tbuckley/cabot-search huggingface dataset:
Abstract LB-227: Combined treatment with radiation and epigenetic regulation improve to targeting cancer stem cells in pancreatic cancer
Authors: Joo Mi Yi, Hyun-Mi Kwon, Eun-Jin Kang, Kwangmo Yang
Journal: Cancer Research (2017)

Abstract Increasing evidences suggests that various cancer types contain a population of cells that display stem cell properties. These cells are called cancer stem cells (CSCs). They are virtually resistant to radiation, and may contribute to treatment resistance and recurrence. Therefore, therapies specifically targeting CSCs will likely be needed for complete tumor eradication. Exposure of cells to ionizing radiation (IR) induces, not only, activation of multiple signaling pathways that play critical roles in cell fate determination, but also alteration of molecular pathways involved in cell death or survival. Recently, DNA methylation has been established as a critical epigenetic process involved in the regulation of gene expression in cancer cells, suggesting that DNA methylation inhibition may be an effective cancer treatment strategy. We therefore investigated the combination effect of a DNA methyltransferase inhibitor, 5-aza-2’-deoxycytidine (5-aza-dC), and radiation treatment in pancreatic cancer. Pancreatic cancer cell lines were initially tested for radiation sensitivity by ionizing radiation (IR) in vitro and were treated with 5-aza-dC. The effects of 5-aza-dC along with irradiation on cell growth, cell cycle distribution, apoptosis, and apoptosis-related gene expression were examined. Combination irradiation treatment with 5-aza-dC significantly decreased growth activity compared with irradiation or 5-aza-dC treatment alone. To understand whether combination treatment can target to pancreatic cancer stem cells, we observed that combination treatment can significantly reduce Oct4, Nanog, Sox2, CD133, and CD44 levels which are key factors for self-renewal pathway or cancer stem cell surface markers in pancreatic cancer cells, respectively. Using transcriptome analysis, OCT4 target genes showed differential expression pattern between irradiation or 5-aza-dC treatment alone and combination treatment. In addition, sphere forming assay supports these data in vitro and in vivo, describing that combination effect of IR and 5-aza-dC can reduce significantly sphere forming ability and proportion of side population (putative CSCs) significantly decreased in combination treated cells compared to control or single treatment. Therefore combined treatment of IR and 5-aza-dC is capable of eliminating pancreatic CSCs. Further investigation of this useful approach may lead to the development of a novel intervention for the cancer therapeutic strategy. Citation Format: Joo Mi Yi, Hyun-Mi Kwon, Eun-Jin Kang, Kwangmo Yang. Combined treatment with radiation and epigenetic regulation improve to targeting cancer stem cells in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-227. doi:10.1158/1538-7445.AM2017-LB-227
Emicizumab Prophylaxis in Hemophilia A with Inhibitors
Authors: Johannes Oldenburg, Johnny N. Mahlangu, Benjamin Kim, Christophe Schmitt, Michael U. Callaghan, Guy Young, Elena Santagostino, Rebecca Kruse-Jarres, Claude Negrier, Craig Kessler, Nancy Valente, Elina Asikanius, Gallia G. Levy, Jerzy Windyga, Midori Shima
Journal: New England Journal of Medicine (2017)

Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors.
Sacroiliac radiographic progression in recent onset axial spondyloarthritis: the 5-year data of the DESIR cohort
Authors: Maxime Dougados, Alexandre Sepriano, Anna Molto, Miranda van Lunteren, Sofia Ramiro, Manouk de Hooge, Rosaline van den Berg, Victoria Navarro Compan, Christophe Demattei, Robert Landewé, Désirée van der Heijde
Journal: Annals of the Rheumatic Diseases (2017)

Objective To estimate sacroiliac joint radiographic (X-SIJ) progression in patients with axial spondyloarthritis (axSpA) and to evaluate the effects of inflammation on MRI (MRI-SIJ) on X-SIJ progression. Methods X-SIJ and MRI-SIJ at baseline and after 2 and 5 years in patients with recent onset axSpA from the DESIR cohort were scored by three central readers. Progression was defined as (1) the shift from non-radiographic (nr) to radiographic (r) sacroiliitis (by modified New York (mNY) criteria) or alternative criteria, (2) a change of at least one grade or (3) a change of at least one grade but ignoring a change from grade 0 to 1. The effects of baseline inflammation on MRI-SIJ on 5-year X-SIJ damage (mNY) were tested by generalised estimating equations. Results In 416 patients with pairs of baseline and 5-year X-SIJ present, net progression occurred in 5.1% (1), 13.0% (2) and 10.3% (3) respectively, regarding a shift from nr-axSpA to r-axSpA (1), a change of at least one grade (2) or a change of at least one grade but ignoring a change from grade 0 to 1 (3). Baseline MRI-SIJ predicted structural damage after 5 years in human leukocyte antigen-B27 (HLA-B27) positive (OR 5.39 (95% CI 3.25 to 8.94)) and in HLA-B27 negative (OR 2.16 (95% CI 1.04 to 4.51)) patients. Conclusions Five-year progression of X-SIJ damage in patients with recent onset axSpA is limited but present beyond measurement error. Baseline MRI-SIJ inflammation drives 5-year radiographic changes.
THE EFFECT OF AN IRONMAN TRIATHLON ON ACHILLES TENDON STRUCTURE:A CASE REPORT
Authors: Seth O'Neill, Barry Simon
Journal: British Journal of Sports Medicine (2017)

Background Transient changes in Achilles tendon structure are known to occur post exercise, it is unknown whether completing an ironman affects tendon structure. Objective Assess the effect of an ironman on Achilles tendon structure. Design Case study of a subject completing an ironman triathlon. The study utilised Ultrasound tissue characterization (UTC) scanning to quantify tendon structure pre and post activity. The UTC scan was completed 1 day prior to the Ironman and on day 2 by one examiner. The quantification of the UTC scan was completed by two experienced users who were blinded to the scan order. Setting UK University. Patients (or Participants) 49 year old male subject. Interventions (or Assessment of Risk Factors) An ironman triathlon involves 3.86 km swim, 180.25 km bicycle ride and a marathon (42.20 km). Main Outcome Measurements UTC quantification of Achilles tendon using percentage volume of each of the four echo types, tendon volume and mean cross-sectional area (mCSA). Results Data is presented as the mean of the two examiners results. The mCSA increased by 10.7 mm 2 and 5.4 mm 2 on the right and left Achilles respectively. Tendon volume of the right Achilles tendon increased by 321.8 mm 3 and whilst the left increased by 162.9 mm 3 . Data for the right and left leg were combined with the mean change in percentage of the different echo types presented post intervention. Echo type I increased by 1.7%, echo type II increased by 0.6% whilst echo type III and IV reduced by 1.7% and 0.6% respectively. Conclusions The results indicate a change in Achilles tendon volume, mCSA and percentage of the different echo types post ironman. This preliminary study suggests that further work is required to assess alterations in Achilles tendon post ironman, specifically this work should determine if this change is observable in a larger group of athletes and whether this change is transient in nature.
Association of Variation in Contrast Volume With Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Intervention
Authors: Amit P. Amin, Richard G. Bach, Mary L. Caruso, Kevin F. Kennedy, John A. Spertus
Journal: JAMA Cardiology (2017)

<h3>Importance</h3> Acute kidney injury (AKI) after percutaneous coronary intervention (PCI) is common, morbid, and costly; increases patients’ mortality risk; and can be mitigated by limiting contrast use. <h3>Objective</h3> To examine the national variation in AKI incidence and contrast use among US physicians and the variation’s association with patients’ risk of developing AKI after PCI. <h3>Design, Setting, and Participants</h3> This cross-sectional study used the American College of Cardiology National Cardiovascular Data Registry (NCDR) CathPCI Registry to identify in-hospital care for PCI in the United States. Participants included 1 349 612 patients who underwent PCI performed by 5973 physicians in 1338 hospitals between June 1, 2009, and June 30, 2012. Data analysis was performed from July 1, 2014, to August 31, 2016. <h3>Main Outcomes and Measures</h3> The primary outcome was AKI, defined according to the Acute Kidney Injury Network criteria as an absolute increase of 0.3 mg/dL or more or a relative increase of 50% or more from preprocedural to peak creatinine. A secondary outcome was the mean contrast volume as reported in the NCDR CathPCI Registry. Physicians who performed more than 50 PCIs per year were the main exposure variable of interest. Hierarchical regression with adjustment for patients’ AKI risk was used to identify the variation in AKI rates, the variation in contrast use, and the association of contrast volume with patients’ predicted AKI risk. <h3>Results</h3> Of the 1 349 612 patients who underwent PCI, the mean (SD) age was 64.9 (12.2) years, 908 318 (67.3%) were men, and 441 294 (32.7%) were women. Acute kidney injury occurred in 94 584 patients (7%). A large variation in AKI rates was observed among individual physicians ranging from 0% to 30% (unadjusted), with a mean adjusted 43% excess likelihood of AKI (median odds ratio, 1.43; 95% CI, 1.41-1.44) for statistically identical patients presenting to 2 random physicians. A large variation in physicians’ mean contrast volume, ranging from 79 mL to 487 mL with an intraclass correlation coefficient of 0.23 (interquartile range, 0.21-0.25), was also observed, implying a 23% variation in contrast volume among physicians after adjustment. There was minimal correlation between contrast use and patients’ AKI risk (<i>r</i> = −0.054). Sensitivity analysis after excluding complex cases showed that the physician variation in AKI remained unchanged. <h3>Conclusions and Relevance</h3> Acute kidney injury rates vary greatly among physicians, who also vary markedly in their use of contrast and do not use substantially less contrast in patients with higher risk for AKI. These findings suggest an important opportunity to reduce AKI by reducing the variation in contrast volumes across physicians and lowering its use in higher-risk patients.
A Research Agenda for Communication Between Health Care Professionals and Patients Living With Serious Illness
Authors: James A. Tulsky, Mary Catherine Beach, Phyllis N. Butow, Susan E. Hickman, Jennifer W. Mack, R. Sean Morrison, Richard L. Street, Rebecca L. Sudore, Douglas B. White, Kathryn I. Pollak
Journal: JAMA Internal Medicine (2017)

Poor communication by health care professionals contributes to physical and psychological suffering in patients living with serious illness. Patients may not fully understand their illness, prognosis, and treatment options or may not receive medical care consistent with their goals. Despite considerable research exploring the role of communication in this setting, many questions remain, and a clear agenda for communication research is lacking.Through a consensus conference and subsequent activities, we reviewed the state of the science, identified key evidence gaps in understanding the impact of communication on patient outcomes, and created an agenda for future research. We considered 7 broad topics: shared decision making, advance care planning, communication training, measuring communication, communication about prognosis, emotion and serious illness communication, and cultural issues. We identified 5 areas in which further research could substantially move the field forward and help enhance patient care: measurement and methodology, including how to determine communication quality; mechanisms of communication, such as identifying the specific clinician behaviors that patients experience as both honest and compassionate, or the role of bias in the clinical encounter; alternative approaches to advance care planning that focus on the quality of serious illness communication and not simply completion of forms; teaching and disseminating communication skills; and approaches, such as economic incentives and other clinician motivators, to change communication behavior.Our findings highlight the urgent need to improve quality of communication between health care professionals and patients living with serious illness through a broad range of research that covers communication skills, tools, patient education, and models of care.
Genes associated with serum estrone, estrone conjugates, and androstenedione concentrations in postmenopausal women with estrogen receptor-positive breast cancer.
Authors: Tanda M. Dudenkov, James N. Ingle, Aman Buzdar, Mark E. Robson, Michiaki Kubo, Anthony Batzler, Gregory D. Jenkins, Tracy L. Pietrzak, Erin E. Carlson, Brooke L. Fridley, Matthew P. Goetz, Donald W. Northfelt, Edith A. Perez, Clark V. Williard, Krishna R. Kalari, Yusuke Nakamura, Liewei Wang, Richard M. Weinshilboum
Journal: Journal of Clinical Oncology (2014)

593 Background: Estrone (E1), the predominant estrogen in postmenopausal women, is synthesized from androstenedione (A) in the ovaries and adipocytes and can be converted to conjugates (E1Cs). Both circulating E1 and E1Cs are known risk factors for breast cancer; and E1C is present at concentrations up to 10 fold higher in breast cancer tissue than in serum. However, little is known regarding the genes that regulate serum A, E1 or E1Cs concentrations. Methods: In a cohort of 776 postmenopausal women with estrogen receptor positive breast cancer, we used a genome-wide association study (GWAS) to identify SNP signals associated with these concentrations. Serum levels of each hormone were measured using GC-MS/MS, and patients were genotyped at ~600,000 SNPs and another 7 million were imputed. Using linear regression models with additive genetic effects, a GWAS was conducted for each hormone level separately as well as the ratio of E1/A, E1Cs/A and E1Cs/E1. SNP effects were adjusted for BMI, population stratification and other relevant variables. Results: Multiple SNPs in SLCO1B1, a gene that encodes a transporter, were genome-wide significantly associated with E1C levels, E1Cs/E1 and E1Cs/A ratios. The variant allele of the top genotyped SNP rs4149056 (p value = 3.74x10-11) is a missense mutation that has an established association with statin-induced myopathy and sex hormone binding globulin levels. SNPs in EMR2 (p=1.39x10-07), ELMO1 (p=3.19x10-07), LDB3 (p=5.67x10-07) and CYP11B1/2 (p=6.65x10-07) genes were associated with androstenedione levels. SNPs downstream of SYNJ2NP2/ARIP2 and upstream of the testis-specific gene ADAM21 (p=1.48x10-06) were associated with E1 levels, with a non-synonymous SNP in ADAM21 showing suggestive association (rs45480894, p=2.58x10-06). The ratio of E1/A was associated with a missense SNP in ANO7 (rs74804606, p=5.69x10-07). Conclusions: These results, particularly those for SLCO1B1 that encodes a liver transporter of E1C, point towards mechanisms that may explain variation in these hormones that are associated with increased risk of breast cancer.
Risk of hospitalization with neurodegenerative disease after moderate-to-severe traumatic brain injury in the working-age population: A retrospective cohort study using the Finnish national health registries
Authors: Rahul Raj, Jaakko Kaprio, Miikka Korja, Era D. Mikkonen, Pekka Jousilahti, Jari Siironen
Journal: PLoS Medicine (2017)

Previous epidemiological studies suggest that working-aged persons with a history of moderate-to-severe traumatic brain injury (TBI) may have an increased risk for developing neurodegenerative disease (NDD) while persons with a history of mild TBI do not. In this comprehensive nationwide study in Finland, we assessed the risk of NDD and history of moderate-to-severe TBI in the working-age population.We performed a population-based follow-up study using the Finnish Care Register for Health Care to identify all persons between the ages of 18 and 65 years hospitalized during 1987-2014 due to TBI who did not have a baseline NDD diagnosis. We compared the risk of hospitalization with NDD between persons hospitalized due to moderate-to-severe TBI (intracranial lesions) and persons hospitalized due to mild TBI (no intracranial lesions). Follow-up NDD diagnoses were recorded from 1 year following the TBI to the end of 2014. NDD diagnoses included dementia, Parkinson disease, and amyotrophic lateral sclerosis. We used a Cox proportional hazards model, adjusting for age, sex, education, and socioeconomic group, to assess the association between TBI and NDD. In total, 19,936 and 20,703 persons with a history of moderate-to-severe TBI and mild TBI, respectively, were included. The overall time at risk was 453,079 person-years (median 10 years per person). In total, 3.5% (N = 696) persons in the moderate-to-severe TBI group developed NDD compared to 1.6% (N = 326) in the mild TBI group. After adjusting for covariates, moderate-to-severe TBI was associated with an increased risk for NDD, with a hazard ratio (HR) of 1.8 (95% CI 1.6-2.1) compared to mild TBI. Of the NDD subtypes, only moderate-to-severe TBI was associated with an increased risk for dementia (HR 1.9, 95% CI 1.6-2.2). Yet, this large-scale epidemiological study does not prove that there is a causal relationship between moderate-to-severe TBI and NDD. Further, the Care Register for Health Care includes only hospitalized persons; thus, patients diagnosed with NDD in the outpatient setting may have been missed. Additional limitations include the potential for miscoding and unmeasured confounds.In working-aged persons, a history of moderate-to-severe TBI is associated with an increased risk for future dementia but not for Parkinson disease or amyotrophic lateral sclerosis.
Association of Playing High School Football With Cognition and Mental Health Later in Life
Authors: Sameer K. Deshpande, Raiden B. Hasegawa, Amanda R. Rabinowitz, John Whyte, Carol L. Roan, Andrew Tabatabaei, Michael Baiocchi, Jason H. Karlawish, Christina L. Master, Dylan S. Small
Journal: JAMA Neurology (2017)

American football is the largest participation sport in US high schools and is a leading cause of concussion among adolescents. Little is known about the long-term cognitive and mental health consequences of exposure to football-related head trauma at the high school level.To estimate the association of playing high school football with cognitive impairment and depression at 65 years of age.A representative sample of male high school students who graduated from high school in Wisconsin in 1957 was studied. In this cohort study using data from the Wisconsin Longitudinal Study, football players were matched between March 1 and July 1, 2017, with controls along several baseline covariates such as adolescent IQ, family background, and educational level. For robustness, 3 versions of the control condition were considered: all controls, those who played a noncollision sport, and those who did not play any sport.Athletic participation in high school football.A composite cognition measure of verbal fluency and memory and attention constructed from results of cognitive assessments administered at 65 years of age. A modified Center for Epidemiological Studies' Depression Scale score was used to measure depression. Secondary outcomes include results of individual cognitive tests, anger, anxiety, hostility, and heavy use of alcohol.Among the 3904 men (mean [SD] age, 64.4 [0.8] years at time of primary outcome measurement) in the study, after matching and model-based covariate adjustment, compared with each control condition, there was no statistically significant harmful association of playing football with a reduced composite cognition score (-0.04 reduction in cognition vs all controls; 97.5% CI, -0.14 to 0.05) or an increased modified Center for Epidemiological Studies' Depression Scale depression score (-1.75 reduction vs all controls; 97.5% CI, -3.24 to -0.26). After adjustment for multiple testing, playing football did not have a significant adverse association with any of the secondary outcomes, such as the likelihood of heavy alcohol use at 65 years of age (odds ratio, 0.68; 95% CI, 0.32-1.43).Cognitive and depression outcomes later in life were found to be similar for high school football players and their nonplaying counterparts from mid-1950s in Wisconsin. The risks of playing football today might be different than in the 1950s, but for current athletes, this study provides information on the risk of playing sports today that have a similar risk of head trauma as high school football played in the 1950s.
CCAT1 and CCAT2 long noncoding RNAs, located within the 8q.24.21 ‘gene desert’, serve as important prognostic biomarkers in colorectal cancer
Authors: T. Ozawa, T. Matsuyama, Y. Toiyama, N. Takahashi, T. Ishikawa, H. Uetake, Y. Yamada, M. Kusunoki, G. Calin, A. Goel
Journal: Annals of Oncology (2017)

Background8q24.21 is a frequently amplified genomic region in colorectal cancer (CRC). This region is often referred to as a 'gene desert' due to lack of any important protein-coding genes, highlighting the potential role of noncoding RNAs, including long noncoding RNAs (lncRNAs) located around the proto-oncogeneMYC. In this study, we have firstly evaluated the clinical significance of altered expression of lncRNAs mapped to this genomic locus in CRC.Patients and methodsA total of 300 tissues, including 280 CRC and 20 adjacent normal mucosa specimens were evaluated for the expression of 12 lncRNAs using qRT-PCR assays. We analyzed the associations between lncRNA expression and various clinicopathological features, as well as with recurrence free survival (RFS) and overall survival (OS) in two independent cohorts.ResultsThe expression of CCAT1, CCAT1-L, CCAT2, PVT1, and CASC19 were elevated in cancer tissues (P=0.039, <0.001, 0.018, <0.001, 0.002, respectively). Among these, high expression of CCAT1 and CCAT2 was significantly associated with poor RFS (P=0.049 and 0.022, respectively) and OS (P=0.028 and 0.015, respectively). These results were validated in an independent patient cohort, in which combined expression of CCAT1 and CCAT2 expression was significantly associated with a poor RFS (HR:2.60, 95% confidence interval [CI]: 1.04–6.06,P=0.042) and a poor OS (HR:8.38, 95%CI: 2.68–37.0,P<0.001). We established a RFS prediction model which revealed that combined expression of CCAT1, CCAT2, and carcinoembryonic antigen was a significant determinant for efficiently predicting RFS in stage II (P=0.034) and stage III (P=0.001) CRC patients.ConclusionsSeveral lncRNAs located in 8q24.21 locus are highly over-expressed in CRC. High expression of CCAT1 and CCAT2 significantly associates with poor RFS and OS. The expression of these two lncRNAs independently, or in combination, serves as important prognostic biomarkers in CRC.