tbuckley/cabot-search huggingface dataset:
Abstract P121: Cardiac Deletion of Aryl Hydrocarbon Nuclear Translocator (Hypoxia-Inducible Factor 1-β) in the Adult Heart Results in Cardiomyopathy
Authors: Rongxue Wu
Journal: Circulation Research (2011)

Rongxue Wu, Kusum Chawla, Yoshihiko Ichikawa, Mohsen Granefar Hossein Ardehali Background: Aryl hydrocarbon receptor nuclear translocator (ARNT) is a member of basic helix-loop-helix Per/ARNT/Sim (bHLH-PAS) proteins and serves as a binding partner for a number of other family members. ARNT is also a required dimerization partner of HIF1a. Although HIF1a is known to be required for normal cardiac development, the role of ARNT in basal cardiac function in the adult heart is not known. We hypothesized that ARNT is required for normal cardiac physiology, and its deletion in adult heart results in cardiomyopathy. Methods and Results: The deletion of ARNT gene in the heart of 3 month old mice was achieved by crossing ARNT flox/flox mice with αMHC-MCM (tamoxifen-inducible heart specific Cre) transgenic mice followed by administration of tamoxifen chow. MHC-MCM/ARNT +/+ (WT) littermates were used as a control. The ARNT knock out (KO) mice exhibited enlarged left ventricle with a significant reduction in ejection fraction (KO vs. WT: 35.8 ± 3.6% vs. 61.2 ± 2.8%, n=12, p&lt;0.01) and fractional shortening (KO vs. WT: 18.3 ± 1.5 % vs. 30.1 ± 1.1%, p&lt;0.01), assessed by Echocardiography. Closed-chest catheterization also demonstrated reduced +dP/dt (KO vs. WT: 4355 ± 538 vs. 9426 ± 180 mmHg, p&lt;0.01) and increased left ventricular end diastolic pressure (KO vs. WT: 3.12 ± 1.1 vs. 8.47± 1.2 mmHg, P&lt;0.05) in KO mice but not in WT mice. The worsened cardiac function in the KO mouse heart was associated with increase in ANF and BNP expression, interstitial fibrosis, and apoptosis as determined by TUNEL staining. Furthermore, electron microscopy reveals a variety of degenerative changes and some lipid droplet in the KO hearts, and histological studies demonstrated intramyocardial lipid accumulation in the perivascular area in the KO mouse hearts. Analysis of gene expression in the KO heart revealed up-regulation of peroxisome proliferator-activated receptor alpha. Conclusion: ARNT is essential for the maintenance of structural and functional homeostasis in the adult heart, and its inactivation leads to cardiac contractile dysfunction. Our findings implicate a novel critical transcriptional requirement for ARNT in the maintenance of adult cardiac function.
Abstract AP29: BRCA1 RING DOMAIN–DEFICIENT PROTEINS PROMOTE PARP INHIBITOR AND PLATINUM RESISTANCE
Authors: Yifan Wang, John J. Krais, Andrea J. Bernhardy, Emmanuelle Nicolas, Kathy Q. Cai, Maria I. Harrell, Hyoung H. Kim, Erin George, Elizabeth M. Swisher, Fiona Simpkins, Neil Johnson
Journal: Clinical Cancer Research (2017)

Abstract Although cancers harboring BRCA1 mutations initially respond well to platinum and poly(ADP-ribose)-polymerase inhibitor (PARPi) therapy, resistance invariably arises and is a major clinical problem. The BRCA1185delAG allele is a common inherited mutation located close to the protein translation start site, thought to produce a short peptide devoid of function. In this study, we utilized the SUM1315MO2 cancer cell line that harbors a hemizygous BRCA1185delAG mutation to study PARPi and platinum resistance. SUM1315MO2 cells were initially PARPi and cisplatin sensitive but readily acquired resistance. PARPi and cisplatin resistant clones did not harbor secondary reversion mutations. Rather, increased expression of a RING domain-deficient BRCA1 protein (Rdd-BRCA1) was required for resistance. Translation initiation occurred downstream of the frameshift mutation, likely at the BRCA1-Met-297 codon. In contrast to full-length BRCA1, Rdd-BRCA1 did not require BARD1 interaction for stability. Functionally, Rdd-BRCA1 formed irradiation-induced foci and supported RAD51 foci-formation. Ectopic overexpression of Rdd-BRCA1 promoted partial PARPi and cisplatin resistance in vitro and in vivo. Furthermore, Rdd-BRCA1 protein expression was detectable in recurrent carcinomas from germline BRCA1185delAG mutation carriers. Taken together, these results indicate that RING-deficient BRCA1 proteins are hypomorphic, and when expressed at high enough levels are capable of contributing to PARPi and platinum resistance. Citation Format: Yifan Wang, John J. Krais, Andrea J. Bernhardy, Emmanuelle Nicolas, Kathy Q. Cai, Maria I. Harrell, Hyoung H. Kim, Erin George, Elizabeth M. Swisher, Fiona Simpkins and Neil Johnson. BRCA1 RING DOMAIN–DEFICIENT PROTEINS PROMOTE PARP INHIBITOR AND PLATINUM RESISTANCE [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP29.
Glycemic Control and Functionality in Nursing Homes—More Than HbA<sub>1c</sub>
Authors: Medha N. Munshi, Robert A. Gabbay
Journal: JAMA Internal Medicine (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Nitric oxide induces human CLA + CD25 + Foxp3 + regulatory T cells with skin-homing potential
Authors: Cunjing Yu, Amanda Fitzpatrick, Duanduan Cong, Chengcan Yao, Jinah Yoo, Andrew Turnbull, Jürgen Schwarze, Mary Norval, Sarah E.M. Howie, Richard B. Weller, Anne L. Astier
Journal: Journal of Allergy and Clinical Immunology (2017)
Regulatory effects of IL-15 on allergen-induced airway obstruction
Authors: Sathisha Upparahalli Venkateshaiah, Xiang Zhu, Priya Rajavelu, Rituraj Niranjan, Murli Manohar, Alok K. Verma, Joseph A. Lasky, Anil Mishra
Journal: Journal of Allergy and Clinical Immunology (2017)
Activation of RHOA–VAV1 signaling in angioimmunoblastic T-cell lymphoma
Authors: M Fujisawa, M Sakata-Yanagimoto, S Nishizawa, D Komori, P Gershon, M Kiryu, S Tanzima, K Fukumoto, T Enami, M Muratani, K Yoshida, S Ogawa, K Matsue, N Nakamura, K Takeuchi, K Izutsu, K Fujimoto, T Teshima, H Miyoshi, P Gaulard, K Ohshima, S Chiba
Journal: Leukemia (2017)

Somatic G17V RHOA mutations were found in 50–70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1–STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1–STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1–STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA–VAV1 axis may provide a new therapeutic target in AITL.
Vitamin D and Breast Cancer Survival: The Good and the Bad—In Reply
Authors: Song Yao, Christine B. Ambrosone, Lawrence H. Kushi
Journal: JAMA Oncology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
PEARLY: A randomized, multicenter, open-label, phase III trial comparing anthracyclines followed by taxane versus anthracyclines followed by taxane plus carboplatin as (neo)adjuvant therapy in patients with early triple-negative breast cancer.
Authors: Gun Min Kim, Hei-Cheul Jeung, Kyung Hae Jung, Se Hyun Kim, Han Jo Kim, Ki Hyeong Lee, Kyong Hwa Park, Ji Eun Lee, Mi Sun Ahn, Sujin Kohn, Sung Sook Lee, Yong Wha Moon, Joohyuk Sohn
Journal: Journal of Clinical Oncology (2017)

TPS587 Background: Triple-negative breast cancer (TNBC) is an aggressive tumor with poor prognosis. There are no molecular targets for TNBC, and there is an unmet need to provide new drugs to patients with TNBC. Platinum agents are known to have an anti-tumor activity in TNBC, especially in BRCA-mutated tumor. Addition of carboplatin significantly increased pathologic complete response rates with neoadjuvant chemotherapy in recent randomized studies. There are no data about adjuvant role of carboplatin for TNBC in a randomized trial. Methods: PEARLY is a randomized, multicenter, open-label, phase III trial comparing anthracyclines followed by taxane versus anthracyclines followed by taxane plus carboplatin as (neo)adjuvant therapy in patients with triple-negative breast cancer (TNBC). Patients with stage II or III TNBC who need adjuvant or neoadjuvant chemotherapy were included. Any prior systemic therapy for breast cancer was not allowed. Bilateral, metastatic, and inflammatory breast cancer are excluded. A total of 840 patients will be enrolled for 3 years. Patients were randomized 1:1, stratified based on the node positivity (N0 vs N+), institution, treatment setting (neoadjuvant vs. adjuvant), and BRCA mutation status (positive vs. negative). Standard arm treatment consists of doxorubicin 60 mg/m2 IV + cyclophosphamide 600 mg/m2 IV every 3 weeks for 4 cycles followed by taxane treatment (paclitaxel 80 mg/m2 IV weekly for 12 doses or docetaxel 75mg/m2 IV every 3 weeks for 4 cycles). Experimental arm added carboplatin AUC5 IV every 3 weeks for 4 cycles during taxane treatment. The primary objective was to evaluate 5-year event free survival (EFS) rate. Secondary objectives included overall survival, distant recurrence free survival, pathologic complete response, and tolerability. The analysis is planned at 248 EFS events, which provides approximately 80% power to detect superiority of standard treatment plus carboplatin versus standard treatment using a log-rank test, assuming a hazard ratio of 0.7 at a two sided alpha of 0.05. Data is expected in 2023. Clinical trial information: NCT02441933.
Abstract 396: Uncontrolled Endothelial Migration In Hereditary Hemorrhagic Telangiectasia: Disease Modeling With Ips Cell
Authors: Makoto Takei, Shinsuke Yuasa, Dai Kusumoto, Akira Kunitomi, Shin Kashiumura, Gakuto Yodu, Masaya Shimojima, Chikaaki Motoda, Atsushi Tanaka, Yusuke Kuroda, Shugo Tohyama, Tomohisa Seki, Keiichi Fukuda
Journal: Circulation Research (2015)

Introduction: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant heritable disease caused by mutation of Activin like receptor-1 (ALK1), an endothelial specific TGF-β family receptor. The histological hallmark in HHT is abnormal atriovenous communication, caused by abnormal migration of endothelial cells (ECs). These findings suggest that the enhanced migration of ECs would have a role in the development of HHT. However, how EC migration is regulated in HHT remains unclear. Hence, the aim of this study is to develop an in vitro HHT model with ECs derived from patient-specific induced pluripotent (iPS) cells. Methods: We generated iPS cells from a HHT patient with ALK1 mutation (ALK1mt) and two control subjects (WT). ECs were derived from these iPS cells with prespecified differentiation method. We compared the effects of BMP-9, a selective agonist of ALK1, between ALK1mt- and WT-ECs. Also, microarray analysis comparing transcriptome of ALK1mt- and WT ECs with or without BMP-9 stimulation was conducted. Results: Migration capacity was significantly reduced with BMP-9 in WT-ECs, but not in ALK1mt-ECs. With BMP-9 stimulation, elevation of genes associated with vascular stabilization and maturation was observed in WT-ECs but not in ALK1mt-ECs. Conclusion: With ECs derived from iPS cells, modeling of HHT phenotype, uncontrolled endothelial migration, was achieved. Clinical implications: By elucidating the biological process with which BMP-9 controls the migration of endothelial cells, new drug targets for HHT may be found. Also, these result may lead to the development of a new experimental drug screening system for HHT.
Social Integration and Reduced Risk of Coronary Heart Disease in Women
Authors: Shun-Chiao Chang, Maria Glymour, Marilyn Cornelis, Stefan Walter, Eric B. Rimm, Eric Tchetgen Tchetgen, Ichiro Kawachi, Laura D. Kubzansky
Journal: Circulation Research (2017)

Higher social integration is associated with lower cardiovascular mortality; however, whether it is associated with incident coronary heart disease (CHD), especially in women, and whether associations differ by case fatality are unclear.
Ethnicity Influences Phenotype and Outcomes in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis of Population-based Studies
Authors: Hai Yun Shi, Alexander N. Levy, Hirsh D. Trivedi, Francis K.L. Chan, Siew C. Ng, Ashwin N. Ananthakrishnan
Journal: Clinical Gastroenterology and Hepatology (2017)
Abstract AP26: SMAC–MIMETIC TREATMENT ENHANCES ANTITUMOR EFFECT OF STANDARD CHEMOTHERAPY IN OVARIAN CANCERS EXPRESSING LOW CASPASE 8 IN VITRO AND IN VIVO
Authors: Lídia Hernandez, Christina M. Annunziata
Journal: Clinical Cancer Research (2017)

Abstract Ovarian cancer is the most lethal gynecological cancer in the US. Standard treatment consists of surgery followed by chemotherapies relying on apoptotic tumor cell death. Most women with advanced stage disease will relapse, suggesting that this disease is characterized by primary and acquired resistance to chemotherapy, and targeted approaches to treatment are greatly needed. We recently demonstrated that low Caspase 8 expression levels in ovarian cancers correlated with resistance to chemotherapy, and a subpopulation of ovarian cancer patients with low Caspase 8 levels exhibits poorer overall survival after standard of care treatment. We hypothesized that the loss of Caspase 8 function reduces the cancer cells' ability to undergo apoptosis when exposed to standard chemotherapy. Here we show that combination treatment with Smac-mimetics targets tumor cells with low Caspase 8 and induces necroptotic cell death. We investigated the in vitro sequential effect of Smac-mimetic added to carboplatin + paclitaxel treatment of ovarian cancer cells expressing wild type, low and mutant Caspase 8 levels, which resulted in a 2-4fold enhancement of cell death. In vivo treatment of mice bearing subcutaneous or intraperitoneal ovarian xenografts showed greater aggressiveness of Caspase 8 deficient vs wild-type tumors; combined treatment with chemotherapy and Smac-mimetic resulted in over 50% decrease in low-Caspase 8 xenograft growth, as well as enhanced overall survival of the mice. Subpopulations of women with low Caspase 8 ovarian cancers that resist apoptosis could benefit from treatments which promote non-apoptotic forms of cell death, such as Smac-mimetic induced necroptosis. Clinical validation of such approaches are needed to increase the effectiveness of current standard ovarian cancer treatment. Citation Format: Lídia Hernandez and Christina M. Annunziata. SMAC–MIMETIC TREATMENT ENHANCES ANTITUMOR EFFECT OF STANDARD CHEMOTHERAPY IN OVARIAN CANCERS EXPRESSING LOW CASPASE 8 IN VITRO AND IN VIVO [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP26.
Randomized controlled comparative clinical pharmacokinetic study of nab-paclitaxel and solvent-based paclitaxel in Chinese patients (pts) with metastatic breast cancer (MBC)
Authors: S. Li, Z. Guan, Z. Yao, X. Teng, H. Liao, L. Deng, Y. Pan, Q. X. Yao, M. J. Hawkins
Journal: Journal of Clinical Oncology (2007)

11505 Background: nab-paclitaxel is a novel solvent-free, 130-nM albumin-bound (nab™) formulation of paclitaxel. In previous studies, nab-paclitaxel demonstrated higher volume of distribution and clearance than that of paclitaxel formulated with Cremophor (Cr-PAC) in Caucasian patients (Sparreboom, Clin Cancer Res 2005;11:4136) and had greater response rate and favorable safety profile in pts with MBC (Gradishar et al., JCO, 2005;23:7794) . The aim of this study was to evaluate nab-paclitaxel blood pharmacokinetics (PK) and compare it with that of Cr-PAC in Chinese MBC patients.Methods: In this randomized controlled, open-label study, patients were assigned to either nab-paclitaxel 260 mg/m 2 intravenously (iv) over 30 minutes q3w or Cr-PAC 175 mg/m 2 iv over 3 hours q3w. At cycle 1, 12 patients in each treatment group participated in the PK study and then continued treatment until PD or unacceptable toxicity. Plasma samples from pts were analyzed for PK parameters. The primary clinical endpoints were ORR and toxicity (Guan et al; submitted, ASCO, 2007). Results: 24 female pts (median age 44.5 years) participated. No statistically significant between group differences were noted in age, height, weight, or baseline liver function. Paclitaxel blood PK parameters in 2 treatment groups are summarized in the Table. ORR: nab-paclitaxel, 75%; Cr-PAC, 25% (P = 0.018). The maximum grade (G) of neutropenia and neuropathy in the nab-paclitaxel and Cr-PAC groups were G3 and G2, respectively, with no significant between-group difference. Conclusion: nab-Paclitaxel had a greater distribution volume, clearance, and smaller dose adjusted AUC 0- inf compared with that of Cr-PAC. There was no significant difference in T 1/2 in the 2 groups. PK results in Chinese pts are identical to data reported in Caucasian pts. The lower CL and V z for Cr-PAC are probably related to sequestration of paclitaxel in the blood by Cremophor. * dose adjusted AUC 0-inf [Table: see text] [Table: see text]
Adjustments in relative dose intensity (RDI) for FECD chemotherapy in breast cancer: A population analysis.
Authors: Zachary William Neil Veitch, Omar Farooq Khan, Derek Tilley, Kostaras Xanthoula, Patricia A. Tang, Karen M. King, Sasha M. Lupichuk
Journal: Journal of Clinical Oncology (2017)

547 Background: Reductions in RDI of adjuvant chemotherapy for breast cancer (BC) has been associated with inferior survival. However, earlier studies may be confounded by uncharacterized BC subtype(s) (TNBC, HER2+) and non-taxane chemotherapy regimens (CMF, AC). This retrospective study evaluates survival (DFS/OS) outcomes for patients receiving RDI reductions for FECD adjuvant chemotherapy in Alberta, Canada. Methods: Patients with stage I-III, ER +/-, HER2- BC receiving adjuvant FECD chemotherapy from 2007-2014 were identified using the Alberta Cancer Registry. RDI of individual chemotherapeutics (cycle 1-6) were recorded. Average RDI was stratified by <85% vs ≥85% of total dose. Subgroup analysis for early (cycle 1-3) versus late (cycle 4-6) RDI reductions were evaluated. Events (recurrence/death) from any cause were identified. Results: FECD patients (n=1304) receiving an average RDI <85% (range 25-84%) compared to ≥85% demonstrated a significant decline in DFS (79% vs 85%; p<0.01) and OS (82% vs 89%; p<0.01). Early reductions (any) compared to no reduction in RDI were correlated with inferior DFS (77% vs 86%; p<0.01) and OS (79% vs 90%; p<0.01). Late reductions in RDI did not affect DFS/OS. Proportions of TNBC were non-significant for comparative cohorts. Significantly more N0 and N1-3 patients were seen in the any and no early reduction cohort respectively. Conclusions: In high risk BC patients, average RDI <85% is correlated with reduced DFS/OS for FECD. Early (FEC) compared with late (docetaxel) reductions in RDI are correlated with inferior survival. This data suggests that where possible, total (<85%) and early (FEC) dose reductions should be avoided in patients receiving adjuvant FEC-D chemotherapy. Baseline patient characteristics. Patient Characteristics FECD Early (FEC) Late (Docetaxel) <85% (n=202) ≥85% (n=1101) Yes (n=238) No (n=1065) Yes (n=688) No (n=1065) n % n % n % n % n % n % Age 56 - 54 - 55 - 54 - 55 - 53 - HR+ 166 82.2 943 85.6 195 81.9 914 85.8 597 86.8 512 83.3 TNBC 36 17.8 158 14.4 43 18.1 151 14.2 91 13.2 103 16.7 Nodes N0 19 9.4 93 8.4 30 12.6** 82 7.7 57 8.3 55 8.9 N1-3 129 63.9 701 91.6 136 57.1 694 65.2* 432 62.8 398 64.7 N>4 54 26.8 307 27.9 72 30.3 289 27.2 199 28.9 162 26.3 *p=0.02; **p=0.015