tbuckley/cabot-search huggingface dataset:
Erythrocyte Membrane Fatty Acids and Subsequent Breast Cancer: a Prospective Italian Study
Authors: V. Pala, V. Krogh, P. Muti, V. Chajes, E. Riboli, A. Micheli, M. Saadatian, S. Sieri, F. Berrino
Journal: JNCI Journal of the National Cancer Institute (2001)

The relationship between erythrocyte membrane fatty acids and postmenopausal breast cancer risk was analyzed previously only by retrospective studies, which suggested a protective effect of increased saturation index (SI), i.e., the ratio of membrane stearic to oleic acid. We investigated the relationships in a prospective study of hormones, diet, and prediagnostic breast cancer (the ORDET study) conducted in northern Italy.A total of 4052 postmenopausal women were followed for an average of 5.5 years; 71 cases of invasive breast cancer were identified. For each case subject, two matched control subjects were chosen randomly from among cohort members. The various fatty acids in erythrocyte membranes were measured as a percentage of total fatty acids. Conditional logistic regression analysis evaluated the association between membrane fatty acid composition and breast cancer risk. The SI, which is influenced by the activity of the enzyme delta 9 desaturase (Delta 9-d), was also investigated. All statistical tests were two-sided.Oleic (highest versus lowest tertile of percentage of total fatty acids, odds ratio [OR] = 2.79; 95% confidence interval [CI] = 1.24 to 6.28) and monounsaturated fatty acids (highest to lowest tertile, OR = 5.21; 95% CI = 1.95 to 13.91) were positively associated with breast cancer risk. The SI (highest to lowest tertile, OR = 0.29; 95% CI = 0.13 to 0.64) was inversely associated with breast cancer risk. The analysis suggested an inverse association between total polyunsaturated fatty acids and breast cancer risk, but individual polyunsaturated fatty acids behaved differently. There was no association between saturated fatty acids and breast cancer risk.We have found that monounsaturated fats and SI in erythrocyte membranes are predictors of postmenopausal breast cancer. Both of these variables depend on the activity of the enzyme Delta 9-d. The dietary, metabolic, and hormonal factors acting on Delta 9-d expression and activity and, therefore, on patterns of fatty acid metabolism, should be further investigated as possible determinants of breast cancer.
Mechanisms of FUS1/TUSC2 deficiency in mesothelioma and its tumorigenic transcriptional effects
Authors: Alla V Ivanova, Sergey V Ivanov, Ljudmila Prudkin, Daisuke Nonaka, Zhandong Liu, Anne Tsao, Ignacio Wistuba, Jack Roth, Harvey I Pass
Journal: Molecular Cancer (2009)

FUS1/TUSC2 is a novel tumor suppressor located in the critical 3p21.3 chromosomal region frequently deleted in multiple cancers. We previously showed that Tusc2-deficient mice display a complex immuno-inflammatory phenotype with a predisposition to cancer. The goal of this study was to analyze possible involvement of TUSC2 in malignant pleural mesothelioma (MPM) - an aggressive inflammatory cancer associated with exposure to asbestos. TUSC2 insufficiency in clinical specimens of MPM was assessed via RT-PCR (mRNA level), Representational Oligonucleotide Microarray Analysis (DNA level), and immunohistochemical evaluation (protein level). A possible link between TUSC2 expression and exposure to asbestos was studied using asbestos-treated mesothelial cells and ROS (reactive oxygen species) scavengers. Transcripional effects of TUSC2 in MPM were assessed through expression array analysis of TUSC2-transfected MPM cells. Expression of TUSC2 was downregulated in ~84% of MM specimens while loss of TUSC2-containing 3p21.3 region observed in ~36% of MPMs including stage 1 tumors. Exposure to asbestos led to a transcriptional suppression of TUSC2, which we found to be ROS-dependent. Expression array studies showed that TUSC2 activates transcription of multiple genes with tumor suppressor properties and down-regulates pro-tumorigenic genes, thus supporting its role as a tumor suppressor. In agreement with our knockout model, TUSC2 up-regulated IL-15 and also modulated more than 40 other genes (~20% of total TUSC2-affected genes) associated with immune system. Among these genes, we identified CD24 and CD274, key immunoreceptors that regulate immunogenic T and B cells and play important roles in systemic autoimmune diseases. Finally, clinical significance of TUSC2 transcriptional effects was validated on the expression array data produced previously on clinical specimens of MPM. In this analysis, 42 TUSC2 targets proved to be concordantly modulated in MM serving as disease discriminators. Our data support immuno-therapeutic potential of TUSC2, define its targets, and underscore its importance as a transcriptional stimulator of anti-tumorigenic pathways.
Clinical and Molecular Characteristics of Malignant Transformation of Low-Grade Glioma in Children
Authors: Alberto Broniscer, Suzanne J. Baker, Alina N. West, Melissa M. Fraser, Erika Proko, Mehmet Kocak, James Dalton, Gerard P. Zambetti, David W. Ellison, Larry E. Kun, Amar Gajjar, Richard J. Gilbertson, Christine E. Fuller
Journal: Journal of Clinical Oncology (2007)

Purpose To analyze the clinical and molecular characteristics of malignant transformation (MT) of low-grade glioma (LGG) in children. Patients and Methods The clinical, radiologic, and histologic characteristics of children treated at our institution who experienced MT of LGG were reviewed. Molecular alterations in these tumors were analyzed by fluorescent in situ hybridization, immunohistochemistry, and TP53 sequencing. Cumulative incidence estimate and risk factors for MT were determined for 65 patients with grade 2 astrocytoma treated at our institution during the study interval. Results Eleven patients who experienced MT were identified (median age at diagnosis of LGG, 13.3 years). Initial diagnoses were grade 2 astrocytoma (n = 6) and other grade 1/2 gliomas (n = 5). The median latency of MT was 5.1 years. Histologic diagnoses after MT were glioblastoma (n = 7) and other high-grade gliomas (n = 4). The 15-year cumulative incidence estimate of MT among 65 patients with grade 2 astrocytoma was 6.7% ± 3.9%; no risk factor analyzed, including radiotherapy, was associated with MT. Tissue was available for molecular analysis in all patients, including nine with samples obtained before and after MT. TP53 overexpression was more common after MT. Deletions of RB1 and/or CDKN2A were observed in 71% of LGGs and in 90% of tumors after MT. PTEN pathway abnormalities occurred in 76% of patients. One of five oncogenes analyzed (PDGFRA) was amplified in one patient. Conclusion The molecular abnormalities that occur during MT of LGG in children are similar to those observed in primary and secondary glioblastoma in adults.
Long-term control of plasma calcitriol concentration in dogs and humans. Dominant role of plasma calcium concentration in experimental hyperparathyroidism.
Authors: H N Hulter, B P Halloran, R D Toto, J C Peterson
Journal: Journal of Clinical Investigation (1985)

Despite great interest in the elevated circulating levels of calcitriol (1,25-[OH]2D) associated with the clinical syndrome of human primary hyperparathyroidism, the relative potencies of known and potential stimuli/suppressors of long-term calcitriol levels have not been evaluated in either clinical or experimentally induced hyperparathyroid states. Based on reports that aparathyroid animals exhibit suppressed plasma calcitriol concentration and that acute administration of parathyroid hormone (PTH) to both humans and experimental animals or to renal slices in vitro results in increased plasma calcitriol concentration/production rate, it might be predicted that a chronic experimental model of either hypercalcemic primary hyperparathyroidism or hypocalcemic secondary hyperparathyroidism would show increased plasma calcitriol concentration. Chronic alterations in plasma calcium concentration have not been implicated as modulating calcitriol levels in any species. Accordingly, we investigated the long-term response of plasma calcitriol concentration in states of sustained experimental primary and secondary hyperparathyroidism. Intact dogs (group I) undergoing continuous intravenous PTH infusion for 12 d developed sustained hypercalcemia and hypophosphatemia, and plasma calcitriol concentration decreased from 23 +/- 3 to 14 +/- 3 pg/ml (P less than 0.01). Subsequent chelator (EGTA)-induced chronic normalization of hypercalcemia during ongoing PTH infusion resulted in a large and sustained increase in plasma calcitriol concentration to supernormal levels, reversible during subsequent cessation of chelator infusion. In additional intact dogs (group II), chronic chelator-induced hypocalcemic secondary hyperparathyroidism resulted in a sustained increase in plasma calcitriol concentration despite hyperphosphatemia. In normal human subjects undergoing a 12-13-d continuous intravenous PTH infusion to result in sustained moderate hypercalcemia (12.0 +/- 0.2 mg/100 ml) and hypophosphatemia, plasma calcitriol concentration decreased significantly (P less than 0.01) as in group I dogs and was followed by reversal to normal levels in a recovery period. The present results provide strong evidence in both humans and dogs that during experimentally induced chronic PTH excess, alterations in plasma calcium concentration dictate the directional response of circulating calcitriol concentrations. The long-term potency of plasma calcium concentration as a modulator of calcitriol metabolism is sufficient to override opposing modulation by plasma phosphorus concentration and PTH.
Breast Cancer Risks in Relatives of Male Breast Cancer Patients
Authors: D. E. Anderson, M. D. Badzioch
Journal: JNCI Journal of the National Cancer Institute (1992)

Previous studies have provided conflicting results concerning the familial effect of male breast cancer on breast cancer risks in female relatives.We studied breast cancer risks in first-degree relatives of male patients and compared them with relatives of female patients.Our study included 88 consecutively ascertained male patients and 320 of their first-degree relatives as well as 186 consecutively ascertained female patients and 633 of their first-degree relatives. Observed numbers of breast cancers in relatives were compared with the expected number derived from the Connecticut Tumor Registry. Multiple logistic regression analysis was also performed.Relatives of male patients exhibited a significant twofold increased risk when compared with expected rates and no difference in risk when compared with that of relatives of female patients. Prostate cancer in the family of a male patient resulted in a significant fourfold increased breast cancer risk compared with a risk of 1.4 in families with no history of prostate cancer. A family history of lung cancer, colon cancer, or melanoma had no effect on increasing risks of breast cancer.The familial effect of male breast cancer is the same as that of female breast cancer.Any estimates of breast cancer risk provided to individuals should also consider the occurrence of prostate cancer in the family, since prostate cancer appears capable of at least doubling the underlying twofold risk.
Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth: population based cohort study
Authors: B. H. Bech, M. I. S. Kjaersgaard, H. S. Pedersen, P. P. Howards, M. J. Sorensen, J. Olsen, E. T. Parner, L. H. Pedersen, M. Vestergaard, J. Christensen
Journal: BMJ (2014)

<b>Objective</b> To determine whether use of antiepileptic drugs during pregnancy may increase the risk of spontaneous abortion or stillbirth. <b>Design</b> Population based cohort study. <b>Setting</b> Register based study in Denmark, 1997-2008. <b>Participants</b> 983 305 pregnancies identified in the Danish medical birth register and the Danish national hospital discharge register from 1 February 1997 to 31 December 2008 were linked to the Danish Register of Medicinal Product Statistics to obtain information on use of antiepileptic drugs. <b>Main outcome measures</b> Risk ratio of spontaneous abortion and stillbirth after use of antiepileptic drugs during pregnancy, estimated by using binomial regression adjusting for potential confounders of maternal age, cohabitation, income, education, history of severe mental disorder, and history of drug misuse. <b>Results</b> Antiepileptic drugs were used in a total of 4700 (0.5%) pregnancies. 16 out of 100 pregnant women using antiepileptics and 13 out of 100 pregnant women not using antiepileptics experienced a spontaneous abortion. After adjusting for potential confounders pregnant women using antiepileptics had a 13% higher risk of spontaneous abortions than pregnant women not using antiepileptics (adjusted risk ratio 1.13, 95% confidence interval 1.04 to 1.24). However, the risk of spontaneous abortion was not increased in women with an epilepsy diagnosis (0.98, 0.87 to 1.09), only in women without a diagnosis of epilepsy (1.30, 1.14 to 1.49). In an analysis including women with at least two pregnancies with discordant antiepileptic drug use (for example, use in the first pregnancy but not in the second), the adjusted hazard ratio for spontaneous abortion was 0.83 (0.69 to 1.00) for exposed pregnancies compared with unexposed pregnancies. Stillbirth was identified in 18 women who used antiepileptic drugs (unadjusted risk ratio 1.29, 0.80 to 2.10). <b>Conclusion</b> Among women with epilepsy and when analysing the risk in antiepileptic drug discordant pregnancies in the same woman, we found no overall association between the use of antiepileptic drugs during pregnancy and spontaneous abortions. Therefore unmeasured confounding may explain the slight increased risk for spontaneous abortion with any antiepileptic drug use (among women both with and without epilepsy). We found no association between antiepileptic drug use during pregnancy and stillbirth, but the statistical precision was low.
Use of Aspirin, Other Nonsteroidal Anti-Inflammatory Drugs, and Acetaminophen and Postmenopausal Breast Cancer Incidence
Authors: Xuehong Zhang, Stephanie A. Smith-Warner, Laura C. Collins, Bernard Rosner, Walter C. Willett, Susan E. Hankinson
Journal: Journal of Clinical Oncology (2012)

The associations between use of aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen and breast cancer incidence in postmenopausal women are uncertain. We examined these associations with breast cancer, both overall and by molecular subtype.We observed 84,602 postmenopausal women, free of cancer in 1980, until June 2008 and prospectively collected data on analgesic use, reproductive history, and other lifestyle factors using biennial questionnaires. Proportional hazards models were used to estimate multivariable relative risks (RRs) and 95% CIs.We documented 4,734 cases of incident invasive breast cancer. Compared with nonuse of aspirin, multivariable RRs of regular aspirin use (≥ two tablets per week) for more than 20 years were 0.91 for overall breast cancer (95% CI, 0.81 to 1.01; P(trend) = 0.16), 0.90 for estrogen receptor (ER) -positive progesterone receptor (PR) -positive breast cancer (95% CI, 0.77 to 1.06; P(trend) = 0.17), and 0.91 for ER-negative PR-negative breast cancer (95% CI, 0.68 to 1.22; P(trend) = 0.97). Results did not vary appreciably by past or current use, days per week of use, or dosage of use. Use of other NSAIDs and acetaminophen was largely not significantly associated with breast cancer risk. Additionally, use of higher doses of each analgesic (≥ six tablets per week) for more than 10 years was generally not significantly associated with risk of breast cancer, either overall or by subtype. Furthermore, largely no substantial associations were noted for breast cancer molecular subtypes, including luminal A, luminal B, triple negative, basal-like, human epidermal growth factor receptor 2 positive, cyclooxygenase-2 (COX-2) negative, and COX-2 positive.Our study suggests that use of aspirin, other NSAIDs, and acetaminophen is not importantly associated with risk of postmenopausal breast cancer, either overall or by specific subtype.
The effects of prolonged substitution of recombinant human growth hormone on renal functional reserve in growth hormone-deficient adults.
Authors: M Riedl, M Hass, R Oberbauer, J Gisinger, A Luger, G Mayer
Journal: Journal of the American Society of Nephrology (1995)

Twelve growth hormone (GH)-deficient adults with normal renal function were recruited for a 6-month, double-blind, placebo-controlled study on the effects of prolonged recombinant human growth hormone (rhGH) substitution therapy on renal functional parameters. RhGH was administered at a dose 0.125 IU/kg per week sc the first 4 wk and 0.25 IU/kg per week thereafter. At baseline and after 6 months of therapy, GFR and RPF were measured by the use of iothalamate and para- aminohippurate clearance techniques before and after an intravenous infusion of amino acids (AA) to determine the renal functional reserve capacity (RFRC). At baseline, GFR and RPF were similar in the GH-deficient patients and a group of normal, healthy controls (GFR, 117 +/- 10 mL/min; RPF, 567 +/- 57 mL/min, and filtration fraction, 22 +/- 1.6% in the patient group and GFR, 117 +/- 10 mL/min; RPF, 509 +/- 54 mL/min; and filtration fraction, 24 +/- 1.3% in the control group). GFR increased significantly in the control and patient group after AA infusion; the RFRC, however, was significantly larger in healthy individuals (GFR post-AA infusion, 141 +/- 10 mL in GH-deficient patients and 182 +/- 20 mL/min in controls). Thereafter, six patients received placebo therapy for 6 months and GFR as well as RFRC remained constant (GFR, 107 +/- 9 and 106 +/- 12 mL/min before AA infusion and 132 +/- 14 and 134 +/- 5 mL/min after AA infusion at baseline and after 6 months, respectively). Four patients of the placebo group then continued with rhGH therapy for another 6 months. They and six patients who had rhGH therapy from the beginning form the rhGH treatment study group. During rhGH treatment, plasma insulin-like growth factor activity increased significantly from 93 +/- 17 to 229 +/- 23 ng/mL. Baseline GFR and RPF as well as RFRC were unaltered by the 6 months of rhGH replacement therapy (basal GFR, 124 +/- 7 mL/min before and 123 +/- 9 mL/min after 6 months of rhGH therapy; GFR after AA infusion, 145 +/- 9 mL/min at baseline and 144 +/- 8 mL/min after 6 months of therapy). Kidney size as evaluated by ultrasonography was normal at baseline when compared with that in age- and sex-matched controls (10.3 +/- 0.2 versus 9.9 +/- 0.1 cm) and was unchanged after 6 months of therapy (10.3 +/- 0.3 cm). It was concluded from this study that rhGH substitution for 6 months at a dose of 0.25 IU/kg per week in GH-deficient patients with normal renal function has no adverse functional effects on the kidney.
Bispecific Antibody Pretargeting of Tumor Neovasculature for Improved Systemic Radiotherapy of Solid Tumors
Authors: Dieter Moosmayer, Dietmar Berndorff, Chien-Hsing Chang, Robert M. Sharkey, Axel Rother, Sandra Borkowski, Edmund A. Rossi, William J. McBride, Thomas M. Cardillo, David M. Goldenberg, Ludger M. Dinkelborg
Journal: Clinical Cancer Research (2006)

Extra domain B (ED-B) fibronectin is a specific tumor matrix marker for targeting angiogenesis in solid tumors. In this study, the radiotherapeutic potential of the directly radioiodinated divalent anti-ED-B antibody fragment, L19 small immunoprotein (L19-SIP; 75,000 Da), was compared with a pretargeting approach using the bispecific antibody AP39xm679 (bsMAb; 75,000 Da).The bsMAb was prepared by coupling an anti-ED-B single-chain Fv (AP39) to the Fab' of the murine antibody m679, which binds to the small peptidic hapten histamine-succinyl-glycine (HSG). As an effector molecule for the pretargeting approach, the 111In-labeled HSG-DOTA complex was injected 25 or 41 hours after the bsMAb. The kinetics of both the iodinated bsMAb and the pretargeted 111In-labeled HSG hapten were investigated in mice bearing human glioblastoma xenografts (U251) and compared with the kinetics and tumor accumulation of radioiodinated L19-SIP. 111In and 125I were used as surrogate marker for the therapeutic radioisotopes 90Y/177Lu and 131I, respectively.Tumor uptake of the pretargeted 111In-labeled peptide was significantly higher than 125I-L19-SIP over 7 days. At the calculated maximally tolerated dose for each agent (with the kidney being the dose-limiting organ for pretargeting and the bone marrow for direct targeting), a mouse tumor dose of 146 Gy could be given by pretargeting versus 45 Gy delivered by the direct approach.These data suggest that pretargeting of ED-B with AP39xm679 and subsequent injection of the 90Y-hapten-peptide would improve the therapeutic efficacy in solid tumors by >3-fold compared with directly radiolabeled 131I-L19-SIP.
A 29-Year-Old Woman With Flu-like Symptoms
Authors: M. Anita Barry
Journal: JAMA (2010)

Peaks of seasonal influenza activity occur annually in many countries, resulting in significant morbidity and mortality. Using the case of Ms R, a 29-year-old woman who presented with acute onset of respiratory symptoms and was evaluated for influenza, considerations regarding symptoms and signs, evaluation, treatment, and prevention of influenza are discussed. Symptoms of influenza can be similar to those of other respiratory viruses, making diagnosis challenging. Laboratory testing should be reserved for patients who are seriously ill or for whom test results may affect management or have public health implications. For most cases of influenza, treatment is supportive and specific antiviral medication is not needed. Annual vaccination is the most effective way to prevent infection. Educating patients on practical steps to reduce the spread of influenza in the community is critical.
Ultradian Variation of Blood Glucose in Intensive Care Unit Patients Receiving Insulin Infusions
Authors: Stephen M. Smith, Kelsey E. Oveson, Wayne Strauss, Kathryn Raven, Mary C. Lefevre, Andrew J. Ahmann, Daniel S. Hagg
Journal: Diabetes Care (2007)

Treatment of hyperglycemia with an insulin infusion protocol (IIP) has improved outcomes in intensive care unit (ICU) patients (1,2). While morning glucose has been reported, little is known about variation of blood glucose for patients on IIP, causing uncertainty about the optimal treatment of ICU patients (3–5). Our objectives were to test whether morning glucose represented whole-day glucose and to determine whether glucose varied over the course of the day. In ICU patients receiving IIP, glucose was lower in the early morning, correlated poorly with average glucose, and varied with an ultradian pattern.

In this prospective, single-center, observational study in the ICUs of a university tertiary care hospital, we recorded all glucose measurements in two cohorts of ICU patients receiving an IIP targeting blood glucose 80–110 mg/dl. Supplementary details are available in an online appendix (available at http://dx.doi.org/10.2337/dc07-0865.).

Between 20 May 2006 and 6 August 2006, 141 ICU patients were treated with IIP, 8 of whom received insulin for two periods, resulting in 149 patient episodes. The average duration of insulin use for an episode was 115 ± 9 h (range 5–604). Forty-one percent ( n = 11,670) of glucose measurements during this period were in the target range (80–110 mg/dl) (Fig. 1 A ). In preliminary data acquired between May 2004 and June 2005, the proportion of measurements in the target range increased initially and then stabilized (Fig. 1). Twenty-six percent of patients experienced at least one glucose value <60 mg/dl, and 2.7% had a glucose value <40 mg/dl.

The IIP was designed to control glucose within 8 h (1), and slightly more glucose measurements beyond 8 h (42%, n = 10,766) were in range ( P = 0.014) (Fig. 1 B ). The mean and median of this positively skewed, non-Gaussian distribution ( P < 0.0001, Kolmogorov-Smirnov test) were 118.5 …