tbuckley/cabot-search huggingface dataset:
Abstract 362: Cardioprotective Effects of Adiponectin in Volume Overload Induced Electrophysiological Remodeling
Authors: Juming Zhong, Lili Wang, Dori Miller, Dean Schwartz, Rajesh Amin, Robert Judd
Journal: Circulation Research (2015)

The electrophysiological hallmark of the failing heart is the prolongation of action potential duration that induces arrhythmia and sudden death. Depressed outward potassium currents (Ito) has been implicated as the major cause of altered action potential during ventricular remodeling. The molecular mechanism underlying depressed Ito in the diseased heart is still poorly understood. Recent studies have demonstrated that adiponectin (APN) has a cardio-protective effect in response to various pathological stimuli; however, little information is available regarding the potential effects of APN on electrophysiological remodeling under pathological conditions. The present study were to determine the effect of adiponectin treatment on ventricular potassium channel function in a rat model of volume overload induced heart failure. Volume-overload was induced by surgical creation of an infrarenal aorta-vena cava fistula. Rats were administrated with or without adenovirus-mediated overexpression of adiponectin (Ad-APN) at 2-, 5- and 8- weeks post-fistula. In vivo ECGs were used to evaluate changes in QT interval in rats at 10 weeks post-fistula. Ventricular myocytes were isolated at 10 weeks post-fistula. Western blots were used to measure cytoplasmic and membrane protein expression of potassium channels Kv4.2 and Kv 4.3, as well as, KChIP2. Whole cell patch clamp was used to evaluate action potential and Ito currents. Results showed that adiponectin levels in serum and myocytes were significantly reduced following fistula. The duration of action potential was prolonged in ventricular myocytes following 10-week fistula, which was correlated with the in vivo QT interval prolongation, as well as a depression of functional Ito and decreased protein expression of Ito channel subunits in ventricular myocytes. In vivo supplementation of Ad-APN increased the protein levels of Ito channel subunits and prevented Ito depression in ventricular myocytes following 10-week fistula. This further restored the duration of action potential and the QT interval on the ECG back to the normal. These results indicate that adiponectin was able to prevent volume overload-induced ventricular electrophysiological remodeling.
Enrichment of PI3K-AKT–mTOR Pathway Activation in Hepatic Metastases from Breast Cancer
Authors: Mariaelena Pierobon, Corinne Ramos, Shukmei Wong, K. Alex Hodge, Jessica Aldrich, Sara Byron, Stephen P. Anthony, Nicholas J. Robert, Donald W. Northfelt, Mohammad Jahanzeb, Linda Vocila, Julia Wulfkuhle, Guido Gambara, Rosa I. Gallagher, Bryant Dunetz, Nicholas Hoke, Ting Dong, David W. Craig, Massimo Cristofanilli, Brian Leyland-Jones, Lance A. Liotta, Joyce A. O'Shaughnessy, John D. Carpten, Emanuel F. Petricoin
Journal: Clinical Cancer Research (2017)

Purpose: Little is known about the molecular signatures associated with specific metastatic sites in breast cancer. Using comprehensive multi-omic molecular profiling, we assessed whether alterations or activation of the PI3K-AKT-mTOR pathway is associated with specific sites of breast cancer metastasis.Experimental Design: Next-generation sequencing-based whole-exome sequencing was coupled with reverse-phase protein microarray (RPPA) functional signaling network analysis to explore the PI3K-AKT-mTOR axis in 32 pretreated breast cancer metastases. RPPA-based signaling data were further validated in an independent cohort of 154 metastatic lesions from breast cancer and 101 unmatched primary breast tumors. The proportion of cases with PI3K-AKT-mTOR genomic alterations or signaling network activation were compared between hepatic and nonhepatic lesions.Results:PIK3CA mutation and activation of AKT (S473) and p70S6K (T389) were detected more frequently among liver metastases than nonhepatic lesions (P < 0.01, P = 0.056, and P = 0.053, respectively). However, PIK3CA mutations alone were insufficient in predicting protein activation (P = 0.32 and P = 0.19 for activated AKT and p70S6K, respectively). RPPA analysis of an independent cohort of 154 tumors confirmed the relationship between pathway activation and hepatic metastasis [AKT (S473), mTOR (S2448), and 4EBP1 (S65); P < 0.01, P = 0.02, and P = 0.01, respectively]. Similar results were also seen between liver metastases and primary breast tumors [AKT (S473) P < 0.01, mTOR (S2448) P < 0.01, 4EBP1 (S65) P = 0.01]. This signature was lost when primary tumors were compared with all metastatic sites combined.Conclusions: Breast cancer patients with liver metastasis may represent a molecularly homogenized cohort with increased incidence of PIK3CA mutations and activation of the PI3K-AKT-mTOR signaling network. Clin Cancer Res; 23(16); 4919-28. ©2017 AACR.
P09.22 Moderate hypofrationated accelerated radiotherapy with concurrent and/or adjuvant temozolomide using tomotherapy for patients with glioblastoma
Authors: Y. Kim, M. Cho
Journal: Neuro-Oncology (2017)

Background: The outcome for patients with Glioblastoma (GM) still remains poor (median survival 16 months and overall survival rates 27% at 2 years). Local progression is common after radiation therapy with or without chemotherapy for GM. So, hypothesizing that a hypofrationated accelerated radiotherapy to the gross tumor volume (GTV) might increase local control of GM. We investigated whether hypofractionated accelerated radiotherapy improved local control in patients with GM. Methods and Materials: Sixteen patients with GM were treated with radiotherapy using tomotherapy. All patients were Karnofsky performance status (KPS) > 60 with a histologically proven GM by operation. All patients were treated by radiotherapy using tomotherapy within 4-6 weeks after operation. Clinical target volume (CTV) contains the GTV, plus a margin 2cm which is determined to consider the anatomic structure. Planning target volume (PTV) margin is 2mm all direction from GTV or CTV. A dose 6100-6750 cGy was delivered in 28-30 fractions, fraction size 210-230 cGy to GTV. Critical structures including the optic chiasm/nerve and brain stem were limited to 4000 cGy. Results: Median follow up for patients was 16.1 months. Only one patient did not complete full dose radiotherapy due to tumor progression. Median OS was 12.9 months (1.9-41.9, and 2 years OS was 43.3 %). Median progression free survival (PFS) was 8.9 months (1.1-41.9, and 2 years PFS was 26.7 %) retrospectively. No grade 4 and 5 toxicity. Conclusions: There was no difference OS and PFS in using moderate hypofrationated accelerated radiotherapy compared with historical reports. More study is needed to improved treatment outcomes for patients with GM.
Characterization of the T-Cell Receptor Repertoire and Immune Microenvironment in Patients with Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck
Authors: Vassiliki Saloura, Aiman Fatima, Makda Zewde, Kazuma Kiyotani, Ryan Brisson, Jae-Hyun Park, Yuji Ikeda, Theodore Vougiouklakis, Riyue Bao, Arun Khattri, Tanguy Seiwert, Nicole Cipriani, Mark Lingen, Everett Vokes, Yusuke Nakamura
Journal: Clinical Cancer Research (2017)

Purpose: Squamous cell carcinoma of the head and neck (SCCHN) is a lethal cancer with a suboptimal 5-year overall survival of approximately 50% with surgery and/or definitive chemoradiotherapy. Novel treatments are thus urgently awaited. Immunotherapy with checkpoint blockade has emerged as a promising option for patients with recurrent/metastatic SCCHN; however, it has not been investigated in the curative-intent setting yet. The purpose of this study was to investigate the T-cell receptor repertoire and the tumor microenvironment in tumor tissues of SCCHN patients with locoregionally advanced disease.Experimental Design: We performed T-cell receptor sequencing of tumor tissues from 44 patients with locoregionally advanced SCCHN prior to treatment with definitive chemoradiotherapy and correlated the T-cell clonality and the mRNA expression levels of immune-related genes with clinicopathologic parameters.Results: Clonal expansion of T cells was significantly higher in human papilloma virus (HPV)-negative compared with HPV-positive tumors, signifying more robust antigen presentation in HPV-negative tumors. The latter was supported by the higher percentage of HPV-negative tumors expressing HLA-A protein compared with HPV-positive tumors (P = 0.049). Higher GRZB levels correlated significantly with longer recurrence-free survival (log-rank, P = 0.003) independent of tumor size, nodal stage, and HPV status.Conclusions: Our findings support clonal expansion of T cells in SCCHN patients with locoregionally advanced disease and imply differences in the antigen presentation capacity between HPV-negative and HPV-positive tumors. Elevated GRZB mRNA levels may also serve as a favorable and independent predictor of outcome in SCCHN patients treated with chemoradiotherapy. These data provide rationale for the introduction of immunotherapeutic approaches in the curative-intent setting. Clin Cancer Res; 23(16); 4897-907. ©2017 AACR.
P08.23 A systematic review and meta-analysis of topoisomerase inhibition in pre-clinical glioma models
Authors: T. J. Jue, T. C. Hirst, E. S. Sena, M. R. Macleod, K. L. McDonald
Journal: Neuro-Oncology (2017)

Background: Glioblastoma is the most common malignant primary brain tumor in adults. Pre-clinical animal studies make an important contribution to the development and planning of novel treatment designs for human clinical trials. We investigated the concordance of the efficacy of topoisomerase inhibition in pre-clinical animal models and human clinical trials. Methods: We systematically searched Pubmed, Medline and Embase using pre-defined terms to identify publications describing pre-clinical animal studies investigating the use of topoisomerase inhibitors. We included studies assessing median survival and tumor volume and extracted data pertaining to study quality and design. Study quality was assessed using a 12-item checklist. We performed random-effects meta-analysis to assess treatment efficacy. Heterogeneity was assessed using the I2 statistic and was further investigated using metaregression. We assessed for publication bias using Egger regression and Trim and Fill analysis. Results: The systematic review identified 52 publications reporting a total of 61 survival and 29 tumor volume experiments. We included 47 and 16 respectively in the meta-analysis. Overall, topoisomerase inhibition prolonged median survival by a factor of 1.33 (95% CI 1.23 – 1.43) and reduced tumor growth by a factor of 3.21 (95% CI 1.99 – 5.18), with considerable heterogeneity in each dataset (I2=92.2% and 95.5% respectively). Study quality was modest (median score 6/12), with infrequent reporting of both randomisation (54%) and blinding (8%). For survival studies, multivariable metaregression identified the glioma model used (F=6.08, p=0.0005) and the route of drug delivery (F=8.61, p=0.0010) as parameters associated with differences in efficacy. We found evidence of significant publication bias in both datasets. CONCLUSION: The meta-analysis showed that the use of topoisomerase inhibitors may be beneficial for the treatment of high grade glioma in adults similar to what has been observed in human clinical trials. However, it should be noted that the data is limited by risk of bias, relatively small numbers and covariance. We have nevertheless identified design features impacting perceived drug efficacy that should be accounted for in future experiment design.
Time-dependent patterns of failure and treatment benefit from adjuvant therapy for resectable colon cancer: Lessons from the 20,800-patient (pt) ACCENT dataset
Authors: D. J. Sargent
Journal: Journal of Clinical Oncology (2007)

4008 Background: To explore and inform 3 critical issues facing trialists and practicing oncologists testing adjuvant therapy (AT) for stage II and III colon cancer: 1) The nature and duration of AT benefit, 2) detailed information on survival and recurrence (rec) rates, including long-term event rates (&gt; 10 years (yrs)), and 3) adequacy of statistical models for power and sample size calculations based on a disease-free survival (DFS) endpoint. Methods: The dataset assembled by the Adjuvant Colon Cancer Endpoints (ACCENT) Group, a collection of individual pt data from 18 trials and over 20,800 pts testing 5-FU based AT for pts with stage II and III colon cancer, was analyzed. Results: 1) Significant DFS benefit from AT were manifest in the first two years post randomization; after 2 years DFS rates in the AT and control groups were not significantly different. Significant Overall Survival (OS) benefit of AT was consistent over the 8 year follow-up period. 2) After 5 yrs, rec rates were &lt;1.5%/yr, and after 8 yrs, &lt; 0.5%/yr. 3) For DFS, a Weibull model provided superior model fit compared to the standard exponential model. In the range of Weibull values seen in trials in the dataset, however, the use of the Weibull model did not meaningfully impact power and sample size (&lt;2% impact on power for the same sample size), assuming a constant effect of AT on DFS. Additionally, modeling a non-constant AT effect (as observed for DFS) had a similar negligible impact on statistical power compared to the standard exponential model, for the same sample size. Conclusions: AT provides significant benefit for DFS, primarily within the first 2 years, translating into long-term OS benefit. Long term follow-up for rec yields few events. Despite some increased complexity, existing methods remain appropriate for power and sample size determination for the DFS endpoint, pending further confirmation. No significant financial relationships to disclose.
Estimating the Prevalence of Sexual Minority Adolescents—Reply
Authors: Laura Kann, Lisa C. Barrios
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Metabolic Reprogramming of Macrophages Exposed to Silk, Poly(lactic‐<i>co</i>‐glycolic acid), and Silica Nanoparticles
Authors: Raquel Saborano, Thidarat Wongpinyochit, John D. Totten, Blair F. Johnston, F. Philipp Seib, Iola F. Duarte
Journal: Advanced Healthcare Materials (2017)

Monitoring macrophage metabolism in response to nanoparticle exposure provides new insights into biological outcomes, such as inflammation or toxicity, and supports the design of tailored nanomedicines. This paper describes the metabolic signature of macrophages exposed to nanoparticles ranging in diameter from 100 to 125 nm and made from silk, poly(lactic-co-glycolic acid) or silica. Nanoparticles of this size and type are currently at various stages of preclinical and clinical development for drug delivery applications. 1 H NMR analysis of cell extracts and culture media is used to quantify the changes in the intracellular and extracellular metabolomes of macrophages in response to nanoparticle exposure. Increased glycolytic activity, an altered tricarboxylic acid cycle, and reduced ATP generation are consistent with a proinflammatory phenotype. Furthermore, amino acids possibly arising from autophagy, the creatine kinase/phosphocreatine system, and a few osmolytes and antioxidants emerge as important players in the metabolic reprogramming of macrophages exposed to nanoparticles. This metabolic signature is a common response to all nanoparticles tested; however, the direction and magnitude of some variations are clearly nanoparticle specific, indicating material-induced biological specificity. Overall, metabolic reprogramming of macrophages can be achieved with nanoparticle treatments, modulated through the choice of the material, and monitored using 1 H NMR metabolomics.
Inferior Survival Rates After Chemoradiation for Rectal Cancer Without Surgery—Reply
Authors: C. Tyler Ellis, Hanna Sanoff, Karyn B. Stitzenberg
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
OS10.1 Genomic landscape of pituitary adenomas
Authors: W. L. Bi, N. F. Greenwald, M. Abedalthagafi, P. Horowitz, E. R. Laws, R. Beroukhim, I. F. Dunn
Journal: Neuro-Oncology (2017)

Introduction: The clinical outcome of pituitary adenomas can be difficult to predict consistently. Methods: We characterized the genomic profile of 150 pituitary adenomas using next-generation sequencing and assessed the correlation between molecular and pathologic characteristics. These adenomas included hormonally active and inactive tumors, ones with typical or atypical histology, and ones that were primary or recurrent. Results: We observed two classes of pituitary adenomas based on their molecular profile. One class, encompassing one-third of the samples, had widespread genomic disruption with high rates of chromosome arm-level copy-number alterations. The other class tumors exhibited somatic copy-number alterations involving less than 6% of the genome. Levels of genomic disruption correlated with tumor pathology, as 75% of the disrupted subclass were functional adenomas or atypical null-cell adenomas, compared to only 13% of the less disrupted groups. Despite these high rates of genomic disruption, we detected relatively few focal events, which is unusual among highly disrupted cancers. We validated our finding by looking at previously published gene-expression data, and found that the disrupted subtype harbored more variable gene-expression profiles than quiet tumors. We validated these observations from the discovery cohort in an independent cohort of over 100 pituitary adenomas using a targeted clinical sequencing panel, and confirmed that a CLIA-approved assay was able to discriminate between disrupted and non-disrupted tumors. Furthermore, we recapitulated the known patterns of GNAS driver alterations in growth hormone secreting adenomas. Conclusion: Sporadic pituitary adenomas have distinct copy number profiles that associate with hormonal and histologic subtypes and influence gene expression. These results contribute to the growing repertoire of molecular data that have been generated in pituitary tumors, and will guide future efforts of pituitary tumor classification and risk-stratification.
Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration
Authors: Riccardo Natoli, Nilisha Fernando, Michele Madigan, Joshua A. Chu-Tan, Krisztina Valter, Jan Provis, Matt Rutar
Journal: Molecular Neurodegeneration (2017)

Chemokine signalling is required for the homing of leukocytes during retinal inflammation, and is associated with pathogenesis of diseases such as age-related macular degeneration (AMD). Here, we explore the role of interleukin-1β (IL-1β) in modulating AMD-associated chemokines Ccl2, Cxcl1, and Cxcl10 during photo-oxidative retinal damage, and the effect on both the accumulation of outer-retinal macrophages, and death of photoreceptors.Inhibition of retinal IL-1β expression was performed using either siRNA or antibody neutralisation, which was intravitreally injected in SD rats prior to photo-oxidative damage. Changes in the expression and localisation of Il-1β, Ccl2, Cxcl1 and Cxcl10 genes were assessed using qPCR and in situ hybridisation, while the recruitment of retinal macrophages was detected using immunohistochemistry for IBA1. Levels of photoreceptor cell death were determined using TUNEL.Photo-oxidative damage elevated the expression of Il-1β and inflammasome-related genes, and IL-1β protein was detected in microglia infiltrating the outer retina. This was associated with increased expression of Ccl2, Cxcl1, and Cxcl10. Intravitreal IL-1β inhibitors suppressed chemokine expression following damage and reduced macrophage accumulation and photoreceptor death. Moreover, in Müller and RPE cell cultures, and in vivo, Ccl2, Cxcl1 and Cxcl10 were variously upregulated when stimulated with IL-1β, with increased macrophage accumulation detected in vivo.IL-1β is produced by retinal microglia and macrophages and promotes chemokine expression by Müller cells and RPE in retinal degeneration. Targeting IL-1β may prove efficacious in broadly suppressing chemokine-mediated inflammation in retinal dystrophies such as AMD.