tbuckley/cabot-search huggingface dataset:
The liver-specific tumor suppressor STAT5 controls expression of the reactive oxygen species-generating enzyme NOX4 and the proapoptotic proteins PUMA and BIM in mice
Authors: Ji Hoon Yu, Bing-Mei Zhu, Gregory Riedlinger, Keunsoo Kang, Lothar Hennighausen
Journal: Hepatology (2012)

Loss of signal transducer and activator of transcription 5 (STAT5) from liver tissue results in steatosis and enhanced cell proliferation. This study demonstrates that liver-specific Stat5-null mice develop severe hepatic steatosis as well as hepatocellular carcinomas at 17 months of age, even in the absence of chemical insults. To understand STAT5's role as a tumor suppressor, we identified and investigated new STAT5 target genes. Expression of Nox4, the gene encoding the reactive oxygen species (ROS)-generating enzyme NOX4, was induced by growth hormone through STAT5. In addition, the genes encoding the proapoptotic proteins PUMA and BIM were induced by growth hormone through STAT5, which bound to GAS motifs in the promoter regions of all three genes. We further show that STAT5-induced activation of Puma and Bim was dependent on NOX4. Treatment of mice with transforming growth factor-β, an inducer of apoptosis, resulted in cleaved caspase-3 in control but not in liver-specific Stat5-null mice. This study demonstrates for the first time that cytokines through STAT5 regulate the expression of the ROS-generating enzyme NOX4 and key proapoptotic proteins.
Association Among Serum Perfluoroalkyl Chemicals, Glucose Homeostasis, and Metabolic Syndrome in Adolescents and Adults
Authors: Chien-Yu Lin, Pau-Chung Chen, Yu-Chuan Lin, Lian-Yu Lin
Journal: Diabetes Care (2008)

Perfluoroalkyl chemicals (PFCs) have been used worldwide in a variety of consumer products. The effect of PFCs on glucose homeostasis is not known.We examined 474 adolescents and 969 adults with reliable serum measures of metabolic syndrome profile from the National Health and Nutrition Examination Survey 1999-2000 and 2003-2004.In adolescents, increased serum perfluorononanoic acid (PFNA) concentrations were associated with hyperglycemia (odds ratio [OR] 3.16 [95% CI 1.39-7.16], P < 0.05). Increased serum PFNA concentrations also have favorable associations with serum HDL cholesterol (0.67 [0.45-0.99], P < 0.05). Overall, increased serum PFNA concentrations were inversely correlated with the prevalence of the metabolic syndrome (0.37 [0.21-0.64], P < 0.005). In adults, increased serum perfluorooctanoic acid concentrations were significantly associated with increased beta-cell function (beta coefficient 0.07 +/- 0.03, P < 0.05). Increased serum perfluorooctane sulfate (PFOS) concentrations were associated with increased blood insulin (0.14 +/- 0.05, P < 0.01), homeostasis model assessment of insulin resistance (0.14 +/- 0.05, P < 0.01), and beta-cell function (0.15 +/- 0.05, P < 0.01). Serum PFOS concentrations were also unfavorably correlated with serum HDL cholesterol (OR 1.61 [95% CI 1.15-2.26], P < 0.05).Serum PFCs were associated with glucose homeostasis and indicators of metabolic syndrome. Further clinical and animal studies are warranted to clarify putative causal relationships.
Pneumomediastinum in a surf lifesaver.
Authors: K E Fallon, K Foster
Journal: British Journal of Sports Medicine (1996)

Pneumomediastinum is an uncommon complication of sporting activity. The case of a young asthmatic surf lifesaver is reported in which several factors are thought to have been involved in the aetiology of his condition. Treatment was expectant and a full recovery was made over a short period. This is the first reported case of pneumomediastinum occurring following training for a surf belt race.
Phagocytic chimeric receptors require both transmembrane and cytoplasmic domains from the mannose receptor.
Authors: B A Kruskal, K Sastry, A B Warner, C E Mathieu, R A Ezekowitz
Journal: The Journal of Experimental Medicine (1992)

Phagocytosis has traditionally been viewed as a specialized function of myeloid and monocytic cells. The mannose receptor (MR) is an opsonin-independent phagocytic receptor expressed on tissue macrophages. When human MR cDNA is transfected into Cos cells, these usually non-phagocytic cells express cell surface MR and bind and ingest MR ligands such as zymosan, yeast, and Pneumocystis carinii. Expression of cDNA for Fc gamma RI (CD64), the high-affinity Fc receptor, in Cos cells confers binding but barely detectable phagocytosis of antibody-opsonized erythrocytes (EA). We report here that chimeric receptors containing the ligand-binding ectodomain of the Fc receptor and the transmembrane and cytoplasmic domains of the MR ingest bound EA very efficiently, whereas chimeras with the Fc receptor ecto- and transmembrane domains and the MR tail, or the Fc receptor ecto- and cytoplasmic domains and the MR transmembrane region, are significantly less phagocytic. All of the chimeric receptors bind ligand with equal avidity, but gain of functional phagocytosis is only conferred by the MR transmembrane and cytoplasmic domains. Endocytosis of monomeric immunoglobulin G by chimeric receptors demonstrates a similar pattern, with optimal uptake by the chimera containing both tail and transmembrane regions from the MR. The chimeric receptors with only the transmembrane or the cytoplasmic domain contributed by the MR were less efficient. Site-directed mutagenesis of the single tyrosine residue in the cytoplasmic tail (which is present in a motif homologous to an endocytosis consensus motif in the LDL receptor cytoplasmic tail [Chen, W.-J., J. L. Goldstein, and M. S. Brown. 1990. J. Biol. Chem. 265:3116]) reduces the efficiency of phagocytosis and endocytosis to a similar extent.
Therapeutic Index: A Vital Component in Selection of Anticancer Agents for Clinical Trial
Authors: J. A. Double, M. C. Bibby
Journal: JNCI Journal of the National Cancer Institute (1989)

In an attempt to identify anticancer agents more active in the major groups of solid cancers, the National Cancer Institute has replaced the primary murine tumor systems with an in vitro system using human cancer cell lines. A broader approach is being followed in Europe, where considerable reliance will still be placed on data from animal tumor systems. We argue the case for broader preclinical evaluation using animal model systems that are resistant to standard anticancer agents and thus reflect the clinical disease. Selection of compounds for clinical trials should be based on a therapeutic index that will give a more realistic representation of the margin between antitumor activity and toxicity to normal cells. Furthermore, preclinical evaluation can establish understanding of the factors responsible for treatment efficacy, including pharmacokinetics, metabolism, and drug bioavailability.
Radiotherapy and Hodgkin's Lymphoma
Authors: Prajnan Das, Chul S. Ha, James D. Cox
Journal: Journal of Clinical Oncology (2005)

Clinical Oncology regarding the National Cancer Institute of Canada (NCI-C) trial. 1,2 In this trial, patients with stage I to IIA Hodgkin's lymphoma were randomly assigned to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone or subtotal nodal radiation.Patients with unfavorable risk disease in the radiotherapy arm also received ABVD.While there was no difference in overall or event-free survival between the two arms, freedom from disease progression was significantly higher in the radiotherapy arm, compared to the chemotherapy alone arm (93% v 87%, P ϭ .006).The NCI-C trial has been the only trial designed to compare survival in adult patients treated with ABVD alone and those treated with radiotherapy, with or without ABVD.However, other recent studies have also investigated the role of radiotherapy in early-stage Hodgkin's lymphoma.As noted in the editorial, a randomized trial from India showed that in patients achieving a complete remission after 6 cycles of ABVD, the addition of radiotherapy significantly improved the 8-year event-free survival (88% v 76%, P ϭ .01)and overall survival (100% v 89%, P ϭ .002). 3 The findings of this trial may not necessarily be applicable to all early-stage Hodgkin's lymphoma patients, since a large number of patients in this trial were under age 15, had stage III-IV lymphoma, or had mixed cellularity histology.The results from the recently presented European Organisation for Research and Treatment of Cancer GELA H9-F trial may be more pertinent. 4 In the H9-F trial, patients with favorable, early stage Hodgkin's lymphoma with a complete remission after six cycles of epirubicin, bleomycin, vinblastine, and prednisone were randomly assigned to one of three arms: no radiotherapy, 20 Gy involved field, or 36 Gy involved field radiotherapy.The no radiotherapy arm of the trial had to be closed early since predefined stopping rules were met.The 4-year event-free survival was significantly lower in the no-radiotherapy arm (70%), compared to the 20 Gy (84%) and 36 Gy (87%) arms (P Ͻ .001).Of note, the epirubicin, bleomycin, vinblastine, and prednisone regimen in this trial may be associated with a higher rate of relapse than ABVD.A randomized trial from Memorial Sloan-Kettering Cancer Center failed to find any significant difference in overall survival or freedom from progression in patients treated with ABVD alone or ABVD followed
Cardiac Autonomic Patterns Preceding Occasional Vasovagal Reactions in Healthy Humans
Authors: Raffaello Furlan, Simona Piazza, Simonetta Dell’Orto, Franca Barbic, Anna Bianchi, Luca Mainardi, Sergio Cerutti, Massimo Pagani, Alberto Malliani
Journal: Circulation (1998)

The wide range of clinical presentation of orthostatic vasovagal syncope suggests different underlying changes in the cardiac autonomic modulation.To evaluate the beat-by-beat modifications in the neural control of heart period preceding a syncopal event, we studied RR interval variability in 22 healthy subjects who experienced fainting for the first time during a 90 degrees head-up tilt and in 22 control subjects by means of time-variant power spectral analysis. Sympathetic and vagal modulations to the sinoatrial node were assessed by the normalized power of the low-frequency (LF, approximately 0.1-Hz) and high-frequency (HF, approximately 0.25-Hz) oscillatory components of RR variability. When the patients were supine, no differences were observed in the hemodynamic and spectral parameters of the 2 groups. During the tilt procedure, RR, LFNU, and HFNU (NU=normalized units) values were relatively stable in control subjects. During early tilt (T1), subjects with syncope had reduced RR intervals compared with control subjects. In 13 subjects with syncope, RR decreased while LFNU and LF/HF increased in the last minute of tilt before syncope (T2). Conversely, in the remaining 9 fainters, LFNU and LF/HF decreased from T1 to T2 and HFNU increased slightly.Two different patterns may be recognized in the cardiac autonomic changes preceding an occasional vasovagal event, namely, one characterized by a progressive increase of the marker of cardiac sympathetic modulation up to the onset of syncope, the other by a sympathetic inhibition with an impending vagal predominance. The recognition of different pathophysiological mechanisms in fainters may have important therapeutic implications.
Independent Factors Associated With Major Depressive Disorder in a National Sample of Individuals With Diabetes
Authors: Leonard E. Egede, Deyi Zheng
Journal: Diabetes Care (2003)

OBJECTIVE—To determine whether perceived poor physical health, duration of diabetes, and smoking are associated with major depressive disorder in a national sample of individuals with diabetes. RESEARCH DESIGN AND METHODS—Data on 1,810 individuals with diabetes from the 1999 National Health Interview Survey (NHIS) were analyzed. The Composite International Diagnostic Interview (CIDI) Short-Form (CIDI-SF) developed by the World Health Organization was used to identify individuals with major depressive disorder. Multiple logistic regression was used to determine whether perceived poor physical health, duration of diabetes, and smoking were associated with major depressive disorder. The model controlled for age, sex, race/ethnicity, education, income, employment, marital status, and health status. Other control variables included BMI, smoking, duration of diabetes, presence or absence of major complications, and type of treatment for diabetes. SUDAAN software was used for statistical analyses to account for the complex sampling design of NHIS. RESULTS—Independent factors associated with major depressive disorder were age &amp;lt;64 years, female sex, at least high school education, income &amp;lt;124% of federal poverty level, perceived worsening of health status, and smoking. CONCLUSIONS—In addition to other psychosocial factors such as younger age, female sex, lower income, at least high school education, and smoking, perceptions about the effect of diabetes on overall health seems to play an important role in the etiology of depression.
Glucose delivery is a major determinant of glucose utilisation in the ischemic myocardium with a residual coronary flow
Authors: Linda M King, Lionel H Opie
Journal: Cardiovascular Research (1998)

Background: Experimental data from isolated rat hearts suggest that glycolysis in severe myocardial ischemia is inhibited by accumulation of glycolytic metabolites. In contrast, positron emission tomography (PET) in patients with myocardial ischemia records a 'mismatch' between the decreased coronary flow in viable ischemic tissue and an increased fluorodeoxyglucose (18FDG) signal. To resolve this contradiction, we investigated glucose uptake at very low coronary flows in the isolated rat heart model. Methods: Rates of glucose uptake were measured in the isolated Langendorff-perfused Wistar rat heart, at control (12–15 ml/g wet wt/min) and low coronary flows (0.1, 0.2 and 0.5 ml/g wet wt/min) and at a range of glucose concentrations (2.75, 5.5, 11 and 22 mM). Results: The steady-state rate of glucose uptake versus glucose concentration could be described by a double rectangular hyperbola at each coronary flow. Glucose uptake fell to levels significantly below control at low coronary flows. However, the extraction of glucose (glucose uptake as % of glucose delivered) rose sharply, from 1% at control coronary flows, to 25–30% at low coronary flows. Crossover analysis of glycolytic intermediates in freeze-clamped tissue indicated little inhibition at any specific site, although phosphofructokinase activity was restricted when glycolytic substrate availability was high. Insulin and preconditioning both increased glucose uptake with 11 mM glucose, possibly by increasing membrane transporter density and thus increasing glucose delivery to the cytosol. Conclusions: Despite the reduction in absolute glucose uptake at low coronary flow-rates, the extraction of glucose was greatly increased, possibly following GLUT4 translocation. Delivery of glucose to the glycolytic pathway appears to be a major controlling site of glycolysis in low-flow ischemia. Downstream regulation is then distributed along the pathway with no one site exerting greater inhibition than reduced glucose delivery.
Intravenous azidothymidine with fluorouracil and leucovorin: a phase I-II study in previously untreated metastatic colorectal cancer patients.
Authors: A Falcone, R Danesi, F Dargenio, E Pfanner, I Brunetti, M Del Tacca, A B Nethersell, P F Conte
Journal: Journal of Clinical Oncology (1996)

PURPOSE To determine the plasma pharmacokinetics and the maximum-tolerated dose (MTD) of intravenous (IV) azidothymidine (AZT) administered 90 to 120 minutes after fluorouracil (5-FU) and leucovorin and to preliminarily evaluate the antitumor activity of this combination in metastatic colorectal cancer. PATIENTS AND METHODS 5-FU 500 mg/m2 IV bolus was administered once a week in the middle of a 2-hour infusion of leucovorin; AZT was given as a 90 to 120-minute IV infusion 60 minutes after 5-FU. Initial AZT dose was 0.5 g/m2, and it was escalated in successive cohorts of three patients by 0.5 to 2 g/m2. RESULTS Thirty-five chemotherapy-naive metastatic colorectal cancer patients were entered onto the study, and AZT doses ranged from 0.5 to 10 g/m2. The peak AZT plasma concentration increased from 21.9 to 995.6 micromol/L. The area under the concentration/time curve (AUC) also showed a progressive, but not linear increase from 40.34 to 3,108 h x micromol/L. The most relevant toxicity was diarrhea, which was severe in six patients (17%). Toxicities were not AZT-dose-related, except fpr hypotension, which occurred in patients treated at AZT doses &gt; or = 7 g/m2 and became dose-limiting for AZT 10 g/m2. Among 34 assessable patients, 15 objective responses were observed (44%; 95% confidence interval 27 to 62), lasting a median of 44 weeks; five (15%) were complete. CONCLUSION AZT doses &gt; or = 6 g/m2 administered IV over 90 to 120 minutes produce maximum plasma concentration and AUC similar to those previously reached in murine tumor models. Dose-limiting toxicity is hypotension, which occurs at AZT 10 g/m2. The recommended AZT dose for further studies is 8 g/m2. The combination of 5-FU plus leucovorin plus AZT is feasible with acceptable toxicities, and has promising activity in metastatic colorectal cancer.
Effect of feeding and obesity on lipoprotein lipase activity, immunoreactive protein, and messenger RNA levels in human adipose tissue.
Authors: J M Ong, P A Kern
Journal: Journal of Clinical Investigation (1989)

Previous studies have demonstrated higher levels of adipose tissue lipoprotein lipase (LPL) catalytic activity in obese subjects, and in response to a meal. To examine the cellular mechanism of this increase in activity, LPL activity, immunoreactive mass, and mRNA level were measured in lean and obese subjects both before and 4 h after a carbohydrate-rich meal. Heparin-releasable (HR) LPL activity was approximately 2.5-fold higher in the 15 obese subjects, when compared with six lean subjects. However, there was no difference in LPL immunoreactive mass between the lean and obese subjects. In response to the meal, there was a 2.2-fold increase in total adipose tissue LPL activity in the lean subjects due to an increase in both the HR fraction, as well as the adipose fraction extracted with detergents. However, no increase in LPL immunoreactive mass was observed in any adipose tissue LPL fraction, resulting in an increase in LPL specific activity in response to the meal. In the obese subjects, there was no significant increase in LPL activity in response to feeding, and also no increase in immunoreactive mass or specific activity. After extraction of RNA, there was no difference in either the relative proportion of the 3.6- and 3.4-kb human LPL mRNA transcripts, nor in the quantity of LPL mRNA in response to feeding. Thus, these data suggest that the increase in LPL activity under these conditions occurs through a posttranslational activation of a previously inactive LPL precursor.
Lung Carcinoma-Reactive Antibodies Isolated From Tumor Tissues and Pleural Effusions of Lung Cancer Patients&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Edward Paluch, Harry L. Ioachim
Journal: JNCI Journal of the National Cancer Institute (1978)

Low pH elution techniques were used on lung cancer tissues and pleural effusions of lung cancer patients to dissociate antigen-antibody complexes. The immunoglobulins obtained were assayed by indirect immunofluorescence against tissue cultures and fresh cell suspensions of various target cells; they reacted positively, in significant titers, with cells of squamous cell carcinomas and adenocarcinomas of the lung but not with cells of normal adult and fetal lung or of nonpulmonary tumors. Immunoglobulins, similarly dissociated from tumor effusions of other organs, showed no reactivity in indirect immunofluorescence tests against lung carcinoma cells.
Regulation of experimental autoimmune encephalomyelitis with insulin-like growth factor (IGF-1) and IGF-1/IGF-binding protein-3 complex (IGF-1/IGFBP3).
Authors: A E Lovett-Racke, P Bittner, A H Cross, J A Carlino, M K Racke
Journal: Journal of Clinical Investigation (1998)

Insulin-like growth factor (IGF)-1 is a cytokine that promotes oligodendrocyte development and myelin production. This study investigated whether treatment of chronic, relapsing murine experimental autoimmune encephalomyelitis (EAE) with IGF-1 or IGF-1 associated with its binding protein, IGFBP3, altered the course of disease. Administration of IGF-1/IGFBP3 (1-100 mg/kg per day) delayed the onset of disease in a dose-dependent manner and histologic examination showed a delay in inflammatory cells entering the central nervous system. However, once signs of EAE developed, disease was enhanced in the mice that had been given the highest dose of IGF-1/IGFBP3. Treatment with IGF-1/IGFBP3 after the onset of signs resulted in a severe relapse. Administration of free IGF-1 (10 mg/kg per day) provided mild protection when given before disease onset, but did not significantly alter the course of disease if given after disease onset. Possible mechanisms that could explain the altered disease in IGF-1/IGFBP3-treated mice included (a) IGF-1/IGFBP3 administration delayed the onset of EAE by downregulating ICAM-1 gene expression in the central nervous system, and (b) IGF-1/IGFBP3 treatment of EAE resulted in more severe disease due to enhanced expansion of encephalitogenic T cells. Although IGF-1 may enhance remyelination, these results indicate that administration of IGF-1 associated with IGFBP3 may also accentuate autoimmune demyelinating disease.
O9.02 * NEEDS OF INFORMAL CAREGIVERS OF PRIMARY MALIGNANT BRAIN TUMOR PATIENTS IN THE UNITED STATES AND THE NETHERLANDS: AN INTERNATIONAL COMPARISON
Authors: F. W. Boele, M. Klein, T. S. Armstrong, J. C. Reijneveld, T. J. Postma, M. J. B. Taphoorn, N. K. Aaronson, J. J. Heimans, P. R. Sherwood
Journal: Neuro-Oncology (2014)

OBJECTIVE: Spouses, family members or friends of patients with high-grade gliomas often have to take on the role of primary informal caregiver, providing daily emotional and instrumental support. For these informal caregivers, the patients' additional neurological symptoms can pose great challenges, which may be influenced by sociodemographic and cultural aspects. We investigated the presence and resolution of needs in two longitudinal samples of caregivers of patients with high-grade gliomas, one from the United States and one from the Netherlands. METHODS: US and Dutch caregivers participating in large, longitudinal studies completed questionnaires about their needs after the patient's diagnosis, and at 4, 8 and 12 months follow-up. The patients provided information on their disease-specific symptoms. We evaluated differences between US and Dutch caregivers in terms of demographics, and the proportion of needs present and met within samples. Specific needs were described. RESULTS: US (N = 50) and Dutch (N = 66) caregivers were comparable in terms of the patient's diagnosis and most disease-specific symptoms. US caregivers reported 50.6% of needs present at baseline, of which 88.1% were met sufficiently. In contrast, Dutch caregivers reported 86.7% of needs present at baseline, of which 48.6% were met sufficiently. In the Dutch sample, the prevalence of caregiver (unmet) needs decreased significantly during follow-up (p = 0.032 at 12 months), while this was not the case for the US sample. In addition, specific unmet needs in US caregivers appear to be related to the phase of the patient's disease, e.g. needs regarding changes in the relationship with the patient emerge after diagnosis, while dealing with the patient's distress and obtaining services become more evident at 4- and 8-months follow-up, respectively. In Dutch caregivers, this is less clear. CONCLUSIONS: Both US and Dutch caregivers of patients with high-grade glioma have a large number of needs, and not all needs are sufficiently met. This may provide leads to improve support for caregivers in clinical practice, both in the Netherlands and in the US.