tbuckley/cabot-search huggingface dataset:
Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice
Authors: Nicholas B. Hastings, Xiaohai Wang, Lixin Song, Brent D. Butts, Diane Grotz, Richard Hargreaves, J. Fred Hess, Kwok-Lam Karen Hong, Cathy Ruey-Ruey Huang, Lynn Hyde, Maureen Laverty, Julie Lee, Diane Levitan, Sherry X. Lu, Maureen Maguire, Veeravan Mahadomrongkul, Ernest J. McEachern, Xuesong Ouyang, Thomas W. Rosahl, Harold Selnick, Michaela Stanton, Giuseppe Terracina, David J. Vocadlo, Ganfeng Wang, Joseph L. Duffy, Eric M. Parker, Lili Zhang
Journal: Molecular Neurodegeneration (2017)

Hyperphosphorylation of microtubule-associated protein tau is a distinct feature of neurofibrillary tangles (NFTs) that are the hallmark of neurodegenerative tauopathies. O-GlcNAcylation is a lesser known post-translational modification of tau that involves the addition of N-acetylglucosamine onto serine and threonine residues. Inhibition of O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc modification, has been shown to reduce tau pathology in several transgenic models. Clarifying the underlying mechanism by which OGA inhibition leads to the reduction of pathological tau and identifying translatable measures to guide human dosing and efficacy determination would significantly facilitate the clinical development of OGA inhibitors for the treatment of tauopathies. Genetic and pharmacological approaches are used to evaluate the pharmacodynamic response of OGA inhibition. A panel of quantitative biochemical assays is established to assess the effect of OGA inhibition on pathological tau reduction. A "click" chemistry labeling method is developed for the detection of O-GlcNAcylated tau. Substantial (>80%) OGA inhibition is required to observe a measurable increase in O-GlcNAcylated proteins in the brain. Sustained and substantial OGA inhibition via chronic treatment with Thiamet G leads to a significant reduction of aggregated tau and several phosphorylated tau species in the insoluble fraction of rTg4510 mouse brain and total tau in cerebrospinal fluid (CSF). O-GlcNAcylated tau is elevated by Thiamet G treatment and is found primarily in the soluble 55 kD tau species, but not in the insoluble 64 kD tau species thought as the pathological entity. The present study demonstrates that chronic inhibition of OGA reduces pathological tau in the brain and total tau in the CSF of rTg4510 mice, most likely by directly increasing O-GlcNAcylation of tau and thereby maintaining tau in the soluble, non-toxic form by reducing tau aggregation and the accompanying panoply of deleterious post-translational modifications. These results clarify some conflicting observations regarding the effects and mechanism of OGA inhibition on tau pathology, provide pharmacodynamic tools to guide human dosing and identify CSF total tau as a potential translational biomarker. Therefore, this study provides additional support to develop OGA inhibitors as a treatment for Alzheimer's disease and other neurodegenerative tauopathies.
Evolutionary Computing Enriched Computer-Aided Diagnosis System for Diabetic Retinopathy: A Survey
Authors: Romany F. Mansour
Journal: IEEE Reviews in Biomedical Engineering (2017)

Complications caused due to diabetes mellitus result in significant microvasculature that eventually causes diabetic retinopathy (DR) that keeps on increasing with time, and eventually causes complete vision loss. Identifying subtle variations in morphological changes in retinal blood vessels, optic disk, exudates, microaneurysms, hemorrhage, etc., is complicated and requires a robust computer-aided diagnosis (CAD) system so as to enable earlier and efficient DR diagnosis practices. In the majority of the existing CAD systems, functional enhancements have been realized time and again to ensure accurate and efficient diagnosis of DR. In this survey paper, a number of existing literature presenting DR CAD systems are discussed and analyzed. Both traditional and varoius evolutionary approaches, including genetic algorithm, particle swarm optimization, ant colony optimization, bee colony optimization, etc., based DR CAD have also been studied and their respective efficiencies have been discussed. Our survey revealed that evolutionary computing methods can play a vital role for optimizing DR-CAD functional components, such as proprocessing by enhancing filters coefficient, segmentation by enriching clustering, feature extraction, feature selection, and dimensional reduction, as well as classification.
Targeting Eosinophils in Eosinophilic Granulomatosis with Polyangiitis
Authors: Ratko Djukanovic, Paul M. O’Byrne
Journal: New England Journal of Medicine (2017)

Eosinophilic granulomatosis with polyangiitis, first described in the early 1950s by Dr. Jacob Churg and Dr. Lotte Strauss (hence the original name, the Churg–Strauss syndrome), is a rare condition that can affect many organ systems, most commonly the lung, with the majority of patients presenting with asthma symptoms, occasionally complicated by the fleeting presence of pulmonary infiltrates.1 Many different treatments have been tried for eosinophilic granulomatosis with polyangiitis, with limited or no success, and systemic glucocorticoids are the standard treatment for both eosinophilic granulomatosis with polyangiitis1 and severe refractory asthma.2The predominance of eosinophils in the peripheral blood and tissues . . .
Regulated, Adenovirus-Mediated Delivery of Tyrosine Hydroxylase Suppresses Growth of Estrogen-Induced Pituitary Prolactinomas
Authors: Judith C. Williams, Daniel Stone, Joseph R. Smith-Arica, Ian D. Morris, Pedro R. Lowenstein, Maria G. Castro
Journal: Molecular Therapy (2002)

The column headings in Table 1 were incorrect as printed. The corrected table is shown below. TABLE 1Reduction in pituitary mass following in vivo gene transfer of THTreatmentPituitary weight (mg)Increase in mean pituitary weight vs placebo (mg)% reduction in pituitary hyperplasia1. Placebo+Doxycycline12.3 ± 0.3——2. Placebo11.8 ± 0.9——3. E/S+Doxycycline26.7 ± 0.94.4 ± 0.4—4. E/S25.3 ± 1.1ns13 ± 0.6ns9 ± 3.9ns5. E+Doxycycline18.0 ± 0.55.7 ± 0.3—6. E15.2 ± 0.4a(P < 0.005) in pituitary weights was observed between groups 5 and 6, which received E pellets in the presence r absence of doxycycline. Pituitary weights are shown ± SEM. ns, not significant.2.9 ± 0.2a(P < 0.005) in pituitary weights was observed between groups 5 and 6, which received E pellets in the presence r absence of doxycycline. Pituitary weights are shown ± SEM. ns, not significant.49 ± 2.9a(P < 0.005) in pituitary weights was observed between groups 5 and 6, which received E pellets in the presence r absence of doxycycline. Pituitary weights are shown ± SEM. ns, not significant.Animals from all groups were sacrificed and the pituitary weights were recorded. No significant difference n pituitary weights was observed between groups 3 and 4, which received E/S pellets in the presence or absence of doxycycline. A significant differencea (P < 0.005) in pituitary weights was observed between groups 5 and 6, which received E pellets in the presence r absence of doxycycline. Pituitary weights are shown ± SEM. ns, not significant. Open table in a new tab Animals from all groups were sacrificed and the pituitary weights were recorded. No significant difference n pituitary weights was observed between groups 3 and 4, which received E/S pellets in the presence or absence of doxycycline. A significant difference Regulated, Adenovirus-Mediated Delivery of Tyrosine Hydroxylase Suppresses Growth of Estrogen-Induced Pituitary ProlactinomasWilliams et al.Molecular TherapyDecember, 2001In BriefProlactin-secreting adenomas are one of the most common types of intracranial neoplasm found in humans. The modalities of clinical treatment currently in use include D2-dopamine receptor agonists, surgery, and radiotherapy, and the success rates for treatment are good. However, there are prolactinomas that are difficult to treat. As an alternative, we have developed a gene therapy strategy in which the rate-limiting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), is overexpressed in the anterior pituitary (AP) gland. Full-Text PDF Open Archive
Cost-Effectiveness Analysis of Corneal Collagen Crosslinking for Progressive Keratoconus
Authors: Daniel A. Godefrooij, Marie-Josee J. Mangen, Elsie Chan, David P.S. O'Brart, Saskia M. Imhof, G. Ardine de Wit, Robert P.L. Wisse
Journal: Ophthalmology (2017)
Testing a Dietary Intervention Called parts per thousand Pro-Heartt" to Reduce Adiposity and Enhance Cardiac Structure, Functional Status, Lipid Profiles, Glycemic Control, and Quality Of Life in Obese, Diabetic Patients with Advanced Heart Failure
Authors: Lorraine S Evangelista, Dawn Lombardo, Dan Cooper, Tamara Horwich, Gregg C Fonarow
Journal: Circulation (2012)

CORE 5. MYOCARDIUM: FUNCTION AND FAILURE SESSION TITLE: HEART FAILURE WITH PRESERVED EJECTION FRACTION AND RELATED DISORDERS Abstract 18390: Testing a Dietary Intervention Called %oPro- Heart to Reduce Adiposity and Enhance Cardiac Structure, Functional Status, Lipid Profiles, Glycemic Control, and Quality Of Life in Obese, Diabetic Patients with Advanced Heart Failure Lorraine S Evangelista, Dawn Lombardo, Dan Cooper, Tamara Horwich and Gregg C Fonarow Publlshed: November 20, 2012 Article Info & Metrics eletters ,.. Jumpto Abstract BACKGROUND: To date, no known clinical trials have been done to test the effects of high protein (HP) diets in obese, diabetic patients with heart failure (HF). The goal of this four-year study is to explicate the role of HP diets in delaying the progression of disease in 90 patients with HF, New York Heart Association class II and Ill, body mass index (BMI) ~30 kglm 2 , and diabetes mellitus. We hypothesize that participants randomized to the HP diet compared to a standard protein (SP) diet will show greater reductions in adiposity (e.g. weight, waist circumference, percent body fat) and greater improvements in cardiac structure, functional status, lipid profiles, glycemic control, and quality of life following the 12-week intervention and that these changes will be maintained overtime. METHODS/DESIGN: Recruitment and enrollment in this prospective, two-group, randomized trial is on-going; participants are randomized to either a HP diet which consists of 30% protein (-110 g/day), 40% carbohydrates (CHO, -150 g/day) and 30% fat (-50 g/day) or standard protein (SP) diet which consists of 15% protein (-55 g/day), 55% CHO (-200 g/day) and 30% fat (-50 g/day). Participants will complete an intensive 12-week
ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines)—executive summary21When citing this document, the American College of Cardiology and the American Heart Association would appreciate the following citation format: Smith SC, Jr, Dove JT, Jacobs AK, Kennedy JW, Kereiakes D, Kern MJ, Kuntz RE, Popma JJ, Schaff HV, Williams DO. ACC/AHA guidelines for percutaneous coronary intervention: executive summary and recommendations: a report of the American …
Authors: Sidney C Smith, James T Dove, Alice K Jacobs, J Ward Kennedy, Dean Kereiakes, Morton J Kern, Richard E Kuntz, Jeffery J Popma, Hartzell V Schaff, David O Williams, Raymond J Gibbons, Joseph P Alpert, Kim A Eagle, David P Faxon, Valentin Fuster, Timothy J Gardner, Gabriel Gregoratos, Richard O Russell, Sidney C Smith
Journal: Journal of the American College of Cardiology (2001)
Quantitative detection of ZAP-70 expression in chronic lymphocytic leukemia.
Authors: Peixuan Zhu, Heba A Degheidy, Gerald E Marti, Shuhong Li, Fatima Abbasi, Adrian Wiestner, Platte T Amstutz, Cha-Mei Tang
Journal: Journal of Clinical Oncology (2012)

6581 Background: Intracellular ZAP-70 protein was recently recognized as prognostic marker in chronic lymphocytic leukemia (CLL). The specific objective of this study was to develop a simple and sensitive assay, for the quantitative detection of ZAP-70 protein in leukemic cells. Methods: Components of the assay system include sample preparation, immunomagnetic fluorescence assay, Signalyte-II spectrofluorometer. The leukemic cells were isolated from CLL patient blood samples and lysed to release the intracellular ZAP-70 protein. ZAP-70 protein was captured by magnetic beads coated with anti-ZAP70 capture antibody, and recognized by a fluorescent detector antibody, forming an immuno-sandwich complex. This complex was dissociated for measurement of the fluorescence signal, which was proportional to ZAP-70 concentration, using the spectrofluorometer. Results: The assay conditions were extensively optimized by selecting an optimal pair of capture/detector antibodies, conjugation of fluorescence dye, cell lysis condition and excitation/emission wavelengths. The protocol was further validated with two positive controls, Jurkat cell lysate and recombinant ZAP70 protein (rZAP70). The limit of detection was determined to be lower than 125 Jurkat cells and 39 pg of rZAP70 protein. The signal response was linear over a wide range of concentration, from 625 to 40,000 Jurkat cells per test (R 2 =0.9987) and from 0 to 40,000 pg rZAP70 protein per test (R 2 =0.9928). The results from 20 CLL patients correlated strongly with flow cytometry analysis. The concordance between the two methods for positive and negative results was 100% (7/7) and 92% (12/13), respectively, while the overall concordance between the two methods was 95%. Conclusions: The assay is a simple, reliable, and reproducible method for quantitative detection of ZAP-70 in patient leukemic cells, without the need for cell fixation or permeabilization. The entire assay could be completed in 5.5 hours. The ZAP-70 signal was linear over a wide dynamic range, which we believe enables quantitative assessment of small changes in ZAP-70 expression over the course of the disease and in response to therapeutic intervention.
Intramuscular (IM) or intravenous (IV): Impact of <i>Erwinia </i>asparaginase route of administration on asparaginase activity.
Authors: Olanrewaju O Okusanya, Patricia A. Dinndorf, Julie Bullock, Bahru A. Habtemariam, Nitin Mehrotra, Albert B. Deisseroth, Gregory H. Reaman, Nam Atiqur Rahman, Ann T. Farrell
Journal: Journal of Clinical Oncology (2015)

10031 Background: Erwinia asparaginase (Erwinia) 25000 IU/m2 IM was approved in 2011 as a component of treatment for patients with acute lymphoblastic leukemia (ALL) with hypersensitivity to E. coli-derived asparaginase. In 2014, FDA approved the IV route of administration for Erwiniabased on the PK and safety findings described herein. Methods: Data from a single arm PK study in children (1 – 17 yrs) with ALL given Erwinia 25000 IU/m2 IV every Monday/Wednesday/Friday (M/W/F) were evaluated. The proportion of patients with 2-day and 3-day nadir serum asparaginase activity (NSAA) levels ≥ 0.1 IU/mL during the first 2 wks of IV Erwinia was compared to that of IM Erwinia. Population PK (PPK)-based simulations were used to determine IV Erwinia doses that would result in the same proportion of patients with 2-day and 3-day NSAA levels as that achieved with 25000 IU/m2 IM. The safety of IV and IM Erwinia administration was also compared. Results: IV dosing resulted in a mean (%CV) t½ of 7.5 h (24%) compared to 16 h (21%) for IM (PMID: 8355045). A smaller proportion of patients achieved 2-day or 3-day NSAA levels ≥ 0.1IU/mL while experiencing more adverse events with IV compared to IM administration (Table). PPK-based simulations showed that IV Erwinia doses of 35000 IU/m2 every M/W/F would be needed to attain NSAA levels of ≥ 0.1 IU/mL in 90% of the patients on Wednesday or Friday (2-day NSAA) and doses > 95000 IU/m2every M/W/F would be needed to achieve the same target on Monday (3-day NSAA). Conclusions: IV administration of Erwinia 25,000 IU/m2 every M/W/F, while clinically acceptable, led to a lower rate of target attainment (NSAA ≥ 0.1 IU/mL) and a higher rate of serious adverse events and discontinuations. Improving target attainment with higher IV doses would require clinical investigation. Efficacy and safety of Erwinia. Endpoint IM Study IV Study Proportion (n/N) and 95% CI Efficacy 2-day NSAA ≥ 0.1 IU/mL 100% (35/35) [90, 100] 83% (20/24) [63, 95] 3-day NSAA≥ 0.1 IU/mL 100% (13/13) [77, 100] 43% (9/21) [22, 66] Safety Serious Adverse Events 32.8% (19/58) 50% (15/30) All Grade Hypersensitivity 9% (5/58) 37% (11/30) Grade 3/4 Hypersensitivity 5% (3/58) 3% (1/30) Discontinuation rates 24% (14/58) 40% (12/30)
Molecular classification of bladder cancer by microarray expression profiling
Authors: Kazumori Kawakami, Tokushi Tachiwada, Takenari Gotanda, Masayuki Nakagawa, Makoto Arai, Yoshinori Nimura, Naohiko Seki
Journal: Cancer Research (2005)

3149  Purpose: Clinicopathological and molecular studies have demonstrated that bladder cancer comprises at least two different types of tumor, superficial and invasive. Molecular genetic evidence indicated that superficial cancer develops as the results of multi-step process of oncogene activation and tumor suppressor gene inactivation. The molecular pathogenesis of superficial cancer is incompletely understood. Large-scale gene expression analysis using high-density oligonucleotide array is an effective strategy for determining gene expression profiles that may be understand for multi-step process of bladder cancer oncogenesis. The aim of this study was to identify genes differentially expressed between normal tissue, superficial and invasive cancer by oligonucleotide array. Method: This study was approved by the bioethics committee in Kagoshima University. Tumor specimens from 14 patients (9 were superficial (T1) and 5 were invasive (T2-3) types) with pathologically confirmed bladder cancer were obtained from surgical resection at Kagoshima University. We have analyzed gene expression signature using the oligonucleotide microarray containing 30,000 probes. Software of Significance Analysis of Microarrays (SAM) was adopted for data mining of the microarray. The validity of the differentially expressed genes by microarray was confirmed using PCR method. Results: We identified 21 up-regulated genes and 18 down-regulated genes in all 14 specimens in common by expression analysis. Genes up-regulated in bladder cancer including associated with cell cycle, cell growth and signal transduction. Most genes selected by microarray analysis were verified by PCR method. Selection of the genes which predicts superficial type (no recurrence) and invasive type of bladder cancer was possible in SAM analysis.Conclusions: This study demonstrated the usefulness of comprehensive gene expression technology for identifying differences in gene expression profiles in bladder oncogenesis. Genome-wide gene analysis of profiles may provide new insight into mechanisms of bladder cancer and effective molecular therapy.
Erratum: Adipokines and incident type 2 diabetes in a Canadian Aborigine population: The Sandy Lake Health and Diabetes Project (Diabetes Care (2008) 31 (1410-1415))
Authors: S. H. Ley, S. B. Harris, P. W. Connelly, M. Mamakeesick, J. Gittelsohn, R. A. Hegele, R. Retnakaran, B. Zinman, A. J.G. Hanley
Journal: Diabetes Care (2008)
Incorporation of high-dose 131I-metaiodobenzylguanidine treatment into tandem high-dose chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma: results of the SMC NB-2009 study
Authors: Ji Won Lee, Sanghoon Lee, Hee Won Cho, Youngeun Ma, Keon Hee Yoo, Ki Woong Sung, Hong Hoe Koo, Eun Joo Cho, Suk-Koo Lee, Do Hoon Lim
Journal: Journal of Hematology & Oncology (2017)

In our previous SMC NB-2004 study of patients with high-risk neuroblastomas, which incorporated total-body irradiation (TBI) with second high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT), the survival rate was encouraging; however, short- and long-term toxicities were significant. In the present SMC NB-2009 study, only TBI was replaced with 131I-meta-iodobenzylguanidine (MIBG) treatment in order to reduce toxicities.From January 2009 to December 2013, 54 consecutive patients were assigned to receive tandem HDCT/auto-SCT after nine cycles of induction chemotherapy. The CEC (carboplatin + etoposide + cyclophosphamide) regimen and the TM (thiotepa + melphalan) regimen with (for metastatic MIBG avid tumors) or without (for localized or MIBG non-avid tumors) 131I-MIBG treatment (18 or 12 mCi/kg) were used for tandem HDCT/auto-SCT. Local radiotherapy, differentiation therapy with 13-cis-retinoic acid, and immunotherapy with interleukin-2 were administered after tandem HDCT/auto-SCT.Fifty-two patients underwent the first HDCT/auto-SCT and 47 patients completed tandem HDCT/auto-SCT. There was no significant immediate toxicity during the 131I-MIBG infusion. Acute toxicities during the tandem HDCT/auto-SCT were less severe in the NB-2009 study than in the NB-2004 study. Late effects such as growth hormone deficiency, cataracts, and glomerulopathy evaluated at 3 years after the second HDCT/auto-SCT were also less significant in the NB-2009 study than in NB-2004 study. There was no difference in the 5-year event-free survival (EFS) between the two studies (67.5 ± 6.7% versus 58.3 ± 6.9%, P = 0.340).Incorporation of high-dose 131I-MIBG treatment into tandem HDCT/auto-SCT could reduce short- and long-term toxicities associated with TBI, without jeopardizing the survival rate.ClinicalTrials.gov NCT03061656.
Dysfunctional T Regulatory Cells in Myeloma: Molecular Mechanisms of Dysregulation.
Authors: Rao H. Prabhala, Paola Neri, Pierfrancesco Tassone, Jooeun E. Bae, Masood A. Shammas, John F. Daley, Weihua Song, Robert Bertheau, Dharminder Chauhan, Ramesh B. Bachu, Hemant Thatte, Kenneth Anderson, Nikhil C. Munshi
Journal: Blood (2005)
Biological features, prognostic factors and outcome of 114 patients with GISTs: A single institution experience.
Authors: Carlo Messina
Journal: Journal of Clinical Oncology (2015)

e21507 Background: To retrospectively analyze the biological features and their impact on clinical outcome in a cohort of 114 patients with GIST treated at the GIST Unit of Palermo University between 2003 and 2015. Methods: We retrospectively analyzed 114 patients with GIST treated during the past 12 years. Patients with localized disease were stratified according to Fletcher and Miettinen criteria. Biological features on tumor specimens, treatment and clinical outcome were recorded and compared with published data. Results: Among 114 patients, 88 had resectable disease, 26 had metastasis at diagnosis. Ninety GISTs were examined for mutational analysis of KIT or PDGFRα, resulting KIT exon 11 mutation in 59%, KIT exon 9 mutation in 16%, PDGFRα mutation in 11% while 14% were wild type. Median 5-years recurrence-free survival of 88 patients with localized disease undergoing radical resection was 60 months. Adjuvant imatinib 400 mg daily was delivered in 21 cases; 5 patients recurred and received standard treatment for advanced disease while 16 are still free of disease. Clinical outcomes were significantly poorer for 19 patients with exon11 delection. Miettinen criteria better predicted the risk of recurrence than Fletcher criteria (p = 0,0046 vs p = 0,1). In patients with metastatic disease undergoing standard I and II line therapy with imatinib and sunitinib (n = 29 and n = 18) median progression-free survival was respectively 36 and 6 months. Six patients progressing prior treatment with TKI were enrolled in a randomized multicenter phase III trial of regorafenib, experiencing 7 months mPFS. This result was comparable to data from the phase II trial of regorafenib (mPFS = 10 months). Conclusions: All data reproduced those from published litterature. Mutational analysis allows risk stratification, predicts response to TKI and should be routinely performed at diagnosis. We experienced that GIST Unit guarantees a high standard for diagnosis, biological assessment for risk stratification, staging and treatment delivery, providing clinical outcomes that are comparable to published data. Therefore is essential for patients with rare tumours to be addressed to highly specialized multidisciplinary centers.