tbuckley/cabot-search huggingface dataset:
Anti-Inflammatory Therapy With Canakinumab for the Prevention of Hospitalization for Heart Failure
Authors: Brendan M. Everett, Jan H. Cornel, Mitja Lainscak, Stefan D. Anker, Antonio Abbate, Tom Thuren, Peter Libby, Robert J. Glynn, Paul M Ridker
Journal: Circulation (2019)

Background: Subclinical inflammation is associated with an increased risk of heart failure and with adverse prognosis in patients with established heart failure. Yet, treatments specifically directed at reducing inflammation in patients with heart failure have not yet shown improved clinical outcomes. We tested the hypothesis that the interleukin-1β inhibitor canakinumab would prevent hospitalization for heart failure (HHF) and the composite of HHF or heart failure–related mortality. Methods: We randomized 10 061 patients with prior myocardial infarction and high-sensitivity C-reactive protein ≥2 mg/L to canakinumab 50, 150, or 300 mg or placebo, given subcutaneously once every 3 months. In total, 2173 (22%) reported a history of heart failure at baseline. We tested the hypothesis that canakinumab prevents prospectively collected HHF events and the composite of HHF or heart failure–related mortality. Results: A total of 385 patients had an HHF event during a median follow-up of 3.7 years. Patients who had HHF were older, had higher body mass index, and were more likely to have diabetes mellitus, hypertension, and prior coronary bypass surgery. As anticipated, median (quartile 1, 3) baseline concentrations of high-sensitivity C-reactive protein were higher among those who had HHF during follow-up than those who did not (5.7 [3.5, 9.9] mg/L versus 4.2 [2.8, 6.9] mg/L, respectively; P &lt;0.0001). The unadjusted hazard ratios for HHF with each dose of canakinumab compared with placebo were 1.04 (95% CI, 0.79–1.36) for 50 mg, 0.86 (95% CI, 0.65–1.13) for 150 mg, and 0.76 (95% CI, 0.57–1.01) for 300 mg ( P for trend=0.025). The composite of HHF or heart failure–related mortality was also reduced by canakinumab, with unadjusted hazard ratios of 1.00 (95% CI, 0.78–1.29) for 50 mg, 0.88 (95% CI, 0.68–1.13) for 150 mg, and 0.78 (95% CI, 0.60–1.02) for 300 mg ( P for trend=0.042). Conclusions: These randomized double-blind placebo-controlled data suggest that therapy with canakinumab, an interleukin-1β inhibitor, is related to a dose-dependent reduction in HHF and the composite of HHF or heart failure–related mortality in a population of patients with prior myocardial infarction and elevations in high-sensitivity C-reactive protein. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01327846.
Abstract 14456: Real World Evidence Characterizing the Association Between Serum Potassium and Clinical Outcomes in Patients With Heart Failure
Authors: Marc Evans, Lei Qin, Phil McEwan, Eirini Palaka, Susan Grandy
Journal: Circulation (2017)

Introduction: The association between serum potassium (K+) and rates of mortality and major adverse cardiovascular events (MACE) has previously been characterised using US healthcare data. This stu...
Abstract 19863: Proprotein Convertase Subtilisin/Kexin Type 9 May Associate With Lipoproteins Through Lipid Interactions
Authors: Samantha K Sarkar, Natalie Goto, Thomas A Lagace
Journal: Circulation (2016)

Background: Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a secreted plasma protein that binds and promotes degradation of cell-surface low density lipoprotein (LDL) receptors in the liv...
Atrial-Specific Gene Delivery Using an Adeno-Associated Viral Vector
Authors: Li Ni, Larry Scott, Hannah M. Campbell, Xiaolu Pan, Katherina M. Alsina, Julia Reynolds, Leonne E. Philippen, Mohit Hulsurkar, William R. Lagor, Na Li, Xander H.T. Wehrens
Journal: Circulation Research (2019)

Rationale: Somatic overexpression in mice using an adeno-associated virus (AAV) as gene transfer vectors has become a valuable tool to analyze the roles of specific genes in cardiac diseases. The lack of atrial-specific AAV vector has been a major obstacle for studies into the pathogenesis of atrial diseases. Moreover, gene therapy studies for atrial fibrillation would benefit from atrial-specific vectors. Atrial natriuretic factor (ANF) promoter drives gene expression specifically in atrial cardiomyocytes. Objective: To establish the platform of atrial specific in vivo gene delivery by AAV-ANF. Methods and Results: We constructed AAV vectors based on serotype 9 (AAV9) that are driven by the atrial-specific ANF promoter. Hearts from mice injected with AAV9-ANF-GFP (green fluorescent protein) exhibited strong and atrial-specific GFP expression without notable GFP in ventricular tissue. In contrast, similar vectors containing a cardiac troponin T promoter (AAV9-TNT4-GFP) showed GFP expression in all 4 chambers of the heart, while AAV9 with an enhanced chicken β-actin promoter (AAV-enCB-GFP) caused ubiquitous GFP expression. Next, we used Rosa26 mT/mG (membrane-targeted tandem dimer Tomato/membrane-targeted GFP), a double-fluorescent Cre reporter mouse that expresses membrane-targeted tandem dimer Tomato before Cre-mediated excision, and membrane-targeted GFP after excision. AAV9-ANF-Cre led to highly efficient LoxP recombination in membrane-targeted tandem dimer Tomato/membrane-targeted green fluorescent protein mice with high specificity for the atria. We measured the frequency of transduced cardiomyocytes in atria by detecting Cre-dependent GFP expression from the Rosa26 mT/mG allele. AAV9 dose was positively correlated with the number of GFP-positive atrial cardiomyocytes. Finally, we assessed whether the AAV9-ANF-Cre vector could be used to induce atrial-specific gene knockdown in proof-of-principle experiments using conditional JPH2 (junctophilin-2) knockdown mice. Four weeks after AAV9-ANF-Cre injection, a strong reduction in atrial expression of JPH2 protein was observed. Furthermore, there was evidence for abnormal Ca 2+ handling in atrial myocytes isolated from mice with atrial-restricted JPH2 deficiency. Conclusions: AAV9-ANF vectors produce efficient, dose-dependent, and atrial-specific gene expression following a single-dose systemic delivery in mice. This vector is a novel reagent for both mechanistic and gene therapy studies on atrial diseases.
DRES-04. CHARACTERIZATION OF A MODEL OF TEMOZOLOMIDE RESISTANCE IN GLIOBLASTOMA
Authors: Elizabeth Bering, Alice Yuan, J Cairncross, Michael Blough
Journal: Neuro-Oncology (2018)

Despite the discovery and widespread use of the chemotherapeutic drug temozolomide (TMZ), glioblastoma (GBM) remains a fatal cancer. TMZ, a DNA alkylating agent, provides a moderate survival benefit to patients whose tumours do not express the O6-methylguanine-methyltransferase (MGMT) gene. However, even these TMZ-sensitive GBMs recur and upon doing so, many are resistant to TMZ. The development of TMZ resistance is commonly associated with mutations in mismatch repair (MMR) and the re-expression of MGMT. Upregulation of homologous recombination (HR) and base excision repair (BER) have also been implicated as mechanisms of acquired TMZ resistance. To better characterize these mechanisms and to develop strategies to prevent or overcome resistance, our laboratory has implemented an in vitro model of inducible resistance in which frequent exposure to TMZ (100µM) yields multiple resistant colonies in the MGMT-methylated GBM cell line U251N (Yip et. al). These colonies displayed varying methods of resistance to TMZ, including those that have been clinically observed in recurrent, TMZ-treated GBMs. Several colonies harboured mutations in MMR genes MSH6, MSH2, and MLH1 with low or absent expression of their respective proteins. In addition, some MMR wild-type colonies had increased expression of poly-ADP ribose (a polymer required for the recognition of DNA breaks by the BER machinery), suggesting that upregulation of BER may be driving resistance. Furthermore, Western Blot analysis revealed that occasional colonies re-expressed MGMT. Interestingly, a few colonies did not possess these alterations, suggesting that their resistance may result from further downstream modifications of MMR or BER, or by mutations in HR. With a more comprehensive characterization of these U251 colonies, we hope to learn more about TMZ resistance in GBM, and refine treatments or preventative therapies for molecularly distinct, TMZ-resistant, recurrent tumours.
PATH-54. UTILITY OF NEXT GENERATION SEQUENCING IN ADULT PRIMARY BRAIN TUMORS: IMPACT ON DIAGNOSIS AND PERSONALIZED THERAPY
Authors: Matthew Smith-Cohn, Howard Colman, Adam Cohen
Journal: Neuro-Oncology (2018)

Historically, the molecular characterization of gliomas and other brain tumors has been controversial. A diagnosis was primarily made by histological analysis alone, despite concordance among neuropathologists being as low as 52% in some cases. Based on the 2016 World Health Organization guideline update, molecular profiling of brain tumors is now considered best practice for central nervous system tumors. In addition to providing a more accurate diagnosis, next generation sequencing of brain tumors can identify molecular alterations amenable to targeted therapy. A retrospective chart review of 251 adult primary brain tumor patients with next generation sequencing performed was conducted at a single institution. Comparison of histological and molecular diagnosis, identification of potentially actionable alterations, and treatment choice based on alterations was analyzed. Clarification of diagnoses was observed in gliomas, but sequencing did not alter diagnosis in ependymomas, meningiomas, or medulloblastomas. Excluding ependymomas, there were 220 gliomas, of which 33 cases (15%) had clarification of the diagnosis. Of these 33 cases, 18 instances had clarification of IDH mutation status and the remaining 15 had a different or narrowed diagnosis based on the molecular features. Potentially actionable molecular alterations were found in 60% (150/251) of patients including CDKN2A/B, CDK4, EGFRvIII, BRAF, BRCA2, SMO, PTCH1, hypermutator genes (MSH2, MSK6, PMS2, MLH1), and increased mutation burden. Patients were treated with therapies targeting at least one actionable alteration in 9% of all cases (22/251). CONCLUSIONS: This study validates next generation sequencing as a clinical tool to obtain an accurate diagnosis and identify targetable alterations in brain tumor patients which have an impact on treatment decisions. These data support that integration of this technology will be essential in clinical trials exploring personalized therapy in neuro-oncology patients.
EXTH-47. DEVELOPMENT OF A NOVEL FLUORESCENT VIRUS-LIKE-PARTICLES AS RNA INTERFERENCE AND TUMOR SUPPRESSOR GENE DELIVERY TOOL FOR BRAIN TUMOR TREATMENT
Authors: Chiungyin Huang, Kuo-Chen Wei
Journal: Neuro-Oncology (2018)

Efficient delivery is a key issue in translating RNA interference (RNAi) technology into a feasible therapy. The efficiency of carrier systems used for this technology is commonly tested by co-transfection, i.e. simultaneous transfection with an exogenous gene and with the siRNA. Here, we describe a fluorescence virus-like particles (fVLPs) platform with self RNAi production and packaging to inhibit gene expression and overexpress tumor suppressor proteins simultaneously for efficient cancer therapy. We have designed an RNAi scaffold (let-7g, c-Met, Wnt-2 siRNA) and co-expressed with Qβ coat protein and mCherry fluorescent protein simultaneously through a two-plasmid system, and self-assembly produced in E. coli. The polylysine (PLL) would be incorporated to the exterior surface of fVLPs to enhance cell uptake and adsorb plasmid DNA on the surface. The PLL-mediated fVLPs have been assessed by cell examination. In our study, The fVLPs revealed no cytotoxicity and could be internalized inside cells. Our data showed that the PLL-mediated fVLPs could effectively knockdown let-7g gene to inhibit the cancer growth and also suggested that this platform is amenable to efficient packaging of functional RNAi and, most recently, simultaneous packaging with plasmid DNA. Then we used brain tumor model animals for testing the tumor suppress efficiency in vivo. The tumor growth rate is significantly reduced in siRNA loaded VLP-administrated animals and longer survival periods is observed. Also, there is no significant alterations to the blood biochemical values of the VLP-administrated animals. We believe this multifunctional PLL-mediated fVLPs platform has potential to overcome impediments as mentioned earlier and well suited for RNAi-based therapeutic tools.
Public Health Emergency Preparedness: Globalizing Risk, Localizing Threats
Authors: Lawrence O. Gostin
Journal: JAMA (2018)

Infectious diseases are a constant reality, yet it takes a shock to jolt the public’s attention and spur political action. The past weeks saw such as a shock at busy US airports, with the emergency quarantine of 3 flights. At the same time, seemingly a world away, insecurity, weak health systems, and distrust are fueling a second major Ebola outbreak in the Democratic Republic of Congo (DRC) this year. Yet reacting to periodic shocks won’t safeguard our collective future. Emergency preparedness requires proactive planning and funding, with US leadership pivotal.
Abstract MP013: Diet High in Sweets and Sugar-sweetened Beverages But Low in Fruits and Vegetables is Associated With Pro-inflammatory Adipokine Profile in Mexican Americans at Risk For Diabetes
Authors: Corinna Koebnick, Mary Helen Black, Jun Wu, Yu-Hsiang Shu, Thomas Buchanan, Anny Xiang
Journal: Circulation (2017)

Background: High consumption of sweets and sugar-sweetened beverages is associated with obesity, insulin resistance and cardiovascular disease. Pro- and anti-inflammatory adipokines may mediate the relationship between dietary intake and poor metabolic profile. However, studies investigating the association between diet and adipokines are scant and often restricted to one or two biomarkers. Study design and methods: Subjects were participants of BetaGene, a study of obesity, insulin resistance and β-cell dysfunction in Mexican Americans (n=1,128, 73% female, age 34.6±8.0, BMI 29.5±5.9). Adiponectin, IL-1β, IL-6, IL-1Ra, leptin, lipocalin, MCP-1, resistin and TNF-α were assayed using Millipore multiplex kits with magnetic bead panels; apelin, CRP, DPP-IV, visfatin, SFRP4 and SFRP5 were measured with ELISA. Dietary intake was assessed by 12-mo recall (126-item Harvard-FFQ). Joint multivariate associations between levels of adipokines and food group consumed (grams/day) were analyzed using canonical correlation after adjustment for age, sex and energy intake. Results: Median (IQR) energy intake was 2.27 (1.75,2.85) Mcal/day. While 55% of total intake was accounted for by carbohydrates, 24% was due to sugar. A total of 37% of the shared variation between diet and adipokines was explained by the top linear association between the two. The top dietary component ( Figure 1 ) was most represented by sugar-sweetened beverages (SSB, loading coefficient ρ=0.55), sweets (ρ=0.53), fruits (ρ=-0.47), fruit juices (ρ=-0.34), and vegetables (ρ=-0.30), while the adipokine component was most represented by leptin (ρ=0.63), CRP (ρ=0.56), and MCP-1 (ρ=0.47). Conclusions: Diets high in sweets and sugar-sweetened beverage but low in fruits and vegetables contribute to a pro-inflammatory profile characterized by high leptin, CRP and MCP-1, which in turn is associated with poor metabolic profile in Mexican Americans at risk for type 2 diabetes.
Breast cancer disparities in the Hispanic population: Is country of origin more predictive than primary language?
Authors: Gillian Haber
Journal: Cancer Research (2006)

674   Introduction: Recent studies confirm that racial and ethnic disparities exist in the diagnosis of breast cancer in women. Breast cancer is the number one killer among Hispanic women and stage at diagnosis is one of the most important prognostic factors for breast cancer morbidity and mortality. Although Hispanics speak the same language, they differ in socio-cultural norms and behavioral practice by country of origin. Cultural beliefs play a significant role in health seeking behavior. The purpose of this study was to determine if the country of origin of Hispanic women is more predictive of breast carcinoma stage at diagnosis (BCSAD) than Spanish as the primary language spoken. Methods: A literature review was conducted to analyze the studies on country of origin and BCSAD. Articles included those dealing with health disparities, country of origin, insurance status, length of stay in the U.S., and socioeconomic status. In addition, census data for the year 2000 were analyzed for the Hispanic population, by country of origin, for both the United States and Miami-Dade County. Results: In 2000, the Hispanic population represented 12.6% of the U.S. population and 57.3% of the Miami-Dade county population. Hispanic whites are more likely to be diagnosed with late-stage breast cancer than non-Hispanic whites. Studies showed that women of Mexican, South and Central American and Puerto Rican descent were 20% to 260% more likely to be diagnosed with late-stage breast cancer when compared to non-Hispanic white women. Additionally, Puerto Rican women are 50% more likely to receive substandard treatment for breast cancer and Mexican women had 30% poorer survival rates compared to non-Hispanic whites. Researchers believe contributing factors include socioeconomic status, diverse cultural practices, parity, dietary customs, length of stay in the U.S., and insurance status. Conclusions: There are few breast cancer studies of Hispanic women by country of origin. The predicted growth of the Hispanic population in the U.S., and the concomitant aging of this population, underscore the importance of keeping breast cancer statistics by country of origin in addition to ethnicity and race. Since mammographic screening is the best tool for early diagnosis and appears to equalize survival among ethnic groups, specific interventions need to be designed to reach each Hispanic subcategory for the greatest impact on breast cancer morbidity and mortality in the Hispanic population. Further research is recommended to examine breast cancer disparities between Hispanic populations.
Recommendations for the assessment and management of measurable residual disease in adults with acute lymphoblastic leukemia: A consensus of North American experts
Authors: Nicholas J. Short, Elias Jabbour, Maher Albitar, Marcos de Lima, Lia Gore, Jeffrey Jorgensen, Aaron C. Logan, Jae Park, Farhad Ravandi, Bijal Shah, Jerald Radich, Hagop Kantarjian
Journal: American Journal of Hematology (2018)

Measurable residual disease (MRD) that persists after initial therapy is a powerful predictor of relapse and survival in acute lymphoblastic leukemia (ALL). However, the optimal use of this information to influence therapeutic decisions is controversial. Herein, we comprehensively review the role of MRD assessment in adults with ALL, including methods to quantify residual leukemia cells during remission, prognostic impact of MRD across ALL subtypes, and available therapeutic approaches to eradicate MRD. This review presents consensus statements and provides an evidence-based framework for practicing hematologists and oncologists to use MRD information to make rational treatment decisions in adult patients with ALL.
Hippo Kinases Mst1 and Mst2 Sense and Amplify IL-2R-STAT5 Signaling in Regulatory T Cells to Establish Stable Regulatory Activity
Authors: Hao Shi, Chaohong Liu, Haiyan Tan, Yuxin Li, Thanh-Long M. Nguyen, Yogesh Dhungana, Cliff Guy, Peter Vogel, Geoffrey Neale, Sherri Rankin, Yongqiang Feng, Junmin Peng, Wufan Tao, Hongbo Chi
Journal: Immunity (2018)
Live imaging and tracking of genome regions in CRISPR/dCas9 knock-in mice
Authors: Jinzhi Duan, Guangqing Lu, Yu Hong, Qingtao Hu, Xueying Mai, Jing Guo, Xiaofang Si, Fengchao Wang, Yu Zhang
Journal: Genome biology (2018)

CRISPR/dCas9 is a versatile tool that can be used to recruit various effectors and fluorescent molecules to defined genome regions where it can modulate genetic and epigenetic markers, or track the chromatin dynamics in live cells. In vivo applications of CRISPR/dCas9 in animals have been challenged by delivery issues. We generate and characterize a mouse strain with dCas9-EGFP ubiquitously expressed in various tissues. Studying telomere dynamics in these animals reveals surprising results different from those observed in cultured cell lines. The CRISPR/dCas9 knock-in mice provide an important and versatile tool to mechanistically study genome functions in live animals.
Prognostic Implications of Mitral Annular Plane Systolic Excursion in Patients with Hypertension and a Clinical Indication for Cardiac Magnetic Resonance Imaging
Authors: Simone Romano, Robert M. Judd, Raymond J. Kim, Han W. Kim, John F. Heitner, Dipan J. Shah, Richard B. Devereux, Pablo Salazar, Michael Trybula, Richard C. Chia, Kaleigh Evans, Afshin Farzaneh-Far
Journal: JACC. Cardiovascular imaging (2018)
NCMP-15. POSTOPERATIVE CEREBELLAR MUTISM SYNDROME FOLLOWING TREATMENT OF MEDULLOBLASTOMA: NEUROLOGICAL CHARACTERISTICS AND SEVERITY BY MOLECULAR SUBTYPE
Authors: Zsila Sadighi, Andrew Kuang, Paul Klimo, Tong Lin, Amar Gajjar, Raja Khan, Zoltan Patay
Journal: Neuro-Oncology (2018)

OBJECT: To examine the neurological characteristics and severity of cerebellar mutism syndrome (CMS) in pediatric medulloblastoma (MB) post-operatively and at one-year post-surgery by MB molecular subtype. We obtained Institutional Review Board (IRB) approval and retrospectively reviewed 146 patients 18 years old with MB treated on SJMB03 protocol at our institution from 2000–2010 for clinical, surgical, radiographical information, molecular subtype, and history of CMS. CMS neurological characteristics and severity were recorded from pre-operative and at 1 year follow-up post-operative times and scored using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, which scores 0 (absent) to 5 (death) for symptoms. CMS characteristics and severity immediately post-resection were scored using the Robertson scoring system, which scores mild (<1 week), moderate (1–4 weeks), and severe (>4 weeks). Forty-two (28.7%) of 146 patients had CMS. Twenty-four (57.1%) of CMS patients were Group 4 subtype (P<0.03). CMS significantly correlated with midline intraventricular tumor location in 39 (92.9%) of CMS patients (P<0.04). Damage to both the dentate nuclei and superior cerebellar peduncles significantly correlated to CMS (P<0.0001 and P<0.0001, respectively). Bilateral damage to the efferent cerebellar pathway significantly correlated in 26 (61.9%) CMS patients (P<0.0001). Initial post-operative severity of eye movement disorders significantly correlated with severity at one year follow up in all patients (P<0.04) and trended in group 4 subtype tumors severity at one year follow (P<0.07). CONCLUSIONS: Group 4 subtype MB tumors and midline intraventricular tumor location are both significant risk factors for CMS. Post-operative MRI findings of bilateral efferent cerebellar pathway damage, dentate nuclei damage, and superior cerebellar peduncle damage are also risk factors for CMS. In all patients as well as group 4 subtype, initial post-operative severity of neurological findings do not correlate with severity at one year follow up except for eye movement disorders.