tbuckley/cabot-search huggingface dataset:
Abstract 078: Differential Phosphorylation of Inositol 1,4,5-triphophate Receptor by CaMKIId During Cardiac Remodeling
Authors: Natesan Sankar
Journal: Circulation Research (2013)

Natesan Sankar 1 , Sukriti Dewan 1 , Joshua Maxwell 1 , Donald Bers 2 , Joan Heller Brown 3 , Jeffery Molkentin 4 , Pieter deTombe 1 , Gregory Mignery 1 . 1 Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL. 2 Department of Physiology, Department of Pharmacology University of California at Davis, Davis, CA. 3 Department of Pharmacology, University of California, San Diego, La Jolla, CA. 4 Howard Hughes Medical Institute, Molecular Cardiovascular Biology, Cincinnati Children’s Hospital, Cincinnati, OH. In cardiac myocytes the type-2 isoform of the inositol 1,4,5-triphosphate receptor (InsP 3 R2) Ca 2+ release channel is expressed predominantly in the nuclear envelope. InsP 3 R2 releases intracellular Ca 2+ bidirectionally towards the cytoplasm and nucleoplasm in response to an array of pro-hypertrophic signaling. Thus, InsP 3 R2 mediated Ca 2+ release may contribute to both Excitation-Contraction Coupling (ECC) and Excitation-Transcription Coupling (ETC) during normal and pathophysiologic conditions such as cardiac remodeling. However, the regulation of InsP 3 R2 mediated Ca 2+ release and its role in ECC and ETC during cardiac remodeling is not fully understood. We have shown that CaMKIIδ and InsP 3 R2 forms a signaling complex in the heart and CaMKII mediated phosphorylation of InsP 3 R2 at S150 modulates its intrinsic Ca 2+ channel activity. Here we show that InsP 3 R2 is differentially phosphorylated by CaMKIIδ B and CaMKIIδ C , the predominant nucleoplasmic and cytoplasmic isoforms respectively, in cardiac myocytes. Using adult rat cardiac myocytes we show that the differential phosphorylation by CaMKII of InsP 3 R2 at S150 leads to elevated nuclear Ca 2+ signaling and diminished release towards the cytoplasm. Additionally we show that the InsP 3 R2 was phosphorylated in the hearts of Angiotensin II infused and pressure overload induced cardiac remodeling animal models. Finally, we show that there was an increase in InsP 3 R2 phosphorylation in human heart-failure samples compared to non-failing hearts. Collectively our studies demonstrate that, CaMKIIδ mediated regulation of InsP 3 R2 Ca 2+ channel activity contributes to ECC and ETC during all the phases of cardiac remodeling processes.
CyberKnife stereotactic radiosurgery: Response and toxicity in a series of 291 lesions
Authors: A. Agarwal, S. A. Burton, S. Kalnicki, P. C. Gerszten
Journal: Journal of Clinical Oncology (2004)

6079 Background: The dose of radiation delivered is typically limited by normal tissue tolerance. CyberKnife Stereotactic Radiosurgery (SRS) confers an ability to deliver radiation more precisely than conventional radiotherapy. The efficacy and toxicity of CyberKnife SRS was evaluated in a large clinical series. Methods: Two hundred ninety-one lesions were treated with CyberKnife SRS with a median dose of 16.0 Gy (range: 10–36 Gy) prescribed to the 80% isodose line. Anatomic location of the lesions was: 21% thoracic spine, 19% lumbar spine, 19% cervical spine, 11% sacrum, 10% intracranial, 9% head and neck, 6% lung/mediastinum, 3% pelvis, and 2% other. 67% of lesions were metastatic, and 33% primary. The median number of fractions was 1 (range 1–5). Prior median radiation dose received was 43.7 Gy (range:7.2–120). Median follow up was 1 month (range:1–26) after completion of SRS. Acute toxicity was graded using the National Cancer Institute Common Toxicity Criteria (CTC) scale. Symptomatic response was documented as “improved,” “stable,” or “progression.” In asymptomatic patients, radiological response was noted by serial comparison of pre- and post-SRS treatment imaging studies. Results: No patients experienced a significant (defined as grade 3, 4, or 5) CTC toxicity. Three patients died prior to scheduled follow-up from non-treatment related causes. Response rates to SRS from the patients assessed at short-term follow-up were: 62.7% improved, 29.3% stable, and 8% progression. Conclusions: In this large clinical series, CyberKnife SRS was safe and effective. Cyberknife SRS resulted in: (1) good palliation, and (2) minimal toxicity, with a (3) very short duration of treatment. Longer follow-up will be needed to fully assess potential late toxicity and response. This technique may offer an important therapeutic option to patients that would otherwise be poor candidates for conventional RT. No significant financial relationships to disclose.
New insights in the pathophysiology of chronic intermittent hypoxia-induced NASH: the role of gut–liver axis impairment
Authors: Judith Aron-Wisnewsky, Jean-Louis Pepin
Journal: Thorax (2015)

Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent condition paralleling the growing epidemic of obesity and type-2 diabetes. This disease shows a continuous spectrum of severity ranging from simple steatosis to overt non-alcoholic steato-hepatitis (NASH) that can further progress towards cirrhosis and hepatocarcinoma.1 Although the complete physiopathology is not fully understood, many factors such as insulin resistance, inflammation, oxidative stress and lipotoxicity are involved in the onset of NAFLD.2 ,3 Obstructive sleep apnoea (OSA) is independently associated with the different components of the metabolic syndrome, particularly visceral obesity, hypertension, insulin resistance and abnormal lipid metabolism.4 The repetitive occurrence of partial or complete pharyngeal collapse during OSA induces chronic intermittent hypoxia (CIH) that subsequently results in low-grade inflammation, sympathetic overactivity and oxidative stress. Since OSA and NAFLD share common intermediary mechanisms, the presence of OSA, especially in the context of severe CIH, has been suggested as contributing to the pathogenesis and exacerbation of the severity of NAFLD.

Animal studies have demonstrated that in obesity, short-term or long-term exposure to CIH mimicking OSA induces NAFLD.5–7 Next, studies in human adults, using either non-invasive surrogate markers of liver injury or biopsies to diagnose NAFLD, have also demonstrated that CIH is involved in the development of NAFLD, independently of body mass index (BMI), and contributes to the deleterious progression into overt NASH.8–11 In contrast, other studies have shown that the absence of OSA seems to protect morbidly obese patients from developing NAFLD.12

In response to the currently emergent worldwide epidemic of childhood obesity, NAFLD has started to be more systematically investigated in children than previously.13 ,14 The prevalence of NAFLD reaches 10% in the paediatric population …
Brief Communication: Chemical Carcinogen-Induced Alveolar Nodules in Organ Culture of Mouse Mammary Gland2
Authors: Mihir R. Banerjee, Bonnie G. Wood, Linda L. Washburn
Journal: JNCI Journal of the National Cancer Institute (1974)

Journal Article Brief Communication: Chemical Carcinogen-Induced Alveolar Nodules in Organ Culture of Mouse Mammary Gland Get access Mihir R. Banerjee, Mihir R. Banerjee 4 3Tumor Biology Laboratory, School of Life Sciences, University of Nebraska-Lincoln, Lincoln, Nebr. 68503. 4Address reprint requests to Dr. M. R. Banerjee. Search for other works by this author on: Oxford Academic PubMed Google Scholar Bonnie G. Wood, Bonnie G. Wood 3Tumor Biology Laboratory, School of Life Sciences, University of Nebraska-Lincoln, Lincoln, Nebr. 68503. Search for other works by this author on: Oxford Academic PubMed Google Scholar Linda L. Washburn Linda L. Washburn 3Tumor Biology Laboratory, School of Life Sciences, University of Nebraska-Lincoln, Lincoln, Nebr. 68503. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 53, Issue 5, November 1974, Pages 1387–1393, https://doi.org/10.1093/jnci/53.5.1387 Published: 01 November 1974 Article history Received: 20 May 1974 Accepted: 23 July 1974 Published: 01 November 1974
Phase I trial of CPI-613, a lipoic acid analog, and gemcitabine in patients with advanced solid tumors.
Authors: A. S. Retter, R. Shorr, R. Rodriguez, K. Hoffman, F. Volterra, A. D. Hoffman, N. Huppert, K. Lee
Journal: Journal of Clinical Oncology (2010)

e13136 Background: Lipoic acid analogs are a novel class of anticancer agents that target the altered form of pyruvate dehydrogenase (PD) and possibly α-ketoglutarate dehydrogenase (KDH) causing a significant inhibition of mitochondrial energy metabolism selectively in tumor cells, leading to apoptosis. CPI-613 (C), a member of this novel class, has shown excellent toxicity and efficacy profiles in preclinical models. We initiated a phase I dose-escalation study utilizing the combination of (C) and gemcitabine (G) in patients with metastatic solid tumors. Methods: Patients were treated with (G) 1000 mg/m2 on days 1, 8, and 15 and (C) at escalating doses on days 1, 4, 8, 11, 15 and 18 of a 21-day cycle. Three cohorts of patients each with 3 patients received (C) at a dose of 21, 42, and 70 mg/m2 respectively. Intrapatient dose escalation was allowed and patients received from 1 to 5 cycles of treatment. Tumor types included breast, colon, and pancreas. Plasma concentrations of (C) were assayed using a validated Liquid Chromatography-Mass Spectroscopy method. Results: 9 patients have been treated to date and accrual is ongoing. No DLT has been seen through the first 3 cohorts. The only AE grade 3 or higher were hematologic and attributable to (G). MTD has not yet been reached. PK studies show that plasma (C) levels are appropriately dose-related and plasma half-life was approx 2-6 hours. Response assessments for 8 patients in the first 3 cohorts show 4 pts (tumor types breast and colon) with stable disease that ranged from 4 to 16 weeks in duration. PET imaging showed a reduction from 4-42% as well in FDG avidity. Conclusions: CPI-613 in combination with (G) appears to be well-tolerated with promising efficacy in patients with solid tumors. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cornerstone Pharmaceuticals Cornerstone Pharmaceuticals Cornerstone Pharmaceuticals Cornerstone Pharmaceuticals
Clinical and pharmacokinetic (PK) findings in a phase I study of 7-t-butyldimethylsilyl-10-hydroxycamptothecin (AR-67) in patients with refractory solid tumors
Authors: S. M. Arnold, J. Horn, J. R. Eckardt, J. J. Rinehart, P. DeSimone, S. Z. Fields, B. K. Kee, J. A. Moscow, J. C. Houchins, M. Leggas
Journal: Journal of Clinical Oncology (2009)

2534 Background: AR-67 is a 3 rd generation camptothecin analog selected for development based on the high in vitro stability of its pharmacologically active lactone form and high potency in preclinical models. This report describes the initial phase I study of intravenous AR-67 in adults with refractory solid tumors. Methods: AR-67 was infused over 1 hour for 5 days of a 21-day cycle using an accelerated titration phase I trial design. PK was performed on the 1 st and 4 th day of cycle 1. AR-67 was assayed with a validated chromatography method. Toxicity and response were assessed using NCI CTC (v3) grading scale and RECIST. Results: In total, 26 patients were treated at 9 dose levels (mg/m2/day): 1.2 (n=2), 1.67 (n=3), 2.34 (n=3), 3.2 (n=3); 4.5 (n=1), 6.3 (n=1), 7.5 (n=7), 8.9 (n=4) and 12.4 (n=2). Median age 62 (range 31–79), 15M/11F, median prior therapies 3 (range 1 to 6). Tumor types included: colorectal (8), non-small cell lung (NSCLC) (4), small cell lung (3), soft tissue sarcoma, (3), head and neck (2), prostate (2), and other (4). 21 subjects completed 2 or more cycles of therapy, 5 subjects received 1 cycle of therapy and had rapid disease progression (1 received 2d of drug prior to PD), 1 subject is still under treatment after 9 cycles. DLTs were observed in 5 patients: 2 of 2 at 12.4 mg/m 2 /day (Gr 4 febrile neutropenia, Gr 3 fatigue); 2 of 4 at 8.9 mg/m 2 /day (Gr 4 thrombocytopenia), 1 of 7 at 7.5 mg/m 2 /day (Gr 4 thrombocytopenia). Common C1 worst-grade drug related toxicities (CTC I/II % vs III/IV %): Hg (27/8), WBC (11/19), ANC (19/8), platelets (19/12), fatigue (15/8) insomnia (8/0), flushing (15//0), constipation (8/0), nausea (23/0), ALT elevation (12/0), hiccups (8/0). Antitumor activity, assessed by development of PR and SD, was observed in NSCLC, SCLC, colon and bladder cancer. The lactone form was predominant in plasma (&gt;85% of AUC) at all time points. Clearance was constant with increasing dose and exposure (AUC) correlated with toxicity. Conclusions: AR-67 has superior lactone stability compared to approved analogs, has a predictable toxicity profile that did not include diarrhea and has activity in NSCLC. The RP2D is 7.5 mg/m 2 /day for 5 days of a 21-day cycle. This work was supported by R21-CA-123867 and Arno Therapeutics. [Table: see text]
Evaluating the use of the interferon-γ response to mycobacterium tuberculosis (MTB) specific antigens to diagnose latent tuberculosis infection in patients with chronic inflammatory joint and skin diseases
Authors: Claire Martyn-Simmons, John Mee, Richard Groves, Heather Milburn
Journal: European Respiratory Journal (2011)

Introduction: The treatment of chronic inflammatory diseases has been transformed with targeted biologic therapies. Patients receiving this treatment are at increased risk of reactivating latent tuberculosis infection (LTBI). Tuberculin skin test (TST) has been the gold standard for detecting latent LTBI, but may be difficult to interpret in patients receiving immunosuppressive therapies. In vitro interferon-gamma-release assays (IGRA) are an alternative.

Aim: Evaluate and compare the effectiveness of IGRA (QFR-TB Gold In Tube assay [QFR] and T-SPOT.TB [TSTB]) against TST in a cohort of patients due to commence biological therapies.

Methods: A prospective cross sectional study was conducted at an inner London tertiary referral centre. Patients were screened for LTBI and a TST was performed. Venous blood samples were obtained for QFR and TSTB.

Results: 102 patients were included, aged between 18 and 83 years. A total of 42 patients were receiving at least one immunosuppressive therapy. A TST result was available in 84 patients. The overall agreement between the QFR vs TSTB excluding the indeterminate results was 69 out 78 (k=0.572), between QFR vs TST was 62 out of 79 (k=0.241) and between TSTB vs TST was 58 out of 72 (k=0.304). 13 patients received chemoprophylaxis for presumed LTBI.

Conclusion: Our study showed variation in results obtained from TST and IGRA's when used in our population, some of whom where immune compromised. For patients where interpretation of the results may prove challenging, LTBI screening tests may be best used in combination
Abstract 345: Tissue-Printed Cardiac Progenitor Cells Improve Myocardial Function in a Mouse Model of MI
Authors: Roberto Gaetani, Dries Feyen, Vera Verhage, Rolf Slaats, Elisa Messina, Alessandro Giacomello, Pieter Doevendans, Joost Sluijter
Journal: Circulation Research (2012)

Introduction: Tissue engineering is emerging as a therapeutic approach to overcome the limitations of cell therapy and mechanically support the ventricular wall. Tissue printing technology (TP) allows for the construction of a defined and organized tissue engineered construct. Hypothesis: The aim of our study was to evaluate the combination of TP and cardiac-derived cardiomyocyte progenitor cells (CMPCs) to build a cardiogenic construct. Methods: Sca-1 + CMPCs were printed in gelatin/hyaluronic acid matrix (30x10 6 cells/ ml) to form a biocomplex made of 6 perpendicularly printed layers with a surface of 2cm x 2cm and a structure 500 µm thick. After in vitro characterization, the printed biocomplex was transplanted in a mouse model of MI. Cardiac function was evaluated by MRI. Results: After printing, CMPCs retain cardiogenic gene expression for up to 4 weeks, as evaluated by PCR (n=4). Immunofluorescence analysis confirmed expression of Nkx2.5 and Ki67 with a slight decrease after 7 days in culture (77% vs 52% and 79% vs 64% respectively, n=5, p&lt;0.05). After differentiation, hCMPCs increased MLC2a and TnI gene levels (n=4). In vivo engrafted hCMPCs expressed Nkx 2.5. TnI expression was also detected after 2 weeks (n=3) and 28 days (n=5). CD31 expression was detected in low number of transplanted hCMPCs. Endogenous CD45 expression was similar at 7 and 14 days, mainly localized at the border of the matrix (n=3). At 28 days, a reduction in EDV and ESV dilation was observed, as compared to control (EDV:107,87 ± 7,41 vs 136,6 ±9,6 and ESV:89 ± 6,6 vs 118 ±12, respectively, n=8 each group, p&lt;0.05), although no significant differences could be observed with matrix only (EDV;107,87 ± 7,41 vs 120,8 ±9,5 and ESV;89 ± 6,6 vs 97 ±10, respectively, n=7). Infarct wall thinning was reduced in both groups compare to the control (457 ± 69,8 vs 357,8 ±18,6 and 201,1± 6,3 μ m, respectively; n=5 each group, p&lt;0.05). Conclusion: Here, we showed that hCMPCs can be printed and cultured in Gel/ HA. Transplantation in a mouse model of MI contributed to an improvement in cardiac function and a better remodeling upon injury. Long-term follow up to address its effect on infarct size, cardiomyocytes survival and regeneration, revascularization, endogenous CPCs activation, and inflammation is ongoing.
Phylogenetic analyses of 55 retroelements on the basis of the nucleotide and product amino acid sequences of the pol gene.
Authors: M D Li, D L Bronson, T D Lemke, A J Faras
Journal: Molecular Biology and Evolution (1995)

Comparisons of pol gene nucleotide and reverse transcriptase (RT) amino acid sequences of 47 retroviruses, 3 caulimoviruses, and 5 hepadnaviruses showed that approximately one-third of the gene at the 5' end is much more conserved than other pol regions. The most conserved regions on both the nucleotide and amino acid sequences were chosen for construction of phylogenetic trees. The maximum-parsimony and distance-matrix methods were used for analyses of aligned amino acid sequences; these two methods, and the compatibility method, were used to analyze the aligned nucleotide sequences. Essentially identical majority-rule consensus trees were produced by these different methods from both the pol gene nucleotide and RT amino acid sequences, which divided the 55 retroelements into six major groups. The reliability of the phylogenetic trees was probed with the bootstrapping of 100 replicates of the original sequence alignments. The grouping results were shown to be statistically significant by multiple comparisons with the least-significant-difference procedure.
Clinical effects of prior trastuzumab on combination eribulin mesylate plus trastuzumab as first-line treatment for HER2+ locally recurrent or metastatic breast cancer (MBC): Results from a phase 2, single-arm, multicenter study.
Authors: Joyce O'Shaughnessy, Shannon Leigh Huggins-Puhalla, Sharon Wilks, Adam Brufsky, Lee Steven Schwartzberg, Erhan Berrak, James X. Song, David Cox, Linda T. Vahdat
Journal: Journal of Clinical Oncology (2014)

139 Background: Eribulin mesylate, a novel nontaxane microtubule dynamics inhibitor in the halichondrin class of antineoplastic drugs, is indicated for women with MBC who previously received ≥ 2 chemotherapy regimens in the metastatic setting. Primary data from a phase 2 trial on first-line combination eribulin + trastuzumab (TRAS) in HER2+ patients (pts) showed a 71% objective response rate (ORR) and tolerability consistent with the known profile of these agents. Here we present prespecified endpoint data for this study by prior TRAS use. Methods: Pts with HER2+ MBC who had not received prior chemotherapy for MBC received eribulin mesylate 1.4 mg/m 2 IV on days 1 and 8 of each 21-day cycle and initial TRAS (8 mg/kg IV/day 1), followed by 6 mg/kg/day 1 of each subsequent cycle. Response, progression-free survival (PFS), and tolerability were assessed in patients who had and had not received prior TRAS treatment. Results: The 52 pts (median age, 59.5 years) received combination eribulin + TRAS, for a median treatment duration of ~30 weeks; 40% (n=21) were previously treated with TRAS in the neo-adjuvant/adjuvant setting. There was median of 23 months since completion of adjuvant treatment prior to retreatment with eribulin + TRAS for first-line MBC.Efficacy, assessed by ORR, clinical benefit rate (CBR), PFS, and duration of response (DOR), was largely consistent in pts who received prior TRAS relative to pts who had not received prior TRAS (see table). Overall, grade (G) 3-5 adverse events (AEs), treatment-related AEs (TRAEs), and discontinuations (d/c) were similar between groups (Table). Conclusions: In this phase 2 single-arm trial in pts with HER2+ MBC, eribulin + TRAS demonstrated activity and was well tolerated as first-line treatment, irrespective of prior (neo) adjuvant TRAS treatment. Clinical trial information: NCT01269346. [Table: see text]
Myeloma, melphalan, and meta-analysis.
Authors: D E Bergsagel
Journal: Journal of Clinical Oncology (1992)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1992.10.2.178 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 1531066 Myeloma, melphalan, and meta-analysis. D E BergsagelxD E BergsagelSearch for articles by this author https://doi.org/10.1200/JCO.1992.10.2.178 PDF "Myeloma, melphalan, and meta-analysis.." Journal of Clinical Oncology, 10(2), pp. 178–179© 1992 by American Society of Clinical Oncology
Breast and ovarian cancer prone women and prophylactic surgery temptation.
Authors: F Eisinger, C Julian-Reynier, D Stoppa-Lyonnet, P Vennin, C Lasset, C Noguès, H Sobol
Journal: Journal of Clinical Oncology (1998)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1998.16.7.2573 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 9667284 Breast and ovarian cancer prone women and prophylactic surgery temptation. F EisingerxF EisingerSearch for articles by this author , C Julian-ReynierxC Julian-ReynierSearch for articles by this author , D Stoppa-LyonnetxD Stoppa-LyonnetSearch for articles by this author , P VenninxP VenninSearch for articles by this author , C LassetxC LassetSearch for articles by this author , C NoguèsxC NoguèsSearch for articles by this author , H SobolxH SobolSearch for articles by this author Show More https://doi.org/10.1200/JCO.1998.16.7.2573 First Page PDF © 1998 by American Society of Clinical Oncology