tbuckley/cabot-search huggingface dataset:
Abstract 16633: Aspirin Ingestion and Omega-3 Fatty Acids Interact: The Framingham Heart Study
Authors: Robert C Block, Greg C Shearer, Xin Tu, Shaker A Mousa, J T Brenna, Nathan Tintle
Journal: Circulation (2018)

Introduction: Aspirin can reduce cardiovascular disease (CVD) events. While eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been associated with CVD benefits, we find this benefit on platelet function, lysolipids, and HDL cholesterol is non-linear when aspirin is taken. EPA and DHA are substrates for cyclooxygenase, while aspirin is a suicide inhibitor of this enzyme. Hypotheses: Aspirin’s CVD effects depend on the abundance of EPA and DHA in tissue, as indicated by red blood cell membrane concentrations (Omega-3 Index or Index). Methods: We included adults recruited in 1971 into the Offspring Cohort of the Framingham Heart Study and attended their 8 th exam (N=2,500 after excluding those missing an Index or had CVD); stratified into those who were and were not taking aspirin. The lowest Index quintile (&lt;4.2%) was used as the comparison. Primary analyses related incident events by date of event (or censoring) to quintiles of the Index after adjusting for numerous demographic and medical history covariates. Secondary analyses explored both linear and quadratic risk patterns across quintiles. All analyses used 2-sided tests and the 0.05 significance level. Results: Those not taking aspirin had a hazard ratio (HR) for total CVD of 0.45 (95% CI 0.23-0.89) and total stroke of 0.27 (0.08-0.9) when their Index was 4.2-4.9%. Those who were taking aspirin with the same Index had a HR for total CVD of 2.12 (1.08-4.13) and total stroke of 2.67 (0.89-8.03). These HRs were not statistically significant (HR crossed 1; ≥0.05) for other Index quintiles (4.9-5.7%, 5.7-6.8%, and &gt;6.8%). The p -value for the linear trend test was 0.029 for total CVD and 0.009 for total stroke in those taking aspirin and ≥0.05 for those not taking aspirin when assessing all of the Index quintiles. The p -value for total quadratic fit was 0.29 for total CVD and 0.04 for total stroke in those taking aspirin and ≥0.05 for those not taking aspirin when assessing all of the Index quintiles. Conclusions: Overall, a low to moderate EPA and DHA red blood cell level was associated with opposite outcomes in those who were or were not taking aspirin. A low to moderate Omega-3 Index may adversely affect the benefits of aspirin ingestion, which is potentially of great importance for individuals at high risk for CVD events.
Association of a Park-Based Violence Prevention and Mental Health Promotion After-School Program With Youth Arrest Rates
Authors: Emily D’Agostino, Stacy L. Frazier, Eric Hansen, Maria I. Nardi, Sarah E. Messiah
Journal: JAMA Network Open (2020)

This cohort study estimates the association of a park-based violence prevention and mental health promotion after-school program with youth arrest rates in Miami-Dade County, Florida.
The significance of exosomes in the development and treatment of hepatocellular carcinoma
Authors: Xin Li, Chuanyun Li, Liping Zhang, Min Wu, Ke Cao, Feifei Jiang, Dexi Chen, Ning Li, Weihua Li
Journal: Molecular Cancer (2020)

Abstract Hepatocellular carcinoma (HCC) is the most commonmalignancy. Exsome plays a significant role in the elucidation of signal transduction pathways between hepatoma cells, angiogenesis and early diagnosis of HCC. Exosomes are small vesicular structures that mediate interaction between different types of cells, and contain a variety of components (including DNA, RNA, and proteins). Numerous studies have shown that these substances in exosomes are involved in growth, metastasis and angiogenesis in liver cancer, and then inhibited the growth of liver cancer by blocking the signaling pathway of liver cancer cells. In addition, the exosomal substances could also be used as markers for screening early liver cancer. In this review, we summarized to reveal the significance of exosomes in the occurrence, development, diagnosis and treatment of HCC, which in turn might help us to further elucidate the mechanism of exosomes in HCC, and promote the use of exosomes in the clinical diagnosis and treatment of HCC.
Blockade of EGFR improves responsiveness to PD-1 blockade in <i>EGFR</i> -mutated non–small cell lung cancer
Authors: Eri Sugiyama, Yosuke Togashi, Yoshiko Takeuchi, Sayoko Shinya, Yasuko Tada, Keisuke Kataoka, Kenta Tane, Eiichi Sato, Genichiro Ishii, Koichi Goto, Yasushi Shintani, Meinoshin Okumura, Masahiro Tsuboi, Hiroyoshi Nishikawa
Journal: Science Immunology (2020)

The clinical efficacy of anti-PD-1 (programmed cell death-1) monoclonal antibody (mAb) against cancers with oncogenic driver gene mutations, which often harbor a low tumor mutation burden, is variable, suggesting different contributions of each driver mutation to immune responses. Here, we investigated the immunological phenotypes in the tumor microenvironment (TME) of epidermal growth factor receptor (EGFR)-mutated lung adenocarcinomas, for which anti-PD-1 mAb is largely ineffective. Whereas EGFR-mutated lung adenocarcinomas had a noninflamed TME, CD4+ effector regulatory T cells, which are generally present in the inflamed TME, showed high infiltration. The EGFR signal activated cJun/cJun N-terminal kinase and reduced interferon regulatory factor-1; the former increased CCL22, which recruits CD4+ regulatory T cells, and the latter decreased CXCL10 and CCL5, which induce CD8+ T cell infiltration. The EGFR inhibitor erlotinib decreased CD4+ effector regulatory T cells infiltration in the TME and in combination with anti-PD-1 mAb showed better antitumor effects than either treatment alone. Our results suggest that EGFR inhibitors when used in conjunction with anti-PD-1 mAb could increase the efficacy of immunotherapy in lung adenocarcinomas.
<i>Notes from the Field:</i> Four Cases of Lyme Disease at an Outdoor Wilderness Camp — North Carolina, 2017 and 2019
Authors: Alexis M. Barbarin, Steven W. Seagle, Susan Creede
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

On June 10, 2019, the North Carolina Division of Public Health was notified by the Buncombe County Health Department of three cases of Lyme disease among children aged 6-8 years.Lyme disease is a bacterial infection transmitted by the bite of an Ixodes scapularis tick that is infected most commonly with the bacterium Borrelia burgdorferi.An investigation conducted by Buncombe County communicable disease nurses determined that all three children were homeschooled and had attended a local, year-round, outdoor wilderness day camp.Each child had attended the camp at least 1 day a week over the course of the previous fall and spring.The camp site for the wilderness program is completely outdoors, with a canopy of hardwood forest providing much of the shelter.Further investigation identified an earlier camp participant who had received a diagnosis of Lyme disease in 2017 (Table ).* To sample the environment for ticks trying to locate a host, light-colored cloths with a wooden leading frame are dragged through grass or a leafy forest floor (dragging), and light colored cloths are used to brush uneven surfaces such as small bushes in wooded areas (flagging).
Abstract 12320: Associations Between Physical Activity, Subclinical Myocardial Injury, and Cardiovascular Mortality in the General Population
Authors: Charles A German, Muhammadimtiaz Ahmad, Yabing Li, Elsayed Z Soliman
Journal: Circulation (2019)

Introduction: Poor levels of physical activity (PA) and subclinical myocardial injury (SC-MI) are both associated with cardiovascular (CVD) mortality. However, the relationship between poor PA and ...
Celebrating 20 Years of IGHV Mutation Analysis in CLL
Authors: Nicholas Chiorazzi, Freda K. Stevenson
Journal: HemaSphere (2020)

Abstract The division of CLL into 2 broad subsets with highly significant differences in clinical behavior was reported in 2 landmark papers in Blood in 1999. 1,2 The simple analysis of the mutational status of the IGV regions provided both a prognostic indicator and an insight into the cellular origins. Derivation from B cells with very low or no IGV mutations generally leads to a more aggressive disease course than derivation from B cells with higher levels. This finding focused attention on surface Ig (sIg), the major B‐cell receptor, and revealed dynamic antigen engagement in vivo as a tumor driver. It has also led to new drugs aimed at components of the intracellular activation cascades. After 20 years, the 2 senior authors of those papers have looked at the history of the observations and at the increasing understanding of the role of sIg in CLL that have emanated from them. As in the past, studies of CLL have provided a link between biology and the clinic, enabling more precise targeting which attacks critical pathways but minimizes side effects.
Randomized phase II study of neratinib with or without temsirolimus in patients (pts) with non-small cell lung cancer (NSCLC) carrying <i>HER2</i>-activating mutations.
Authors: Leena Gandhi, Jean-Charles Soria, Richard Bryce, Benjamin Besse
Journal: Journal of Clinical Oncology (2013)

TPS8124 Background: Recent advances in NSCLC have highlighted the importance of identifying mutations in driver oncogenes (eg EGFR, ALK) and the use of targeted agents to treat genetically-defined pt populations. HER2 (ERBB2) is a member of the ERBB receptor tyrosine kinase (TK) family which, once activated, stimulates several downstream effector pathways including PI3K, MAPK and JAK/STAT. Activating HER2 mutations are documented in approx 2–4% of pts with NSCLC and occur independently of EGFR, KRAS, NRAS and BRAF mutations. The efficacy of single-agent neratinib in HER2-mutated NSCLC is currently unknown; however, in vivo studies suggest that dual inhibition with an irreversible TK inhibitor (TKI) and an mTOR inhibitor is a promising therapeutic approach for HER2-mutated NSCLC [Perera et al. PNAS 2009]. This concept has been supported recently by a phase I study of neratinib, an irreversible pan-ERBB TKI, plus temsirolimus, which showed tumor regression in 5/6 evaluable pts with HER2-mutated NSCLC [Gandhi et al. WCLC, Amsterdam, Netherlands, 2011]. Methods: This international, randomized, open-label phase II study includes pts with previously treated stage IIIB/IV NSCLC and HER2-activating mutations. Pts are randomized 1:1 to oral neratinib 240mg od continuously ± IV temsirolimus 8mg/w (dose escalation to 15mg/w after one 4w cycle if tolerated). The addition of temsirolimus is permitted in pts assigned to neratinib monotherapy after progression. Tumor evaluations will be conducted every 8w. The primary endpoint is overall response rate (RECIST 1.1). Secondary endpoints are: clinical benefit rate; response duration; progression-free and overall survival; safety; health outcomes. Exploratory analyses include: correlative studies between tumor and plasma biomarkers and outcomes; pharmacokinetics. The trial has an optimal 2-stage design. Sample size (13–52 pts/arm) is based on a null response rate of 0.09, an alternative response rate of 0.25, power of 80% and 0.05 type I error rate. Both arms will be compared independently against historical controls. Enrollment is scheduled to open in March 2013. EudraCT identifier: 2012-004743-68. Clinical trial information: 2012-004743-68.
9O_PR Gene Modules and Pathological Complete Response to Neoadjuvant Chemotherapy in Breast Cancer. A Pooled Analysis
Authors: M. Ignatiadis, S.K. Singhal, C. Desmedt, B. Haibe-Kains, C. Criscitiello, F. Andre, S. Loi, M. Piccart, S. Michiels, C. Sotiriou
Journal: Annals of Oncology (2012)
Detailed Comparison of the Safety of Tivozanib Versus Sorafenib in Patients with Advanced/Metastatic Renal Cell Carcinoma (MRCC) from a Phase 3 Trial
Authors: T.Q.G. Eisen, C.N. Sternberg, P. Tomczak, M. Harza, V. Jinga, B. Esteves, R.J. Motzer
Journal: Annals of Oncology (2012)
Long-term surveillance needed to detect Zika virus outbreaks in endemic regions
Authors: Shashika Lavangi Wijesooriya, Co Thach Nguyen, T Thi Thuy Nguyen, Thi Bich Hau Vu, Takemura Taichiro, Kouichi Morita, Thi Quynh Mai Le, Duc Anh Dang, Futoshi Hasebe, Meng Ling Moi
Journal: The Lancet Infectious Diseases (2020)
IKKε phosphorylates kindlin-2 to induce invadopodia formation and promote colorectal cancer metastasis
Authors: Ge Liu, Yantao Bao, Chaohua Liu, Qinchang Zhu, Lin Zhao, Xiaopeng Lu, Qian Zhu, Yafei Lv, Feng Bai, He Wen, Yujie Sun, Wei-Guo Zhu
Journal: Theranostics (2020)

Invadopodia formation is a key driver of cancer metastasis. The noncanonical IkB-related kinase IKKε has been implicated in cancer metastasis, but its roles in invadopodia formation and colorectal cancer (CRC) metastasis are unclear. Methods: Immunofluorescence, gelatin-degradation assay, wound healing assay and transwell invasion assay were used to determine the influence of IKKε over-expression, knockdown and pharmacological inhibition on invadopodia formation and the migratory and invasive capacity of CRC cells in vitro. Effects of IKKε knockdown or pharmacological inhibition on CRC metastasis were examined in mice. Immunohistochemistry staining was used to detect expression levels of IKKε in CRC patient tissues, and its association with prognosis in CRC patients was also analyzed. Immunoprecipitation, western blotting and in vitro kinase assay were constructed to investigate the molecular mechanisms. Results: IKKε co-localizes with F-actin and the invadopodia marker Tks5 at the gelatin-degrading sites of CRC cells. Genetic over-expression/knockdown or pharmacological inhibition of IKKε altered invadopodia formation and the migratory and invasive capacity of CRC cells in vitro. In vivo, knockdown or pharmacological inhibition of IKKε significantly suppressed metastasis of CRC cells in mice. IKKε knockdown also inhibited invadopodia formation in vivo. Clinical investigation of tumor specimens from 191 patients with CRC revealed that high IKKε expression correlates with metastasis and poor prognosis of CRC. Mechanistically, IKKε directly binds to and phosphorylates kindlin-2 at serine 159; this effect mediates the IKKε-induced invadopodia formation and promotion of CRC metastasis. Conclusions: We identify IKKε as a novel regulator of invadopodia formation and a unique mechanism by which IKKε promotes the metastasis of CRC. Our study suggests that IKKε is a potential target to suppress CRC metastasis.
Baricitinib in patients with moderate‐to‐severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase<scp>III</scp>trials
Authors: E.L. Simpson, J.‐P. Lacour, L. Spelman, R. Galimberti, L.F. Eichenfield, R. Bissonnette, B.A. King, J.P. Thyssen, J.I. Silverberg, T. Bieber, K. Kabashima, Y. Tsunemi, A. Costanzo, E. Guttman‐Yassky, L.A. Beck, J.M. Janes, A.M. DeLozier, M. Gamalo, D.R. Brinker, T. Cardillo, F.P. Nunes, A.S. Paller, A. Wollenberg, K. Reich
Journal: British Journal of Dermatology (2020)

Background Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids. Objectives To evaluate the efficacy and safety of baricitinib in patients with moderate-to-severe AD who had an inadequate response to topical therapies. Methods In two independent, multicentre, double-blind, phase III monotherapy trials, BREEZE-AD1 and BREEZE-AD2, adults with moderate-to-severe AD were randomized 2 : 1 : 1 : 1 to once-daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks. Results At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE-AD1 [N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%], and BREEZE-AD2 [N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%]. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night-time awakenings, skin pain and quality-of-life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage. Conclusions Baricitinib improved clinical signs and symptoms in patients with moderate-to-severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns. Linked Comment: Drucker. Br J Dermatol 2020; 183:199–200.
Abstract 176: Genetic Ablation of Cyclophilin-D in Mice Increases Physical and Cognitive Performance During Hypoxia
Authors: Jeejabai Radhakrishnan, Alvin Baetiong, Harrison Kaufman, Michelle Huynh, Angela Leschinsky, Raul J Gazmuri
Journal: Circulation (2019)

Introduction: We previously reported that silencing of the mitochondrial peptidyl-prolyl isomerase Cyclophilin-D (Cyp-D) in HEK 293T cells reduces oxygen consumption (VO 2 ). In vivo Cyp-D ablation using constitutive Cyp-D knockout (KO) mice also reduced VO 2 while paradoxically increased exercise endurance, thus demonstrating increased oxygen utilization efficiency. Therefore, we hypothesized that Cyp-D KO mice will display improved physical and cognitive performance during hypoxic conditions. Methods: Two groups of 9 mice each, age and gender-matched, representing wild-type (WT) and Cyp-D KO were subjected to treadmill running first under normobaric normoxic conditions (20.9% O 2 , simulating ground level O 2 levels), and the next day under normobaric hypoxic conditions (8% O 2 simulating 7,600 meters altitude O 2 levels). Total running time and distance, V max , and work performed were measured. A separate set of 9 mice each (Cyp-D KO and WT), were subjected to behavioral assessments; a pole test to assess motor function and an elevated plus-maze test to assess anxiety levels. The tests were conducted first under normoxia and then under hypoxia. Results: Cyp-D KO mice exposed to 8% O 2 displayed increased treadmill work (12±1 vs 8±1 Joules; p =0.02) demonstrating increased exercise capacity, shorter pole-climbing time (21±3 vs 37±4 sec; p =0.006) demonstrating increased agility and cognitive function, and increased elevated plus-maze open arm time (91±31 vs 23±12 sec; p =0.046) demonstrating anti-anxiety like behavior. Conclusions: Cyp-D KO mice demonstrated increased exercise capacity, improved motor function, decreased anxiety, and improved cognitive function under hypoxia. Thus, targeting Cyp-D and modulating its activity may impact several acute and chronic conditions in which oxygen availability is limited. The increased cognitive performance could be helpful when working at low environmental O 2 levels (e.g., high-altitude, underground caves, etc.).
Preventive or Deferred Ablation of Ventricular Tachycardia in Patients With Ischemic Cardiomyopathy and Implantable Defibrillator (BERLIN VT)
Authors: Stephan Willems, Roland Richard Tilz, Daniel Steven, Stefan Kääb, Karl Wegscheider, László Gellér, Christian Meyer, Christian-Hendrik Heeger, Andreas Metzner, Moritz F. Sinner, Michael Schlüter, Peter Nordbeck, Lars Eckardt, Harilaos Bogossian, Arian Sultan, Beate Wenzel, Karl-Heinz Kuck, C. Piorkowski, D. Lebedev, J. Kautzner, C. Sticherling, T. Deneke, T. Rostock, C. Ukena, M. Kuniss, H. Makimoto, G. Hindricks, D. Bänsch, J. Schreieck, C. Kolb, J. Geller, E. Pokushalov, K. Gutleben, P. Sommer, L.H. Boldt, A. Parwani
Journal: Circulation (2020)

Catheter ablation for ventricular tachycardia (VT) reduces the recurrence of VT in patients with implantable cardioverter-defibrillators (ICDs). The appropriate timing of VT ablation and its effects on mortality and heart failure progression remain a matter of debate. In patients with life-threatening arrhythmias necessitating ICD implantation, we compared outcomes of preventive VT ablation (undertaken before ICD implantation to prevent ICD shocks for VT) and deferred ablation after 3 ICD shocks for VT. The BERLIN VT study (Preventive Ablation of Ventricular Tachycardia in Patients With Myocardial Infarction) was a prospective, open, parallel, randomized trial performed at 26 centers. Patients with stable ischemic cardiomyopathy, a left ventricular ejection fraction between 30% and 50%, and documented VT were randomly assigned 1:1 to a preventive or deferred ablation strategy. The primary outcome was a composite of all-cause death and unplanned hospitalization for either symptomatic ventricular arrhythmia or worsening heart failure. Secondary outcomes included sustained ventricular tachyarrhythmia and appropriate ICD therapy. We hypothesized that preventive ablation strategy would be superior to deferred ablation strategy in the intention-to-treat population. During a mean follow-up of 396±284 days, the primary end point occurred in 25 (32.9%) of 76 patients in the preventive ablation group and 23 (27.7%) of 83 patients in the deferred ablation group (hazard ratio, 1.09 [95% CI, 0.62-1.92]; P=0.77). On the basis of prespecified criteria for interim analyses, the study was terminated early for futility. In the preventive versus deferred ablation group, 6 versus 2 patients died (7.9% versus 2.4%; P=0.18), 8 versus 2 patients were admitted for worsening heart failure (10.4% versus 2.3%; P=0.062), and 15 versus 21 patients were hospitalized for symptomatic ventricular arrhythmia (19.5% versus 25.3%; P=0.27). Among secondary outcomes, the proportions of patients with sustained ventricular tachyarrhythmia (39.7% versus 48.2%; P=0.050) and appropriate ICD therapy (34.2% versus 47.0%; P=0.020) were numerically reduced in the preventive ablation group. Preventive VT ablation before ICD implantation did not reduce mortality or hospitalization for arrhythmia or worsening heart failure during 1 year of follow-up compared with the deferred ablation strategy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02501005.