tbuckley/cabot-search huggingface dataset:
Interferences With Thyroid Function Immunoassays: Clinical Implications and Detection Algorithm
Authors: Julien Favresse, Maria-Cristina Burlacu, Dominique Maiter, Damien Gruson
Journal: Endocrine Reviews (2018)

Automated immunoassays used to evaluate thyroid function are vulnerable to different types of interference that can affect clinical decisions. This review provides a detailed overview of the six main types of interference known to affect measurements of thyroid stimulating hormone (TSH), free thyroxine (T4) and free triiodothyronine (T3): macro-TSH, biotin, antistreptavidin antibodies, anti-ruthenium antibodies, thyroid hormone autoantibodies, and heterophilic antibodies. Because the prevalence of some of these conditions has been reported to approach 1% and the frequency of testing for thyroid dysfunction is important, the scale of the problem might be tremendous. Potential interferences in thyroid function testing should always be suspected whenever clinical or biochemical discrepancies arise. Their identification usually relies on additional laboratory tests, including assay method comparison, dilution procedures, blocking reagents studies, and polyethylene glycol precipitation. Based on the pattern of thyroid function test alterations, to screen for the six aforementioned types of interference, we propose a detection algorithm, which should facilitate their identification in clinical practice. The review also evaluates the clinical impact of thyroid interference on immunoassays. On review of reported data from more than 150 patients, we found that ≥50% of documented thyroid interferences led to misdiagnosis and/or inappropriate management, including prescription of an unnecessary treatment (with adverse effects in some situations), inappropriate suppression or modification of an ongoing treatment, or use of unnecessary complementary tests such as an I123 thyroid scan. Strong interaction between the clinician and the laboratory is necessary to avoid such pitfalls.
Abstract 18995: Absence of the NLRP3 Inflammasome Improves Survival but Not Cardiac Remodeling Following Myocardial Infarction
Authors: Mieke C Louwe, Ole J Kaasbøll, Katrine Alfsnes, Azita Rashidi, Elisabeth Schrumpf, Solveig B Haugstad, Espen Melum, Håvard Attramadal, Ivar Sjaastad, Pål Aukrust, Arne Yndestad
Journal: Circulation (2016)

Introduction: Myocardial infarction (MI) causes a sterile inflammatory response through activation of the innate immune system. Upon activation of NLRP3, a cytosolic pattern recognition receptor, i...
Progress in PTSD
Authors: Spencer Eth
Journal: American Journal of Psychiatry (2018)

an informative overview, published in the June 2018 issue of the Journal, of the history of posttraumatic stress disorder (PTSD), with lessons learned, forgotten, and rediscovered (1).The current era reflects substantial progress in phenomenology and therapeutics.Admittedly, many patients with PTSD continue to experience distress and disability despite treatment, but that is a common challenge in our field of psychiatry.However, what is missing in this scholarly review are traumatized children and adolescents, an oversight that parallels the absence of a reference to this substantial clinical population when PTSD was first named as a disorder in DSM-III in 1980 (2).The study of childhood PTSD has a notable record of accomplishment that complements our understanding of PTSD in adults, many of whom had first experienced traumatic adversity as children (3).Stein and Rothbaum begin their article with the statement, "Traumatic stressors have always been a part of the human experience" (1, p. 508).Let's not forget that human experience starts at birth.
Age-Specific Associations of Ozone and Fine Particulate Matter with Respiratory Emergency Department Visits in the United States
Authors: Heather M. Strosnider, Howard H. Chang, Lyndsey A. Darrow, Yang Liu, Ambarish Vaidyanathan, Matthew J. Strickland
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Whereas associations between air pollution and respiratory morbidity for adults 65 years and older are well documented in the United States, the evidence for people under 65 is less extensive. To address this gap, the Centers for Disease Control and Prevention's National Environmental Public Health Tracking Program collected respiratory emergency department (ED) data from 17 states.To estimate age-specific acute effects of ozone and fine particulate matter (particulate matter ≤2.5 mm in aerodynamic diameter [PM2.5]) on respiratory ED visits.We conducted time-series analyses in 894 counties by linking daily respiratory ED visits with estimated ozone and PM2.5 concentrations during the week before the date of the visit. Overall effect estimates were obtained with a Bayesian hierarchical model to combine county estimates for each pollutant by age group (children, 0-18; adults, 19-64; adults ≥ 65, and all ages) and by outcome group (acute respiratory infection, asthma, chronic obstructive pulmonary disease, pneumonia, and all respiratory ED visits).Rate ratios (95% credible interval) per 10-μg/m3 increase in PM2.5 and all respiratory ED visits were 1.024 (1.018-1.029) among children, 1.008 (1.004-1.012) among adults younger than 65 years, and 1.002 (0.996-1.007) among adults 65 and older. Per 20-ppb increase in ozone, rate ratios were 1.017 (1.011-1.023) among children, 1.051 (1.046-1.056) among adults younger than 65, and 1.033 (1.026-1.040) among adults 65 and older. Associations varied in magnitude by age group for each outcome group.These results address a gap in the evidence used to ensure adequate public health protection under national air pollution policies.
Efficacy of Radium-223 in Bone-metastatic Castration-resistant Prostate Cancer with and Without Homologous Repair Gene Defects
Authors: Pedro Isaacsson Velho, Fahad Qazi, Sayeedul Hassan, Michael A. Carducci, Samuel R. Denmeade, Mark C. Markowski, Daniel L. Thorek, Theodore L. DeWeese, Daniel Y. Song, Phuoc T. Tran, Mario A. Eisenberger, Emmanuel S. Antonarakis
Journal: European Urology (2018)
Ras-induced senescence in pancreatic ductal adenocarcinoma
Authors: Jennifer Morton, Saadia Karim, T.R. Jeffry Evans, Owen Sansom
Journal: Cancer Research (2008)

1942  Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the UK, with an estimated 5-year overall survival of less than 5%. This poor prognosis is due to the aggressive nature of the disease, such that 90% of patients have surgically unresectable disease at the time of diagnosis, and a profound resistance to chemotherapy. We have adapted a mouse model to investigate the mechanisms involved in the development of this disease. Targeting endogenous expression of Trp53R172H and KrasG12D to the mouse pancreas, via the Pdx1 pancreatic progenitor cell gene promoter, results in the formation of pre-invasive pancreatic intraepithelial neoplasia (PanIN) which develops into invasive and metastatic pancreatic cancer reminiscent of the human disease, with malignant disease burden apparent in animals by 10 weeks of age. By adapting this model so that Pdx1 positive cells express GFP, direct imaging of the pancreas and subsequent tumors is feasible, thus allowing visualization of pancreatic cancer progression and metastasis in situ. Animals expressing wild-type Kras express GFP within the pancreas, as detected by in vivo imaging, irrespective of p53 status. Expression of KrasG12D results in loss of this signal in mice expressing one or more copies of wild-type p53 within the pancreas, however the tumors that develop in these mice express GFP. β-galactosidase staining indicated senescence in PanINs in mice expressing KrasG12D. Tumors observed in these mice however, did not exhibit positive staining, suggesting that these tumor cells had escaped Ras-induced senescence. We found that in these tumors, loss of heterozygosity of p53 had occurred. Interestingly, GFP expression was observed in the normal pancreata of mice expressing KrasG12D and homozygous for the Trp53R172H mutation, in contrast with those mice bearing at least one copy of wild-type p53. We also observed nestin positivity in all PanINs and tumors tested, suggesting an increased tumorigenic potential in nestin expressing cells within the pancreas. Together these data suggest that cells expressing activated Kras within the pancreas are able to form precursor lesions, but require loss of the p53 tumor suppressor to escape senescence and progress to adenocarcinoma.
Abstract 13031: A Randomized Trial Comparing the Effects of Ticagrelor versus Clopidogrel on Myocardial Perfusion in Patients With Coronary Artery Disease
Authors: Matthieu Pelletier-Galarneau, Chad R Hunter, Kathryn J Ascah, Rob S Beanlands, Aun Yeong Chong, Benjamin J Chow, Girish Dwivedi, Renee C Hessian, Glenn R Wells, Robert A deKemp, Terrence D Ruddy
Journal: Circulation (2015)

Introduction: Ticagrelor is a reversible P2Y12 receptor antagonist used in patients with acute coronary syndrome (ACS). In the PLATO trial, treatment with ticagrelor reduced mortality compared to clopidogrel, to which pleotropic mechanisms may have contributed. In this study, we compared the effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease on myocardial blood flow (MBF) at rest and during intermediate and high dose adenosine infusion. Methods: Patients (n=22) were randomized using a double-blind crossover design to ticagrelor 90 mg orally twice a day for 10 days and clopidogrel 75 mg orally once a day for 10 days, with a washout period of at least 5 days between the treatments. MBF was measured using Rb-82 PET-CT at baseline and at intermediate (80 mcg/kg/min) and high dose adenosine (140 mcg/kg/min). Results: Global MBF was significantly greater with ticagrelor versus clopidogrel at intermediate dose adenosine (1.28±0.55 versus 1.13±0.47, p=0.002), and not different at baseline (0.65±0.19 versus 0.60±0.15, p=0.4254) nor at high dose adenosine (1.64±0.40 versus 1.61±0.19, p=0.5302). In abnormal segments with low MBF reserve (&lt;2.5), MBF was significantly greater with ticagrelor compared to clopidogrel at intermediate and high dose of adenosine (p&lt;0.0001), with no difference at baseline. For segments with high MBF reserve (≥2.5 and &lt; 3.5), segmental MBF was significantly greater with ticagrelor compared to clopidogrel at baseline (p&lt;0.001) and at intermediate adenosine dose (p&lt;0.0001). Conclusions: Global stress MBF was greater with ticagrelor compared to clopidogrel during intermediate dose adenosine infusion. Regional MBF in segments with reduced MBF reserve was greater with ticagrelor compared to clopidogrel during intermediate and high dose adenosine. This suggests that ticagrelor may potentiate adenosine-induced myocardial blood coronary flow increases in patients with stable CAD compared to clopidogrel; an effect that may explain the observed incremental mortality benefit observed with ticagrelor.
Abstract 12528: ALR Protein, a Critical Protein in Cardiac Development, Regulates Cellular Iron Homeostasis by Modulating Mitochondrial Transport of ATP-Binding Cassette (ABC)-B8
Authors: Hsiang-Chun Chang, Xinghang Jiang, Grant Senyei, Jason S Shapiro, Konrad T Sawicki, Hossein Ardehali
Journal: Circulation (2016)

Introduction: Iron is an essential molecule for normal cellular physiology, and altered cellular iron homeostasis is commonly observed in diseases with disruption of iron/sulfur (Fe/S) cluster maturation, such as cardiomyopathy associated with Friedreich’s ataxia. Inhibition of Augmenter of Liver Regeneration (ALR), a mitochondrial inter-membrane-space protein involved in mitochondrial protein import, results in cardiac developmental defect in zebrafish, and its deletion is associated with increased oxidative stress and cytosolic Fe/S cluster maturation defects. ABCB8 is one of only two mitochondrial membrane proteins known to regulate cytosolic Fe/S cluster maturation. We hypothesized that ALR is critical for cytosolic Fe/S cluster maturation and iron homeostasis by regulating mitochondrial import of ABCB8. Results: Downregulation of ALR in vitro resulted in reduced cytosolic Fe/S cluster-containing enzyme activities and increased cellular iron uptake. Using a knockdown-rescue approach, we further demonstrated that only the mitochondrial, but not the cytosolic, ALR isoform is involved in the maturation of cytosolic Fe/S clusters. Because Fe/S clusters are synthesized in the mitochondria, we then assessed whether ALR can alter the levels or activity of ABCB7 and ABCB8, the two mitochondrial proteins known to regulate the maturation of cytosolic Fe/S clusters. Downregulation of ALR reduced the mitochondrial levels of ABCB8, while ABCB7 levels were not affected. We also identified defects in mitochondrial transport of ABCB8 as the mechanism for reduced mitochondrial ABCB8 levels with ALR knockdown. Finally, we demonstrated that ABCB8 physically interacts with the protein import system consisting of ALR and Mia40, thus providing a mechanism for reduced ABCB8 mitochondrial transport with ALR downregulation. Conclusion: Our results indicate that ALR and its interaction partner Mia40 are involved in the transport of ABCB8 into the mitochondria, which in turn regulates cytoplasmic Fe/S cluster maturation. These findings provide insights into cellular iron regulation, with implications in cardiovascular disease and cardiac development.
SKESA: strategic k-mer extension for scrupulous assemblies
Authors: Alexandre Souvorov, Richa Agarwala, David J. Lipman
Journal: Genome biology (2018)

SKESA is a DeBruijn graph-based de-novo assembler designed for assembling reads of microbial genomes sequenced using Illumina. Comparison with SPAdes and MegaHit shows that SKESA produces assemblies that have high sequence quality and contiguity, handles low-level contamination in reads, is fast, and produces an identical assembly for the same input when assembled multiple times with the same or different compute resources. SKESA has been used for assembling over 272,000 read sets in the Sequence Read Archive at NCBI and for real-time pathogen detection. Source code for SKESA is freely available at https://github.com/ncbi/SKESA/releases .
Abstract 18357: Hypertension in Mice Lacking 3-Mercaptopyruvate Sulfurtransferase
Authors: Masato Tsutsui, Yuichi Totsuka, Mayuko Sakanashi, Toshihiro Matsuzaki, Katsuhiko Noguchi, Junko Nakasone, Yukio Kuniyoshi
Journal: Circulation (2016)

Background: Hydrogen sulfide (H2S) is synthesized by three distinct H2S synthase isoforms, including cystathionine gamma-lyase (CSE), cystathionine beta-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3MST). Although the regulatory roles of CSE and CBS in the cardiovascular system have been described, little is known about the role of 3MST. In this study, we investigated our hypothesis that 3MST regulates arterial blood pressure in mice. Methods and Results: Experiments were performed in male 3MST gene-deficient (3MST-/-) mice and wild-type (WT) littermates. Blood pressure in those mice was measured under conscious conditions by two different analytical methods (i.e., the tail-cuff and telemetry methods). Cardiac output and peripheral vascular resistance were assessed by hemodynamic measurements in the ascending aorta using a Doppler-type ultrasonic flowmeter under inhalation anesthesia with isoflurane. We confirmed deletion of the 3MST mRNA and protein in the 3MST-/- genotype by real-time PCR a...
Abstract P338: Adults With Obstructive Sleep Apnea Have Lower Adherence to Weight Loss Behaviors in a Behavioral Weight Loss Intervention
Authors: Christopher E Kline, Lora E Burke, Yaguang Zheng, Susan M Sereika, Christopher C Imes, Dara D Mendez, Bonny J Rockette-Wagner, Patrick J Strollo, Stephen L Rathbun, Eileen R Chasens
Journal: Circulation (2018)

Introduction: Obesity is a primary risk factor for obstructive sleep apnea (OSA), and weight loss is a common recommendation for adults with OSA. However, we previously found that adults with OSA lost less weight than those without OSA during a 12-month behavioral weight loss intervention. The potential mechanisms underlying the blunted weight loss among those with OSA are currently unclear; however, one potential explanation may be lower adherence to the intervention and its prescribed behaviors. Purpose: These analyses examined whether measures of adherence to a behavioral weight loss intervention differed between adults with and without OSA. Methods: The sample was comprised of adults who were overweight or obese (N=114; 50.4±10.5 y, body mass index [BMI]: 34.0±4.6 kg/m 2 ; 90.4% female, 82.5% white) who participated in a 12-mo behavioral weight loss intervention study. Participants wore a home sleep testing device (ResMed ApneaLink Plus) for one night at baseline (BL), 6 mo (6M), and 12 mo (12M). Those with an apnea-hypopnea index ≥ 5 were categorized as having OSA. Adherence to the intervention was assessed by: 1) attendance at group intervention sessions over 12 mo; 2) frequency of meeting daily caloric intake goals over 12 mo; 3) objectively-measured changes from BL in physical activity (steps/day, sedentary time, moderate-vigorous physical activity [MVPA]). Linear mixed models estimated the impact of OSA on these measures of intervention adherence following adjustment for sex, age, race, marital status, smoking status, and baseline BMI, while considering participant to be a random effect. Results: About half (52%) of the participants had OSA at BL, while 41 % had OSA at 6M. Attendance at group sessions did not differ between those with and without OSA over 12 mo (74.5 vs. 75.7%; P=.72). However, adults with OSA met their caloric intake goal less frequently than those without OSA (25.2 vs. 34.8%; P=.006), and adults with OSA increased their steps/day (+378.3 vs. 1060.1; P=.047) and MVPA min/day (+2.1 vs. +6.4; P=.056) less than those without OSA. Reductions in sedentary behavior (min/day) did not differ between those with and without OSA (-7.1 vs. -9.1; P=.81). Conclusions: These data suggest that the blunted weight loss observed among adults with OSA may be at least partially attributable to lower levels of adherence to prescribed goals for caloric intake and physical activity. Additional strategies (e.g., OSA screening and treatment referral, supplemental sessions on diet and MVPA) may be needed to achieve improved adherence to the lifestyle behaviors that lead to weight loss among adults with OSA.
Abstract 14209: Day-by-day Home Blood Pressure Variability is Associated With Cardiovascular Outcome Independent of Target Organ Damage: The J-HOP Study
Authors: Satoshi Hoshide, Yuichiro Yano, Hiroshi Kanegae, Kazuo Eguchi, Kazuomi Kario
Journal: Circulation (2017)

Introduction: Day-by-day home blood pressure (BP) variability has been reportedly associated with target organ damages and with incident cardiovascular disease (CVD). Whether the home BP variabilit...
GENOMIC PROFILING OF PRIMARY AND MATCHED RECURRENT GLIOBLASTOMA TUMOURS REVEALS THAT THE MUTATIONAL LANDSCAPE INCLUDES CLINICALLY ACTIONABLE VARIATION
Authors: Caitríona McInerney, Hayley Ellis, Daniel Schrinpf, Felix Sahm, Alexei Stupnikov, Marc Wadsley, Christopher Wragg, Paul White, Darragh McArt, Kathreena Kurian
Journal: Neuro-Oncology (2018)

Glioblastomas account for 90% of adult brain tumours and patient survival remains low. Understanding genetic alterations in subtypes could improve therapeutic intervention. Tumours from 41 patients, 8 with matched recurrent glioblastomas were genomically profiled for 130 neuro-oncology genes using a diagnostic panel. Single nucleotide variants(SNVs), copy number variations(CNVs) and potentially clinically actionable mutations were assessed for IDH-wildtype(n=38) and IDH-mutant glioblastomas(n=3). Mutational landscape revealed discrete differences and similarities between subtypes. TSC2, MSH6, TP53, CREBBP and IDH1 were co-mutated and putatively pathogenic in both subtypes, suggesting they are driver mutations. Recurrent tumours were not hypermutated and matched analysis revealed inter-tumour heterogeneity. IDH-wildtype: SNVs(145) impacted RTK/Ras/PI(3)K(82%), p53(63%), WNT(58%), SHH(13%), NOTCH(11%), Rb(5%) and G-protein(8%) pathways. SNV burden was a predictor of overall survival(P = 0.003) but no pathway was individually responsible. SNVs(40) in BRAF, DAXX, EGFR, FGFR2, JAK2, MYB, PIK3CA, PIK3R1, PTEN, ATM, BRCA1, CHEK2, PPM1D, PTCH1 and SMO were also putatively pathogenic. Many initial tumours had BRCA1/2(21;18%) variants, including confirmed somatic mutations in haemangioblastoma. Survival analysis suggested GNAS variation was prognostic(P<0.001). Recurrent tumours had fewer pathways(RTK/Ras/PI(3)K,p53,WNT,G-protein) impacted by genetic alterations. Possible resistance signatures included a private mutation in PIK3C2G and CNV gains(BRCA2,GNAS,EGFR) and losses(TERT,SMARCA4). Recurrent tumours(57%;4/7) harboured potentially actionable variation in PTEN, BRCA1, BRCA2, ATR and EGFR. Combination therapies with erlotinib, everolimus or dasatinib, olaparib, ATR inhibitors and EGFR-targeting antibodies, vaccines or TK inhibitors could provide therapeutic intervention. IDH-mutant: SNVs(15) impacted RTK/Ras/PI(3)K(66%), p53(100%) and WNT pathways(33%). SNVs were also putatively pathogenic in KLK1 exclusively in this subtype. The recurrent tumour had fewer pathways(p53,WNT,G-protein) impacted by genetic alterations and a private mutation in TCF4. Potentially actionable variation in ATR could be targeted using inhibitors. In conclusion, TCGA-GBM and GDC datasets corroborated results confirming the clinical significance of findings. Combination therapies targeting subtype clinically actionable mutations may hold the best promise for patient oncological management.
1,589家系における片頭痛の家族性凝集に寄与する一般的な変異負荷【JST・京大機械翻訳】
Authors: Gormley Padhraig, I Kurki Mitja, Hiekkala Marjo Eveliina, Veerapen Kumar, Haeppolae Paavo, A Mitchell Adele, Lal Dennis, Palta Priit, Surakka Ida, Kaunisto Mari Anneli, Haemaelaeinen Eija, Vepsaelaeinen Salli, Havanka Hannele, Harno Hanna, Ilmavirta Matti, Nissilae Markku, Saeko Erkki, Sumelahti Marja-Liisa, Liukkonen Jarmo, Sillanpaeae Matti, Metsaehonkala Liisa, Koskinen Seppo, Lehtimaeki Terho, Raitakari Olli, Maennikko Minna, Ran Caroline, Belin Andrea Carmine, Jousilahti Pekka, Anttila Verneri, Salomaa Veikko, Artto Ville, Faerkkilae Markus, Runz Heiko, J Daly Mark, M Neale Benjamin, Ripatti Samuli, Kallela Mikko, Wessman Maija, Palotie Aarno
Journal: Neuron (2018)