tbuckley/cabot-search huggingface dataset:
Abstract 410: Interleukin-21 Promotes Pulmonary Arterial Hypertension Through M2 Macrophage Polarization
Authors: Yoshikazu Nakaoka, Takahiro Hashimoto-Kataoka, Mikiyasu Shirai, Yasushi Sakata
Journal: Circulation Research (2015)

Interleukin-6 (IL-6) is a multifunctional proinflammatory cytokine that is elevated in the serum of pulmonary arterial hypertension (PAH) patients and can predict the survival of idiopathic (I)PAH patients. Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a novel downstream target of IL-6-signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Furthermore, the hypoxia-induced upregulation of IL-17 and IL-21, which are primarily produced by Th17 cells, was also ameliorated by IL-6 blockade in mice. Whereas IL-17 blockade with an anti-IL-17 neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. Consistently, IL-21 indeed promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Moreover, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH through M2 macrophage polarization, downstream of IL-6-signaling. IL-6/Th17/IL-21-signaling axis may be a novel potential target for treating PAH.
Morphologic variation of circulating tumor cells in metastatic breast cancer patients visualized by immunofluorescent stain pattern.
Authors: Daniel Adams, Stuart S Martin, Monica Charpentier, Olga V Makarova, Peixuan Zhu, Shuhong Li, Platte T Amstutz, Cha-Mei Tang
Journal: Journal of Clinical Oncology (2012)

e21079 Background: Isolation of circulating tumor cells (CTCs) using microfiltration is a growing utility in the field of CTC detection. The microfiltration approach can be used on peripheral blood as a non-invasive liquid biopsy for cancer detection and subtyping. We present a utilization of the CellSieve microfilter to subtype CTCs based on immunofluorescent staining pattern of cytokeratin filamentation and EpCAM surface marker expression. Our initial study on CTCs in patient blood indicates that disseminated CTC populations have high rates of phenotypic heterogeneity. Further detailed molecular analysis and patient tracking of these phenotypes may lead to individualized patient assessment based on CTC characterization. Methods: 7.5 mL of whole blood collected from metastatic breast cancer patients were diluted in a fixative solution. An 8 µm CellSieve precision microfilter was placed into a filter holder and the samples were passed through the filter (~ 90 seconds). The cells captured on the filter were fixed, permeabilized, and stained with DAPI, cytokeratin (FITC), EpCAM (PE), and CD45 (Cy5). Cells without CD45 staining were classified by their morphology, nuclear integrity and the presence of cytokeratin and EpCAM staining. Results: In our initial assessment, patient samples were found to have a number of phenotypic CTC subtypes. Cytokeratin filamentation was clearly seen on a number of CTCs while other cells presented with spotted patterns, implying CTCs in various stages of apoptosis. Later stage apoptosis, with segmented nuclear signature, was also seen in various samples. Cell clusters and cells in division were DAPI positive, while EpCAM positivity was negligible, 0-3 cells/sample, correlating with established data from the CellSearch CTC assay. Conclusions: In addition to enumeration, phenotypic variation of CTCs may be a valuable tool for the personalized care of cancer patients. We have shown that individual breast cancer patients have overlapping phenotypes of CTCs circulating in their peripheral blood. We have begun categorizing patients based on these phenotypes and plan to correlate them with overall prognosis.
Re: Julien Dagenais, Matthew J. Maurice, Pascal Mouracade, Onder Kara, Ercan Malkoc, Jihad J. Kaouk. Excisional Precision Matters: Understanding the Influence of Excisional Volume Loss on Renal Function After Partial Nephrectomy. Eur Urol 2017;72:168–70.
Authors: Jae Heon Kim, Benjamin I. Chung
Journal: European Urology (2017)
MEDU-38. NEXT GENERATION MOLECULAR CHARACTERIZATION OF LOCALLY RECURRENT WNT PATHWAY MEDULLOBLASTOMA: A CASE REPORT
Authors: Mohamed S. AbdelBaki, Daniel R. Boue, David Ellison, Jeffrey Leonard, Olaf Witt, David Capper, Stefan M. Pfister, Jonathan L. Finlay
Journal: Neuro-Oncology (2017)

BACKGROUND: Wnt pathway medulloblastoma has high relapse-free survival following standard cranio-spinal irradiation with primary site boost and adjuvant chemotherapy. However, rare patients do develop recurrences. We report a case with comprehensive molecular characterization of both initial and recurrent tumor. CASE REPORT: A seven year old girl had local recurrence of a gross totally resected non-metastatic classic Wnt pathway medulloblastoma, 21 months after receiving 18Gy craniospinal irradiation with primary site boost to 54Gy, with weekly vincristine, followed by a modified maintenance chemotherapy regimen including 9 cycles of vincristine, temozolomide, oral etoposide, alternating with vincristine and carboplatin or cyclophosphamide. The original tumor was YAP-1 and nuclear beta-catenin positive, GAB1 and monosomy 6 negative, cmyc and nmyc non-amplified. Rare tumor cells were noted to be HMB45 or desmin and/or myogenin positive. The recurrent lesion demonstrated classic Wnt pathway medulloblastoma without HMB45 or desmin reactivity or monosomy 6. The child has since received marrow-ablative thiotepa and carboplatin with autologous stem cell rescue. Analysis of both initial and recurrent tumors was performed using Illumina Human Methylation 850K Array. Mutational analysis on tumor DNA was performed via NextGen sequencing on Illumina NextGen platform for 130 brain tumor-related genes. DNA methylation profile of the recurrent tumor demonstrated classic medulloblastoma, Wnt activated. A copy number profile demonstrated several chromosomal aberrations without amplifications. MGMT promoter was unmethylated, while the gene panel sequencing revealed a variant in CTNNB1 (same as the original tumor). Germ line analyses are pending. CONCLUSION: The absence of monosomy 6 in the face of CTNNB1 mutation may highlight a worse prognostic variant of Wnt pathway medulloblastoma. The presence of melanocytic and/or rhabdomyoblastic markers by IHC may also indicate a less optimal prognosis even amongst Wnt pathway activated medulloblastoma.
Aggressive End-of-Life Care for Metastatic Cancer Patients Younger Than Age 65 Years
Authors: Aaron D Falchook, Stacie B Dusetzina, Fang Tian, Ramsankar Basak, Nandini Selvam, Ronald C Chen
Journal: JNCI Journal of the National Cancer Institute (2017)

Aggressive medical care at the end of life can be harmful to patients and families, but its prevalence in use among younger cancer patients is unknown. The goal of the study was to report on the use of aggressive care and hospice services for patients younger than age 65 years. Using the HealthCore Integrated Research Database, we analyzed patients who died between 2007 and 2014 with metastatic lung (n = 12 764), colorectal (n = 5207), breast (n = 5855), pancreatic (n = 3397), or prostate (n = 1508) cancer. Based on published quality measures, we assessed uses of chemotherapy, intensive care, emergency room visits, and hospice care at the end of life. We examined additional items including radiotherapy, invasive procedures, hospitalization, and in-hospital deaths. Multivariable modified Poisson regression models were used to adjust for age, sex, geographic region, rural/urban location, year of death, and regional education and income measures. Across the five cancers, 10.1% to 14.1% of patients received chemotherapy within the last 14 days of life, 15.9% to 20.6% received intensive care in last 30 days, and 1.5% to 2.5% went to the emergency room two or more times in last 30 days. Hospice enrollment at least three days before death was 54.4% to 59.6%. However, 55.3% to 59.3% of patients had a hospital admission in the last 30 days, and one-third died (30.3%–35.4%) in the hospital. There was low use of cancer-directed treatment at the end of life for younger cancer patients, and hospice use was higher than 50%. However, there was a relatively high utilization of hospital-based care. These results demonstrate an opportunity for continued improvements in the provision of high-value, patient-centered care at the end of life.
Abstract 427: Micrornas Have Differential Degree of Expression in Pathological Cardiac Hypertrophy Compared to Physiological Cardiac Hypertrophy
Authors: Nidiane C Martinelli, Carolina Cohen, Daiane Silvello, Andréia Biolo, Michael Andrades, Kátia dos Santos, Nadine Clausell, Luis E Rohde, Ursula Matte
Journal: Circulation Research (2015)

Physiological and pathological left ventricular hypertrophies (LVH) are distinct processes that have differential pattern of gene expression. Based on initial stimuli, miRs expression levels can fluctuate and then cause a variance on their targets culminating in diverse cellular pathway activation. AIM: Here we compared miRs expression between pathological cardiac hypertrophy induced by transverse aortic constriction (TAC) and physiological cardiac hypertrophy induced by voluntary exercise in running wheels (EXE). METHODS: Adult male Balb/c mice (12-14 weeks old) mice were subjected to TAC or EXE protocol and data were evaluated at 7 (TAC-7D; EXE-7D) and 35 (TAC-35D; EXE-35D) days. Hypertrophy was measured by normalizing left ventricular weight to body weight (LVW/BW). We evaluated left ventricular expression levels of miRs: -26b, 27a, -143, -150, -195 and -499 by qRT-PCR in TAC and EXE groups. Comparisons between groups were performed by ANOVA with Bonferroni correction. Results are shown as mean±SEM. Results: Sedentary and Sham groups were similar among all variables tested. Animals subjected to TAC surgery demonstrated a greater hypertrophy than EXE animals at both time points (7D: 16% vs. 7%; 35D 26% vs 12%, p&lt;0.05 for both). MiR-26b had increased levels in TAC group at both time points (7D: 1.14±0.1 vs 0.6±0.01; 35D: 4.8±1.4 vs 1.17±0.12; p&lt;0.01 for both). We only detected an increase in miR-27a levels in TAC-7D compared to EXE-7D (2.7±1.0 vs 0.78±0.1, p &lt;0.05). We identified an augmentation in miR-143 levels in TAC group at both time points (7D: 1.1±0.1 vs 0.75±0.1; 35D: 1.42±0.2 vs 0.9±0.1; p&lt;0.05 for both). We detected an increase in miR-499 levels at both time points in TAC group (7D: 4.1±0.5 vs 0.67±0.2, p&lt;0.001; 35D: 2.2±0.4 vs 0.9±0.2, p&lt;0.01). We found an increase in miR-195 levels only in TAC-35D group compared to EXE-35D (2.6±0.3 vs 0.9±0.1, p&lt;0.05). We did not notice any change in miR-150 levels neither at 7 days nor at 35 days. Conclusions: These preliminary data demonstrate a differential degree of miR expression between physiological and pathological hypertrophy. Further studies comparing physiological and pathological cardiac hypertrophy are necessary to find out the turning point that deviates heart from adaptive to maladaptive growth.
MEDU-14. OTX2 CONTROLS AN AXON GUIDANCE GENE EXPRESSION NETWORK TO REGULATE MEDULLOBLASTOMA SELF-RENEWAL
Authors: Margaret Stromecki, Nazanin Tatari, Ludivine Morrison, Ravinder Kaur, Gareth Palidwor, Chris Porter, Patryk Skowron, Matthias Wölfl, Michael Taylor, Tamra Werbowetski-Ogilvie
Journal: Neuro-Oncology (2017)

Medulloblastoma (MB) is a highly heterogeneous primary malignant pediatric brain cancer that is frequently accompanied by metastatic dissemination and poor long-term prognosis. The most aggressive tumors are refractory to conventional chemotherapy and radiation. Our goal is to identify new signaling pathways that regulate the treatment-resistant MB cellular phenotypes, namely the stem cells. We previously discovered that the OTX2 gene, which is amplified or overexpressed in the majority of aggressive MBs, is a central regulator of stem cell function or self-renewal in these tumors. However, the molecular mechanisms by which OTX2 regulates these functions are still unknown. Here, we employed complementary bioinformatics approaches to characterize the OTX2 regulatory network and identified a novel relationship between OTX2 and genes associated with axon guidance signaling in Group 3 and Group 4 MB stem/progenitor cells. Following OTX2 knockdown, transcripts associated with semaphorin, netrin, ephrin and slit signaling were predominantly upregulated. ChIP-sequencing identified putative OTX2 DNA binding sites and revealed statistically significant associations between OTX2 and these axon guidance pathway genes. Group 3 and 4 MB patient samples were evaluated for correlations between expression of axon guidance pathway genes, OTX2 and survival. Semaphorin signaling was the most overrepresented pathway across all datasets with expression of all pathway genes being upregulated following OTX2 KD. Moreover, SEMA4D expression was identified as a novel prognostic biomarker. Functional validation studies demonstrated that increased levels of semaphorin pathway genes are associated with a decrease in self-renewal underscoring a potential tumor suppressive role in these tumors. Downstream pathways known to mediate the effects of semaphorin signaling including, RHOA and MAPK were also differentially expressed following OTX2 KD. Our results offer critical insights into the molecular drivers of the most aggressive MB tumors and provide an informed framework to pursue novel targeted therapies aimed at differentiating MB tumors cells.
Multiple Arterial Grafts Improve Late Survival of Patients Undergoing Coronary Artery Bypass Graft Surgery
Authors: Chaim Locker, Hartzell V. Schaff, Joseph A. Dearani, Lyle D. Joyce, Soon J. Park, Harold M. Burkhart, Rakesh M. Suri, Kevin L. Greason, John M. Stulak, Zhuo Li, Richard C. Daly
Journal: Circulation (2012)

Background— Use of the left internal mammary artery (LIMA) in multivessel coronary artery disease improves survival after coronary artery bypass graft surgery; however, the survival benefit of multiple arterial (MultArt) grafts is debated. Methods and Results— We reviewed 8622 Mayo Clinic patients who had isolated primary coronary artery bypass graft surgery for multivessel coronary artery disease from 1993 to 2009. Patients were stratified by number of arterial grafts into the LIMA plus saphenous veins (LIMA/SV) group (n=7435) or the MultArt group (n=1187). Propensity score analysis matched 1153 patients. Operative mortality was 0.8% (n=10) in the MultArt and 2.1% (n=154) in the LIMA/SV ( P =0.005) group, which was not statistically different ( P =0.996) in multivariate analysis or the propensity-matched analysis ( P =0.818). Late survival was greater for MultArt versus LIMA/SV (10- and 15-year survival rates were 84% and 71% versus 61% and 36%, respectively [ P &lt;0.001], in unmatched groups and 83% and 70% versus 80% and 60%, respectively [ P =0.0025], in matched groups). MultArt subgroups with bilateral internal mammary artery/SV (n=589) and bilateral internal mammary artery only (n=271) had improved 15-year survival (86% and 76%; 82% and 75% at 10 and 15 years [ P &lt;0.001]), and patients with bilateral internal mammary artery/radial artery (n=147) and LIMA/radial artery (n=169) had greater 10-year survival (84% and 78%; P &lt;0.001) versus LIMA/SV. In multivariate analysis, MultArt grafts remained a strong independent predictor of survival (hazard ratio, 0.79; 95% confidence interval, 0.66–0.94; P =0.007). Conclusions— In patients undergoing isolated coronary artery bypass graft surgery with LIMA to left anterior descending artery, arterial grafting of the non–left anterior descending vessels conferred a survival advantage at 15 years compared with SV grafting. It is still unproven whether these results apply to higher-risk subgroups of patients.
Effect of protective helmets on vision and sensory performance
Authors: Michelle R Kramer, Erin B Wasserman, Elizabeth F Teel, Jason P Mihalik
Journal: British Journal of Sports Medicine (2017)

Objective The purpose of this study was to determine the effect of protective helmets (i.e., football, lacrosse, and ice hockey helmets) on vision and sensory performance. Design Experimental cross-over study. Setting Clinical research centre. Subjects A convenience sample of 24 healthy college-aged males who played American football (n=14), lacrosse (n=5), or ice hockey (n=5) at a minimum of a high school level. Intervention Participants completed vision and sensory performance assessments under two counterbalanced conditions: helmeted and unhelmeted. Outcome measures The Senaptec Sensory Station assesses visual clarity (LogMAR), contrast sensitivity (logarithm of contrast sensitivity), depth perception (arcsec), near-far quickness (# cycles complete), target capture (threshold response time), perception span (# correct responses), multiple object tracking (tracking capacity), eye-hand coordination (average response time), go/no go (correct minus incorrect hits), and hand reaction time (average reaction time). The overall helmet effect and helmet-by-sport interactions were assessed. Results Participants performed 40.7ms slower on eye-hand coordination (95% Confidence Interval [CI]: −66.64, −14.83; p&lt;0.01) and 3.4 points lower on go/no go (95% CI: 1.56, 5.32; p&lt;0.01) when wearing a helmet. Hockey helmets significantly affected visual clarity (95% CI: −0.3701, −0.0883; p=0.01) and hand reaction time (95% CI: −38.67, −9.73; p&lt;0.01), but football and lacrosse helmets did not. Conclusions Vision and sensory performance was negatively impacted by wearing a helmet. This inability to see and respond to visual stimuli could have implications for athlete safety and performance, and should be explored further in other at-risk populations such as youth and female athletes. Competing interests Kramer: None. Wasserman: None. Teel: None. Mihalik: Dr. Mihalik has an equity interest in Senaptec LLC Keywords: Concussion, Injury prevention, Vision, Helmet, Facemask
Evaluation of a Hepatitis B Virus Reactivation Prevention Program in Lymphoma Patients Receiving Immunochemotherapy
Authors: Blanca Sanchez-Gonzalez, Montserrat Garcia-Retortillo, Teresa Murcia, Mariana Ferraro, Francesc Garcia-Pallarols, Dolors Gimenez, Sara Montesdeoca, Eva Gimeno, Eugenia Abella, Ricard Sola, Carlos Besses, Antonio Salar
Journal: Blood (2016)
Phase II trial of inflammation markers and symptom control in metastatic lung cancer: Insync.
Authors: Chipman Robert Geoffrey Stroud, Paul R. Walker, Susan Eubanks, Teresa Parent
Journal: Journal of Clinical Oncology (2014)

TPS9659 Background: Palliative care with focused symptom management and control can improve quality of life outcomes and survival in metastatic non-small cell lung cancer (NSCLC) beyond standard chemotherapy. (Temel et al NEJM 2010) Many symptoms in cancer are related to inflammation. (Laird et al The Oncologist 2013) Smoldering inflammation in the tumor microenvironment is now a recognized 7th hallmark of cancer (Colotta et al Carcinogenesis 2009) as it regulates and escalates cancer invasion, angiogenesis, immune surveillance escape and the metastatic cascade. (Balkwill and Mantovani Lancet 2001) The Veristrat protein test is dominated by inflammatory proteins and is prognostic and predictive in metastatic NSCLC after treatment with platinum based chemotherapy. (Gregorc et al ASCO 2013 #LBA8005) C-reactive protein (CRP) is also a well studied inflammatory marker in cancer. The hypothesis of this study is that the remarkable survival benefit in the Temel study is mediated by reduced inflammation with symptom improvement and control. Methods: In this study, patients with metastatic NSCLC will be seen in consultation by our institutional Symptom Management Service PharmD upon presentation to our Thoracic Oncology Program and subsequently managed concurrently with the treating medical oncologist. Inflammatory protein marker studies with Versitrat and CRP will be evaluated at baseline, monitored at 4 and 10 months and correlated with ongoing symptom improvement and a quality of life (FACT-L) study. The primary objective is reduced inflammation markers with Veristrat ‘poor’ changing to Veristrat ‘good’ and a decreasing CRP. The secondary objectives are overall survival, quality of life FACT-L improvement and correlation with disease status.
TET2 Activity Is Modulated By SIRT1-Mediated Protein Deacetylation: A Potential Therapeutic Target in Myelodysplastic Syndrome
Authors: Jie Sun, Yinghui Zhu, Zonghui Ding, Haojie Dong, Yimei Feng, Qiang Chen, Xiaochun Yu, Dandan Zhao, Herman Wu, Lifeng Feng, Kaoru Tohyama, Philipp Oberdoerffer, Bin Zhang, Ya-Huei Kuo, Ravi Bhatia, Hongchuan Jin, Guido Marcucci, Ling Li
Journal: Blood (2016)
Pros and cons of blurring gesture-language lines: An evolutionary linguistic perspective
Authors: Matthew L Hall
Journal: Behavioral and Brain Sciences (2017)

Abstract The target article's emphasis on distinguishing sign from gesture may resolve one important objection to gesture-first theories of language evolution. However, this approach risks undervaluing the gradual progression from nonlanguage to language over hominin evolution, and in emerging sign systems today. I call for less emphasis on drawing boundaries and more emphasis on understanding the processes of change.
Heart rate variability reductions following a season of sub-concussive head hits are related to the magnitude of impacts experienced
Authors: Jonathan D Smirl, Alexander D Wright, Harjas S Grewal, Michael Jakovac, Kelsey Bryk, Paul van Donkelaar
Journal: British Journal of Sports Medicine (2017)

Objective To examine the effect of repetitive contact sport-related head trauma on indices ofheart rate variability (HRV). Design Prospective Cohort. Setting Laboratory. Participants Forty-ninemale contact-sport (hockey or football) and four non-contact control athletes (age range: 17–22). Intervention Prior to (T1) and upon completion of (T2) the competitive athletic season, a three-lead electrocardiogram and Kubios software (Kuopio, Finland) were used to assess heart rate variability during 5-minutes of quiet stance and while actively squatting at 0.10 Hz. Independent variables included condition (rest-vs-active) and time (T1-vs-T2). Outcome measures Time-Domain: square root of mean squared differences of successive R-R intervals (RMSSD), percentage of successive R-R intervals that differ by more than 50 milliseconds (pNN50); Non-Linear: approximateentropy (ApEn). In a subset of participants (n=29) biomechanical head-impact exposure data was estimated usingthe xPatch (X2 Biosystems), affixed to the right mastoid. Main results RM-ANOVA indicateda significant main effect of timein contact sport but not control athletes (all p&gt;0.133). HRV metrics were decreased post-season relative to baseline (95% CI:s for differences: MeanRR4–48 ms, p=0.045; RMSSD 1–9 ms, p=0.018; pNN50 0.689–5.98, p=0.010; ApEn 0.022–0.163, p=0.044). Significant correlations were observed between the average peak linear acceleration per hit experienced and the change in MeanRR(R²=0.1382), and RMSSD (R²=0.1525). Conclusions Exposure to repetitive subconcussive impacts overone season of contact-sport leads to decreases in heart rate variability. The magnitude of HRV reduction is related to the average magnitude of the linear component of hits to the head experienced during play Competing interests None.