tbuckley/cabot-search huggingface dataset:
Life History Traits Impact the Nuclear Rate of Substitution but Not the Mitochondrial Rate in Isopods
Authors: Nathanaëlle Saclier, Clémentine M François, Lara Konecny-Dupré, Nicolas Lartillot, Laurent Guéguen, Laurent Duret, Florian Malard, Christophe J Douady, Tristan Lefébure
Journal: Molecular Biology and Evolution (2018)

The rate of molecular evolution varies widely among species. Life history traits (LHTs) have been proposed as a major driver of these variations. However, the relative contribution of each trait is poorly understood. Here, we test the influence of metabolic rate (MR), longevity, and generation time (GT) on the nuclear and mitochondrial synonymous substitution rates using a group of isopod species that have made multiple independent transitions to subterranean environments. Subterranean species have repeatedly evolved a lower MR, a longer lifespan and a longer GT. We assembled the nuclear transcriptomes and the mitochondrial genomes of 13 pairs of closely related isopods, each pair composed of one surface and one subterranean species. We found that subterranean species have a lower rate of nuclear synonymous substitution than surface species whereas the mitochondrial rate remained unchanged. We propose that this decoupling between nuclear and mitochondrial rates comes from different DNA replication processes in these two compartments. In isopods, the nuclear rate is probably tightly controlled by GT alone. In contrast, mitochondrial genomes appear to replicate and mutate at a rate independent of LHTs. These results are incongruent with previous studies, which were mostly devoted to vertebrates. We suggest that this incongruence can be explained by developmental differences between animal clades, with a quiescent period during female gametogenesis in mammals and birds which imposes a nuclear and mitochondrial rate coupling, as opposed to the continuous gametogenesis observed in most arthropods.
Abstract 16391: The Impact of Smoking on Clinical Outcomes and the Role of Double-Dose versus Standard-Dose Clopidogrel Among Individuals With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention - Insights From the CURRENT-OASIS 7 Trial
Authors: Matthias Bossard, Darar Al Khdair, David P Faxon, Christopher B Granger, Sanjit Jolly, Madhu Natarajan, Jean-Francois Tanguay, Gabriel Steg, Gilles Montalescot, Petr Widimsky, Kari Niemela, Peggy Gao, Keith A Fox, Salim Yusuf, Shamir R Mehta
Journal: Circulation (2016)

Introduction: Smoking is associated with worse outcomes after percutaneous coronary interventions (PCI). It remains unknown if double-dose clopidogrel mitigates this risk in smokers with acute coronary syndromes (ACS) and treated with PCI. Methods: We analyzed 17263 ACS patients with early PCI enrolled into the multinational CURRENT-OASIS 7 trial, which compared double-dose (600mg on day 1, 150mg on days 2-7 then 75mg daily) vs standard-dose (300mg on day 1 then 75mg daily) clopidogrel in ACS patients. Interaction tests between treatment allocation and smoking status (current vs non-smoker) were performed. The primary outcome (cardiovascular death, myocardial infarction, or stroke at 30 days) was evaluated in smokers and non-smokers. Results: Overall, 6394 patients (37%) were current smokers. Smokers were younger (55 vs 65 years), predominately male (84% vs 70%), and had more STEMIs (45% vs 32%), p for all <0.0001. The primary endpoint and major bleeding rates differed between smokers and non-smokers (int...
Abstract 15714: Aortic Stenosis Severity Grading: Resolving the Conundrum of Discordant Grading in a Very Large Cohort
Authors: Marie-Annick Clavel, Joseph Malouf, Hector I Michelena, Maurice Enriquez-Sarano
Journal: Circulation (2016)

Introduction: Aortic stenosis (AS) with discordant severity grading (low mean gradient [MG], tight indexed aortic valve area [AVAi] despite normal ejection fraction [EF]) is frequent and alternativ...
Reducing the impact of distance on hematopoietic cell therapy patients.
Authors: Diane Burns, Vicky Simanovski, Victoria Karuna Hagens, Garth Matheson
Journal: Journal of Clinical Oncology (2018)

74 Background: Hematopoietic Cell Therapy (HCT) patients experience unique travel challenges and high out-of-pocket costs due to the highly specialized care required. We conducted a mixed methods study to understand current patient support programs in Ontario and other jurisdictions and a cost analysis to inform the development of recommendations to reduce the impact of remoteness on HCT patients and caregivers. Methods: Qualitative information on patient transportation and accommodation supports was gathered through informal and structured input from fourteen Ontario Regional Cancer Program Directors, Hematologists, Patient and Family Advisory Council and Aboriginal Navigators. An environmental scan of medical travel assistance programs within Ontario and in other jurisdictions was performed. A scoping literature review was conducted of published studies focused on inequities in receipt of cancer care in countries with Universal Health care. HCT patient travel patterns to each of the transplant facilities in Ontario were obtained from analysis of Cancer Care Ontario data holdings. Results: We concluded that travel assistance for cancer patients in Ontario varies considerably across the province, and that Ontario lags behind other jurisdictions in Canada and internationally. The scoping literature review revealed that patients who live far from specialist centres, for some diseases, have later stage at diagnosis, less timely access to specialist care, poorer outcomes, lower patient experience scores, and make treatment decisions based on distance. From the analysis of travel patterns for HCT patients, provincially 4 – 79% of patients travel for HCT based on their location (see table below). Conclusions: This study highlights the need to better support HCT patients in Ontario. As a result, a proposal to support accommodations for HCT patients was developed and approved by the Ontario government for implementation in 2018/19.[Table: see text]
Comparing Adjuvant vs Early-Salvage Radiotherapy After Radical Prostatectomy—Reply
Authors: William L. Hwang, Andrzej Niemierko, Jason A. Efstathiou
Journal: JAMA Oncology (2018)

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Abstract 18789: BRCA2 is a Novel Regulator of Endothelial Cell Function and Apoptosis Following Hyperglycemia
Authors: Pratiek N Matkar, Mohammed Al-Omran, Subodh Verma, Howard Leong-Poi, Krishna K Singh
Journal: Circulation (2015)

Background: Germ-line mutations in the tumor suppressor gene BRCA2 (breast cancer 2, early onset) predispose carriers mostly to breast cancer, and BRCA2 mutation carriers also face a 2-fold increase in the risk of developing diabetes.Hyperglycemia, the hallmark of diabetes, is a major risk factor for endothelial dysfunction leading to vascular complications. The relationship linking role of BRCA2 in the development of diabetes and endothelial dysfunction remains mainly unexplored. Methods: To elucidate the role of BRCA2 in diabetes and endothelial apoptosis/dysfunction in vitro, we silenced BRCA2 in human umbilical vein endothelial cells (ECs) and evaluated the markers of EC function and apoptosis following hyperglycemia. Results: We first confirmed the basal expression of BRCA2 in ECs at transcript and protein levels by qPCR and immunoblotting, respectively. Interestingly, hyperglycemia significantly induced BRCA2 expression after 48 hours of treatment. We then silenced BRCA2 in ECs and confirmed successful silencing at transcript and protein levels. Hyperglycemia significantly increased the reactive oxygen species (ROS) production in the BRCA2-deficient ECs in comparison to control ECs. Increased ROS production was associated with exacerbated DNA-damage in BRCA2-silenced ECs as evidenced by increased expression and activation of DNA double-stranded breaks (DSBs) marker H2A.X and reduced RAD51-foci formation, an essential regulator of DSB repair. Increased DSBs were associated with significantly increased activation of p53. Elevated levels of DNA-damage and activated-p53 were further associated with significantly increased hyperglycemia-induced apoptosis in BRCA2-silenced ECs as measured by immunoblotting for cleaved-caspase-3, Bax and by TUNEL-staining.Key indices of endothelial function, including tube formation and NO production, were significantly reduced following hyperglycemia-treatment in BRCA2-deficient ECs. Conclusion: Our data for the first time, show an entirely novel role of BRCA2 as a regulator of endothelium in the setting of hyperglycemia, and provide important clues regarding the potential susceptibility of BRCA2 mutation carriers to hyperglycemia-induced cardiovascular complications.
Circular RNA hsa_circ_0008305 (circPTK2) inhibits TGF-β-induced epithelial-mesenchymal transition and metastasis by controlling TIF1γ in non-small cell lung cancer
Authors: Longqiang Wang, Xin Tong, Zhengyu Zhou, Shengjie Wang, Zhe Lei, Tianze Zhang, Zeyi Liu, Yuanyuan Zeng, Chang Li, Jun Zhao, Zhiyue Su, Cuijuan Zhang, Xia Liu, Guangquan Xu, Hong-Tao Zhang
Journal: Molecular Cancer (2018)

TGF-β promotes tumor invasion and metastasis through inducing epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC). Circular RNAs (circRNAs) are recognized as functional non-coding RNAs involved in human cancers. However, whether and how circRNAs contribute to TGF-β-induced EMT and metastasis in NSCLC remain vague. Here, we investigated the regulation and function of Circular RNA hsa_circ_0008305 (circPTK2) in TGF-β-induced EMT and tumor metastasis, as well as a link between circPTK2 and transcriptional intermediary factor 1 γ (TIF1γ) in NSCLC. Circular RNAs were determined by human circRNA Array analysis, real-time quantitative reverse transcriptase PCR and northern blot. Luciferase reporter, RNA-binding protein immunoprecipitation (RIP), RNA pull-down and fluorescence in situ hybridization (FISH) assays were employed to test the interaction between circPTK2 and miR-429/miR-200b-3p. Ectopic overexpression and siRNA-mediated knockdown of circPTK2, TGF-β-induced EMT, Transwell migration and invasion in vitro, and in vivo experiment of metastasis were used to evaluate the function of circPTK2. Transcription and prognosis analyses were done in public databases. CircPTK2 and TIF1γ were significantly down-regulated in NSCLC cells undergoing EMT induced by TGF-β. CircPTK2 overexpression augmented TIF1γ expression, inhibited TGF-β-induced EMT and NSCLC cell invasion, whereas circPTK2 knockdown had the opposite effects. CircPTK2 functions as a sponge of miR-429/miR-200b-3p, and miR-429/miR-200b-3p promote TGF-β-induced EMT and NSCLC cell invasion by targeting TIF1γ. CircPTK2 overexpression inhibited the invasion-promoting phenotype of endogenous miR-429/miR-200b-3p in NSCLC cells in response to TGF-β. CircPTK2 overexpression significantly decreased the expression of Snail, an important downstream transcriptional activator of TGF-β/Smad signaling. In an in vivo experiment of metastasis, circPTK2 overexpression suppressed NSCLC cell metastasis. Moreover, circPTK2 expression was dramatically down-regulated and positively correlated with TIF1γ expression in human NSCLC tissues. Especially, circPTK2 was significantly lower in metastatic NSCLC tissues than non-metastatic counterparts. Our findings show that circPTK2 (hsa_circ_0008305) inhibits TGF-β-induced EMT and metastasis by controlling TIF1γ in NSCLC, revealing a novel mechanism by which circRNA regulates TGF-β-induced EMT and tumor metastasis, and suggesting that circPTK2 overexpression could provide a therapeutic strategy for advanced NSCLC.
Abstract 18201: Effects of Epinephrine Administration on Cerebral Oxygenation During Cardiopulmonary Resuscitation
Authors: Charles D Deakin, Jie Yang, Robert Nguyen, Jiawen Zhu, Sam Parnia
Journal: Circulation (2015)

Introduction: Epinephrine has been presumed to improve cerebral oxygen delivery during CPR. Animal studies however have demonstrated that epinephrine-induced capillary vasoconstriction may actually decrease cerebral capillary blood flow and registry studies have suggested that adrenaline may actually worsen neurological outcome, The effects of epinephrine on cerebral oxygenation (rSO2) during CPR has not been documented in the clinical setting. Methods: Following ethics approval, rSO2 was measured continuously using cerebral oximetry in patients undergoing in-hospital cardiac arrest. During CPR, time event markers recorded the administration of 1mg epinephrine. rSO2% values were analysed for a 5 min window prior to and then 5 mins after the first epinephrine administration. Results: A total of 56 epinephrine doses were analyzed in 36 patients during CPR. Results are shown below. The average rSO2% in the 5 mins following epinephrine administration was 1.40% higher (95% CI=0.41-2.40%, P=0.0059) than in the 5 min period prior to epinephrine administration. After adjusting, for patients’ ROSC status, initial rhythm, hemoglobin and Charlson comorbidity index, this difference remained statistically significant (1.42% with 95% CI: 0.35-2.49%, P=0.009). There was no statistically significant difference in the gradient of rSO2% during the 5 min period immediately before (0.88) compared with immediately after (1.09) epinephrine administration. Conclusion: IV administration of 1mg epinephrine during CPR results in minimal changes to rSO2%. This is the first clinical data to demonstrate the effects of epinephrine on rSO2 and is consistent with animal studies. These results may go some way to explaining the limited effect of epinephrine on improving neurological recovery from cardiac arrest.
Prime and target immunization protects against liver-stage malaria in mice
Authors: Anita Gola, Daniel Silman, Adam A. Walters, Saranya Sridhar, Stefan Uderhardt, Ahmed M. Salman, Benedict R. Halbroth, Duncan Bellamy, Georgina Bowyer, Jonathan Powlson, Megan Baker, Navin Venkatraman, Ian Poulton, Eleanor Berrie, Rachel Roberts, Alison M. Lawrie, Brian Angus, Shahid M. Khan, Chris J. Janse, Katie J. Ewer, Ronald N. Germain, Alexandra J. Spencer, Adrian V. S. Hill
Journal: Science Translational Medicine (2018)

Despite recent advances in treatment and vector control, malaria is still a leading cause of death, emphasizing the need for an effective vaccine. The malaria life cycle can be subdivided into three stages: the invasion and growth within liver hepatocytes (pre-erythrocytic stage), the blood stage (erythrocytic stage), and, finally, the sexual stage (occurring within the mosquito vector). Antigen (Ag)-specific CD8+ T cells are effectively induced by heterologous prime-boost viral vector immunization and known to correlate with liver-stage protection. However, liver-stage malaria vaccines have struggled to generate and maintain the high numbers of Plasmodium-specific circulating T cells necessary to confer sterile protection. We describe an alternative "prime and target" vaccination strategy aimed specifically at inducing high numbers of tissue-resident memory T cells present in the liver at the time of hepatic infection. This approach bypasses the need for very high numbers of circulating T cells and markedly increases the efficacy of subunit immunization against liver-stage malaria with clinically relevant Ags and clinically tested viral vectors in murine challenge models. Translation to clinical use has begun, with encouraging results from a pilot safety and feasibility trial of intravenous chimpanzee adenovirus vaccination in humans. This work highlights the value of a prime-target approach for immunization against malaria and suggests that this strategy may represent a more general approach for prophylaxis or immunotherapy of other liver infections and diseases.
Sustaining operational excellence in the oncology intensive care unit.
Authors: Sharon Barniak, Jennifer Leahy, Jason Brash, Dana Wright, Joanne McGovern
Journal: Journal of Clinical Oncology (2018)

248 Background: In a high risk setting such as an oncology Intensive Care Unit (ICU), providing quality care and maintaining a culture of safety is vital to patient outcomes. Operational excellence built a foundational operating framework in the ICU, created process reliability and connected value streams through standardization, while increasing value to patients and employees. The purpose of this investigation was for the ICU and operational excellence teams to examine and eradicate defects. Five areas: Safety, Quality, Engagement, Innovation/Finance were determined to be most impactful and aligned with the unit’s key performance indicators. Metrics centered on patient safety and hospital-acquired complications (VTE, HAPU, VAE’s and CLABSI) became the focus of data collection and daily discussion. Methods: A multidisciplinary team designed and implemented a Lean Daily Management Board based on five predetermined metrics. The team met daily for a brief huddle to review a checklist confirming documentation adherence, patient outcomes, productivity, and employee engagement. Fallouts are addressed using a problem solving tool, displayed for awareness and corrective measures. Results: Initial data collected starting in January 2014, noted medication scan rate of 75%, fall rates at 1.32/1000 patient days, VTE 77%, HAPU 1/1000 patient days, VAE’s 1/1000 patient days, and CLABSI 0.3/1000 patient days. Continuing education and certifications among nurses were not defined at baseline. After implementation of the Lean Daily Management Board, 2015 data revealed an increase in medication scanning to 98.9% and 99.05% in 2017. Fall rates remain consistent at 1/1000 patient days and VTE prophylaxis climbed to 100% in 2015 and through 2017. HAPU’s decreased to 0.6/1000 patient days, and VAE’s were reduced to 1 in 2015, 0 in 2016 and 2017. CLABSI rates decreased to 0. Nursing certifications rose from 28% to 62% in 2017. Conclusions: Lean daily management empowered the staff to drive quality and safety in the ICU. Deficiencies fostered accountability and implementation of evidence-based patient care practices. Process improvement, positive patient outcomes, and increasing nurse engagement were achieved utilizing operational excellence.
What factors are associated with oncologist discussions of the costs of genomic testing and related treatment?
Authors: K Robin Yabroff, Jingxuan Zhao, Janet de Moor, Helmneh M. Sineshaw, Andrew N Freedman, Zhiyuan Zheng, Xuesong Han, Ashish Rai, Carrie N. Klabunde
Journal: Journal of Clinical Oncology (2018)

95 Background: Use of genomic testing to inform cancer treatment is an increasingly common practice in the US. Genomic testing and related treatment can be expensive and not all tests and treatments are covered by health insurance plans. Little is known about how often physicians discuss costs of genomic testing and related treatment with their patients, nor about the physician and/or practice factors associated with those discussions. Methods: We identified 1220 oncologists who participated in the National Survey of Precision Medicine in Cancer Treatment in 2017 and reported discussing genomic testing with their patients within 12 months. Weighted percentages were used to describe the frequency of cost discussions and multivariable polytomous logistic regression analyses were used to assess associations between physician and practice characteristics and the frequency of cost discussions. Results: Among oncologists who discussed genomic testing, 50.0% reported often discussing the likely costs of testing and related treatment; 26.3% reported sometimes discussing costs; and the remaining 23.7% reported never or rarely discussing costs. In adjusted analyses, oncologists who used next-generation sequencing gene panel tests were more likely to have cost discussions with their patients often (OR = 2.3; 95% CI: 1.6,3.2) or sometimes (OR = 1.8; 95% CI: 1.2, 2.7) compared to rarely or never. Other physician and practice factors associated with more frequent cost discussions were treating solid tumors only (rather than hematologic only or both hematologic and solid tumors), training in genomic testing, and working in practices with electronic medical record (EMR) alerts for genomic tests (all p &lt; 0.05). Conclusions: Physician and practice factors are associated with discussions of the costs of genomic testing and related treatments. As professional organizations increasingly recommend discussions of costs with cancer patients, consideration of modifiable physician and practice factors, such as training in genomic testing and use of EMR alerts, may help achieve these aims.
A filter-free blood-brain barrier model to quantitatively study transendothelial delivery of nanoparticles by fluorescence spectroscopy
Authors: Edwin De Jong, David S. Williams, Loai K.E.A. Abdelmohsen, Jan C.M. Van Hest, Inge S. Zuhorn
Journal: Journal of Controlled Release (2018)

The delivery of therapeutics to the brain is greatly hampered by the blood-brain barrier (BBB). The use of nanoparticles that can cross the BBB via the process of receptor-mediated transcytosis at blood-brain barrier endothelial cells seems a promising strategy to transport therapeutics into the brain. To screen for suitable nanocarriers, and to study the process of transcytosis, a cultured polarized monolayer of brain microvascular endothelial cells on an extracellular matrix-coated porous membrane filter is widely used as an in vitro BBB model. However, due to the adhesion of numerous types of nanoparticles to the membrane filter and within the filter pores, such a model is unsuitable for the quantification of transendothelial delivery of nanoparticles. Hence, there is a pressing need for a filter-free in vitro BBB model. Ideally, the model is inexpensive and easy to use, in order to allow for its wide use in nanomedicine and biology laboratories around the world. Here, we developed a filter-free in vitro BBB model that consists of a collagen gel covered with a monolayer of brain microvascular endothelial (hCMEC/D3) cells. The paracellular leakage of differently sized dextrans and the transcellular transport of LDL were measured to demonstrate the validity of the filter-free model. Finally, the transendothelial delivery of fluorescently-labelled PEG-P(CL-g-TMC) polymersomes that were functionalized with GM1-targeting peptides was assessed by fluorescence spectroscopy measurement of the luminal, cellular, and abluminal parts of the filter-free BBB model. Our data confirm the effectiveness of the G23 peptide to mediate transport of polymersomes across the BBB and the suitability of this filter-free in vitro model for quantification of nanoparticle transcytosis.