tbuckley/cabot-search huggingface dataset:
Vascular endothelial growth factor B (VEGF-B) is up-regulated and exogenous VEGF-B is neuroprotective in a culture model of Parkinson's disease
Authors: Torsten Falk, Shiling Zhang, Scott J Sherman
Journal: Molecular Neurodegeneration (2009)

Parkinson's disease (PD) results from the degeneration of dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine released in the striatum. Current oral dopamine replacement or surgical therapies do not address the underlying issue of neurodegeneration, they neither slow nor halt disease. Neurotrophic factors have shown preclinical promise, but the choice of an appropriate growth factor as well as the delivery has proven difficult. In this study, we used a rotenone rat midbrain culture model to identify genes that are changed after addition of the neurotoxin. (1) We challenged rat midbrain cultures with rotenone (20 nM), a pesticide that has been shown to be toxic for dopaminergic neurons and that has been a well-characterized model of PD. A gene chip array analysis demonstrated that several genes were up-regulated after the rotenone treatment. Interestingly transcriptional activation of vascular endothelial growth factor B (VEGF-B) was evident, while vascular endothelial growth factor A (VEGF-A) levels remained unaltered. The results from the gene chip array experiment were verified with real time PCR and semi-quantitative western analysis using β-actin as the internal standard. (2) We have also found evidence that exogenously applied VEGF-B performed as a neuroprotective agent facilitating neuron survival in an even more severe rotenone culture model of PD (40 nM rotenone). VEGF-B has very recently been added to the list of trophic factors that reduce effects of neurodegeneration, as was shown in an in vivo model of motor neuron degeneration, while lacking potential adverse angiogenic activity. The data of an in vivo protective effect on motor neurons taken together with the presented results demonstrate that VEGF-B is a new candidate trophic factor distinct from the GDNF family of trophic factors. VEGF-B is activated by neurodegenerative challenges to the midbrain, and exogenous application of VEGF-B has a neuroprotective effect in a culture model of PD. Strengthening this natural protective response by either adding exogenous VEGF-B or up-regulating the endogenous VEGF-B levels may have the potential to be a disease modifying therapy for PD. We conclude that the growth factor VEGF-B can improve neuronal survival in a culture model of PD.
X‐chromosome <i>Forkhead Box P3</i> polymorphisms associate with atopy in girls in three Dutch birth cohorts
Authors: R. W. B. Bottema, M. Kerkhof, N. E. Reijmerink, G. H. Koppelman, C. Thijs, F. F. Stelma, H. A. Smit, B. Brunekreef, C. P. Van Schayck, D. S. Postma
Journal: Allergy (2009)

The Forkhead Box P3 (FOXP3) gene, located on the X-chromosome, encodes a transcription factor that directs T cells toward a regulatory phenotype. Regulatory T cells may suppress development of atopy. We evaluated whether single-nucleotide polymorphisms (SNPs) of FOXP3 are associated with atopy development in childhood.Seven SNPs in FOXP3 were genotyped in 3062 children (51% boys) participating in the Allergenic study, which consists of three Dutch birth cohorts (PIAMA, PREVASC and KOALA). Association of FOXP3 SNPs with total serum IgE and sensitisation (presence of specific serum IgE to egg, milk, and indoor, i.e. house-dust mite, cat, and/or dog allergens) was investigated at ages 1, 2, 4, and 8. Analysis of variance and logistic regression were performed, stratified for gender.Our most consistent finding was observed for sensitisation to egg and indoor allergens. In girls, five FOXP3 SNPs (rs5906761, rs2294021, rs2294019, rs6609857 and rs3761548) were significantly associated with sensitisation to egg at ages 1 and 2 and with sensitisation to indoor allergens at age 2 (P < 0.05), but not at 4 and 8, a finding that was observed across the three cohorts. Rs5906761 and rs2294021 were associated with remission of sensitisation to food allergens in boys, as tested in the PIAMA cohort.This is the first study showing across three cohorts that X-chromosomal FOXP3 genotypes may contribute to development of sensitisation against egg and indoor allergens in girls in early childhood. In addition, an association with remission of sensitisation to food allergens existed in boys only.
African American Men With Very Low–Risk Prostate Cancer Exhibit Adverse Oncologic Outcomes After Radical Prostatectomy: Should Active Surveillance Still Be an Option for Them?
Authors: Debasish Sundi, Ashley E. Ross, Elizabeth B. Humphreys, Misop Han, Alan W. Partin, H. Ballentine Carter, Edward M. Schaeffer
Journal: Journal of Clinical Oncology (2013)

Active surveillance (AS) is a treatment option for men with very low-risk prostate cancer (PCa); however, favorable outcomes achieved for men in AS are based on cohorts that under-represent African American (AA) men. To explore whether race-based health disparities exist among men with very low-risk PCa, we evaluated oncologic outcomes of AA men with very low-risk PCa who were candidates for AS but elected to undergo radical prostatectomy (RP).We studied 1,801 men (256 AA, 1,473 white men, and 72 others) who met National Comprehensive Cancer Network criteria for very low-risk PCa and underwent RP. Presenting characteristics, pathologic data, and cancer recurrence were compared among the groups. Multivariable modeling was performed to assess the association of race with upgrading and adverse pathologic features.AA men with very low-risk PCa had more adverse pathologic features at RP and poorer oncologic outcomes. AA men were more likely to experience disease upgrading at prostatectomy (27.3% v 14.4%; P < .001), positive surgical margins (9.8% v 5.9%; P = .02), and higher Cancer of the Prostate Risk Assessment Post-Surgical scoring system (CAPRA-S) scores. On multivariable analysis, AA race was an independent predictor of adverse pathologic features (odds ratio, [OR], 3.23; P = .03) and pathologic upgrading (OR, 2.26; P = .03).AA men with very low-risk PCa who meet criteria for AS but undergo immediate surgery experience significantly higher rates of upgrading and adverse pathology than do white men and men of other races. AA men with very low-risk PCa should be counseled about increased oncologic risk when deciding among their disease management options.
A comparative study of IgG subclass antibodies in patients allergic to wasp or bee venom
Authors: A. B. Wilson, J. Deighton, P. J. Lachmann, P. W. Ewan
Journal: Allergy (1994)

IgG1 and IgG4 antivenom antibody responses were compared in groups of patients who had experienced systemic reactions to wasp ( Vespula spp.) or bee stings. Pretreatment serum IgG4 antibody levels were low in both groups, but IgG4 antibodies were significantly raised in bee‐allergic patients ( P &lt;0.002), probably reflecting their greater exposure to stings than wasp‐reactive patients. No direct or indirect relationships were found, in untreated bee or wasp patients, between IgG1, IgG4, or IgE antibody levels and the severity of a patient's last systemic reaction to a sting. After a 12‐week course of venom immunotherapy (VIT), IgG1 antibodies increased significantly only in wasp‐sensitive patients ( P &lt;0.001), although both groups responded with marked increases in venom‐specific IgG4 ( P &lt;0.01). Wasp‐allergic subjects who responded to VIT with high production of specific IgG4 showed the greatest increases (pre‐ to post‐VIT) in IgE antibodies (P&lt;0.05). This group also demonstrated a direct correlation ( P &lt;0.05) between post‐VIT levels of IgE and IgG1 antibodies, a finding contrary to an IgE‐immunoregulatory role for IgG 1. High levels of venom‐specific IgG1 alone, or in combination with IgG4, were not protective in three patients who suffered repeated adverse reactions to bee VIT, showing that absolute levels of IgG subclass antivaenom antibodies are not reliably indicative of clinical responsiveness in individual patients.
Antibodies to human caudate nucleus neurons in Huntington's chorea.
Authors: G Husby, L Li, L E Davis, E Wedege, E Kokmen, R C Williams
Journal: Journal of Clinical Investigation (1977)

Antibodies reacting with neuronal cytoplasmic antigens present in normal human caudate and subthalamic nuclei were detected in 37 of 80 probands afflicted with Huntington's disease (HD). IgG antibodies were detected by immunofluorescence using frozen sections of unfixed normal human and rat brain. Specificity of IgG binding was confirmed using pepsin F(ab')2 fragments of IgG isolated from positive sera. In vitro complement fixation of IgG antibody was detected in 22 of 31 sera tested. Neuronal cytoplasmic antigens reacting with positive HD sera were diminished after trypsin or RNAase treatment of tissue sections but were not removed by DNAase, neuraminidase, EDTA, or dithiothreitol treatment. Antibody staining of neurons could be removed after absorption with isolated caudate nucleus neurons or by using perchloroacetic acid extracts of caudate nucleus. Prevalence of antibody reacting with neuronal cytoplasm was 3% in 60 normal controls and 6% among a wide variety of patients with diverse neurological disorders. However, one-third of 33 patients with Parkinson's disease showed presence of antineuronal antibody. Among patients with HD, a significant association was noted between duration of clinical disease greater than 7 yr and titers of antibody of 1:2 or greater (P less than 0.001). When 115 family members of HD probands were tested, 30% of unaffected spouses showed presence of antineuronal antibody. 23.2% of first-degree relatives at risk for developing HD was also positive (P less than 0.001). 10.5% of second-degree relatives showed presence of antineuronal antibody. These data may support an environmental or infectious factor somehow involved in the ultimate expression of HD.
Physical Training in the Management of Coronary Artery Disease
Authors: JAN PRAETORIUS CLAUSEN, OLE ANDREÉE LARSEN, JENS TRAP-JENSEN
Journal: Circulation (1969)

The effects of 4 to 6 weeks' physical conditioning on the cardiovascular and respiratory response to exercise were studied in nine patients with coronary artery disease. Clinical improvement and increased physical working capacity were observed in all patients. The average cardiac output during exercise was unchanged. The stroke volume increased and the myocardial work, assessed by the tension-time index, decreased during exercise at a given work load. It is suggested that at submaximal work loads a reduction of the blood flow to the working muscles occurs after training. Such change might be fundamental for the altered circulatory regulation by allowing a reduced general sympathetic vasoconstriction during exercise. It is concluded that the hemodynamic changes form a rational physiologic basis for the use of physical training in the management of patients with coronary artery disease.
IVOX in ARDS: respiratory effects and serious complications
Authors: Y Gasche, JA Romand, R Pretre, PM Suter
Journal: European Respiratory Journal (1994)

We describe the beneficial effects of an intravenous oxygenator (IVOX) on ventilatory pressure requirement, and also several severe complications related to its use in a young trauma victim developing severe acute respiratory distress syndrome (ARDS). In this patient, adequate systemic oxygenation could not be maintained despite the use of fractional inspired oxygen of 1.0, high level positive end-expiratory pressure (PEEP), and nitric oxide inhalation (30 ppm). The introduction of an intravenous oxygenator improved arterial oxygenation and CO2 elimination, allowing a decrease in minute ventilation and airway pressure. However, hepatic cytolysis, acute renal dysfunction and iliac vein thrombosis developed concomitantly, in spite of full anticoagulation with heparin. These complications resolved rapidly after removal of the IVOX device and the patient made a good recovery.
Steroid 5α-Reductase Isozymes I and II in Recurrent Prostate Cancer
Authors: Mark A. Titus, Christopher W. Gregory, O. Harris Ford, Michael J. Schell, Susan J. Maygarden, James L. Mohler
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Prostate cancer recurs during androgen deprivation therapy despite reduced circulating androgens. We showed that recurrent prostate cancer tissue has testosterone levels similar to androgen-stimulated benign prostate, whereas dihydrotestosterone levels were reduced 82% to 1.45 nmol/L, sufficient for androgen receptor activation. The altered testosterone/dihydrotestosterone ratio in recurrent prostate cancer suggests loss of 5α-reducing capability. The aim of this study was to characterize steroid 5α-reductase isozymes I (S5αRI) and II (S5αRII) in prostate tissues. Experimental Design: A tissue microarray was constructed from 22 recurrent prostate cancer specimens and matched pairs of androgen-stimulated benign prostate and androgen-stimulated prostate cancer from 23 radical prostatectomy specimens. Immunoblots were constructed from eight recurrent prostate cancers, eight androgen-stimulated benign prostate, and eight androgen-stimulated prostate cancer specimens. Isozyme expression was examined in microarray sections and immunoblots using S5αRI and S5αRII polyclonal antibodies. Isozyme activities were measured in 12 recurrent prostate cancer, 12 androgen-stimulated benign prostate, and 12 androgen-stimulated prostate cancer specimens. Results: Nuclear immunostaining exhibited higher S5αRI expression than S5αRII in recurrent prostate cancer, androgen-stimulated benign prostate, and androgen-stimulated prostate cancers (P &amp;lt; 0.0001); mean expression was 125, 150, and 115 for S5αRI versus 10, 29, and 37 for S5αRII, respectively. Cytoplasmic immunostaining was moderate and similar for both isozymes in the three tissue types (P &amp;gt; 0.05). Immunoblots confirmed immunohistochemistry; S5αRI was expressed in recurrent prostate cancer specimens and S5αRII was not detected. The activity of S5αRI (114.4 pmol/mg epithelial protein/minute) was 3.7-fold higher than S5αRII (30.7 pmol/mg epithelial protein/minute) in recurrent prostate cancer specimens. Conclusions: Expression levels and isozyme activity shifts from S5αRII toward S5αRI in recurrent prostate cancer. Dual inhibition of S5αRI and S5αRII should reduce dihydrotestosterone biosynthesis and may prevent or delay growth of recurrent prostate cancer.
Antivascular Therapy of Human Follicular Thyroid Cancer Experimental Bone Metastasis by Blockade of Epidermal Growth Factor Receptor and Vascular Growth Factor Receptor Phosphorylation
Authors: Maher Nabil Younes, Orhan Gazi Yigitbasi, Young Wook Park, Sun-Jin Kim, Samar A. Jasser, Valerie Stone Hawthorne, Yasemin Dakak Yazici, Mahitosh Mandal, Benjamin Nebiyou Bekele, Corazon D. Bucana, Isaiah J. Fidler, Jeffrey N. Myers
Journal: Cancer Research (2005)

Abstract Patients suffering from bone metastases of follicular thyroid carcinoma (FTC) have a poor prognosis because of the lack of effective treatment strategies. The overexpression of epidermal growth factor receptor (EGFR) associated with increased vascularity has been implicated in the pathogenesis of FTC and subsequent bone metastases. We hypothesized that inhibiting the phosphorylation of the EGFR and vascular endothelial growth factor receptor (VEGFR) by AEE788, a dual tyrosine kinase inhibitor of EGFR and VEGFR, in combination with paclitaxel would inhibit experimental FTC bone lesions and preserve bone structure. We tested this hypothesis using the human WRO FTC cell line. In culture, AEE788 inhibited the EGF-mediated phosphorylation of EGFR, VEGFR2, mitogen-activated protein kinase, and Akt in culture. AEE788, alone and in combination with paclitaxel, inhibited cell growth and induced apoptosis. When WRO cells were injected into the tibia of nude mice, tumor and endothelial cells within the lesions expressed phosphorylated EGFR, VEGFR, Akt, and mitogen-activated protein kinase that were inhibited by the oral administration of AEE788. Therapy consisting of orally given AEE788 and i.p. injected paclitaxel induced a high level of apoptosis in tumor-associated endothelial cells and tumor cells with the inhibition of tumor growth in the bone and the preservation of bone structure. Collectively, these data show that blocking the phosphorylation of EGFR and VEGFR with AEE788 combined with paclitaxel can significantly inhibit experimental human FTC in the bone of nude mice.
CD4+CD25+ Regulatory T-Cell Frequency in HER-2/<i>neu</i> (HER)-Positive and HER-Negative Advanced-Stage Breast Cancer Patients
Authors: Sonia A. Perez, Michael V. Karamouzis, Dimosthenes V. Skarlos, Alexandros Ardavanis, Nectaria N. Sotiriadou, Eleni G. Iliopoulou, Maria L. Salagianni, George Orphanos, Constantin N. Baxevanis, Gerasimos Rigatos, Michael Papamichail
Journal: Clinical Cancer Research (2007)

Abstract Purpose: CD4+CD25bright regulatory T cells (Tregs) are increased in patients with several malignancies and correlate with disease stage and prognosis. Breast cancer patients represent a heterogeneous population with unpredictable disease progression even at advanced stages. Circulating Tregs in correlation with HER-2/neu (HER) status and treatment with chemotherapy, either alone or in combination with trastuzumab therapy, were monitored in advanced-stage breast cancer patients. Experimental Design: Circulating Treg frequency and absolute counts of 46 HER+ and 28 HER−, stage III and IV, breast cancer patients before therapy and during trastuzumab therapy and/or chemotherapy have been compared with 24 healthy donors and correlated with plasma HER extracellular domain concentration and clinical outcome. Results: Treg frequency in HER+ patients was significantly increased compared with both HER− patients and healthy donors. Trastuzumab therapy, with or without combined chemotherapy, resulted in a progressive decrease of circulating Tregs. Percentage change in Tregs statistically correlated with percentage change in plasma HER extracellular domain. Furthermore, decrease in Tregs correlated with either objective clinical response or stable disease, whereas increased Treg frequency during trastuzumab therapy coincided with disease progression. No statistically significant change in Treg frequency following chemotherapy was observed in HER− patients. Conclusions: Treg cell frequency does not directly correlate with clinical stage in breast cancer, as stage III and IV HER+ and HER− patients exhibit significantly different Treg profiles. Trastuzumab therapy, either alone or combined with chemotherapy, results in decreased Treg frequency in HER+ advanced patients with an objective clinical response.
Transcriptional Repression of <i>SKP2</i> Is Impaired in <i>MYCN</i>-Amplified Neuroblastoma
Authors: Daniel Muth, Seda Ghazaryan, Isabella Eckerle, Emily Beckett, Christina Pöhler, Julia Batzler, Claudia Beisel, Sina Gogolin, Matthias Fischer, Kai-Oliver Henrich, Volker Ehemann, Paul Gillespie, Manfred Schwab, Frank Westermann
Journal: Cancer Research (2010)

Abstract The cell cycle regulator, SKP2, is overexpressed in various cancers and plays a key role in p27 degradation, which is involved in tumor cell dedifferentiation. Little is known about the mechanisms leading to impaired SKP2 transcriptional control in tumor cells. We used neuroblastoma as a model to study SKP2 regulation because SKP2 transcript levels gradually increase with aggressiveness of neuroblastoma subtypes. The highest SKP2 levels are found in neuroblastomas with amplified MYCN. Accordingly, we found 5.5-fold (range, 2–9.5) higher SKP2 core promoter activity in MYCN-amplified cells. Higher SKP2 core promoter activity in MYCN-amplified cells is mediated through a defined region at the transcriptional start site. This region includes a specific E2F-binding site that makes SKP2 activation largely independent of mitogenic signals integrated through the SP1/ELK-1 site. We show by chromatin immunoprecipitation that SKP2 activation through the transcriptional start site in MYCN-amplified cells is associated with the low abundance of pRB-E2F1 complexes bound to the SKP2 promoter. Transcriptional control of SKP2 through this regulatory mechanism can be reestablished in MYCN-amplified cells by restoring pRB activity using selective small compound inhibitors of CDK4. In contrast, doxorubicin or nutlin-3 treatment—both leading to p53-p21 activation—or CDK2 inhibition had no effect on SKP2 regulation in MYCN-amplified cells. Together, this implies that deregulated MYCN protein levels in MYCN-amplified neuroblastoma cells activate SKP2 through CDK4 induction, abrogating repressive pRB-E2F1 complexes bound to the SKP2 promoter. Cancer Res; 70(9); 3791–802. ©2010 AACR.
Intracellular Clusterin Inhibits Mitochondrial Apoptosis by Suppressing p53-Activating Stress Signals and Stabilizing the Cytosolic Ku70-Bax Protein Complex
Authors: Ioannis P. Trougakos, Magda Lourda, Marianna H. Antonelou, Dimitris Kletsas, Vassilis G. Gorgoulis, Issidora S. Papassideri, Yonglong Zou, Lukas H. Margaritis, David A. Boothman, Efstathios S. Gonos
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Secretory clusterin (sCLU)/apolipoprotein J is an extracellular chaperone that has been functionally implicated in DNA repair, cell cycle regulation, apoptotic cell death, and tumorigenesis. It exerts a prosurvival function against most therapeutic treatments for cancer and is currently an antisense target in clinical trials for tumor therapy. However, the molecular mechanisms underlying its function remained largely unknown. Experimental Design: The molecular effects of small interfering RNA-mediated sCLU depletion in nonstressed human cancer cells were examined by focusing entirely on the endogenously expressed sCLU protein molecules and combining molecular, biochemical, and microscopic approaches. Results: We report here that sCLU depletion in nonstressed human cancer cells signals stress that induces p53-dependent growth retardation and high rates of endogenous apoptosis. We discovered that increased apoptosis in sCLU-depleted cells correlates to altered ratios of proapoptotic to antiapoptotic Bcl-2 protein family members, is amplified by p53, and is executed by mitochondrial dysfunction. sCLU depletion-related stress signals originate from several sites, because sCLU is an integral component of not only the secretory pathway but also the nucleocytosolic continuum and mitochondria. In the cytoplasm, sCLU depletion disrupts the Ku70-Bax complex and triggers Bax activation and relocation to mitochondria. We show that sCLU binds and thereby stabilizes the Ku70-Bax protein complex serving as a cytosol retention factor for Bax. Conclusions: We suggest that elevated sCLU levels may enhance tumorigenesis by interfering with Bax proapoptotic activities and contribute to one of the major characteristics of cancer cells, that is, resistance to apoptosis.