tbuckley/cabot-search huggingface dataset:
SURG-09. AWAKE CRANIOTOMY FOR BRAIN TUMOR IN OCTOGENARIANS AND NONAGENARIANS
Authors: John Sinclair, Tomasz Polis, Janna Malone, Gregory Krolczyk, Reva Ramlogan
Journal: Neuro-Oncology (2018)

Awake craniotomy allows for maximal tumor resection while improving survival and preserving functional status. This procedure is well tolerated in the elderly population (age 65–80). We report the Ottawa Hospital experience with patients 80 years old. A chart review (research ethics board approved) of awake craniotomies performed between July 2009 and February 2018 was completed. 14 patients 80 years old at the time of surgery were identified, with ages ranging from 80–93, averaging 83 ± 3.6 years old. Preoperatively, 12 patients had Karnofsky Performance Status (KPS) 80, 2 patients KPS 70. 8 tumors were frontal, 4 temporal, and 2 parietal. Average tumor volume was 23.9 ± 17.9 ml. Pathologies revealed 8 high grade gliomas, 4 metastatic lesions, 1 atypical meningioma and 1 case of radiation necrosis. Intraoperative functional mapping was successful in all the cases. Neuroanesthesiologists followed the protocol involving continuous infusion of low-ultra low dose of propofol, remifentanil and ketamine. Surgical time was 335 ± 84 min. Gross total resection was achieved in 8 patients; near total resection in 6 patients as confirmed by postoperative MRI. Ten patients (62%) had very good outcome with improvement or similar, as before surgery functional status at the time of discharge home, which averaged 4.7 ± 2 days post-operatively. Four patients (38%) had prolonged hospital stay of 37 ± 37 days post-operatively. Two of those patients had low KPS pre and post-operatively. The other two patients had transient increase in neurological deficit postoperatively requiring hospitalization. After initial improvement their functional status deteriorated post radiation therapy, which was started 1 month after surgery. There was no mortality over 30 days postoperatively. CONCLUSIONS: Octogenarians and nonagenarians tolerate surgery well following Ottawa Awake Craniotomy Protocol, especially when their preoperative functional status is good. Early good postoperative outcomes may be affected by their ensuing radiation therapy.
Abstract 19016: Stem Cell Based Therapy in PAD Exerts Multifaceted Effects on the Diabetic Ischemic Microenvironment
Authors: Jamila Hedhli, Christian J Konopka, Kim Minwoo, Sarah Schuh, Hannah Bouvin, John A Cole, Heather Huntsman, Kristopher A Kilian, Iwona T Dobrucki, Marni Boppart, Michael Insana, Wawrzyniec Dobrucki
Journal: Circulation (2017)

Introduction: Diabetes mellitus (DM) is associated with impaired neovascularization, which can lead to compromised peripheral blood perfusion, ulcerations of the foot, and ultimately amputation. Cu...
Carolyn Emery #FierceScientist #PassionateLeader
Authors: Alexandra Ross
Journal: British Journal of Sports Medicine (2018)

I have been fortunate to experience sport as a participant (modified following bilateral total hip arthroplasties), coach (okay so the 9- and 10-year-old players might have had a better slapshot), mom (team and extreme sports — no wonder I have grey hair!), youth sport team physiotherapist (well timed with the ice hockey and field hockey experiences of my kids), sport injury epidemiologist (reportedly also experiencing higher rates of injury than many professions… perhaps a predictive pathway to choice of field), at the 2012 Paralympics in London (need I say more), and unfortunately as a patient (l gained lots of patient perspective in ICU following a hockey puck to larynx injury mechanism).

Dear high school Carolyn,

For as long as I can remember, people have told you that there are two versions of yourself: one going 100 miles an hour and one who is sound asleep (I guess you have slept through more movies than most). While it is true that there are only 24 hours in a day, and while you always wanted to make the most of each hour, perhaps you should slow down just a little. You should know that the bar can be high, and it is important to stop to smell the roses (…and lily of the valley and lilacs and gardenia…) along the way. Be kind to yourself. As a wise person once said, “It’s not the destination, it’s the journey”.

Take care,

Carolyn (aka wise old bird)



Tenacity—set your goals and never give up.

There was a midcareer moment when I realized that rigorous and interdisciplinary research evidence could indeed inform best practice and policy, and have a significant public health impact in reducing the burden of injury and their consequences in youth earlier than the predicted 17-year time frame. This is made …
IMMU-01. NOVEL RNA-TARGETING STRATEGY FOR TREATING T CELL-DRIVEN IMMUNOSUPPRESSION IN HUMAN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Alicia Lenzen, Kristen L Lauing, Lijie Zhai, Erik Ladomersky, Pichai Raman, Komal Rathi, Rishi R Lulla, Rintaro Hashizume, Derek A Wainwright
Journal: Neuro-Oncology (2019)

PURPOSE: Our laboratory's work in adult high-grade glioma has discovered a therapeutically-targetable pathway through the inducible expression of indoleamine 2,3 dioxygenase 1 (IDO1). IDO1 is an immunosuppressive enzyme that metabolizes tryptophan. Our project's purpose is to delineate the role of T-cell-driven IDO1 expression in human DIPG, and to develop the therapeutic potential for inhibiting human IDO1 with novel, specific, small inhibitory (si)RNA oligonucleotides. METHODS: Gene expression for human IDO1, T-cell specific, CD3e, and the proinflammatory cytokines, IFNγ and IFNb, were investigated among surgically-resected pediatric brain tumor specimens obtained from the Childhood Brain Tumor Tissue Consortium (CBTTC). IDO1 and CD3e were also explored in a novel, humanized DIPG mouse model (NSG-SGM3-BLT), by injecting SF8628 into the brain stem. Humanized mice were either untreated or depleted for human CD4+ and CD8+ T cells. In vitro analysis included unique patient-derived DIPG cell lines, stimulated with human IFNγ, and analyzed for IDO1 mRNA and protein levels, with and without the addition of IDO1 siRNA. RESULTS: IDO1 expression is normally low in cultured human DIPG, but rapidly induced by IFNγ. Analysis of surgically-resected human pediatric brain tumor specimens confirms the association between IDO1 levels and the co-expression of IFNγ and IFNb. Strikingly, human T cells directly increase human IDO1 expression in intracranial DIPG, while our siRNA specifically decreases IDO1 mRNA, protein and enzyme activity/levels. DISCUSSION: The poor prognosis of children with DIPG, combined with the lack of therapies, emphasizes the importance of understanding immunosuppressive IDO1 and its potential therapeutic value. These data also confirm that, immunotherapies aimed at enhancing T cell effector functions in DIPG patients, also need to consider resulting effects on intratumoral IDO1-mediated immunosuppression. Ongoing work by our laboratory aims to weaponize our novel IDO1-targeted siRNA for in vivo delivery, and for adjuvant treatment in DIPG patients receiving immunotherapy.
EXTH-13. REDUCTION OF TUMOR BURDEN AND HEARING LOSS WITH A MULTIPLE RECEPTOR TYROSINE KINASE INHIBITOR BRIGATINIB IN A GENETICALLY ENGINEERED MOUSE MODEL OF NEUROFIBROMATOSIS TYPE 2
Authors: Abbi Smith, Waylan Bessler, Li Jiang, Xiaohong Li, Qingbo Lu, Jin Yuan, Yongzheng He, Andi Masters, David Jones, Charles Yates, D Wade Clapp
Journal: Neuro-Oncology (2018)

Neurofibromatosis Type 2 (NF2) is an autosomal dominant genetic disorder caused by germline mutations in the tumor suppressor gene NF2, which encodes the protein Merlin. Patients with NF2 may develop bilateral vestibular schwannomas, which cause hearing impairment, and schwannomas in other regions of the nervous system. Due to the nature and location of the tumors, there is high morbidity and mortality associated with NF2, and no known effective chemotherapeutic intervention. A high-throughput in vitro cell viability screen revealed an Anaplastic Lymphoma Kinase (ALK) inhibitor as a top contender for selective inhibition of Nf2-deficient murine Schwann cells. Brigatinib (Alunbrig®) is a small molecule multiple receptor tyrosine kinase inhibitor that is FDA-approved for ALK-positive metastatic non-small cell lung cancer. Therefore, we hypothesized that brigatinib would prevent tumorigenesis in our genetically engineered mouse model of NF2 (Nf2f/f; Postn-Cre+). 50mg/kg Brigatinib was administered to Nf2f/f; Postn-Cre+ mice by oral gavage daily for 12 weeks. Pharmacokinetic analyses paired with immunohistochemistry showed brigatinib is orally bioavailable, and treatment resulted in a therapeutically relevant concentration of brigatinib in the plasma (cmax = 4.8µM; tmax = 4hrs), which was sufficient to induce a biological response in the dorsal root ganglia (DRG) schwannomas. The volume of DRG in brigatinib-treated mice was 55% less than vehicle-treated mice. Additionally, brigatinib-treated mice did not have significant progression of hearing loss at the end of treatment, whereas vehicle-treated mice had a statistically significant 7.4dB increase in ABR threshold. Finally, histopathological assessment of DRG shows that brigatinib treatment prevented the progressive morphological disruption observed in the vehicle-treated mice. These data provide evidence that brigatinib targets may play a significant role in Merlin-deficient schwannomagenesis, and implicate brigatinib as a promising therapeutic intervention of NF2.
TMIC-25. DISSECTING THE ROLE OF HOST GENETICS IN GLIOMA EVOLUTION USING GENETICALLY-ENGINEERED MOUSE MODELS AND THE COLLABORATIVE CROSS
Authors: Kasey Skinner, Martin Ferris, Ryan Bash, Abigail Shelton, Erin Smithberger, Steven Angus, Brian Golitz, Noah Sciacky, Jeremy Simon, Jason Stein, Glenn Matsushima, Quinn Ostrom, Lindsay Stetson, Jill Barnholtz-Sloan, Harshil Dhruv, Michael Berens, Fernando Pardo Manuel de Villena, Ryan Miller
Journal: Neuro-Oncology (2018)

Gliomas have fatal outcomes and few effective treatments. Precision medicine promises to target somatic tumor mutations, but the impact of host genetics on glioma biology remains unclear. Germline polymorphisms have been associated with glioma risk, but such studies cannot disambiguate loci affecting cancer cell-autonomous versus tumor microenvironment (TME) phenotypes, since germline variation is shared by both. Here, we implement a novel platform to discover genetic modifiers of both cancer cell autonomous and TME phenotypes using genetically defined non-germline genetically-engineered mouse (nGEM) glioma models and genetically diverse hosts from the Collaborative Cross (CC). We stereotactically injected Nf1;Trp53-/- oligodendrocyte progenitor-derived tumor cells into syngeneic C57/BL6 control mice and 14 different CC strains. Survival analysis showed 7 strains with significantly prolonged survival relative to controls (P<0.05), suggesting slower tumor growth (Gs, growth slow). The remaining 7 strains survived similarly to controls, suggesting fast growth (Gf, growth fast). Variable tumor growth in CC mice suggests host genetic background influences molecular processes in the TME that potentiate or inhibit tumor growth. To identify such candidates, we performed RNA sequencing on 36 tumors from 3 Gf strains, 4 Gs strains, and controls. We identified differentially expressed genes that segregated Gf, Gs, and control tumors (P<0.05). Gene ontology analyses showed that these genes were significantly associated with immune response or extracellular matrix biology. These results suggest that Gs strains activate immune and TME processes that slow tumor growth. Quantitative trait locus (QTL) analyses of mouse host genetics and tumor data will facilitate identification of genetic variants that influence tumor progression. Future studies using human datasets are planned for validation of candidate host loci identified in mice.
Abstract #376: Arsenic trioxide induces autophagy in ovarian cancer cells
Authors: Ibrahim Tekedereli, Bulent Ozpolat, Gamze Gezgen, Ugur Akar, Yasuko Kondo, Seiji Kondo, Gabriel Lopez-Berestein
Journal: Cancer Research (2009)

Autophagy is an evolutionary conserved lysosomal digestion process of cellular proteins and organelles. Under physiological conditions autophagy function as a protective mechanism and is induced in response to nutrient and growth factor deprivation. It has been suggested that the autophagy is also one of the programmed cell death mechanisms called programmed cell death type II. Autophagic cell death is observed in general when the apoptotic threshold of the cancer cells high or apoptosis defective cells. Also, autophagic cell death is triggered when the autophagy pressure is massive or persistent or prolonged. Recently, several studies showed that autophagy or autophagic cell death is induced by anticancer therapies. Therefore, the modulation of autophagy may be a possible therapeutic target or a useful tool for sensitizing tumors to the chemotherapy. Arsenic trioxide (ATO), which is approved by FDA for the treatment of acute promyelocytic leukemia (APL) and leads to remission in APL and multiple myeloma, has been shown to induce autophagic cell death in leukemia and glioblastoma cell lines. Currently, whether ATO induces autophagy in ovarian cancer is not known. Here, we investigated whether ATO induces autophagy and if so whether it functions as protective or pro-death mechanism. The A2780 ovarian cancer cell line was treated with the increasing doses of ATO at different time points. We found that ATO induced formation of autophagic vacuoles in a dose dependent manner and 30-50 % of the cells underwent autophagy with 4 uM ATO in 72 hours as detected by acridine orange staining and flow cytometry (FACS) analysis. The electron microscopic studies confirmed the formation of autophagic vacuoles after the treatments with ATO at 72h. The autophagy was also observed in A2780 cells by formation GFP-LC3 labeled autophagosomes as indicated by punctuated pattern in GFP-LC3 transfected A2780 cells after ATO treatment. ATO also up-regulated Beclin-1 and ATG5 autophagy promoting proteins detected by Western blot analysis in a dose and time dependant manner. These results suggest that ATO activates the autophagic pathway in ovarian cancer cells. We are currently knocking down ATG5 and Beclin-1 and ATG5 by RNA interference to see the autophagy is a protective process against the cytotoxic effects or a cell death mechanism in ovarian cancer. In conclusion, provided the first evidence that ATO induces the autophagy in ovarian cancer and autophagy may be used as a therapeutic strategy to modulate cell death in ovarian cancer cells.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 376.
Abstract P142: Social Jetlag is Associated With Adiposity in 8-10 Year Old New Zealand Children
Authors: Lee Stoner
Journal: Circulation (2017)

Background: Childhood obesity has been associated with poor sleep behaviour, including sleep duration, sleep disorders and social jetlag. Social jetlag is the discrepancy between an individual’s circadian clock and social rhythms, and is measured as the difference in hours between the midpoint of sleep at work/school and free days. While social jetlag has been associated with being overweight adults, no known studies have examined whether obesity is associated with social jetlag in children. We hypothesized that poor sleep behavior, including sleep duration, sleep disorders and social jetlag, would be associated with body composition in in 8-10 year old New Zealand children. Methods: This cross-sectional study recruited 341 children (50% F) aged 8-10 years from three representative sample sites across New Zealand. Four dependant variables were calculated: body fat (%), fat mass index (FMI, kg/m 2 ), waist to hip ratio (WHR), and body mass index (BMI, kg/m 2 ). The three independent variables were: average sleep duration, social jetlag, and sleep disorders. Sleep duration was recorded using a parent-reported, single item habitual school/weekday sleep survey. Social jetlag was calculated as the absolute difference between the midpoints of sleep on weekdays versus weekend days. Sleep disorders were estimated using the Children’s Sleep Habits Questionnaire. Results: Following adjustment for confounders, sleep duration was only associated WHR ( β = -0.008, 95%CI: -0.015, 0.000), and sleep disorders was only associated with FMI ( β = -0.034, 95%CI: 0.002, 0.067 kg/m 2 ), while social jetlag was associated with all four body composition variables. A one hour increase in social jetlag was associated with a 2.98 % (95%CI: 0.41, 5.55 %) increase in body fat, 0.51 kg/m 2 (95%CI: 0.11, 0.91 kg/m 2 ) increase in FMI, a 0.90 kg/m 2 95%CI: 0.21, 1.58 kg/m 2 ) increase in BMI, and a 0.13 (95%CI: 0.003, 0.023 increase in WHR. Conclusions: In conclusion, Social jetlag may be a particularly important sleep behaviour correlate of adiposity in children. Moreover, social jetlag provides an opportunity for a relatively simple and measurable public health strategy.
Human equilibrative nucleoside transporter 1 (hENT1) expression correlates with gemcitabine uptake and cytotoxicity in mantle cell lymphoma (MCL)
Authors: Silvia Marce, Miriam Molina-Arcas, Neus Villamor, F. Javier Casado, Elias Campo, Marçal Pastor-Anglada, Dolors Colomer
Journal: Cancer Research (2006)

2348  Nucleoside transporters (NTs) might play a relevant role in the intracellular targeting of many nucleoside analogues used in anticancer therapy. Two gene families (SLC28 and SLC29) encode the two types of human NTs, Concentrative Nucleoside Transporter (CNT) and Equilibrative Nucleoside Transporter (ENT) proteins. We have previously described that chronic lymphocytic leukemia (CLL) cells express both SLC28- and SLC29-related mRNAs, although transport function seems to be mostly related to ENT-type transporters. In this study we have analyzed the role of ENTs in nucleoside-derived drug bioavailability and action in mantle cell lymphoma (MCL) cells. We have analyzed the expression of hENT1 and hENT2 by real time RT-PCR and by Western Blot, using polyclonal antibodies against hENT1 and hENT2 in five MCL cell lines and 20 primary MCL cells. High levels of hENT1 protein expression (0.15 ± 0.14) in MCL cells were detected in contrast to hENT1 expression in CLL cells (0.08 ± 0.02), and a good correlation was found between protein and mRNA levels of hENT1 (p= 0.03), thus indirectly suggesting that hENT1 might be transcriptionally regulated in MCL cells. Uridine transport significantly correlated with hENT1-related mRNA expression and protein levels (p = 0.009 and 0.042, respectively). Similar results were obtained for gemcitabine transport (p = 0.036 and p = 0.013, respectively), but no correlation was found for fludarabine uptake. Unless the doses of gemcitabine to induce a cytototxic effect in primary MCL cells (LD50
THU-053-Usefulness of lactate-free Asian Pacific Association for The Study of Liver acute-on-chronic liver failure research consortium ACLF score for predicting short-term mortality in patient with alcoholic liver disease
Authors: Do Seon Song, Tae Yeob Kim, Hee Yeon Kim, Eileen L Yoon, Dong Joon Kim, Ji-Dong Jia, Ashok Choudhury, Mamun Al-Mahtab, Harshad Devarbhavi, Zhongping Duan, Yu Chen, CE Eapen, Ashish Goel, Qin Ning, Ke Ma, Yogesh Chawla, Radha Krishan Dhiman, Ajay Duseja, Sunil Taneja, Saeed Sadiq Hamid, Amna Subhan, Wasim Jafri, Soek-Siam Tan, Hasmik Ghazinian, Deepak Amarapurkar, Sombat Treeprasertsuk, Guan Huei Lee, Seng Gee Lim, Jinhua Hu Hu, Laurentius A. Lesmana, Rinaldi Lesmana, Akash Shukla, Samir Shah, Chetan Kalal, Manoj Sahoo, Zaigham Abbas, Joyes s, Gian Carpio, Md. Fazal Karim, George Lau, Nagaraja Rao Padaki, Diana Payawal, A. Kadir Dokmeci, Man-Fung Yuen, V GM, Osamu Yokosuka, Ananta Shrestha, Priyanka Jain, Irene Paulson, Shiv Kumar Sarin
Journal: Journal of Hepatology (2019)
Abstract 12375: Vascular Inflammation Evaluated by 18F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography is Associated With Endothelial Dysfunction
Authors: Akihiro Honda, Nobuhiro Tahara, Atsuko Tahara, Sachiyo Igata, Yoshikazu Nitta, Norihiro Kodama, Minori Mizoguchi, Sho-ichi Yamagishi, Yoshihiro Fukumoto
Journal: Circulation (2014)

Background: Endothelial dysfunction is an initial step for atherosclerotic cardiovascular disease. However, involvement of vascular inflammation in endothelial dysfunction is not fully investigated in humans. We assessed the relationship between endothelial function and vascular inflammation evaluated by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging. Methods and Results: We examined endothelial function and vascular inflammation, which were evaluated by flow-mediated dilation (FMD) of the brachial artery functionally and FDG-PET imaging of carotid arteries, respectively, in 128 subjects (83 males and 45 females; mean age 61.8 ± 10.0 years) who underwent a risk-screening test for cardiovascular disease in Kurume University Hospital. Vascular inflammation of the carotid arteries was measured by blood-normalized standardized uptake value, known as a target-to-background ratio (TBR). Mean percent change in vasodilation (percent change over the baseline values; %FMD) and carotid TBR were 5.60 ± 2.24 % and 1.43 ± 0.22, respectively. %FMD was less in men than in women. In univariate analysis, %FMD was inversely correlated with age (p=0.011), systolic blood pressure (p=0.014), carotid artery maximum intima-media thickness (p=0.014), HbA1c (p=0.020), visceral fat volume (p=0.005), or TBR values (p&lt;0.001). Multiple stepwise regression analysis revealed that age (p=0.034), visceral fat volume (p=0.002), and TBR values (p&lt;0.001) were independently associated with decreased %FMD (R2=0.245). Conclusions: We found here that vascular inflammation in the carotid arteries evaluated by FDG-PET was one of the independent association of decreased %FMD, thus suggesting that vascular inflammation might contribute to endothelial dysfunction in humans.
ACTR-68. INITIAL TREATMENT OF GBM WITH A KETOGENIC DIET ALONG WITH RADIATION AND CHEMOTHERAPY: FEASIBILITY, TOXICITY AND RESPONSE
Authors: Kenneth Schwartz, Mary Noel, Michele Nikolai, Karl Olson, Mohamed Elnabtity, Micheal Zakem, Justin Clark, Bryan Figueroa, Howard Chang
Journal: Neuro-Oncology (2018)

INTRODUCTION: We initiated and now report early outcomes of a pilot clinical trial study using a ketogenic diet (KD) combined with radiation and chemotherapy as initial therapy for aggressive gliomas (glioblastoma, GBM). Eligibility criteria included: 1. Tissue diagnosis; 2. Age over 18; 3. ECOG performance status of 2 or better; and 4. Not having diabetes or being pregnant. An isocaloric KD diet with 3:1 weight ratio of fat to combined weight of carbohydrate and protein was supervised by an experienced dietitian. Per protocol the KD together with radiation and chemotherapy was maintained for 6 weeks. 9 patients (mean age 45, 8F,1M) completed 6 weeks of this trial. Blood counts, chemistries, lipid profiles and uric acids were not markedly changed. No other significant side effects were observed. Ketosis was maintained for the 6 week study period with blood ketone and glucose levels checked twice daily: The ketones ranged between 0.9 and 4.1 and glucose ranged between 80.3 and 120. Patients’ daily AM weights decreased on average < 10% during the study. 3 patients (mean age 28) showed no progression of their gliomas at 34 (IDH +), 19 (IDH +), and 25 (IDH WT) months since diagnosis. 6 patients (mean age 54) have died at 25, 25, 13, 12, 9 and 9 months after diagnosis. 1. Combining an adjuvant KD with standard therapy of radiation and chemotherapy right after tissue diagnosis is feasible and safe. 2. Daily measurements of blood ketones and glucose are necessary to assure continued ketosis; 3. KD may be a helpful adjuvant initial treatment of GBM patients, especially in younger patients. A larger study will be required to test this hypothesis.