tbuckley/cabot-search huggingface dataset:
SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study
Authors: Antoni Ribas, Theresa Medina, Shivaani Kummar, Asim Amin, Anusha Kalbasi, Joseph J. Drabick, Minal Barve, Gregory A. Daniels, Deborah J. Wong, Emmett V. Schmidt, Albert F. Candia, Robert L. Coffman, Abraham C.F. Leung, Robert S. Janssen
Journal: Cancer Discovery (2018)

Abstract PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase Ib trial evaluated intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab in patients with unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection-site reactions and transient, mild-to-moderate “flu-like” symptoms. Among the 9 patients naïve to anti–PD-1 therapy, the overall response rate (ORR) was 78%. The estimated 12-month progression-free survival rate was 88%, and the overall survival rate was 89%. Among 13 patients having prior anti–PD-1 therapy, the ORR was 15%. RNA profiling of tumor biopsies demonstrated increased CD8+ T cells, natural killer cells, cytotoxic cells, dendritic cells, and B cells. The combination of intratumoral SD-101 and pembrolizumab was well tolerated and induced broad immune activation in the tumor microenvironment with durable tumor responses in both peripheral and visceral lesions. Significance: These early data demonstrate that the combination of pembrolizumab with intratumoral SD-101 is well tolerated and can induce immune activation at the tumor site. Combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially increase clinical efficacy with minimal additional toxicity relative to PD-1 blockade alone. Cancer Discov; 8(10); 1250–7. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195
Cytogenetic abnormalities in systemic mastocytosis: WHO subcategory‐specific incidence and prognostic impact among 348 informative cases
Authors: Sahrish Shah, Animesh Pardanani, Yoseph C. Elala, Terra L. Lasho, Mrinal M. Patnaik, Kaaren K. Reichard, Curtis A. Hanson, Rhett P. Ketterling, Ayalew Tefferi
Journal: American Journal of Hematology (2018)

Abstract The World Health Organization (WHO) system lists five morphological categories of systemic mastocytosis (SM): indolent (ISM), smoldering, SM with an associated hematological neoplasm (SM‐AHN), aggressive (ASM) and mast cell leukemia (MCL). Recent studies have highlighted the prognostic importance of mutations in SM, including ASXL1 , RUNX1 , and SRSF2. In contrast, information on incidence of cytogenetic abnormalities in SM and their prognostic relevance, especially in the context of mutations, is limited. In the current study, we retrospectively reviewed the cytogenetic findings in 348 consecutive cases of SM (median age 59 years; 53% males); 41% constituted ISM, 45% SM‐AHN, 14% ASM and two cases of MCL. Karyotype was abnormal in 53 (15%) cases with incidences of 6% for ISM, 26% for SM‐AHN and 8% for ASM ( P &lt; .001); among SM‐AHN cases, abnormal karyotype incidences were 0% for SM‐AHN‐lymphoid and 28% for SM‐AHN‐myeloid ( P &lt; .001). Clinical correlative studies disclosed significant associations between abnormal karyotype and male sex ( P = .002), age &gt; 60 years ( P = .04), thrombocytopenia ( P &lt; .001) and anemia ( P &lt; .001), but not with the presence of adverse mutations ( P = .19). In univariate analysis, abnormal karyotype was associated with inferior survival (HR 3.0, 95% CI 2.0‐4.3), specifically confirmed for ASM (HR 4.9, 95% CI 1.1‐16.1) and SM‐AHN (HR 1.8, 95% CI 1.2‐2.7). Sample size adequacy allowed additional multivariable analysis in SM‐AHN‐myeloid, which disclosed independent prognostic contribution from adverse mutations ( P = .003), anemia ( P = .003) and thrombocytopenia ( P = .001), but not from abnormal karyotype ( P = .31). Our observations suggest that mutations are prognostically more relevant than karyotype in SM.
Authors’ response: Association between IBD and Parkinson’s disease: seek and you shall find?
Authors: Marie Villumsen, Susana Aznar, Bente Pakkenberg, Tomasz Brudek, Tine Jess
Journal: Gut (2018)

Dr Weimers and colleagues have drawn attention1 to the possibility that our recently published observation of an association between IBD and Parkinson’s disease (PD) in a nationwide Danish cohort study2 may reflect surveillance bias.

In a recently published Swedish cohort study, Dr Weimers and colleagues found that adjusting for number of healthcare visits during follow-up of patients with IBD attenuated the risk of developing PD markedly.3 They also found that the risk of future PD was …
Serial monitoring of circulating tumor DNA in patients with metastatic colorectal cancer to predict the therapeutic response.
Authors: Jianfeng Zhou, Ning Jia, Zhao Sun, Xin Gao, Yuejuan Cheng, Wei Chen, Chunying Shen, Chunmei Bai
Journal: Journal of Clinical Oncology (2018)

713 Background: Early biomarkers of therapeutic responses could help optimize the treatment of metastatic colorectal cancer (mCRC). This prospective study was designed to explore the serial changes in plasma-circulating tumor DNA (ctDNA) as an early marker of therapeutic response to systemic treatment in mCRC. Methods: Twenty-six mCRC patients receiving standard first-line therapy once every two weeks were enrolled. Plasma ctDNA, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) were assessed serially before each of the first four cycles. Somatic mutations in plasma ctDNA were detected via next-generation sequencing using a panel of 50 cancer-related genes, and the mutation of maximal frequency in pretreatment ctDNA was selected as the candidate mutation for analysis. Radiologic responses were assessed after the fourth cycle. Results: Mutations in pretreatment ctDNA could be detected in 25 (96.2%) of the 26 initially enrolled patients. Among the 20 patients monitored serially, changes in ctDNA could differentiate patients with progressive disease two cycles (approximately four weeks) earlier than the changes in CEA and CA19-9 levels could, and changes in ctDNA levels as early as prior to cycle 2 predicted the radiologic responses after cycle 4. A log2 value of fold-change in ctDNA after cycle 1 (log2 (C1/C0)) &gt; 0.044 predicted progressive disease, with a sensitivity and specificity of 100.0% (95%CI: 47.8-100.0%) and 86.7% (95%CI: 59.5-98.3%), respectively, and an accuracy of 90.0% (95%CI: 68.3-98.8%). Patients with log2 (C1/C0) &gt; 0.044 showed worse progression-free survival than did those with log2 (C1/C0) ≤0.044 (median 2.0 versus 17.0 months; P = 0.092). Conclusions: Early changes in ctDNA that are detected via targeted sequencing could predict later radiologic responses in mCRC.
Fe–S Cluster Assembly in Oxymonads and Related Protists
Authors: Vojtěch Vacek, Lukáš V F Novák, Sebastian C Treitli, Petr Táborský, Ivan Čepička, Martin Kolísko, Patrick J Keeling, Vladimír Hampl
Journal: Molecular Biology and Evolution (2018)

The oxymonad Monocercomonoides exilis was recently reported to be the first eukaryote that has completely lost the mitochondrial compartment. It was proposed that an important prerequisite for such a radical evolutionary step was the acquisition of the SUF Fe-S cluster assembly pathway from prokaryotes, making the mitochondrial ISC pathway dispensable. We have investigated genomic and transcriptomic data from six oxymonad species and their relatives, composing the group Preaxostyla (Metamonada, Excavata), for the presence and absence of enzymes involved in Fe-S cluster biosynthesis. None possesses enzymes of mitochondrial ISC pathway and all apparently possess the SUF pathway, composed of SufB, C, D, S, and U proteins, altogether suggesting that the transition from ISC to SUF preceded their last common ancestor. Interestingly, we observed that SufDSU were fused in all three oxymonad genomes, and in the genome of Paratrimastix pyriformis. The donor of the SUF genes is not clear from phylogenetic analyses, but the enzyme composition of the pathway and the presence of SufDSU fusion suggests Firmicutes, Thermotogae, Spirochaetes, Proteobacteria, or Chloroflexi as donors. The inventory of the downstream CIA pathway enzymes is consistent with that of closely related species that retain ISC, indicating that the switch from ISC to SUF did not markedly affect the downstream process of maturation of cytosolic and nuclear Fe-S proteins.
Abstract 14464: Prospective Study Of Waist Circumference Trajectories And Incident Cardiovascular Disease
Authors: Yujin Lee, Cheng Jin, Jingli Gao, Yuntao Wu, Shouling Wu, Penny M Kris-Etherton, Xiang Gao
Journal: Circulation (2016)

Introduction: Single measurement of waist circumference (WC) predicts the incident cardiovascular disease (CVD); however, long term patterns of WC and their association with the incidence of CVD ar...
Abstract 20476: Ticagrelor : Similar Rates of Perioperative Hemorrhagic Complications and Mid-Term Survival Compared With Clopidogrel
Authors: Vincent Chauvette, Émile Voisine, Anne-Sophie Moisan, Siamak Mohammadi, François Dagenais, Pierre Voisine
Journal: Circulation (2016)

Introduction: The PLATO trial suggested that ticagrelor is associated with better survival at 1 year for patients with acute coronary syndrome (ACS) undergoing coronary artery bypass grafting (CABG...
Abstract 11434: Air Pollution is Associated With Ischemic Stroke via Cardiogenic Embolism
Authors: Jong-Won Chung, Oh Young Bang, Kangmo Ahn, Sang-Soon Park, Tai Hwan Park, Jae Guk Kim, Youngchai Ko, SooJoo Lee, Kyung Bok Lee, Jun Lee, Kyusik Kang, Jong-Moo Park, Yong-Jin Cho, Keun-Sik Hong, Hyun-Wook Nah, Dae-Hyun Kim, Jae-Kwan Cha, Wi-Sun Ryu, Dong-Eog Kim, Joon-Tae Kim, Jay Chol Choi, Mi-Sun Oh, Kyung-Ho Yu, Byung-Chul Lee, Ji Sung Lee, Juneyoung Lee, Hong-Kyun Park, Beom Joon Kim, Moon-Ku Han, Hee-Joon Bae
Journal: Circulation (2016)

Introduction: Both individual and environmental factors influence stroke risk and the effect might differ across stroke subtypes. The prevalence of cardioembolic stroke is increasing in Asian and other developing countries, which may be associated with the ambient air pollution as well as an aging population. However, the association between air pollution and stroke subtype remains unclear. Hypothesis: This study investigated the impact of short-term exposure to air pollution on ischemic stroke subtype, while focusing on stroke caused via cardioembolism. Methods: From a nationwide multicenter prospective stroke registry database, 13,535 acute ischemic stroke patients hospitalized to 12 participating centers were enrolled in this study. Data on the hourly concentrations of particulate matter &lt;10μm (PM 10 ), nitrogen dioxide (NO 2 ), sulfur dioxide (SO 2 ), ozone (O 3 ), and carbon monoxide (CO) were collected from 181 nationwide air pollution surveillance stations. The average values of these air pollutants over the 7 days prior to stroke onset from nearest air quality monitoring station in each patient were used to determine association with stroke subtype. Results: PM 10 and SO 2 concentrations were independently associated with an increased risk of cardioembolic stroke, as compared to large artery atherosclerosis and non-cardioembolic stroke. In sensitivity analyses, the proportion of cases of cardioembolic stroke was positively correlated with the PM 10 , NO 2 , and SO 2 quintiles. Moreover, seasonal (including Asian dust storms in spring and winter) and geographic (including polluted mid-sized cities) factors were related to an increased proportion of cardioembolic stroke, which may be attributed to the high levels of air pollution. Conclusions: Our findings suggest that the short-term exposure to air pollutants is associated with cardioembolic stroke subtype, and greater care should be taken for those susceptible to cerebral embolism during peak pollution periods. Public and environmental health policies to reduce air pollution could help slow down global increasing trends of cardioembolic stroke.
The Coexistence of a Horseshoe Kidney and Meckel Diverticulum With Dramatic Mobility Revealed Through 99mTc Pertechnetate Imaging
Authors: Jun Yang, Meng-jie Dong, Qin Xu, Jun Zhang
Journal: Clinical Nuclear Medicine (2018)

Abstract A previously healthy 11-year-old boy with intermittent abdominal pain and bloody stool underwent Meckel scintigraphy. On the initial images, there was a faint U-shaped activity in the mid-abdominal region, which gradually faded and evolved into distinct foci of radiotracer accumulation in the later images. One of the foci changed its location during the study, suspected as moving Meckel diverticulum. A horseshoe kidney was noted by subsequent CT images, which corresponded to nonmoving foci. A Meckel diverticulum was confirmed after exploratory laparotomy, accounted for moving focus on Merkel scintigraphy.
Abstract 20993: Role of Noncoding scaRNA20 in Differentiation of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes
Authors: Sheeja Rajasingh, Douglas C Bittel, Saheli Samanta, Zhigang Zhou, Bahar Barani, Nicholas Drosos, Buddhadeb Dawn, Johnson Rajasingh
Journal: Circulation (2017)

Introduction: Studies have shown that mRNA splicing is regulated by scaRNAs and plays a significant role in mammalian cardiac development and differentiation, but the potential contribution to human in vitro differentiation of iPSCs into CMCs remains unknown. In this study, the comparison of scaRNA20 modified and unmodified iPSCs derived-CMCs (iCMCs) will allow us to understand the role of scaRNAs in cardiac differentiation. Hypothesis: We hypothesize that CMCs modulated with scaRNA20 plays an important role in iPSCs-derived CMC differentiation. Methods and Results: Recently, our RNA sequencing analysis of iCMCs indicated that scaRNA20 plays an important role in CMC differentiation. We observed that si-scaRNA20 knockdown iPSCs underwent CMCs differentiation. They failed to grow as mature functional CMCs ( Fig. A ) and the number of beating clusters were reduced compared to the scrambled control cells (Fig. B). Our FACS data showed that there was a significant reduction in the expression of Gata4 and CTT in the CMC-derived from iPSCs kockdown with si-scaRNA20-1 but not in those with si-scaRNA-2 (Fig. C) . Similarly, our FACS data from scaRNA20 overexpressing iPSCs differentiated into CMCs showed a significant increase in the number of Gata4- and CTT-expressing cells, suggesting the role of scaRNA20 in CMC differentiation. Conclusions: We report for the first time the role scaRNA20 in the regulation of in-vitro cardiac development.
Abstract 15652: Prediction of Left Ventricular Ejection Fraction 6 Months after Surgical Correction of Organic Mitral Regurgitation: The Value of Exercise Echocardiography and Deformation Imaging
Authors: Erwan Donal, Sophie Mascle, Herve Corbineau, Christophe Thebault, Alain Leguerrier, Philippe Mabo
Journal: Circulation (2012)

AIMS: Left ventricular (LV) end-systolic diameter and LV ejection fraction (LVEF) are correlated with postoperative LVEF and prognosis in patients with organic mitral regurgitation (MR). However, i...
Tertiary Hyperparathyroidism With Renal Osteodystrophy on 18F-Fluorocholine PET/CT
Authors: Wouter A.M. Broos, Maurits Wondergem, Friso M. van der Zant, Remco J.J. Knol
Journal: Clinical Nuclear Medicine (2018)

A 27-year-old man, with a history of chronic renal failure due to obstructive uropathy, treated with hemodialysis and awaiting kidney transplantation, presented with tertiary hyperparathyroidism. Despite regulation of phosphate and calcium and treatment with cinacalcet, the serum parathyroid hormone levels remained elevated. The patient was referred for parathyroidectomy, and a F-fluorocholine PET/CT was acquired for preoperative planning. Besides visualization of the hyperfunctioning parathyroid glands, the scan also showed a typical picture of renal osteodystrophy, a finding on F-fluorocholine PET/CT that has not been reported before.
Association of Medication Nonadherence Among Adult Survivors of Stroke After Implementation of the US Affordable Care Act
Authors: Deborah A. Levine, James F. Burke, Colman F. Shannon, Bailey K. Reale, Lena M. Chen
Journal: JAMA Neurology (2018)

Among adults with chronic disease, survivors of stroke have high out-of-pocket financial burdens. The US government enacted the Affordable Care Act (ACA) in 2010 and implemented the law in 2014 to provide more low-income adults with health insurance coverage.To assess whether ACA implementation is associated with cost-related nonadherence (CRN) to medication among adult survivors of stroke.This study analyzed data from the 2000 to 2016 National Health Interview Survey, an in-person household survey of the noninstitutionalized US population conducted annually by the National Center for Health Statistics. Conducted at the University of Michigan Medical School, Ann Arbor, from July 24, 2017, to February 28, 2018, the study had a sample of 13 930 survivors of stroke. Analyses were stratified by age (45-64 years vs ≥65 years). Time was treated as a continuous variable and as a categorical variable across 4 periods (2000-2005, historical control; 2006-2010, economic recession and peak unemployment; 2011-2013, before ACA implementation; and 2014-2016, after ACA implementation). Percentages are weighted to reflect US population estimates.The primary outcome was the self-report of CRN, defined as the inability to afford prescribed medications within the past 12 months.Among the 13 930 total survivors of stroke, 38.1% were aged 45 to 64 years (50.5% were female and 49.5% were male, with a mean [SE] age of 56.0 [0.10] years), and 61.9% were aged 65 years or older (54.9% were female and 45.1% were male, with a mean [SE] age of 76.2 [0.09] years). From 2011 to 2013 through 2014 to 2016, Medicaid increased (from 24.0% [95% CI, 21.0%-27.2%] in 2011-2013 to 30.8% [95% CI, 27.3%-34.6%] in 2014-2016; P < .001) and uninsurance decreased (from 13.7% [95% CI, 11.3%-16.4%] to 6.8% [95% CI, 5.3%-8.8%]; P < .001) among survivors of stroke aged 45 to 64 years. Among survivors aged 45 to 64 years, CRN increased over time before ACA implementation (from 18.6% [95% CI, 16.5%-20.9%] in 2000-2005, to 22.6% [95% CI, 19.7%-25.9%] in 2006-2010, to 23.8% [95% CI, 20.7%-27.3%] in 2011-2013) and decreased after ACA implementation to 18.1% (95% CI, 15.4%-21.3%; P = .01) in 2014 to 2016. The period after ACA implementation was associated with lower odds of CRN after adjustment for sociodemographics, year, and clinical factors (odds ratio [OR], 0.63; 95% CI, 0.47-0.85). The difference was attenuated after further adjustment for health insurance coverage (OR, 0.76; 95% CI, 0.56-1.03).After the ACA implementation, health insurance coverage increased and CRN decreased among adult survivors of stroke, suggesting that further expansion of Medicaid coverage is likely to be advantageous for survivors.
Vaccine safety: Russian bots and trolls stoked online debate, research finds
Authors: Owen Dyer
Journal: BMJ (2018)

Russian internet bots and trolls—including some of those indicted by special counsel Robert Mueller for interfering in the 2016 US election—have been stoking divisions by creating fake online debate about vaccine safety, say researchers whose study looked at nearly two million Twitter messages posted from 2014 to 2017.

These efforts included a Twitter campaign under the hashtag #VaccinateUS that was entirely created by the St Petersburg based Internet Research Agency, an entity charged in a February indictment by a US grand jury.

Known Russian trolls, identified in lists compiled by the US Congress and NBC News, were over 20 times as likely as average Twitter accounts to tweet about vaccines, said researchers writing in the American Journal of Public Health .1

The lead author, David Broniatowski of George Washington University in Washington, DC, told The BMJ that the researchers, who …
Spoiled for choice: Identifying the building blocks of folk-economic beliefs
Authors: Shaylene Nancekivell, Ori Friedman
Journal: Behavioral and Brain Sciences (2018)

Abstract Boyer &amp; Petersen suggest that folk-economic beliefs result from evolved domain-specific cognitive systems concerned with social exchange. However, a major challenge for their account is that each folk-economic belief can be explained by different combinations of evolved cognitive systems. We illustrate this by offering alternative explanations for several economic beliefs they discuss.
Abstract 19698: The Impact of Genetic Variability of eNOS on Progression of Microvascular Disease in Type 2 Diabetes Patients: Effects on Angiogenesis Mechanisms
Authors: Theodosia Konsola, Alexios Antonopoulos, Gerasimos Siasos, Christina Kollia, Nikolaos Gouliopoulos, Evangelos Oikonomou, Eva Kassi, Maria Moschou, Nikolaos Tentolouris, Dimitris Tousoulis
Journal: Circulation (2016)

Introduction: Microvascular disease of type 2 diabetes (T2D) patients progresses despite strict glycaemic control, and the mechanisms are poorly understood. Endothelial dysfunction and adiponectin ...
The burden of disease in Russia from 1980 to 2016: a systematic analysis for the Global Burden of Disease Study 2016
Authors: Vladimir I Starodubov, Laurie B Marczak, Elena Varavikova, Boris Bikbov, Sergey P Ermakov, Julia Gall, Scott D Glenn, Max Griswold, Bulat Idrisov, Michael Kravchenko, Dmitry Lioznov, Enrique Loyola, Ivo Rakovac, Sergey K Vladimirov, Vasiliy Vlassov, Christopher J L Murray, Mohsen Naghavi
Journal: The Lancet (2018)

Over the past few decades, social and economic changes have had substantial effects on health and wellbeing in Russia. We aimed to use data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to evaluate trends in mortality, causes of death, years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and associated risk factors in Russia from 1980 to 2016.We estimated all-cause mortality by use of a multistage modelling process that synthesised data from vital registration systems, surveys, and censuses. A composite measure of health loss due to both fatal and non-fatal disease burden (DALYs) was calculated as the sum of YLLs and YLDs for each age, sex, year, and location. Health progress was evaluated in comparison with patterns of change in similar countries by use of the Socio-demographic Index that was developed for GBD 2016.Following rapid decreases in life expectancy after the collapse of the Soviet Union, life expectancy at birth in Russia improved between 2006 and 2016. The all-cause mortality rate decreased by 16·6% (95% uncertainty interval 9·4-33·8) between 1980 and 2016. This overall decrease encompasses the cycles of sharp increases and plateaus in mortality that occurred before 2005. Child mortality decreased by 57·5% (53·5-61·1) between 2000 and 2016. However, compared with countries at similar Socio-demographic Index levels, rates of mortality and disability in Russia remain high and life expectancy is low. Russian men have a disproportionate burden of disease relative to women. In 2016, 59·2% (55·3-62·6) of mortality in men aged 15-49 years and 46·8% (44·5-49·5) of mortality in women were attributable to behavioural risk factors, including alcohol use, drug use, and smoking.Trends in mortality in Russia from 1980 to 2016 might be related to complicated patterns of behavioural risk factors associated with economic and social change, to shifts in disease burden, and to changes in the capacity of and access to health care. Ongoing mortality and disability from causes and risks amenable to health-care interventions and behaviour modifications present opportunities to continue to improve the wellbeing of Russian citizens.Bill & Melinda Gates Foundation.