tbuckley/cabot-search huggingface dataset:
Inhaled Sodium Nitrite Improves Rest and Exercise Hemodynamics in Heart Failure With Preserved Ejection Fraction
Authors: Barry A. Borlaug, Vojtech Melenovsky, Katlyn E. Koepp
Journal: Circulation Research (2016)

Abnormalities in nitric oxide signaling play a pivotal role in heart failure with preserved ejection fraction (HFpEF). Intravenous sodium nitrite, which is converted to nitric oxide in vivo, improves hemodynamics in HFpEF, but its use is limited by the need for parenteral administration. Nitrite can also be administered using a novel, portable micronebulizer system suitable for chronic use.Determine whether inhaled nitrite improves hemodynamics in HFpEF.In a double-blind, randomized, placebo-controlled, parallel-group trial, subjects with HFpEF (n=26) underwent cardiac catheterization with simultaneous expired gas analysis at rest and during exercise before and after treatment with inhaled sodium nitrite (90 mg) or placebo. The primary end point was the pulmonary capillary wedge pressure during exercise. Before study drug administration, HFpEF subjects displayed an increase in pulmonary capillary wedge pressure with exercise from 20±6 to 34±7 mm Hg (P<0.0001). After study drug administration, exercise pulmonary capillary wedge pressure was substantially improved by nitrite as compared with placebo (baseline-adjusted mean 25±5 versus 31±6 mm Hg; analysis of covariance P=0.022). Inhaled nitrite reduced resting pulmonary capillary wedge pressure (-4±3 versus -1±2 mm Hg; P=0.002), improved pulmonary artery compliance (+1.5±1.1 versus +0.6±0.9 mL/mm Hg), and decreased mean pulmonary artery pressures at rest (-7±4 versus -3±4 mm Hg; P=0.007) and with exercise (-10±6 versus -5±6 mm Hg; P=0.05). Nitrite reduced right atrial pressures, with no effect on cardiac output or stroke volume.Acute administration of inhaled sodium nitrite reduces biventricular filling pressures and pulmonary artery pressures at rest and during exercise in HFpEF. Further study is warranted to evaluate chronic effects of inhaled nitrite in HFpEF.This single center randomized clinical trial is registered at clinicaltrials.gov (NCT02262078).
Effect of Single-Drug Therapy on Reduction of Left Ventricular Mass in Mild to Moderate Hypertension
Authors: John S. Gottdiener, Domenic J. Reda, Barry M. Massie, Barry J. Materson, David W. Williams, Robert J. Anderson
Journal: Circulation (1997)

Background Antihypertensive drugs may differ in their ability to reduce LV mass. Covariates other than drug selection, such as pretreatment LV mass, body weight, the magnitude of blood pressure reduction, race, and age may modify the response of LV mass to therapy. Methods and Results Patients with mild to moderate hypertension (diastolic blood pressure, 95 to 109 mm Hg) were randomly allocated to treatment with atenolol, captopril, clonidine, diltiazem, hydrochlorothiazide, or prazosin in a double-masked trial. Patients achieving the goal diastolic blood pressure of &lt;90 mm Hg during drug titration entered a 1-year maintenance period. Longitudinal analysis examined changes from baseline echocardiogram in LV mass at 8 weeks and at 1 year, statistically adjusted for pretreatment LV mass, systolic blood pressure, body weight, sodium excretion, physical activity, race, and age. Significant reductions at 1 year in adjusted LV mass were seen for patients in the highest tertile of pretreatment LV mass treated with hydrochlorothiazide (mean, −42.9; 95% confidence limits, −65.5, −20.2 g), captopril (mean, −38.7; 95% confidence limits, −61.0, −16.4 g), and atenolol (mean, −28.1; 95% confidence limits, −50.9, −5.3 g). These treatment effects differed from those of prazosin, diltiazem, or clonidine. Conclusions Antihypertensive drugs have disparate effects on LV mass independent of the magnitude of blood pressure reduction. Patients with adequate blood pressure control on captopril, hydrochlorothiazide, and atenolol show a reduction of LV mass after 1 year of treatment, whereas patients on diltiazem, clonidine, or prazosin do not.
Five-Year Safety and Performance Results from the Argus II Retinal Prosthesis System Clinical Trial
Authors: Lyndon da Cruz, Jessy D. Dorn, Mark S. Humayun, Gislin Dagnelie, James Handa, Pierre-Olivier Barale, José-Alain Sahel, Paulo E. Stanga, Farhad Hafezi, Avinoam B. Safran, Joel Salzmann, Arturo Santos, David Birch, Rand Spencer, Artur V. Cideciyan, Eugene de Juan, Jacque L. Duncan, Dean Eliott, Amani Fawzi, Lisa C. Olmos de Koo, Allen C. Ho, Gary Brown, Julia Haller, Carl Regillo, Lucian V. Del Priore, Aries Arditi, Robert J. Greenberg
Journal: Ophthalmology (2016)

<h3>Purpose</h3> The Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) was developed to restore some vision to patients blind as a result of retinitis pigmentosa (RP) or outer retinal degeneration. A clinical trial was initiated in 2006 to study the long-term safety and efficacy of the Argus II System in patients with bare or no light perception resulting from end-stage RP. <h3>Design</h3> Prospective, multicenter, single-arm clinical trial. Within-patient controls included the nonimplanted fellow eye and patients' native residual vision compared with their vision with the Argus II. <h3>Participants</h3> Thirty participants in 10 centers in the United States and Europe. <h3>Methods</h3> The worse-seeing eye of blind patients was implanted with the Argus II. Patients wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. <h3>Main Outcome Measures</h3> The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. Secondary measures included functional vision performance on objectively scored real-world tasks. <h3>Results</h3> Twenty-four of 30 patients remained implanted with functioning Argus II Systems at 5 years after implantation. Only 1 additional serious adverse event was experienced after the 3-year time point. Patients performed significantly better with the Argus II on than off on all visual function tests and functional vision tasks. <h3>Conclusions</h3> The 5-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind as a result of RP. The Argus II is the first and only retinal implant to have market approval in the European Economic Area, the United States, and Canada.
Elacytarabine Is More Effective Preclinically Than Cytarabine In Combination With Daunorubicin In Primary Patient Xenografts Of AML
Authors: Tereza Osdal, Mihaela Lucia Popa, Lene Mari Vikebø, Andre Sulen, Siv Lise Bendringaas, Marit Liland Sandvold, Birgitte Booij, Øystein Bruserud, Bjørn Tore Gjertsen, Emmet McCormack
Journal: Blood (2013)
Abstract 2870: Serine/arginine rich proteins show different distribution patterns in stratum of oral epidermoid carcinoma
Authors: Cynthia J. Ceja-Lopez, Reyna Lara-Martínez, Lourdes Segura-Valdés, Luz Ruíz Godoy Rivera, Javier A. Ambrosio Hernandez, Jorge Alberto Guadarrama-Orozco, Erika Ruíz-García, Luis Felipe Jiménez García, Abelardo Meneses-García
Journal: Cancer Research (2016)

Abstract Serine/arginine proteins increased their activity during the alternative splicing in cell nucleus. The nuclear speckles, also known as interchromatin granule clusters, are enriched with SR splicing factors and are implicated in gene expression. Nuclear speckle formation is developmentally regulated; in certain cases phosphorylated SR proteins are absent from the nucleus and are instead localized at granular structures in the cytoplasm. SR proteins are related with splicing during different types of cancers and metástasis. We search for phosphorylated SR proteins and the nuclear pattern and speckle formation in human oral carcinomas. Methods: To address nuclear pattern and speckle formation, we performed a series of immunostaining experiments, with SC35 antibody for phosphorylated srsf2 on sections derived from oral epidermoid tumor from 33 patients. The images were obtained with a microscope (Leica TCS SPE/CTR 4000). For imaging cytometry analyses, a Leica LAS AF Lite software (Leica Microsystems) was used to capture images automatically; images and recognition of nuclear speckles were quantitatively analyzed using analysis software (ImageJ). ANOVA analysis was performed for the cellular and staining correlation. Results: There are significant differences in morphology and distribution of intranuclear mottled pattern of SR proteins in each tissue layer between oral epithelial without neoplasia and oral squamous cell carcinoma (P &amp;lt; 0.0001). We also found that number, size and pattern (p &amp;lt;0.05) is different between the stratum layers of the oral squamous cells, showing more transcriptional activity in the granulosum stratum related with a decreased in nucleus numbers. In oral squamous cells the pattern changes become homogeneous and similar to the basal layer of normal tissue. We found that is in the granulosum stratum of oral squamous carcinomas where the SR proteins shows more transcriptional activity. This finding could be related with the increased metabolism of this layer. Citation Format: Cynthia J. Ceja-Lopez, Reyna Lara-Martínez, Lourdes Segura-Valdés, Luz Ruíz Godoy Rivera, Javier A. Ambrosio Hernandez, Jorge Alberto Guadarrama-Orozco, Erika Ruíz-García, Luis Felipe Jiménez García, Abelardo Meneses-García. Serine/arginine rich proteins show different distribution patterns in stratum of oral epidermoid carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2870.
Lung adenocarcinoma harboring concomitant SPTBN1-ALK fusion, c-Met overexpression, and HER-2 amplification with inherent resistance to crizotinib, chemotherapy, and radiotherapy
Authors: Fei-fei Gu, Yong Zhang, Yang-yang Liu, Xiao-hua Hong, Jin-yan Liang, Fan Tong, Jing-song Yang, Li Liu
Journal: Journal of Hematology & Oncology (2016)

Crizotinib is a multi-targeted tyrosine kinase inhibitor (TKI) with activity against mesenchymal-epithelial transition factor (MET) and anaplastic lymphoma kinase (ALK). However, the concomitant oncogenic drivers may affect the sensitivity of crizotinib. Herein, we present a 69-year-old never-smoker Chinese male with advanced lung adenocarcinoma harboring concomitant spectrin beta non-erythrocytic 1 (SPTBN1)-ALK fusion, c-Met overexpression, and human epidermal growth factor receptor-2 (HER-2) amplification with inherent resistance to crizotinib, chemotherapy, and radiotherapy. Although the patient received timely and comprehensive treatment, the overall survival was only 8 months. Therefore, c-Met overexpression, HER-2 gene amplification, and SPTBN1-ALK gene fusion can coexist in lung adenocarcinoma and may become a potential biomarker of cancer refractory to crizotinib, chemotherapy, and radiotherapy as well as of a relatively poor prognosis. In addition, the novel SPTBN1-ALK fusion gene may become a potential target for anti-tumor therapy.
Abstract 1461: MHCII-expressing breast cancer cells can induce anti-tumor immune response
Authors: Mei Li, Tyler R. McCaw, Selene Meza-Perez, Troy D. Randall, Amy Weinmann, Donald J. Buchsbaum, Andres Forero, Albert F. LoBuglio
Journal: Cancer Research (2016)

Abstract We recently reported that the mRNA expression of genes in the Major Histocompatibility Complex class II (MHCII) antigen processing and presentation pathway in breast tumor tissues was strongly prognostic of good clinical outcome in triple negative breast cancer (TNBC) patients (J Clin Oncol 33, 2015 suppl; abstr 1066). Although MHCII expression is most often observed on antigen-presenting cells, such as dendritic cells, macrophages and B cells, we observed MHCII protein expression on TNBC tumor cells. These observations suggested that TNBC cells expressing MHCII may have the ability to directly stimulate CD4 T cells and promote anti-tumor immune responses. To test this hypothesis, we transfected murine TS/A tumor cells (syngeneic, non-immunogenic, and metastatic breast cancer model) with a vector encoding the human MHCII Transcriptional Activator (hCIITA) under the control of a doxycycline (Dox)-inducible promoter. We found that TS/A-hCIITA cells did not express MHCII or CD74 until exposed to Dox, whereupon they expressed MHCII and CD74 mRNA and protein in a dose-dependent fashion. We also found that TS/A-hCIITA cells injected into the mammary fat pad expressed MHCII genes and cell surface MHCII proteins on tumor cells if mice received Dox in their drinking water. Importantly, tumor-bearing, Dox-exposed mice exhibited significantly impaired tumor growth compared to mice that were not exposed to Dox. We also found that tumor-bearing, Dox-exposed mice had a significantly enhanced tumor-specific CD8 T cell response in both the tumor-draining lymph node and tumor bed. Thus, breast cancer tumor cells expressing MHCII proteins promote anti-tumor immune responses, which likely contribute to the control of tumor growth in vivo. Citation Format: Mei Li, Tyler R. McCaw, Selene Meza-Perez, Troy D. Randall, Amy Weinmann, Donald J. Buchsbaum, Andres Forero, Albert F. LoBuglio. MHCII-expressing breast cancer cells can induce anti-tumor immune response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1461.
Checkpoint Immunotherapy: Picking a Winner
Authors: Michele W.L. Teng, Rajiv Khanna, Mark J. Smyth
Journal: Cancer Discovery (2016)

Abstract Summary: Robust biomarkers of response that predict which patients will or will not respond to immune checkpoint blockade need to be identified. New data suggest that the presence of an adaptive immune signature in the tumor biopsies of patients with melanoma early on therapy compared to pretreatment can identify responders from nonresponders. Cancer Discov; 6(8); 818–20. ©2016 AACR. See related article by Chen et al., p. 827.
US officials issue travel alert for Miami area as Zika cases rise to 15
Authors: Michael McCarthy
Journal: BMJ (2016)

The US Centers for Disease Control and Prevention (CDC) is warning pregnant women not to travel to the area north of Miami, Florida, where health officials say that as many as 15 people have become infected with the Zika virus from local mosquitoes.

It is the first time in the agency’s 70 year history that it has issued a travel alert for a region in the United States.

“We advise pregnant women to …
Abstract 4805: In vitro characterization of novel inhibitors of ROCK and MRCK kinases as anticancer agents
Authors: Dhimant H. Desai, Vijay P. Kale, Jeremy A. Hengst, Taryn E. Dick, Ashley L. Colledge, Shantu G. Amin, Jong K. Yun
Journal: Cancer Research (2016)

Abstract Metastatic cancers are the second leading cause of deaths in the USA. RhoA and Cdc42 play critical roles in the regulation of plasticity of cancer cell migration/invasion and cell proliferation. ROCK1/2 and MRCKá/â are downstream kinases in the signaling pathways associated with cancer cell migration and invasion. Hence, we hypothesized that simultaneous targeting of these two kinase families would be an effective therapeutic strategy to block migration, invasion, and growth of metastatic cancers. We have identified DJ4 as a novel inhibitor of ROCK and MRCK kinases. In the cellular functional assays, DJ4 treatment significantly blocked stress fiber formation, and inhibited migration and invasion of multiple cancer cell lines in a concentration dependent manner. To study the critical functional groups required for its activity, we have modified the chemical structure of DJ4 at various functional groups and synthesized several analogs of DJ4 to perform the structural activity relationship (SAR) study for their ROCK1 inhibition. The effectiveness of these compounds were further investigated using National Cancer Institute's drug screening program in 60 human cancer cell lines representing nine different cancer types. These compounds effectively inhibit migration and invasion of multiple cancer cell types. Selected analogs were tested for their anti migration, pro-apoptotic, and anti-proliferative effects in breast cancer cells. Our studies strongly indicate that DJ4 and its analog, DJ110, are potent inhibitors of ROCK1, ROCK2, MERKá and MRCKâ. The results of our finding will be discussed. Citation Format: Dhimant H. Desai, Vijay P. Kale, Jeremy A. Hengst, Taryn E. Dick, Ashley L. Colledge, Shantu G. Amin, Jong K. Yun. In vitro characterization of novel inhibitors of ROCK and MRCK kinases as anticancer agents. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4805.
Abstract 1226: Highly specific ATR inhibitors as a therapeutic approach for a broad spectrum of cancers
Authors: Laura R. Butler, Ryan L. Ragland, Hank J. Breslin, Tina Gill, Erin George, Fiona Simpkins, Eric J. Brown, Oren Gilad
Journal: Cancer Research (2016)

Abstract Ataxia Telangiectasia and Rad3-related (ATR) and Checkpoint kinase 1 (CHK1) stabilize stalled replication forks and prevent their collapse into DNA double strand breaks (DSBs). Inhibition of ATR in cells experiencing oncogenic stress or harboring other cancer-associated defects synergistically increases the formation of DSBs and causes synthetic lethality. Thus specific targeting of ATR represents an emerging strategy to treat a broad spectrum of cancers, most notably those that currently lack effective treatments. Atrin Pharmaceuticals has synthesized a novel series of small molecules that inhibit ATR at low nanomolar concentrations in cultured cells. These compounds have the highest known potency for inhibiting ATR and maintain &amp;gt;800-fold lower cellular activity towards other kinases of the same family (ATM, DNA-PKcs and mTOR), which are substantially off-targeted by previously reported ATR inhibitors. Atrin's lead compound (ATRN-119), as a single agent, selectively kills cancer cells subjected to oncogenic stress, alternative lengthening of telomeres (ALT) or loss of double strand break (DSB) homologous recombination repair mechanism (BRCA1 or BRCA2 deficiency). Furthermore, ATRN-119 cytotoxicity is synergistically enhanced when combined with conventional chemotherapeutics, such as etoposide, cisplatin and olaparib. Therefore, this inhibitor can be used in combination with other therapeutics to potentiate its anti-tumor activity. In vivo studies of RAS oncogene driven HCT116 p53-null flank tumors in mice demonstrate the ability of our lead compound to slow tumor progression, with minimal toxicity to tissues under normal proliferative control, including the bone marrow and intestine. Additionally, mice engrafted with BRCA2-mutant patient-derived ovarian tumors show a significant reduction in progression after 5 weeks treatment (100 mg/kg BID) of ATRN-119, and display no toxicity or significant weight loss. Thus, ATRN-119 is highly efficacious in suppressing tumor growth in multiple murine models, including suppression of patient-derived BRCA2-mutant ovarian cancer, suggesting that the clinical application of the ATRN series will provide a new and effective treatment for human malignancies with fewer side effects than conventional chemotherapies. Citation Format: Laura R. Butler, Ryan L. Ragland, Hank J. Breslin, Tina Gill, Erin George, Fiona Simpkins, Eric J. Brown, Oren Gilad. Highly specific ATR inhibitors as a therapeutic approach for a broad spectrum of cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1226.
Abstract 4500: Normal tissue and data resources for cancer research from the GTEx program
Authors: Ping Guan, Abhi Rao, Simona Volpi, Susan Koester, Helen M. Moore
Journal: Cancer Research (2016)

Abstract The NIH Common Fund's Genotype-Tissue Expression (GTEx) project aims to study gene expression and regulation across multiple human tissues from approximately 1000 healthy normal postmortem donors. GTEx will provide valuable insights into gene regulation and its tissue specificity, to identify correlations between genetic variations and variations in gene expression levels as expression quantitative trait loci (eQTLs), and to help understand inherited susceptibility to disease. Initiated in 2010, the GTEx program has generated a large volume of data associated with each donor, including clinical and histopathological, as well as genotyping and gene expression data from whole genome sequencing, whole exome sequencing, expression array, and RNAseq data. The program has published research results in multiple scientific journals over the past year. The following public resources are available from the GTEx program: 1. GTEx Portal: an open access database of GTEx expression data and analysis results: http://www.gtexportal.org 2. Database of Genotypes and Phenotypes (dbGaP): controlled access of comprehensive GTEx clinical data and raw sequencing data: http://www.ncbi.nlm.nih.gov/gap 3. Access to residual GTEx biospecimens for research: http://www.gtexportal.org/home/samplesPage 4. SOPs and best practices from GTEx biospecimen collections: http://biospecimens.cancer.gov/resources/sops/library.asp 5. GTEx histological image viewer: http://biospecimens.cancer.gov/resources/tissue_image_library.asp 6. GTEx donors’ families website: a lay description of the GTEx project tailored to the GTEx donors’ families: http://www.genome.gov/gtex GTEx data can be used in combination with other data sets such as The Cancer Genome Atlas (TCGA) and genome-wide association studies (GWAS) to further explore the genetic causes and biology of cancer. The eQTL data from multiple tissues will help prioritize candidate genes within GWAS-associated loci; allow evaluation of tissue specificity of associated loci, and pinpoint target tissues for disease studies. Researchers are using GTEx resources to: study cancer heterogeneity by subtracting normal tissue expression; identify mutations in protein-truncating variants which may cause cancer; and explore gene activity from multiple donors across multiple tissue types to better understand the age/gender bias in cancer and other diseases. Citation Format: Ping Guan, Abhi Rao, Simona Volpi, Susan Koester, Helen M. Moore, GTEx consortium. Normal tissue and data resources for cancer research from the GTEx program. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4500.