tbuckley/cabot-search huggingface dataset:
The 46th David A. Karnofsky Memorial Award Lecture: Oligometastasis—From Conception to Treatment
Authors: Ralph R. Weichselbaum
Journal: Journal of Clinical Oncology (2018)

Metastasis from most adult solid tumors generally has been considered to be widespread and incurable. Here, I present clinical and molecular data to support the hypothesis that some metastases are limited in number and pace and are curable with ablative therapies. I advance the hypothesis that immunotherapy combined with radiotherapy may be a general strategy to increase the number of patients with metastatic cancer amenable to cure. I further suggest that, in the context of ablative radiotherapy, the potential synergies between immunotherapy and radiotherapy are principally within the local tumor microenvironment and require treatment of all or most sites of metastatic disease. Improvements in the molecular staging of metastasis, immunotherapy strategies, and radiotherapy delivery are likely to improve outcomes for patients with metastatic cancer.
Hybrid epithelial/mesenchymal phenotypes promote metastasis and therapy resistance across carcinomas
Authors: Mohit Kumar Jolly, Jason A. Somarelli, Maya Sheth, Adrian Biddle, Satyendra C. Tripathi, Andrew J. Armstrong, Samir M. Hanash, Sharmila A. Bapat, Annapoorni Rangarajan, Herbert Levine
Journal: Pharmacology & Therapeutics (2018)
Loss of hepatocyte β-catenin protects mice from experimental porphyria-associated liver injury
Authors: Harvinder Saggi, Dhiman Maitra, An Jiang, Rong Zhang, Pengcheng Wang, Pamela Cornuet, Sucha Singh, Joseph Locker, Xiaochao Ma, Harry Dailey, Marc Abrams, M. Bishr Omary, Satdarshan P. Monga, Kari Nejak-Bowen
Journal: Journal of Hepatology (2018)
Abstract 15046: Lower Occurrence of Atrial Fibrillation on 48-Hour Holter in African-Americans Than Whites
Authors: Laura R Loehr, Elsayed Z Soliman, Anna K Poon, Eric A Whitsel, Alvaro Alonso, Lin Y Chen, Lisa Wruck, Thomas H Mosley, Lynne Wagenknecht, Gerardo Heiss
Journal: Circulation (2016)

Introduction: Studies of atrial fibrillation (AF) based on 12-lead ECGs, hospital claims, and medical records have found a lower AF prevalence, but counterintuitively an adverse cardiovascular dise...
A qualitative evaluation of barriers and facilitators to hepatocellular carcinoma care in North Carolina.
Authors: Emily Miller Ray, Randall Teal, Maihan Vu, Erin Coffman, Mary Elizabeth Bell, Jessica Carda-Auten, Hanna Kelly Sanoff
Journal: Journal of Clinical Oncology (2018)

72 Background: Hepatocellular carcinoma (HCC) is a common cause of cancer-related morbidity and mortality worldwide, yet many patients with HCC never receive cancer-directed therapy, for reasons that are not well documented. In order to tailor interventions to increase access to appropriate therapy, it is critical to understand the barriers and facilitators to access to care and receipt of treatment in HCC. Methods: This study includes 10 patients with HCC, within 6 months of diagnosis, identified through either the University of North Carolina (UNC) multidisciplinary HCC clinic or the UNC Rapid Case Ascertainment (RCA) Core which identifies cancer patients through registrars at local hospitals. Recruitment is ongoing with a target of 20 patients, expected to complete in July 2018. In-depth, semi-structured interviews were conducted by two qualitative researchers. Interviews were audiotaped, transcribed verbatim, and coded independently by two coders, using a common codebook. Coding discrepancies were reconciled by consensus. Results: Most participants described that they had been incidentally diagnosed with HCC during evaluation for another health issue. Key facilitators of care were: physician knowledge about HCC; clear, honest, and timely communication regarding test results, plan of care, and prognosis; access to transportation; strong social support; and financial support through friends, family, insurance, or charity care. Barriers to care included: lack of transportation; delays in receipt of information or in scheduling appointments; or poor communication with the medical team. Conclusions: This study identifies key facilitators and barriers to accessing care for HCC in North Carolina (NC). Further investigation of a broader sample of HCC patients is warranted, and the qualitative data from this study will be used to create a survey to be administered to all patients with incident HCC in NC. Ultimately, this information will serve as the basis for tailored interventions aimed at improving access to appropriate, life-prolonging care for patients with HCC.
Reduction of radiation safety incident reporting following implementation of the radiation oncology incident learning system (RO-ILS).
Authors: Carl Nelson, Lori Ann Roy, H. James Wallace
Journal: Journal of Clinical Oncology (2018)

236 Background: The Radiation Oncology Incident Learning System (RO-ILS) was initiated nationally June 2014 and is free, web-based, and currently used in more than 425 U.S. radiation facilities. RO-ILS was implemented at University of Vermont Medical Center (UVMMC) in October 2016 to facilitate safer, higher quality care. This implementation of RO-ILS was reviewed in order to determine whether the conversion to a new reporting system at UVMMC impacted radiation incident reporting at our institution. Methods: Radiation safety reporting at UVMMC included radiation incidents submitted by radiation therapists, dosimetrists and medical physics. Prior to RO-ILS, safety/quality incidents were submitted via a specified reporting form and submissions were reviewed monthly by the Radiation Oncology Quality Committee. After implementation of RO-ILS, radiation safety incidents were entered in RO-ILS and reviewed by the UVMMC RO-ILS administrator. Radiation incidents reported prior to October 2016 were entered into RO-ILS with the initial safety incident date. Results: Between April 2014 and May 2018, 136 radiation safety incidents were reported. There was a median of 7 incidents reported per quarter, decreasing from 8 to 6 per quarter after RO-ILS was implemented. Similarly, the average incidents per quarter was 8 and decreased from 8.9 to 6.7 per quarter after RO-ILS was implemented. Radiation incident types reported prior to RO-ILS were 78% “Near Miss” events but after RO-ILS decreased to 34%, while “Operational/Process Improvement” incidents increased from 17% pre RO-ILS to 49% post RO-ILS. The rate of radiation incidents reported per new patient starting radiation (the most frequent process associated with reported radiation incidents) was 0.59% and showed no significant trends or shifts before or after implementation of RO-ILS. Conclusions: Following implementation of RO-ILS at UVMMC, reported radiation incidents per quarter and the proportion of “Near Miss” events decreased, while the percentage of “Process Improvement” submissions increased. Further training and awareness of RO-ILS is planned with the goal of increasing staff participation and more robust reporting.
Abstract 18502: Mass and Genetic Polymorphism of Group IIA Secretory Phospholipase A2, Rosuvastatin Therapy, and Risk of Cardiovascular Events: An Analysis From the JUPITER Trial
Authors: Akintunde O Akinkuolie, Audrey Y Chu, Michael Caulfield, Jianying Mu, Hurt-Camejo Eva, Bo Ding, Fredrik Nyberg, Robert J Glynn, Paul M Ridker, Daniel I Chasman, Samia Mora
Journal: Circulation (2015)

Background: Although group IIA secretory phospholipase A2 (sPLA2-IIA) is well appraised for its involvement in atherosclerosis by modifying LDL, its role in managing CVD risk in a primary prevention setting with low LDL-C is unknown. Furthermore, the utility of sPLA2-IIA mass for assessing future CVD risk relative to statin therapy in a population free of CVD is unknown. Methods: We analyzed data from JUPITER (NCT00239681) in which participants with LDL cholesterol &lt;130 mg/dL and hsCRP≥2 mg/L were randomized to rosuvastatin 20mg/day vs placebo. sPLA2-IIA was quantified by sandwich-type ELISA (Cayman) in 11269 participants before and 1 year after randomization. Cox regression was used to examine the association of sPLA2-IIA with CVD. The impact of lifelong reduction in sPLA2-IIA on CVD risk was assessed by Mendelian randomization analysis in 6692 participants. Results: 313 first CVD events occurred during maximum follow-up of 5.0 (median, 1.9) years. Baseline sPLA2-IIA levels (median, 25th-75th percentile: 3.81, 2.49-6.03 ng/ml) were associated with increased risk of CVD: after adjusting for age, sex, race, treatment, smoking, family history, BMI, blood pressure, glucose, HDL-C, LDL-C, and triglycerides, HR (95%CI, p-value) per SD in sPLA2-IIA was 1.22 (1.08-1.38; p= 0.002). This association was slightly attenuated after additionally adjusting for hsCRP (1.18, 1.04-1.35; p=0.01) and there was no statistical heterogeneity by rosuvastatin therapy. In the rosuvastatin arm, on-treatment sPLA2-IIA levels trended towards an increased residual risk of CVD; HR 1.19 (0.97-1.45; p=0.09) in multivariable adjusted model, this was attenuated after additionally adjusting for hsCRP (HR: 1.08 95% CI 0.87-1.34; p=0.50). rs11573156C in PLA2G2A (encoding sPLA2-IIA) had the strongest effect on sPLA2-IIA levels, median (25th-75th percentile) for the CC and GG genotype were 2.79 (1.97-4.01 ng/mL) and 7.38 (5.38-10.19 ng/mL), respectively; but showed a non-significant association with CVD risk (HR: 1.11, 95% CI 0.89-1.38, p=0.34). Conclusion: While sPLA2-IIA may be a measurable biomarker to assess the prognostic impact of inflammation on baseline and residual CVD risk, this result do not support sPLA2-IIA as a viable pharmacological target for reducing CVD risk.
A Sticky Situation
Authors: Rahul Vedula, Anand Vaidya, Kristin Galetta, Jacob Laubach
Journal: New England Journal of Medicine (2018)

A 71-year-old man was brought to the hospital by his family, who reported that for the past week he had had severe, persistent confusion, visual hallucinations, and lethargy. One year before presentation, the patient had been cognitively and functionally normal, but during that year mild, progressive fatigue had developed and he had undergone functional decline. . . .
Impact of Oncology Care Model (OCM) on episode costs and performance revenues: Considerations for oncology practices.
Authors: Rahul Shenolikar, Kellie Ryan, Ben Shand, Richard Kane
Journal: Journal of Clinical Oncology (2018)

102 Background: The OCM is focused on providing high-quality, cost-efficient oncology care in Medicare. The episode payment approach introduces performance-based payments (PBPs) alongside traditional fee-for-service reimbursements. There is not yet a clear picture of the impact of the OCMs implementation on oncology practices. Methods: Using the Medicare Standard Analytic Files (5% sample) Part A and B claims, this study replicates the OCM benchmarking payment methodology. OCM episodes were triggered by qualifying Part B cancer therapies administered in an outpatient setting; all Part A and B costs that occurred in the following 6-months were included in episode costs. Claims for the baseline period (July 2012 – June 2015) were used to calculate actual episode costs, and predicted episode costs were used for benchmarks. Claims were also used to estimate OCM claims-based quality measure scores. Quality measure scores determined a practice’s performance multiplier, which is part of the PBP calculation. Results: The average ratio of OCM actual-to-predicted costs varied by tumor type. Of the 21 tumor types, 12 underpredicted costs and 7 overpredicted costs. The underpredicted tumors accounted for 43% of OCM episodes, and the overpredicted account for 51%. Central nervous system tumors and malignant melanoma were the most underpredicted cost ratios at 1.29 and 1.27, respectively. Claims-based quality measures also varied by tumor type. Aggregate scores for the three claims-based measures were &lt; 50% for 18 tumors (65% of episodes) and ≥50% for 3 tumors (35% of episodes). Practices treating patients with tumors that are underpredicted on cost and/or score low on quality measures will have greater difficulty achieving PBPs. Conclusions: This analysis suggests that the ability of a participant to succeed in the OCM will vary depending on the types of cancers treated at the practice. Both savings and quality, as measured by OCM, will vary across cancers. For some cancers, achieving an ‘average’ cost and an ‘average’ quality score could result in below-average performance for the practice. Understanding these dynamics are critical to understanding the potential impact of the OCM at the practice level.
Tight junction, mucin, and inflammasome‐related molecules are differentially expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice
Authors: Hern‐Tze Tina Tan, Stefanie Hagner, Fiorella Ruchti, Urszula Radzikowska, Ge Tan, Can Altunbulakli, Andrzej Eljaszewicz, Marcin Moniuszko, Mübeccel Akdis, Cezmi A. Akdis, Holger Garn, Milena Sokolowska
Journal: Allergy (2018)

Abstract Background Asthma is a chronic respiratory disease with marked clinical and pathophysiological heterogeneity. Specific pathways are thought to be involved in the pathomechanisms of different inflammatory phenotypes of asthma; however, direct in vivo comparison has not been performed. Methods We developed mouse models representing three different phenotypes of allergic airway inflammation—eosinophilic, mixed, and neutrophilic asthma via different methods of house dust mite sensitization and challenge. Transcriptomic analysis of the lungs, followed by the RT‐PCR, western blot, and confocal microscopy, was performed. Primary human bronchial epithelial cells cultured in air‐liquid interface were used to study the mechanisms revealed in the in vivo models. Results By whole‐genome transcriptome profiling of the lung, we found that airway tight junction (TJ), mucin, and inflammasome‐related genes are differentially expressed in these distinct phenotypes. Further analysis of proteins from these families revealed that Zo‐1 and Cldn18 were downregulated in all phenotypes, while increased Cldn4 expression was characteristic for neutrophilic airway inflammation. Mucins Clca1 (Gob5) and Muc5ac were upregulated in eosinophilic and even more in neutrophilic phenotype. Increased expression of inflammasome‐related molecules such as Nlrp3, Nlrc4, Casp‐1, and IL‐1β was characteristic for neutrophilic asthma. In addition, we showed that inflammasome/Th17/neutrophilic axis cytokine—IL‐1β—may transiently impair epithelial barrier function, while IL‐1β and IL‐17 increase mucin expressions in primary human bronchial epithelial cells. Conclusion Our findings suggest that differential expression of TJ, mucin, and inflammasome‐related molecules in distinct inflammatory phenotypes of asthma may be linked to pathophysiology and might reflect the differences observed in the clinic.
Preterm Delivery and Maternal Cardiovascular Disease in Young and Middle-Aged Adult Women
Authors: Lauren J. Tanz, Jennifer J. Stuart, Paige L. Williams, Eric B. Rimm, Stacey A. Missmer, Kathryn M. Rexrode, Kenneth J. Mukamal, Janet W. Rich-Edwards
Journal: Circulation (2017)

Background: Preterm delivery has been shown to be associated with increased risk of cardiovascular disease (CVD), but it is unknown whether this risk remains after adjustment for prepregnancy lifestyle and CVD risk factors. Methods: We examined the association between history of having delivered an infant preterm (&lt;37 weeks) and CVD in 70 182 parous women in the Nurses’ Health Study II. Multivariable Cox proportional-hazards models were used to estimate hazards ratios (HRs) and 95% confidence intervals (CIs) for CVD events (myocardial infarction and stroke, n=949); we also adjusted for intermediates to determine the proportion of the association between preterm and CVD accounted for by postpartum development of CVD risk factors. Results: After adjusting for age, race, parental education, and prepregnancy lifestyle and CVD risk factors, preterm delivery in the first pregnancy was associated with an increased risk of CVD (HR, 1.42; 95% CI, 1.16–1.72) in comparison with women with a term delivery (≥37 weeks) in the first pregnancy. When preterm delivery was split into moderate preterm (≥32 to &lt;37 weeks) and very preterm (&lt;32 weeks), the HRs were 1.22 (95% CI, 0.96–1.54) and 2.01 (95% CI, 1.47–2.75), respectively. The increased rate of CVD in the very preterm group persisted even among women whose first pregnancy was not complicated by hypertensive disorders of pregnancy (HR, 2.01; 95% CI, 1.38–2.93). In comparison with women with at least 2 pregnancies, all of which were delivered at term, women with a preterm first birth and at least 1 later preterm birth had a HR of CVD of 1.65 (95% CI, 1.20–2.28). The association between moderate preterm first birth and CVD was accounted for in part by the development of postpartum chronic hypertension, hypercholesterolemia, type 2 diabetes mellitus, and changes in body mass index (proportion accounted for, 14.5%; 95% CI, 4.0–41.1), as was the very-preterm-CVD relationship (13.1%; 95% CI, 9.0–18.7). Conclusions: Preterm delivery is independently predictive of CVD and may be useful for CVD prevention efforts. Because only a modest proportion of the preterm-CVD association was accounted for by development of conventional CVD risk factors, further research may identify additional pathways.
Developing a standard approach to immune checkpoint inhibitor toxicity management in Ontario.
Authors: Andrea Crespo, Lourdes Abella, Tara D. Baetz, Daniela Gallo-Hershberg, Nita Lakhani, Natasha B. Leighl, Mark Pasetka, Lesley Seymour, Kathy Vu, Leta Marie Forbes
Journal: Journal of Clinical Oncology (2018)

255 Background: The use of immune checkpoint inhibitor medications (ICIs) in the province of Ontario, Canada has increased in volume by almost 4 fold between 2015/16 to 2017/18 and has expanded from use primarily in melanoma to lung, genitourinary, and other cancers. Lack of widespread clinical experience with ICIs and provincial variation in the management of the potentially life-threatening immune-related adverse effects (irAEs) was identified as a safety and quality gap. Cancer Care Ontario (CCO) set out to develop user-friendly health care provider and patient resources to facilitate a standard approach to ICI toxicity management in Ontario. Methods: A multidisciplinary working group of oncology clinicians with ICI experience reviewed available literature and current approaches to ICI toxicity management. An iterative consensus-building process was used to develop a practical guideline. This was circulated to an external expert review panel for content validity. Complementary patient/caregiver information was created based on best practices in health literacy and input from patient and family advisors. All resources were made publicly available via the CCO website and disseminated broadly to relevant stakeholders. Results: A user-friendly clinical practice guideline was created. It contains a description of irAEs associated with ICIs, guidance on the general management of irAEs, detailed algorithms describing the assessment and management of ten specific irAEs, and general considerations for patients on ICIs. A toolkit was developed with direct links to the algorithms, a customizable wallet card, a “Dear Healthcare Professional” letter template, and a patient information sheet. The guideline and toolkit webpages were accessed over 1500 times in the first month, suggesting that broad dissemination has been successful. Informal reports of guideline implementation were received from several Ontario hospitals. Conclusions: Careful analysis of the available literature and application of oncology professionals’ expertise resulted in evidence-informed, consensus-based practical resources to help facilitate safe, standardized ICI toxicity management across the Ontario health care system.
DeepNitro: Prediction of Protein Nitration and Nitrosylation Sites by Deep Learning
Authors: Yubin Xie, Xiaotong Luo, Yupeng Li, Li Chen, Wenbin Ma, Junjiu Huang, Jun Cui, Yong Zhao, Yu Xue, Zhixiang Zuo, Jian Ren
Journal: Genomics Proteomics & Bioinformatics (2018)

Abstract Protein nitration and nitrosylation are essential post-translational modifications (PTMs) involved in many fundamental cellular processes. Recent studies have revealed that excessive levels of nitration and nitrosylation in some critical proteins are linked to numerous chronic diseases. Therefore, the identification of substrates that undergo such modifications in a site-specific manner is an important research topic in the community and will provide candidates for targeted therapy. In this study, we aimed to develop a computational tool for predicting nitration and nitrosylation sites in proteins. We first constructed four types of encoding features, including positional amino acid distributions, sequence contextual dependencies, physicochemical properties, and position-specific scoring features, to represent the modified residues. Based on these encoding features, we established a predictor called DeepNitro using deep learning methods for predicting protein nitration and nitrosylation. Using n-fold cross-validation, our evaluation shows great AUC values for DeepNitro, 0.65 for tyrosine nitration, 0.80 for tryptophan nitration, and 0.70 for cysteine nitrosylation, respectively, demonstrating the robustness and reliability of our tool. Also, when tested in the independent dataset, DeepNitro is substantially superior to other similar tools with a 7%−42% improvement in the prediction performance. Taken together, the application of deep learning method and novel encoding schemes, especially the position-specific scoring feature, greatly improves the accuracy of nitration and nitrosylation site prediction and may facilitate the prediction of other PTM sites. DeepNitro is implemented in JAVA and PHP and is freely available for academic research at http://deepnitro.renlab.org.
Bi<sub>2</sub>S<sub>3</sub>–Tween 20 Nanodots Loading PI3K Inhibitor, LY294002, for Mild Photothermal Therapy of LoVo Cells In Vitro and In Vivo
Authors: Li Song, Xinghua Dong, Shuang Zhu, Chunfang Zhang, Wenyan Yin, Xiao Zhang, Xiangfeng Liu, Zhanjun Gu
Journal: Advanced Healthcare Materials (2018)

Abstract Although various types of photothermal agents are developed for photothermal cancer therapy, relatively few photothermal agents exhibit high tumor inhibition rate under relatively mild conditions. Herein, a multifunctional Bi 2 S 3 –Tween 20 nanoplatform loaded with PI3K inhibitor LY294002 is designed as a novel photothermal agent for inhibitor and photothermal synergistic therapy of tumors under mild photothermal therapy conditions. The LY294002 of PI3K inhibitor, after being loaded by Bi 2 S 3 –Tween 20 nanodots, exhibits greatly increased drug utilization and reduced side effects on normal tissues. In vivo, Bi 2 S 3 –Tween 20@LY294002 upon near‐infrared 808 nm laser irradiation shows potent antitumor activity under relatively mild conditions (power density: 0.6 W cm −2 ). Moreover, the mechanism studies also demonstrate that Bi 2 S 3 –Tween 20@LY294002 potently kills LoVo cancer cells under low‐power near‐infrared light irradiation, by downregulating the expression of heat shock protein 70 (HSP70) so as to increase the sensitivity of tumor cell hyperthermia and activating BAX/BAK‐regulated mitochondrial apoptosis pathway. The results demonstrate that the newly synthesized multifunctional nanoplatform paves a new avenue for accurate therapy of photothermal‐resistant cancer.