tbuckley/cabot-search huggingface dataset:
Evaluating the 2014 sugar-sweetened beverage tax in Chile: An observational study in urban areas
Authors: Ryota Nakamura, Andrew J. Mirelman, Cristóbal Cuadrado, Nicolas Silva-Illanes, Jocelyn Dunstan, Marc Suhrcke
Journal: PLoS Medicine (2018)

Background In October 2014, Chile implemented a tax modification on sugar-sweetened beverages (SSBs) called the Impuesto Adicional a las Bebidas Analcohólicas (IABA). The design of the tax was unique, increasing the tax on soft drinks above 6.25 grams of added sugar per 100 mL and decreasing the tax for those below this threshold. Methods and findings This study evaluates Chile's SSB tax, which was announced in March 2014 and implemented in October 2014. We used household-level grocery-purchasing data from 2011 to 2015 for 2,836 households living in cities representative of the urban population of Chile. We employed a fixed-effects econometric approach and estimated the before–after change in purchasing of SSBs controlling for seasonality, general time trend, temperature, and economic fluctuations as well as time-invariant household characteristics. Results showed significant changes in purchasing for the statistically preferred model: while there was a barely significant decrease in the volume of all soft drinks, there was a highly significant decrease in the monthly purchased volume of the higher-taxed, sugary soft drinks by 21.6%. The direction of this reduction was robust to different empirical modelling approaches, but the statistical significance and the magnitude of the changes varied considerably. The reduction in soft drink purchasing was most evident amongst higher socioeconomic groups and higher pretax purchasers of sugary soft drinks. There was no systematic, robust pattern in the estimates by household obesity status. After tax implementation, the purchase prices of soft drinks decreased for the items for which the tax rate was reduced, but they remained unchanged for sugary items, for which the tax was increased. However, the purchase prices increased for sugary soft drinks at the time of the policy announcement. The main limitations include a lack of a randomised design, limiting the extent of causal inference possible, and the focus on purchasing data rather than consumption or health outcomes. Conclusions The results of subgroup analyses suggest that the policy may have been partially effective, though not necessarily in ways that are likely to reduce socioeconomic inequalities in diet-related health. It remains unclear whether the policy has had a major, overall population-level impact. Additionally, because the present study examined purchasing of soft drinks for only 1 year, a longer-term evaluation—ideally including an assessment of consumption and health impacts—should be conducted in future research. Trial registration ClinicalTrials.gov Identifier: NCT02926001
Red blood cell indices and anaemia as causative factors for cognitive function deficits and for Alzheimer’s disease
Authors: Laura M. Winchester, John Powell, Simon Lovestone, Alejo J. Nevado-Holgado
Journal: Genome Medicine (2018)

Studies have shown that low haemoglobin and anaemia are associated with poor cognition, and anaemia is known to be associated with Alzheimer's disease (AD), but the mechanism of this risk is unknown. Here, we first seek to confirm the association between cognition and anaemia and secondly, in order to further understand the mechanism of this association, to estimate the direction of causation using Mendelian randomisation.Two independent cohorts were used in this analysis: AddNeuroMed, a longitudinal study of 738 subjects including AD and age-matched controls with blood cell measures, cognitive assessments and gene expression data from blood; and UK Biobank, a study of 502,649 healthy participants, aged 40-69 years with cognitive test measures and blood cell indices at baseline. General linear models were calculated using cognitive function as the outcome with correction for age, sex and education. In UK Biobank, SNPs with known blood cell measure associations were analysed with Mendelian randomisation to estimate direction of causality. In AddNeuroMed, gene expression data was used in pathway enrichment analysis to identify associations reflecting biological function.Both sample sets evidence a reproducible association between cognitive performance and mean corpuscular haemoglobin (MCH), a measure of average mass of haemoglobin per red blood cell. Furthermore, in the AddNeuroMed cohort, where longitudinal samples were available, we showed a greater decline in red blood cell indices for AD patients when compared to controls (p values between 0.05 and 10-6). In the UK Biobank cohort, we found lower haemoglobin in participants with reduced cognitive function. There was a significant association for MCH and red blood cell distribution width (RDW, a measure of cell volume variability) compared to four cognitive function tests including reaction time and reasoning (p < 0.0001). Using Mendelian randomisation, we then showed a significant effect of MCH on the verbal-numeric and numeric traits, implying that anaemia has causative effect on cognitive performance.Lower haemoglobin levels in blood are associated to poor cognitive function and AD. We have used UK Biobank SNP data to determine the relationship between cognitive testing and haemoglobin measures and suggest that haemoglobin level and therefore anaemia does have a primary causal impact on cognitive performance.
Abstract 16044: Measurements of Tissue Oxygen and Hemoglobin on A Near Infra-red Spectroscopy in Emergency Patients With Poor General Conditions
Authors: Takeji Saitoh, Hiroshi Satoh, Naohiro Kanayama, Masatsugu Niwayama, Hironao Hozumi, Yoshiaki Takahashi, Toshiyuki Uchida, Masao Saotome, Tsuyoshi Urushida, Hideki Katoh, Hideharu Hayashi, Atsuto Yoshino
Journal: Circulation (2015)

Introduction: In patients with poor general conditions, the conventional pulse oximetry is sometimes unable to determine the oxygen saturation because of peripheral arteriole constriction. The near infra-red spectroscopy (NIRS) can measure absolute concentration of oxygenated, deoxygenated, and total tissue hemoglobin. Purpose: This study aimed to investigate the potential of a novel minimized NIRS system in terms of measurements of tissue oxygen and hemoglobin. Methods: We enrolled 22 normal controls and 83 emergency patients who came to the emergency department with poor general conditions. The tissue oxygen saturation (StO2) and tissue hemoglobin index (T-HbI) on second finger pulp (SFP), thenar eminence (TE), and sternocleid muscle (SM) were measured in both groups. Results: (1) In all subjects including patients with cardio-pulmonary arrest, both the StO2 and T-Hbl values were obtained stably. (2) In the emergency patients, the StO2 value on SFP was lower than those on TE and SM (53% [49-56] vs. 57% [55-60] and 58% [53-62], median [inter-quartile range], p&lt;0.01), whereas those in the normal controls were not different. The StO2 value on SFP was lower in the emergency patients than that in normal controls (60% [58-61], p&lt;0.01). (3) In the emergency patients, the T-Hbl value on SBP was also lower than those on TE and SM (0.13 mM [0.11-0.15] vs. 0.25 [0.22-0.29] and 0.23 [0.18-0.29], p&lt;0.01). The T-HbI value on SFP was also lower in the emergency patients than that in normal controls (0.18 mM [0.17-0.21], p&lt;0.01). Conclusion: NIRS detected peripheral circulatory failure easily and immediately in the emergency patients.
JDP2: An oncogenic bZIP transcription factor in T cell acute lymphoblastic leukemia
Authors: Marc R. Mansour, Shuning He, Zhaodong Li, Riadh Lobbardi, Brian J. Abraham, Clemens Hug, Sunniyat Rahman, Theresa E. Leon, You-Yi Kuang, Mark W. Zimmerman, Traci Blonquist, Evisa Gjini, Alejandro Gutierrez, Qin Tang, Laura Garcia-Perez, Karin Pike-Overzet, Lars Anders, Alla Berezovskaya, Yi Zhou, Leonard I. Zon, Donna Neuberg, Adele K. Fielding, Frank J.T. Staal, David M. Langenau, Takaomi Sanda, Richard A. Young, A. Thomas Look
Journal: The Journal of Experimental Medicine (2018)

A substantial subset of patients with T cell acute lymphoblastic leukemia (T-ALL) develops resistance to steroids and succumbs to their disease.
Modulating Neural Circuits with Transcranial Magnetic Stimulation: Implications for Addiction Treatment Development
Authors: Colleen A. Hanlon, Logan T. Dowdle, J. Scott Henderson
Journal: Pharmacological Reviews (2018)

Although the last 50 years of clinical and preclinical research have demonstrated that addiction is a brain disease, we still have no neural circuit-based treatments for substance dependence or cue reactivity at large. Now, for the first time, it appears that a noninvasive brain stimulation technique known as transcranial magnetic stimulation (TMS), which is Food and Drug Administration approved to treat depression, may be the first tool available to fill this critical void in addiction treatment development. The goals of this review are to 1) introduce TMS as a tool to induce causal change in behavior, cortical excitability, and frontal-striatal activity; 2) describe repetitive TMS (rTMS) as an interventional tool; 3) provide an overview of the studies that have evaluated rTMS as a therapeutic tool for alcohol and drug use disorders; and 4) outline a conceptual framework for target selection when designing future rTMS clinical trials in substance use disorders. The manuscript concludes with some suggestions for methodological innovation, specifically with regard to combining rTMS with pharmacotherapy as well as cognitive behavioral training paradigms. We have attempted to create a comprehensive manuscript that provides the reader with a basic set of knowledge and an introduction to the primary experimental questions that will likely drive the field of TMS treatment development forward for the next several years.
Association of Coffee Drinking With Mortality by Genetic Variation in Caffeine Metabolism
Authors: Erikka Loftfield, Marilyn C. Cornelis, Neil Caporaso, Kai Yu, Rashmi Sinha, Neal Freedman
Journal: JAMA Internal Medicine (2018)

Prospective cohorts in North America, Europe, and Asia show consistent inverse associations between coffee drinking and mortality, including deaths from cardiovascular disease and some cancers. However, concerns about coffee, particularly among people with common genetic polymorphisms affecting caffeine metabolism and among those drinking more than 5 cups per day, remain.
Abstract 62: Effect of cancer cell-derived exosome on energy metabolism associated with macrophage activation
Authors: Yoonseok Kam, Brian P. Dranka
Journal: Cancer Research (2018)

Abstract Macrophage is a critical microenvironmental component which can control tumor progression, and dynamic changes in cellular metabolism accompany the polarization. As well as other immune cells, the activation of macrophages can be modulated by cancer cells. Cancer-derived exosome is a newly emerging microenvironmental factor enables cancer cells to communicate with macrophages. In this study, examined were the activation-associated bioenergetic changes and the effect of cancer cell-derived exosome on the changes by a) monitoring the early metabolic kinetics and b) profiling bioenergetic phenotype resulted. In vitro activation of RAW264.7 macrophage cell line by injecting lipopolysaccharide (LPS) and interferon γ (IFNγ) in a Seahorse XF analyzer induced an immediate early increase in glycolytic rate. It also showed a delayed down-regulation of mitochondrial respiration, which resulted in a secondary elevation of glycolytic rate. This secondary glycolytic response was only obtained by LPS-IFNγ co-stimulation and mediated by induced nitric oxide synthase (iNOS) signaling. In contrast to the dynamic changes in metabolic phenotype, the total ATP production rate appeared to be stably maintained according to the XF data normalized by cell number. However, macrophage activation significantly increased glycolysis-dependent portion of ATP production. ATPs were generated almost solely by glycolysis after the delayed mitochondrial down-regulation by iNOS. Co-injection of cancer cell-derived exosomes with LPS slightly but significantly accelerated the immediate early glycolytic response as well as the delayed mitochondrial down-regulation. Furthermore, exosomes induced the immediate early glycolytic response even in the absence of LPS. These results imply that presence of cancer cell-derived exosomes may promote macrophage activation and accelerate pro-inflammatory immune response in a tumor microenvironment. Citation Format: Yoonseok Kam, Brian P. Dranka. Effect of cancer cell-derived exosome on energy metabolism associated with macrophage activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 62.
Macchiarini case: seven researchers are guilty of scientific misconduct, rules Karolinska’s president
Authors: Nigel Hawkes
Journal: BMJ (2018)

Seven researchers, including the now disgraced surgeon Paolo Macchiarini, are guilty of scientific misconduct, the president of the Karolinska Institute in Sweden has ruled.

Ole Petter Ottersen, who took office in 2017 with a mission to clean up the institute after a scandal over bioengineered implants damaged its reputation, asked for six articles to be retracted, including two published in the Lancet .

More controversially, he included in his list one of Macchiarini’s co-workers, Karl-Henrik Grinnemo, who had alerted the institute to defects in the articles as long ago as 2014. Whistleblowing after the event, said Ottersen, could not exculpate a researcher from criticism if he was a coauthor of the relevant article.

He said, “It is KI’s [the Karolinska Institute’s] firm opinion that a whistleblower who has participated in in a scientific …
FDA approves its first cannabis based medicine
Authors: Jacqui Wise
Journal: BMJ (2018)

The US Food and Drug Administration has approved the first prescription drug derived from marijuana for treating two rare and severe forms of epilepsy.

Epidiolex has been approved for treating seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged 2 years or older.1 These forms of epilepsy are frequently resistant to currently available treatments.

The oral solution, developed by the UK based company GW Pharmaceuticals, contains purified cannabidiol (CBD), a chemical component of the Cannabis sativa plant. However, CBD does not cause the intoxication or euphoria that comes from tetrahydrocannabinol (THC). Before the drug can be marketed the Drug Enforcement Administration must reclassify cannabidiol: it is currently considered a schedule drug, meaning that it has no medical value and a high risk of misuse. It is expected …
Reply to E.L. Pollom et al, N. Ohri et al, A. Fiorentino et al, D.R. Wahl et al, N. Kim et al, J. Boda-Heggemann et al, S. Rana et al, N. Sanuki et al, J.R. Olsen et al, G.L. Smith et al, and A. Shinde et al
Authors: Devalkumar J. Rajyaguru, Andrew J. Borgert, Thorvardur R. Halfdanarson, Mark J. Truty, A. Nicholas Kurup, Ronald S. Go
Journal: Journal of Clinical Oncology (2018)
Restricted immune activation and internalisation of anti-idiotype complexes between drug and antidrug antibodies
Authors: Karin A van Schie, Simone Kruithof, Pleuni Ooijevaar-de Heer, Ninotska I L Derksen, Fleur S van de Bovenkamp, Anno Saris, Gestur Vidarsson, Arthur E H Bentlage, Wim Jiskoot, Stefan Romeijn, Roman I Koning, Erik Bos, Eva Maria Stork, Carolien A M Koeleman, Manfred Wuhrer, Gertjan Wolbink, Theo Rispens
Journal: Annals of the Rheumatic Diseases (2018)

Objectives Therapeutic antibodies can provoke an antidrug antibody (ADA) response, which can form soluble immune complexes with the drug in potentially high amounts. Nevertheless, ADA-associated adverse events are usually rare, although with notable exceptions including infliximab. The immune activating effects and the eventual fate of these ‘anti-idiotype’ complexes are poorly studied, hampering assessment of ADA-associated risk of adverse events. We investigated the in vitro formation and biological activities of ADA-drug anti-idiotype immune complexes using patient-derived monoclonal anti-infliximab antibodies. Methods Size distribution and conformation of ADA-drug complexes were characterised by size-exclusion chromatography and electron microscopy. Internalisation of and immune activation by complexes of defined size was visualised with flow imaging, whole blood cell assay and C4b/c ELISA. Results Size and conformation of immune complexes depended on the concentrations and ratio of drug and ADA; large complexes (&gt;6 IgGs) formed only with high ADA titres. Macrophages efficiently internalised tetrameric and bigger complexes in vitro, but not dimers. Corroborating these results, ex vivo analysis of patient sera demonstrated only dimeric complexes in circulation. No activation of immune cells by anti-idiotype complexes was observed, and only very large complexes activated complement. Unlike Fc-linked hexamers, anti-idiotype hexamers did not activate complement, demonstrating that besides size, conformation governs immune complex potential for triggering effector functions. Conclusions Anti-idiotype ADA-drug complexes generally have restricted immune activation capacity. Large, irregularly shaped complexes only form at high concentrations of both drug and ADA, as may be achieved during intravenous infusion of infliximab, explaining the rarity of serious ADA-associated adverse events.
Abstract 2862: Inhibition of DNA repair pathways in breast cancer is a potential mechanism of action of IT-139
Authors: Isabel Conde, Yassi Fallah, Diane Demas, Suzanne Bakewell, Filipa Lynce, Ayesha N. Shajahan-Haq
Journal: Cancer Research (2018)

Abstract IT-139 is a novel small-molecule drug that demonstrated a manageable safety profile at the maximum tolerated dose and modest antitumor activity as a monotherapy in a phase I clinical trial. A high affinity for albumin and unique chemistry allow increased uptake and activation of IT-139 within tumor cells, respectively. To date, IT-139 has been reported to inhibit the endoplasmic reticulum stress-sensing protein GRP78. However, different cancer cells show disparate responses to IT-139 and the precise mechanism of action in high-response versus low-response cancer cells remains unclear. In vitro studies have indicated that IT-139 induces cytostatic rather than cytotoxic effects as a monotherapy. In this study, to understand IT-139 mediated signaling mechanism in breast cancer cells, we used estrogen receptor-positive (ER+) MCF7 breast cancer cells to obtain gene-metabolite integrated models following IT-139 treatment (10 or 100 μM for 72 h). Our data showed that IT-139 significantly reduced expression of genes involved in the DNA repair pathway, including BRCA1 and RAD51, following treatment with IT-139 in MCF7 cells. Validation of our findings in other breast cancer cell lines including MDA-MB-175 (ER+), MDA-MB-231 and MDA-MB-468 (both ER-) cells also showed increased phosphorylation of H2AX (Ser139) following IT-139 treatment, suggesting lack of proper DNA surveillance and subsequent accumulation of DNA double-stranded breaks (DSB). Consequently, we investigated the effects of combination treatment approaches with IT-139 and other clinical anticancer therapies that interfere with nucleotide synthesis or DNA damage repair pathways, particularly in ER- breast cancers. Our data showed additive effects of IT-139 in combination with capecitabine (5-FU prodrug) or olaparib (PARP inhibitor) and a synergistic effect with carboplatin in ER- breast cancer cell lines. Further analysis of IT-139 mediated signal transduction in breast cancer cells will reveal whether it can be combined with aforementioned chemotherapies to circumvent resistance. Citation Format: Isabel Conde, Yassi Fallah, Diane Demas, Suzanne Bakewell, Filipa Lynce, Ayesha N. Shajahan-Haq. Inhibition of DNA repair pathways in breast cancer is a potential mechanism of action of IT-139 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2862.
Abstract 11923: Perceived Discrimination and Cardiovascular Outcomes in Older African Americans: Insights From the Jackson Heart Study
Authors: Shannon M Dunlay, Steven J Lippmann, Melissa A Greiner, Emily C O’Brien, Alanna M Chamberlain, Robert J Mentz, Mario Sims
Journal: Circulation (2016)

Introduction: Perceived discrimination is known to play a role in the development of cardiovascular (CV) risk factors such as hypertension, but the association with CV outcomes is less clear. A recent report from a multi-ethnic cohort study found a modestly increased risk of CV disease in participants reporting discrimination. We explored this association in an African American (AA) cohort. Hypothesis: Greater perceived discrimination is associated with a higher risk of CV disease Methods: We examined CV outcomes among 5085 AAs in the Jackson Heart Study enrolled in 2000-2004 and followed through December 31, 2012. We stratified participants by quartiles of perceived everyday discrimination and estimated the associations with CV outcomes (all-cause mortality, incident coronary heart disease [CHD], incident stroke, and heart failure [HF] hospitalization) using Cox models. Results: Greater perceived discrimination was more common in participants who were younger, male, had higher education and income, a lower perceived standing in the community, worse perceived healthcare access, and fewer comorbidities. Over a median follow-up of 9.8 years (8.0 years for HF), 573 deaths, 193 incident CHD, 156 incident strokes, and 348 HF hospitalizations occurred. Prior to adjustment, greater perceived discrimination was associated with a lower risk of death, incident CHD, stroke, and HF hospitalization (Table). After adjustment for potential confounders, we found no association of perceived discrimination with incident CHD, stroke or HF hospitalization; however, a decrease in all-cause mortality risk with higher perceived discrimination persisted. Conclusions: We found no independent association of perceived discrimination with risk of incident CV disease or HF hospitalization and a paradoxical negative association with mortality in this AA population. The unexpected finding of a lower risk of death with greater perceived discrimination requires further study.