plasma metabolite levels were measured using on-line sampling and high-pressure liquid chromatography. 2-[11C]Thymidine retention in tissue was measured as the standardized uptake value at the end of the scan (SUVend), the area under the time-activity curve (AUC0-1 hour), and the fractional retention of thymidine (FRT). A group of seven patients were scanned 1 week apart with no intervening anticancer therapy. Results: There was interpatient variability in the levels of 2-[11C]thymidine and its main metabolite, 11CO2, in plasma. Variability in 2-[11C]thymidine PET data was greater between (COV: SUVend = 38%, AUC0-1 hour = 32%, FRT = 47%) than within (COV: SUVend = 8%, AUC0-1 hour = 2%, FRT = 9%) patients. There was a borderline significant difference between the paired tumor data for SUVend (P = 0.041), but not for AUC0-1 hour (P = 0.81) or FRT (P = 0.90). There was a good correlation between paired data for SUVend (r = 0.98), AUC0-1 hour (r = 0.99), and FRT (r = 0.95). Conclusions: This is the first report showing that 2-[11C]thymidine PET scanning is reproducible in humans. Repeat scanning of tumor proliferation using 2-[11C]thymidine PET is feasible to perform in human intra-abdominal malignancies and should aid the future rapid assessment of antiproliferative tumor agents.
INFLUENCE OF THE PITUITARY AND THE RENIN-ANGIOTENSIN SYSTEM ON THE SECRETION OF ALDOSTERONE, CORTISOL, AND CORTICOSTERONE
Authors: J. D. H. Slater, B. H. Barbour, H. H. Henderson, A. G. T. Casper, F. C. Bartter
Journal: Journal of Clinical Investigation (1963)

TABLE I Granularity of the juxtaglomerular cells in normal dogs given extra NaCl and desoxycorticosterone acetate and in hypophysectomized dogs deprived of NaCl Glomeruli Glomeruli Animals counted granulated JGI* no.no.no.O Na-deprived 2 689 13 1.9 7.1 Na-loaded 3 658 3 0.4 1.2
Inflammation, Insulin Resistance, and Diabetes—Mendelian Randomization Using CRP Haplotypes Points Upstream
Authors: Eric J Brunner, Mika Kivimäki, Daniel R Witte, Debbie A Lawlor, George Davey Smith, Jackie A Cooper, Michelle Miller, Gordon D. O Lowe, Ann Rumley, Juan P Casas, Tina Shah, Steve E Humphries, Aroon D Hingorani, Michael G Marmot, Nicholas J Timpson, Meena Kumari
Journal: PLoS Medicine (2008)

Background Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables. Methods and Findings We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29–1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p = 0.52–0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p = 0.007–0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p = 0.25–0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations. Conclusions Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP.
Outpatient Care Compared with Hospitalization for Community-Acquired Pneumonia
Authors: Jordi Carratalà, Núria Fernández-Sabé, Lucía Ortega, Xavier Castellsagué, Beatriz Rosón, Jordi Dorca, Ana Fernández-Agüera, Ricard Verdaguer, Joaquín Martínez, Frederic Manresa, Francesc Gudiol
Journal: Annals of Internal Medicine (2005)

Background: The Pneumonia Severity Index (PSI) has been advocated as an objective measure of risk stratification to help determine the initial site of treatment for patients with community-acquired pneumonia. Objective: To determine whether outpatient care of PSI-defined low-risk patients with community-acquired pneumonia is as safe and effective as hospitalization. Design: Unblinded, randomized, controlled trial. Setting: 2 tertiary care hospitals. Patients: 224 immunocompetent adults in risk class II or III (PSI scores ≤90 points) who received a diagnosis of community-acquired pneumonia in the emergency department and had no extenuating circumstances. Intervention: Outpatient care with oral levofloxacin therapy or hospitalization with sequential intravenous and oral levofloxacin therapy. Measurements: The primary end point was the percentage of patients with an overall successful outcome at the end of treatment, according to 7 predefined criteria. Secondary end points included patients' quality of life and satisfaction. Results: Overall successful outcome was achieved in 83.6% of outpatients and 80.7% of hospitalized patients (absolute difference, 2.9 percentage points [95% CI, −7.1 to 12.9 percentage points]). More outpatients were satisfied with their overall care (91.2% vs. 79.1%; absolute difference, 12.1 percentage points [CI, 1.8 to 22.5 percentage points]). Quality of life and the percentages of patients with adverse drug reactions (9.1% vs. 9.6%), medical complications (0.9% vs. 2.6%), subsequent hospital admissions (6.3% vs. 7.0%), and overall mortality (0.9% vs. 0%) were similar in the outpatient and hospitalization groups. Limitations: The power to detect a serious complication, such as death, was limited given the relatively small sample size. Conclusions: In selected patients who had community-acquired pneumonia, PSI risk class II and III, and were treated with levofloxacin, outpatient care in the absence of respiratory failure, unstable comorbid conditions, complicated pleural effusions, and social problems was as safe and effective as hospitalization and provided greater patient satisfaction.
We need a Public Health Act fit for 21st century
Authors: J. R. Ashton
Journal: BMJ (2015)

If I ruled the NHS, strengthened public health and primary and community care would go further than the currently fashionable talk of integration, to re-embrace housing and town planning and the “hidden lay healthcare system” that accounts for most care.

Other challenges I would tackle include bringing back robust local public health intelligence, no longer provided by the public health observatories, and a new approach to workforce development that recognises the importance of practical nursing and the reservoir of untapped young talent in our communities. It is lunacy to reject well …
Molecular Detection of Localized Prostate Cancer Using Quantitative Methylation-Specific PCR on Urinary Cells Obtained Following Prostate Massage
Authors: Morgan Rouprêt, Vincent Hupertan, David R. Yates, James W.F. Catto, Ishtiaq Rehman, Mark Meuth, Sylvie Ricci, Roger Lacave, Géraldine Cancel-Tassin, Alexandre de la Taille, François Rozet, Xavier Cathelineau, Guy Vallancien, Freddie C. Hamdy, Olivier Cussenot
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The diagnosis of localized prostate cancer is difficult due to a lack of cancer-specific biomarkers. Many patients require repeat prostate biopsies to diagnose the disease. We investigated whether aberrant promoter hypermethylation in prostatic fluid could reliably detect prostate cancer. Experimental Design: Urine samples were collected after prostate massage from 95 patients with localized prostate cancer undergoing radical prostatectomy (63 pT1, 31 pT2, and 1 pT3) and from 38 control patients. Ten genes (GSTP1, RASSF1a, ECDH1, APC, DAPK, MGMT, p14, p16, RARβ2, and TIMP3) were investigated using quantitative real-time methylation-specific PCR. Receiver operator curves were generated. Results: The frequency of gene methylation ranged from 6.3% (p14) to 83.2% (GSTP1) in prostate cancer patients. At least one gene was hypermethylated in 93% of cancer patients. The specificity of methylation was 0.74. Methylation was significantly more frequent (P &amp;lt; 0.05) in cancer than control patients for all genes except p14 and p16. According to receiver operator curve analysis, the four-gene combination of GSTP1 (0.86), RASSF1a (0.85), RARβ2 (0.80), and APC (0.74) best discriminated malignant from nonmalignant cases. The sensitivity and accuracy of this four-gene set were 86% and 89%, respectively. Conclusions: The presence of aberrant methylation in urinary cells obtained after prostate massage is significantly associated with prostate cancer. A panel of four genes could stratify patients into low and high risk of having prostate cancer and optimize the need for repeat prostatic biopsies.
Reawakening the cellular death program in neoplasia through the therapeutic blockade of IAP function
Authors: C. W. Wright
Journal: Journal of Clinical Investigation (2005)

Recent studies have shown that members of the inhibitor of apoptosis (IAP) protein family are highly expressed in several classes of cancer. The primary implication of these findings is that the elevated expression of IAPs is not coincidental but actually participates in oncogenesis by helping to allow the malignant cell to avoid apoptotic cell death. This concept, together with the discovery of several IAP-regulatory proteins that use a conserved mode of action, has stimulated a major effort by many research groups to devise IAP-targeting strategies as a means of developing novel antineoplastic drugs. In this Review, we consider the evidence both for and against the IAPs being valid therapeutic targets, and we describe the types of strategies being used to neutralize their functions.
Phase I and pharmacokinetic study of the multitargeted antifolate pemetrexed in combination with oxaliplatin in patients with advanced solid tumors
Authors: J.L. Misset, E. Gamelin, M. Campone, S. Delaloge, J.E. Latz, L. Bozec, P. Fumoleau
Journal: Annals of Oncology (2004)