tbuckley/cabot-search huggingface dataset:
IMPS-43IDO1 DOES NOT FUNCTION AS A TRYPTOPHAN CATABOLIC ENZYME IN MALIGNANT GLIOMA
Authors: Lijie Zhai, Kristen Lauing, Jun Qian, Galina Gritsina, Carlos Dostal, Robert McCusker, Derek Wainwright
Journal: Neuro-Oncology (2015)

The upregulation of indoleamine 2,3 dioxygenase 1 (IDO1) in glioblastoma (GBM) is associated with significantly decreased survival in patients. We have previously demonstrated that glioma-derived IDO1 is required for Treg accumulation and immune-evasion of brain tumors in the immunocompetent intracranial GL261 model of GBM. Notably, IDO1-deficient (IDO1-/-) mice bearing GL261 brain tumors have no deficit in tumor-infiltrating Treg levels and an overall survival similar to wild-type (WT; IDO1-competent) mice. Since IDO1 is associated with the catabolic conversion of tryptophan (Trp) into kynurenine (Kyn), combined with recent clinical efforts aimed at inhibiting IDO1, we sought to determine the enzymatic contribution of IDO1 in brain tumors. WT and IDO1-/- mice intracranially-injected IDO1-competent or -deficient GL261 cells were analyzed by HPLC to determine total Trp and Kyn levels in the serum and brain. Indicative of enzymatic activity, naive (non-tumor bearing) WT mice possessed a Kyn/Trp ratio in the serum and brain of 2.44 ± 0.09 and 2.22 ± 0.32, respectively, which was significantly higher than in IDO1-/- mice (0.374 ± 0.09 and 0.834 ± 0.05, respectively) (P < 0.01; n = 5-6/group). Unexpectedly, WT mice bearing 2 week post-intracranially-injected (2wp-ic.) IDO1-competent and -deficient GL261 tumors possessed a brain Kyn/Trp ratio of 2.04 ± 0.05 and 1.88 ± 0.17, respectively, which was not significantly different from one another. In contrast, IDO1-/- mice bearing 2wp-ic. IDO1-competent and -deficient tumors possessed a brain Kyn/Trp ratio of 0.77 ± 0.06 and 0.72 ± 0.03, respectively, which was not different from one another, but significantly decreased when compared to respective tumors from WT mice (P < 0.01; n = 4-7/group). To the best of our knowledge, these novel findings suggest for the first time that, IDO1 does not behave as a tryptophan catabolic enzyme in brain tumor cells. Given the indispensable role of IDO1 in mediating immune-evasion to GBM, we are currently pursuing this mechanism.
Potentially modifiable lifestyle factors, cognitive reserve, and cognitive function in later life: A cross-sectional study
Authors: Linda Clare, Yu-Tzu Wu, Julia C. Teale, Catherine MacLeod, Fiona Matthews, Carol Brayne, Bob Woods
Journal: PLoS Medicine (2017)

Potentially modifiable lifestyle factors may influence cognitive health in later life and offer potential to reduce the risk of cognitive decline and dementia. The concept of cognitive reserve has been proposed as a mechanism to explain individual differences in rates of cognitive decline, but its potential role as a mediating pathway has seldom been explored using data from large epidemiological studies. We explored the mediating effect of cognitive reserve on the cross-sectional association between lifestyle factors and cognitive function in later life using data from a population-based cohort of healthy older people.We analysed data from 2,315 cognitively healthy participants aged 65 y and over in the Cognitive Function and Ageing Study Wales (CFAS-Wales) cohort collected in 2011-2013. Linear regression modelling was used to investigate the overall associations between five lifestyle factors-cognitive and social activity, physical activity, diet, alcohol consumption, and smoking-and cognition, adjusting for demographic factors and chronic conditions. Mediation analysis tested for indirect effects of the lifestyle factors on cognition via cognitive reserve. After controlling for age, gender, and the presence of chronic conditions, cognitive and social activity, physical activity, healthy diet, and light-to-moderate alcohol consumption were positively associated with cognitive function, together accounting for 20% (95% CI 17%-23%) of variance in cognitive test scores. Cognitive reserve was an important mediator of this association, with indirect effects via cognitive reserve contributing 21% (95% CI 15%-27%) of the overall effect on cognition. The main limitations of the study derive from the cross-sectional nature of the data and the challenges of accurately measuring the latent construct of cognitive reserve.Cross-sectional associations support the view that enhancing cognitive reserve may benefit cognition, and maintenance of cognitive health may be supported by a healthy and active lifestyle, in later life.
The subcellular localization of neuronal nitric oxide synthase determines the downstream effects of NO on myocardial function
Authors: Ricardo Carnicer, Silvia Suffredini, Xing Liu, Svetlana Reilly, Jillian N. Simon, Nicoletta C. Surdo, Yin H. Zhang, Craig A. Lygate, Keith M. Channon, Barbara Casadei
Journal: Cardiovascular Research (2017)

AimsIn healthy hearts, the neuronal nitric oxide synthase (nNOS) is predominantly localized to the sarcoplasmic reticulum (SR), where it regulates the ryanodine receptor Ca2+ release channel (RyR2) and phospholamban (PLB) phosphorylation, and to a lesser extent to the sarcolemmal membrane where it inhibits the L-type Ca2+ current (ICa). However, in failing hearts, impaired relaxation and depressed inotropy are associated with a larger proportion of nNOS being localized to the sarcolemmal membrane. Whether there is a causal relationship between altered myocardial function and subcellular localization of nNOS remains to be assessed.
Transgenic Expression of Bach1 Transcription Factor Results in Down-Regulation of the p45 Target Genes in Megakaryocytic Lineage Cells.
Authors: Tsutomu Toki, Fumiki Katsuoka, Rika Kanezaki, Seiji Watanabe, Takuya Kamio, Satoru Tandai, Hidekachi Kurotaki, Soroku Yagihashi, Jiying Sun, Norio Komatsu, Kazuhiko Igarashi, Masayuki Yamamoto, Etsuro Ito
Journal: Blood (2004)
Vascular Cognitive Impairment
Authors: Martin Dichgans, Didier Leys
Journal: Circulation Research (2017)

Cerebrovascular disease typically manifests with stroke, cognitive impairment, or both. Vascular cognitive impairment refers to all forms of cognitive disorder associated with cerebrovascular disease, regardless of the specific mechanisms involved. It encompasses the full range of cognitive deficits from mild cognitive impairment to dementia. In principle, any of the multiple causes of clinical stroke can cause vascular cognitive impairment. Recent work further highlights a role of microinfarcts, microhemorrhages, strategic white matter tracts, loss of microstructural tissue integrity, and secondary neurodegeneration. Vascular brain injury results in loss of structural and functional connectivity and, hence, compromise of functional networks within the brain. Vascular cognitive impairment is common both after stroke and in stroke-free individuals presenting to dementia clinics, and vascular pathology frequently coexists with neurodegenerative pathology, resulting in mixed forms of mild cognitive impairment or dementia. Vascular dementia is now recognized as the second most common form of dementia after Alzheimer's disease, and there is increasing awareness that targeting vascular risk may help to prevent dementia, even of the Alzheimer type. Recent advances in neuroimaging, neuropathology, epidemiology, and genetics have led to a deeper understanding of how vascular disease affects cognition. These new findings provide an opportunity for the present reappraisal of vascular cognitive impairment. We further briefly address current therapeutic concepts.
True Public Access Defibrillator Coverage is Overestimated
Authors: Christopher L.F. Sun, Derya Demirtas, Steven C. Brooks, Laurie J. Morrison, Timothy C.Y. Chan
Journal: Circulation (2015)

Background: Out-of-hospital cardiac arrests (OHCAs) occur at all times of the day and night. Immediate access to an AED increases survival. However, most public-location AEDs are placed in buildings without 24 hour access.   
Objective: To measure fixed-location public AED coverage of OHCAs by time of day and day of week in a Canadian urban setting.   
Methods: We identified all atraumatic public OHCAs occurring in Toronto, Canada from Jan. 2006 – Aug. 2014. We obtained a list of registered AEDs from Toronto Emergency Medical Services as of March 2015 and determined the hours that each AED was available based on operating hours of the building housing the AED. We counted the number of OHCAs that occurred within 100 m of an AED (“assumed 24/7 coverage”) and the number that occurred both within 100 m of an AED and when the AED was available (“actual coverage”). Statistical analysis was performed using a [chi]2 test.   
Results: We identified 2440 atraumatic public OHCAs and 737 registered AED locations. A total of 451 OHCAs were covered under assumed 24/7 coverage. In terms of actual coverage, 354 OHCAs were covered, representing a coverage loss of 25.5%. The figure shows coverage decreased by 8.6% during the day (8am-3:59pm), 28.6% in the evening (4pm-11:59pm), and 48.4% at night (12am-7:59am); the differences were statistically significant (p<0.001). During the evenings, nights, and weekends the coverage loss was 31.6%, which is when the majority (66.1%) of the OHCAs occurred. The largest coverage losses were found in schools (39.7%), industrial facilities (39.3%), recreation facilities (37.1%), and offices (35.7%). Transportation facilities, long term care homes and homeless shelters had no coverage loss.   
Conclusion: One out of every four OHCAs in proximity of an AED occurs when that AED is inaccessible due to lack of 24/7 access. When deciding on candidate locations for placement of AEDs, temporal access should be considered to maximize the number of lives saved.
Immune Globulin for Patients with Primary Immune Deficiency: An Evidence Based Practice Guideline
Authors: Nadine Shehata, Heather Ann Hume, Valerie Palda, David Anderson, Tom Bowen, Richard Warrington, Bruce Mazer, Elie Haddad, Thomas Issekutz, Bob Schellenberg, David Easton
Journal: Blood (2008)
The effect of activation of angiogenesis pathways independent of VEGF in renal cell carcinoma on resistance to VEGF-targeted antiangiogenic therapy.
Authors: Kyung Seok Han, Kilian Gust, Shannon Awrey, Peter A. Raven, Estelle Li, Ladan Fazli, Martin E. Gleave, Alan I. So
Journal: Journal of Clinical Oncology (2012)

409 Background: VEGF-targeted anti-angiogenic therapy provides significant growth inhibition in clear cell type renal cell carcinoma (CCRCC). However, evasive resistance develops in most responding cases due to unclear mechanisms. We investigated the mechanism of resistance to VEGF-targeted therapy in CCRCC both in vitro and in vivo. Methods: Two different conditioned cell lines were developed from wild type Caki-1. Sunitinib-conditioned Caki-1 was developed by chronic exposures to sunitinib (up to 15uM) and hypoxia-conditioned Caki-1 was developed by chronic exposures to hypoxia (1% oxygen). We characterized these conditioned cells in vitro and response patterns to sunitinib were evaluated using subcutaneous xenograft models with parental and conditioned cells. In vivo angiogenesis assays were performed to characterize angiogenesis potentials in these cells. Finally, mRNA microarray was performed to find pathways that induce resistance to anti-angiogenic therapy. Results: Sunitinib inhibited proliferation of HUVEC cells, but did not inhibit tumor proliferation in CCRCC cells at pharmacologically relevant doses. In vitro sunitinib-conditioned Caki-1 cells did not show obvious resistance to sunitinib compared to parental cells, but when tested in vivo these cells appeared to be highly resistant to sunitinib therapy. In contrast, hypoxia-conditioned Caki-1, although more resistant to hypoxia and showing increased vascularity by upregulating VEGF production, did not develop sunitinib resistance either in vitro or in vivo compared to parental cells. In vivo matrigel plug assay with sunitinib treatment confirmed that tumor angiogenesis was relatively intact and less affected by sunitinib treatment in xenografts of sunitinib-conditioned cells compared to parental cells. Conclusions: Resistance to VEGF-targeted therapy is acquired by activation of VEGF-independent angiogenesis pathways induced by interactions with VEGF-targeted drug but not by hypoxia. Our results suggest that more broad inhibitions of tumor angiogenesis are required to prevent development of resistance to anti-angiogenic therapy in CCRCC.
Effect of Corticosteroids and Cyclophosphamide on Sex Hormone Profiles in Male Patients With Systemic Lupus Erythematosus or Systemic Sclerosis
Authors: Laurent Arnaud, Annica Nordin, Hannes Lundholm, Elisabet Svenungsson, Erik Hellbacher, Johan Wikner, Agneta Zickert, Iva Gunnarsson
Journal: Arthritis & Rheumatology (2017)

Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are autoimmune diseases that predominantly affect female patients, and therefore fewer investigations have been conducted in men. The aim of this study was to analyze sex hormone levels in male patients with SLE and those with SSc, compared to matched controls, in relation to the use of corticosteroids and cyclophosphamide (CYC).Sex hormone levels were measured in fasting blood samples from male patients with SLE (n = 71) and those with SSc (n = 29) and compared to population-based, age-matched male controls. Relevant hormone profiles were identified using cluster analysis.Male SLE patients had higher levels of luteinizing hormone (LH) (P < 0.0001) and more frequent bioactive testosterone deficiency (P = 0.02) than their matched controls. The current dosage of prednisolone correlated inversely with the levels of bioactive testosterone (r = -0.36, P = 0.03). Cluster analysis identified a subset of SLE patients with increased levels of follicle-stimulating hormone, LH, and prolactin as well as lower levels of bioactive testosterone (P < 0.0001) in relation to higher daily doses of prednisolone. In male SSc patients, levels of testosterone (P = 0.03) and bioactive testosterone (P = 0.02) were significantly lower than those in matched controls. Use of CYC during the previous year was associated with lower bioactive testosterone levels in both SLE patients (P = 0.02) and SSc patients (P = 0.01), after adjustment for age.The results of this study highlight the negative impact of corticosteroids on gonadal function in men with SLE. Furthermore, use of CYC during the year prior to study inclusion impaired bioactive testosterone levels in male patients with either SLE or SSc. Physicians should be more aware of the possibility of hypogonadism in male patients with autoimmune diseases. The need for hormonal supplementation remains to be formally evaluated in these patients.
Select High Risk Genetic Features Predict Earlier Progression Following Chemoimmunotherapy with Fludarabine and Rituximab in Chronic Lymphocytic Leukemia (CLL): Preliminary Justification for Risk-Adapted Therapy.
Authors: John C. Byrd, John G. Gribben, Bercedis Peterson, Michael R. Grever, Gerard Lozanski, David M. Lucas, Richard A. Larson, Michael A. Caligiuri, Nyla A. Heerema
Journal: Blood (2004)
Spontaneous Alleviation Of Growth Impairment In Tyrosine Kinase Inhibitor-Treated Chronic Myeloid Leukemia Children
Authors: Haruko Shima, Akihiko Tanizawa, Chikako Tono, Akihiro Watanabe, Hidemitsu Kurosawa, Masaki Ito, Yuki Yuza, Noriko Hotta, Hideki Muramatsu, Masahiko Okada, Mika Tokuyama, Koji Kato, Katsuyoshi Koh, Akiko M. Saito, Souichi Adachi, Keizo Horibe, Shuki Mizutani, Hiroyuki Shimada
Journal: Blood (2013)
Ibrutinib Inhibits Concomitant TLR and BCR- Driven Proliferation of Chronic Lymphocytic Leukemia Cells and Overrides the Supportive Survival-Promoting Effects of Microenvironmental Signals
Authors: Sonal Temburni, Jacqueline C. Barrientos, Jonathan E. Kolitz, Steven L. Allen, Kanti R. Rai, Betty Y. Chang, Nicholas Chiorazzi, Rajendra N Damle
Journal: Blood (2014)
Mutations of Calreticulin in Myeloproliferative Neoplasms Contribute to Disease Progression Not through Inhibition of Phagocytosis, but through Enhanced Proliferation Production of Myeloid Myelo-Erythroid Progenitor Cells
Authors: Shinya Daitoku, Katsuto Takenaka, Takuji Yamauchi, Koichi Akashi
Journal: Blood (2014)
IMPS-13IMMUNOLOGIC PROFILING OF PEDIATRIC CNS MALIGNANCIES FOR THE RATIONAL SELECTION OF IMUNOTHERAPEUTIC TRIALS
Authors: Kellie Haworth, Michael Arnold, Christopher Pierson, Jonathan Finlay, Timothy Cripe
Journal: Neuro-Oncology (2015)

BACKGROUND: Although clinical trials have resulted in significant improvements in childhood brain cancer treatments, further progress using strategically targeted, potentially less toxic modalities are needed. Immunotherapy is one such emerging treatment approach. The degree of tumor-infiltrating cytotoxic T-lymphocytes (CTLs) directly correlates with prognosis for several cancer types. MHC Class I is down-regulated in 40-90% of adult cancers, rendering them resistant to CTL attack, correlating with poorer prognosis. MHC I expression in medulloblastomas is associated with poor prognostic factors, a pattern opposite of most other cancer-MHC I associations described. Natural Killer (NK)-cell based therapies, dependent upon low MHC I expression, are therefore proposed as an immunotherapeutic approach to medulloblastomas. Very little literature exists classifying MHC I expression in other pediatric brain cancers, despite several ongoing trials using MHC I-dependent strategies. This lack of data raises uncertainty of which immunotherapies are optimal for these diseases. Toward this end, we classified key immunologic characteristics of pediatric brain tumors. METHODS: We interrogated pre-clinical and clinical mRNA microarray databases to identify tumor types which exhibit MHC I and the associated b-2-microglobulin molecule expression. We up-regulated MHC I expression in vitro in pediatric CNS tumor cell lines and identified intra-tumoral innate and adaptive immunologic cellular infiltrates within pediatric CNS tumor samples through immunohistochemistry. RESULTS: We found that atypical teratoid/rhabdoid tumors (AT/RT) and ependymomas exhibit decreased, whereas medulloblastomas and glioblastomas express higher MHC I mRNA levels than most other pediatric cancer types. We discovered MHC I can be up-regulated in vitro in medulloblastomas and AT/RT's, indicating a reversible epigenetic mechanism for down-regulation. There were decreased NK and regulatory T-cell, while increased CTL infiltrates in recurred versus diagnostic pediatric glioblastoma tumor samples. CONCLUSIONS: The immunologic profiling of pediatric brain cancers will guide rational selection of immune-based therapies, serving as an important biomarker for patient inclusion in immunotherapeutic trials.
The role of arousal in predictive coding
Authors: Fernando Ferreira-Santos
Journal: Behavioral and Brain Sciences (2016)

Within a predictive coding approach, the arousal/norepinephrine effects described by the GANE (glutamate amplifies noradrenergic effects) model seem to modulate the precision attributed to prediction errors, favoring the selective updating of predictive models with larger prediction errors. However, to explain how arousal effects are triggered, it is likely that different kinds of prediction errors (including interoceptive/affective) need to be considered.
STEM-22LARGE-SCALE SINGLE-CELL RNA-seq REVEALS A DEVELOPMENTAL CELLULAR HIERARCHY IN HUMAN OLIGODENDROGLIOMA
Authors: Andrew Venteicher, Itay Tirosh, Christine Hebert, Leah Escalante, Brian Nahed, Daniel Cahill, William Curry, Robert Martuza, Bradley Bernstein, David Louis, Aviv Regev, Mario Suva
Journal: Neuro-Oncology (2015)

The heterogeneity among tumor cells within human glioma underlie their ability resist chemotherapy and radiation, ultimately leading to disease progression. While current chemotherapy and radiation treatment focuses on the effect on bulk tumor, mounting evidence indicates that rarer subpopulations of tumor cells are endowed with stem-like properties, which are capable of resisting these treatments, proliferating, and causing more aggressive recurrent tumors. However, unbiased evidence for cancer stem-like cells (CSCs) in solid human malignancies remains elusive. To better understand intratumoral heterogeneity, we sequenced the transcriptome of 3,348 single cells from human oligodendrogliomas using RNA-seq and reconstructed the cellular architecture within freshly resected tumor specimens from consented patients. We found that most tumor cells are differentiated along two specialized glial programs, while a third, rarer subpopulation of tumor cells express a neural stem/progenitor-like program. Surprisingly, cellular proliferation was restricted to this rare stem/progenitor-like subpopulation, consistent with the existence of a stem/progenitor-like compartment that is solely responsible for fueling growth of oligodendrogliomas in humans. By studying chromosomal copy number variation, we detect distinct genetic clones in which these three tumor subpopulations are preserved, indicating that the cellular hierarchy and genetic influences together determine tumor architecture. These results provide unprecedented insight into the cellular composition of brain tumors at single-cell resolution and have the potential to harmonize the cancer stem cell and genetic models of cancer, with critical implications for disease management.
A phase II and biomarker study (MET111644) of the dual Met/VEGFR-2 inhibitor foretinib in patients with sporadic and hereditary papillary renal cell carcinoma: Final efficacy, safety, and PD results.
Authors: Toni K. Choueiri, Ulka N. Vaishampayan, Jonathan E. Rosenberg, Theodore Logan, Andrea Lynne Harzstark, Brian I. Rini, Sandy Srinivas, Laurel M. Adams, Laurie Jill Sherman, Lone Harild Ottesen, David F. McDermott, Donald P. Bottaro, W. Marston Linehan, Ramaprasad Srinivasan
Journal: Journal of Clinical Oncology (2012)

355 Background: Foretinib is an oral multi-kinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations and/or amplifications in MET have been described in patients (pts) with papillary renal cell carcinoma (PRC). The aim of this study was to evaluate the efficacy and safety of 2 dosing regimens of single agent foretinib bisphosphate (foretinib) in pts with PRC and to explore modulation of plasma proteins indicative of target inhibition. Methods: Pts were enrolled in 2 cohorts with different dosing schedules of foretinib: 240 mg/day on days 1–5 of every 14 days (intermittent arm) or 80 mg/day (daily dosing arm). The primary endpoint was overall response rate (ORR) targeting an ORR of at least 25%. Pts were stratified based on status of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, chromosome 7 gain or none of these). Plasma markers reflecting potential target effects of MET and VEGFR inhibition were also analyzed. Results: Overall, 74 pts were enrolled with 37 in each dosing cohort. ORR was 13.5%, progression-free survival 9.3 months, 1 year overall survival (OS) was 70% and median OS was not reached. The median duration of response was 18.5 months. Of 68 pts with adequate tumor assessment data available, 50 experienced some reduction in the sum of the longest tumor diameters (SLD) ranging from −2% to −75%. The most frequent grade 3/4 adverse events related to foretinib were fatigue (6.8%), hypertension (50%), and diarrhea (6.8%). A high rate of non-fatal pulmonary embolism was observed (11%). There were no significant differences in efficacy or safety between the two cohorts. In both arms, plasma sMET and VEGF increased and sVEGFR2 decreased after 2 cycles indicating target inhibition, but these changes were not associated with response or PFS. Outcomes based on molecular characterization are presented separately at this meeting. Conclusions: In the largest clinical trial devoted to papillary RCC, foretinib demonstrated anti-tumor activity in patients with PRC, modulation of several target indicator plasma proteins, and a manageable toxicity profile.