tbuckley/cabot-search huggingface dataset:
P01.06 Chemical ROCK inhibition induces neurite-like outgrowth and connectivity in undifferentiated glioblastoma cells
Authors: B. da Silva, E. Polson
Journal: Neuro-Oncology (2017)

Introduction: Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumour in adults and despite treatment the prognosis is extremely poor. One major challenge is the therapeutic targeting of GBM cell migration and infiltration of healthy brain tissue, a complex phenomenon that involves the dynamic reorganization of the actin cytoskeleton. The RHO-associated serine/threonine kinases 1 and 2 (ROCK1 and ROCK2) play a central role regulating downstream effectors of cytoskeletal dynamics. The notion of using ROCK inhibition as a potential anti-cancer treatment strategy and the dearth of tumour type-specific data in this context, motivated us to address the question as to whether chemical pan-ROCK inhibition affects GBM cell morphology, motility, and/or differentiation. To this end, we phenotypically investigated the effects of several different ROCK inhibitors, in patient-derived GBM cells that we have previously used to quantify changes in GBM stem cell-like behaviour. METHODS: We assessed cellular behaviour in the presence or absence of chemical ROCK inhibitors through live cell imaging, gene expression studies, immunocytochemistry and image analysis. Results: The chemical inhibition of the ROCK pathway resulted in a dose-dependent and reversible neurite-like outgrowth phenotype. Notably, the development of neural protrusions was observed across a spectrum of different small molecule-inhibitors and different patient-derived cell models. Interestingly, cell fate was not significantly altered by chemical obstruction of ROCK as indicated by the reversibility of the ROCK inhibitor-induced phenotype and lack of differentiation-associated gene expression changes. However, we observed that the ROCK-induced formation of neurite-like protrusions was associated with decreased cellular motility and allowed the cells to form an interactive cellular network. Strikingly, ROCK inhibition had a significant protective effect on the neurite-growing GBM stem-like cells under DNA damaging treatment. CONCLUSION: Our findings suggest that GBM stem-like cells remain undifferentiated and proliferative in response to chemical ROCK inhibition. Concomitantly, cells form an interactive network, which could attenuate the efficacy of pharmacological ROCK inhibition in the context of GBM combination therapy. Bárbara da Silva is supported by the Ian Meek PhD training fellowship of Brain Tumour Research and Support across Yorkshire.
Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia
Authors: E Togasaki, J Takeda, K Yoshida, Y Shiozawa, M Takeuchi, M Oshima, A Saraya, A Iwama, K Yokote, E Sakaida, C Hirase, A Takeshita, K Imai, H Okumura, Y Morishita, N Usui, N Takahashi, S Fujisawa, Y Shiraishi, K Chiba, H Tanaka, H Kiyoi, K Ohnishi, S Ohtake, N Asou, Y Kobayashi, Y Miyazaki, S Miyano, S Ogawa, I Matsumura, C Nakaseko, T Naoe
Journal: Blood Cancer Journal (2017)

Although tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML), the ability of TKIs to eradicate CML remains uncertain and patients must continue TKI therapy for indefinite periods. In this study, we performed whole-exome sequencing to identify somatic mutations in 24 patients with newly diagnosed chronic phase CML who were registered in the JALSG CML212 study. We identified 191 somatic mutations other than the BCR-ABL1 fusion gene (median 8, range 1-17). Age, hemoglobin concentration and white blood cell counts were correlated with the number of mutations. Patients with mutations ⩾6 showed higher rate of achieving major molecular response than those<6 (P=0.0381). Mutations in epigenetic regulator, ASXL1, TET2, TET3, KDM1A and MSH6 were found in 25% of patients. TET2 or TET3, AKT1 and RUNX1 were mutated in one patient each. ASXL1 was mutated within exon 12 in three cases. Mutated genes were significantly enriched with cell signaling and cell division pathways. Furthermore, DNA copy number analysis showed that 2 of 24 patients had uniparental disomy of chromosome 1p or 3q, which disappeared major molecular response was achieved. These mutations may play significant roles in CML pathogenesis in addition to the strong driver mutation BCR-ABL1.
Subject Index Vol. 73, 2004
Authors: Jane Irvine, Zachary M. Shnek, Donna E. Stewart, E. Micali, C. Giorgianni, F. Munaò, R. Brecciaroli, L. Salmaso, D. Germanò, Madelon Y. Bolling, Robert J. Kohlenberg, Nicoletta Sonino, Tommi Tolmunen, Jukka Hintikka, Anu Ruusunen, Sari Voutilainen, Antti Tanskanen, Veli-Pekka Valkonen, Heimo Viinamäki, George A. Kaplan, Jukka T. Salonen, Giovanni A. Fava, Jenny Guidi, Secondo Fassino, Paolo Leombruni, Federico Amianto, Giovanni Abbate-Daga, C. Abbate, Anne-Mette Hvas, Svend Juul, Per Bech, Ebba Nexø, Roland von Känel, Brigitte M. Kudielka, Renate Schulze, Marie-Louise Gander, Joachim E. Fischer, Erwin Lemche, Gisela Klann-Delius, Rainer Koch, Peter Joraschky, Bernd Löwe, Kerstin Gräfe, Stephan Zipfel, Steffen Witte, Bernd Loerch, Wolfgang Herzog, Sherry L. Grace, Susan E. Abbey
Journal: Psychotherapy and Psychosomatics (2004)

family intervention, impact 312 Cell-mediated immunity 243, 286 Character traits, HIV outpatients 361 Childhood, sexual/physical abuse 107 Chronic fatigue syndrome
National Academies Report Cites Flaws in VA’s Burn Pit Registry
Authors: Jennifer Abbasi
Journal: JAMA (2017)

Collectively, burn sites at large US military bases in Iraq and Afghanistan incinerated 60 000 to 85 000 pounds of waste—including plastics, chemicals, petroleum, and human refuse—daily during the 2000s. The practice was banned due to health concerns in 2009.

In a new report, the National Academies of Science, Engineering, and Medicine concluded that a congressionally mandated volunteer registry for military personnel exposed to toxic airborne chemicals and fumes from these open-air burn pits “has limited value for improving individual patient care.”
Immunogenicity of 2 vs 3 Doses of the Quadrivalent Human Papillomavirus Vaccine in Girls Aged 9 to 13 Years After 60 Months
Authors: Gina Ogilvie, Chantal Sauvageau, Marc Dionne, Shelly McNeil, Mel Krajden, Deborah Money, Simon Dobson
Journal: JAMA (2017)

This study uses long-term follow-up clinical trial data to compare antibody response 60 months after girls younger than 15 years were randomized to 2 vs 3 doses of quadrivalent human papillomavirus vaccine.
Abstract 18348: Total Mast Cell Numbers in Human Carotid Atherosclerotic Plaques and Tryptase Plasma Levels are Predictive for Future Cardiovascular Events
Authors: Sanne Willems, Aryan Vink, Paul Quax, Gert-Jan de Borst, Jean-Paul de Vries, Sander M van de Weg, Frans L Moll, Dominique P de Kleijn, Imo E Hoefer, Gerard Pasterkamp
Journal: Circulation (2012)

Mast cells (MCs) are inflammatory cells known to contribute to the pathogenesis of atherosclerotic disease. Experimental studies have revealed that MCs might be involved in the progression of atherosclerosis by inducing intraplaque neovascularization. OBJECTIVE: This study was designed to assess total MC numbers and relate the score to neovascularization in human atherosclerotic plaques. In addition we related the presence of plaque MCs with the occurrence of adverse cardiovascular events during follow-up. METHODS AND RESULTS: In the current study atherosclerotic plaques of 270 patients suffering from carotid artery stenosis, were stained for the presence of MCs (MC tryptase), macrophages (CD68), neutrophils (CD66) and microvessels (CD34). Furthermore, during a follow-up of 3 years, cardiovascular related endpoints were assessed in all patients. Counting of mast cells revealed a surprising high number of MCs that were present in plaques (165 ± 10 MC per plaque). We equally divided the patient cohort into a group with low (n=126) and high (n=127) total MC numbers. High MC numbers were associated with high microvessel density 6,0 [4,3-9,0] versus 10,7 [6,5-14,2] vessels per hotspot (P&lt;0.001). Patients with high plaque MC numbers showed significantly more cardiovascular events during follow up (35 [28%] versus 54 [43%] events (P&lt;0.05)). Macrophage and neutrophil presence did not show this association with the occurrence of cardiovascular events. In addition, in 80 patients (1:1 event versus no event) MC tryptase and chymase have been measured in plasma. Patients with high plasma tryptase showed significantly more cardiovascular events (11 [28%] versus 24 [60%] events (P&lt;0.01)). Plasma chymase levels did not show predictive value in our cohort. CONCLUSIONS: MCs are highly prevalent in carotid atherosclerotic lesions and associated with plaque neovessel density. Total intraplaque MC numbers and MC plasma tryptase levels are predictive for future cardiovascular events. These data support the view that MCs could play an important role in progression of atherosclerotic disease.
Impact of Induction Regimen and of Allogeneic Hematopoietic Cell Transplantation on the Outcome in Younger Adults Patients with Acute Myeloid Leukemia with a Monosomal Karyotype: Results from the EORTC/Gimema AML-10 and AML-12 Trials
Authors: Frederic Baron, Marian Stevens-Kroef, Giovanna Meloni, Petra Muus, Jean-Pierre Marie, Constantijn J.M. Halkes, Xavier Thomas, Radovan Vrhovac, Giorgina Specchia, Francois Lefrere, Simona Sica, Marco Mancini, Adriano Venditti, Anne Hagemeijer, Joop H. Jansen, Sergio Amadori, Theo de Witte, Roelof Willemze, Stefan Suciu
Journal: Blood (2016)
P16.28 Solitary fibrous tumor / Hemangiopericytoma: treatment results based on 2016 WHO classification
Authors: K. Sung, J. Moon, E. Kim, W. Chang, S. Kang, S. Kim, S. Kim, K. Lee, J. Chang
Journal: Neuro-Oncology (2017)

Purpose: Solitary fibrous tumor / hemangiopericytoma (SFT/HPC) is a new combined entity for introduction of a soft tissue-type grading system from grade I to III in the 2016 World Health Organization (WHO) Classification of tumors of the central nervous system. The treatment results of this new disease entity need to be evaluated. We retrospectively reevaluated the pathologic findings and medical records of SFT/HPC. Materials and Methods: This study consisted of 60 patients (27 men and 33 women, 43.5 (13-69) years of age) treated at our institute between February 1981 and February 2016. SFT/HPC grade I, II, and III consisted of 4, 40, and 16 patients, respectively. Among them, there were 7 patients of solitary fibrous tumor and they were re-graded as grade I (n=4), grade II (n=2), and grade III (n=1). Results: Mean overall survival was 79.4 (1.4-275.7) months and progression free survival after first operation was 56.9 (1.4-217.7) months. Six patients (10%) showed extracranial metastasis and median period to extracranial metastasis was 103.7 ± 51.4 (31.9-182.3) months. Nineteen patients (31.6%) presented recurrence. Grade III group had shorter progression free survival, overall survival, and period to extracranial metastasis than grade II group. In grade II group, total resection group showed longer progression free survival than subtotal resection group. However, there was no difference in overall survival. The patients who had adjuvant radiation therapy after surgery had some benefit of longer progression free survival, compared to the patients without adjuvant radiation therapy. Conclusion: SFT/HPC grade I group showed relatively benign course than other groups. The long-term follow-up and periodic systemic evaluation is mandatory to detect systemic metastasis. Grade III group presented more aggressive nature, compared to grade II group. In grade II group, extent of resection and adjuvant radiation therapy is significant for longer progression free survival.
P10.06 surgical selection for 23 thalamic gliomas
Authors: K. G. Cho, J. J. Lim
Journal: Neuro-Oncology (2017)

Background: The ideal surgical approach to thalamic gliomas varies according to their location within the thalamus and consideration of adjuvant vital structures. We report 23 cases of thalamic gliomas treated via various surgical approach. Methods: A retrospective study over a 11-year period (from 2005 to 2016) was performed in 23 patients (1 patient received 2 operation due to recurrence) with thalamic tumors. We reviewed the clinical presentation, surgical approach, perioperative mortality and morbidity and outcomes of 23 operated patients with thalamic tumor. The seletion of the surgical approach for thalamic gliomas was based on the exact location and extension of the tumors and the location of the motor fibers in relation to the tumor. The location of the the motor fibers was identified on the diffusion tensor image and the shortest route to reach the tumor without injuring the motor fibers and disrupting the uninvolved thalamus was decided based on the axial and coronal contrast images. Results: This study included 14 males and 9 females with a mean age of 39.2 years (range 9- 68 years). The most common symptoms were motor deficits(52.2%, 12/23patients) and mental confusion(21.7%, 5/23patients). Most common approaches were transcortical transventricular approach(9, 37.5%). The other approaches were transcortical approach (5, 20.8%), anterior and posterior interhemispheric transcallosal approach (4, 16.6%), occipital transtentorial approach (4, 16.6%), eyebrow approach (The modified lateral supraorbital approach) (1, 4.1%) and transsylvian-transinsular approach (1, 4.1%). The most common location was the posterolateral thalamus (6, 26%). The glioblastoma (12, 52.1%) was the most common pathology followed by anaplastic astrocytoma (4,17.4%), diffuse astrocytoma(3, 13.0%), pilocytic astrocytoma(2, 8.7%), etc. All patients underwent maximal safe tumor resection with awaken craniotomy and/or navigation assisted insertion of tumor markers. Gross total resection was achieved in 15 cases(65.2%), subtotal resection in 4cases(17.4%), and partial resection in 4 cases(17.4%). Mean survival of glioblastoma and WHO grade III glioma patients were 22.6 months and 25.4 months, respectively. Conclusions: Surgical selection for thalamic tumors must be individualized according to tumor location within the thalamus and the extension of the tumor. Also the relation of the motor tract and the tumor is very important. Gross total resection can be achieved in thalamic gliomas with acceptable complications and conferred a better prognosis.
Neuromodulation of Innate Behaviors in <i>Drosophila</i>
Authors: Susy M. Kim, Chih-Ying Su, Jing W. Wang
Journal: Annual Review of Neuroscience (2017)

Animals are born with a rich repertoire of robust behaviors that are critical for their survival. However, innate behaviors are also highly adaptable to an animal's internal state and external environment. Neuromodulators, including biogenic amines, neuropeptides, and hormones, are released to signal changes in animals' circumstances and serve to reconfigure neural circuits. This circuit flexibility allows animals to modify their behavioral responses according to environmental cues, metabolic demands, and physiological states. Aided by powerful genetic tools, researchers have made remarkable progress in Drosophila melanogaster to address how a myriad of contextual information influences the input-output relationship of hardwired circuits that support a complex behavioral repertoire. Here we highlight recent advances in understanding neuromodulation of Drosophila innate behaviors, with a special focus on feeding, courtship, aggression, and postmating behaviors.
P08.22 Targeting glioblastoma mitochondrial metabolism to inhibit cell proliferation &amp; tumor growth
Authors: T. J. Jue, S. A. Chung, R. W. Rapkins, P. Dilda, P. Hogg, K. L. McDonald
Journal: Neuro-Oncology (2017)

Background: Abrogating tumor mitochondrial metabolism by targeting the mitochondria and inhibiting the mTOR pathway is an effective mechanism to impede glioblastoma growth. Inhibiting the mitochondrial activity with an organic arsenide compound, PENAO, has been previously shown to decrease oxidative phosphorylation eventuating in the inhibition of glucose metabolism in patient derived glioblastoma cell lines. Temsirolimus, an inhibitor of the mTOR pathway, has also been shown to interfere with glycolysis. We combined PENAO and temsirolimus to determine if the drugs act synergistically to inhibit glioblastoma tumor metabolism and cell proliferation. Methods: In vitro experimentation of PENAO and temsirolimus as single agents, and in combination, were performed on glioblastoma patient-derived cell lines (PDCLs). Both agents were also assessed in vivo using an orthotopic mouse model in which the animals were implanted with the PDCL, RN1. Once tumor growth was confirmed, we randomized the animals into different treatment arms: (i) untreated control; (ii) PENAO alone (3 mg/kg/day); (iii) low dose temsirolimus alone (1mg/kg/day); (iv) high dose temsirolimus alone (5mg/kg/day); (v) combined PENAO and low dose temsirolimus; and (vi) combined PENAO and high dose temsirolimus. Results: A significant synergistic effect on tumor cell growth was observed in vitro using a panel of PDCLs treated with the combination of PENAO and temsirolimus. Apoptosis, measured by FACS analysis for the expression of the marker, Annexin was observed in approximately 90% of the cell population when treated with the combined treatment of PENAO and temsirolimus compared to 25% for PENAO alone and 44% for temsirolimus alone. An orthotopic model was established by intracranially injecting the PDCL, RN1 in balb/c nude mice. Temsirolimus was delivered by gavage while PENAO was continuously administered subcutaneously with an osmotic pump. While high dose temsirolimus alone improved the overall survival times of mice (12-day advantage compared to the control) which is more than what was observed in the combination treatment of PENAO with temsirolimus (5-day advantage compared to control). CONCLUSION: Highly synergistic effects observed in vitro were not translated to the in vivo model. Although the combination of PENAO and temsirolimus was highly effective in PDCLs in vitro, it did not translate into a significant survival improvement in vivo. Ongoing studies have identified that the concentration levels of PENAO crossing the blood brain barrier were inadequate to deliver the synergistic effects observed in vitro. Future studies will investigate mechanisms of enhancing drug delivery of PENAO to the brain.
Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial
Authors: Stewart Tepper, Messoud Ashina, Uwe Reuter, Jan L Brandes, David Doležil, Stephen Silberstein, Paul Winner, Dean Leonardi, Daniel Mikol, Robert Lenz
Journal: The Lancet Neurology (2017)
P12.02 Demographics and Outcome of Meningioma patients treated in a tertiary care center in the Middle East
Authors: I. Abu Gheida
Journal: Neuro-Oncology (2017)

Introduction: Meningioma is the most frequently diagnosed intracranial primary brain tumor. Many risk and prognostic factors have been previously reported from various centers in different parts of the world. To our knowledge, data from the Middle East region is lacking. We set to study the risk factors and outcomes of meningioma patients treated in a multidisciplinary tertiary-care center in the Middle East treating patients from the entire region. Material and Methods: Patients with pathologic diagnosis of meningioma from January 2005 to December 2015 at the American Univeristy of Beirut Medical Center (AUBMC) were included. Baseline demographics and risk factors were retrospectively collected and reviewed. Follow up and current disease status were then collected from the patients’ charts and updated by a specific questionnaire phone call interviews done by a third party. Results: Two-hundred and seven patients were analyzed. The mean overall survival (OS) and Progression free survival (PFS) for the entire cohort was 81 and 30 months respectively. Patients’ area of residence (city VS country side), occupation, alcohol use, oral contraceptive use, family history of meningioma, previous head trauma, exposure to radiation head/brain imaging, cell phone use, and finally their current meningioma’s Ki-67 stain were examined in univariate analysis and found not to correlate with survival outcome. On the other hand, high BMI (>25), male gender, intermediate/high grade and subtotal resection were significant predictors of worse OS. Multivariate analysis showed that subtotal resection and intermediate/high grade tumors were significant independent predictors of poor survival. Conclusion: In conclusion, our findings coincide with other results reported in the literature from other regions. Complete surgical resection and low-grade disease remain the two most important prognostic factors for patients diagnosed with meningioma.
P14.14 Dural endometrial adenocarcinoma metastasis in intracranial meningioma
Authors: R. Malcata Nogueira, L. Santos Cardoso
Journal: Neuro-Oncology (2017)

Introduction: Brain metastasis from endometrial carcinoma are very rare and usually develop as part of a widespread disseminated disease. Even more rare are endometrial adenocarcinoma dural metastases. Most often is located in the cerebrum and is solitary lesion. Age, performance status of the patient and state of control of the primary disease affect the prognosis and guide treatment decisions in these patients. METHODS: A 66-year-old woman was admitted with inaugural seizures in the emergency department (ED). The patient had a history of endometrial adenocarcinoma previous submitted to surgery 3 years before, without signs of relapse. At the ED the patient had a Glasgow Coma Scale of 7 (O1V1M5), after the seizure and medication with benzodiazepines. CT-Scan and posteriorly MRI showed an expansive lesion with epicenter in the bony structures of the sphenoid triangle and roof of the left orbit, epidural extension and probable infiltration of the brain parenchyma with edema associated and consequently regional mass effect through the parenchyma and adjacent ventricular system with collapse of the frontal horn. The lesion also had an anatomical relationship with bone structures (orbital roof, frontal bone) with thickness of these structures and areas of bone erosion with some grade of compression of the ocular globe. Body CT didn’t show any lesion in other organs or systems. Differential diagnosis was intraosseous meningioma or a secondary lesion in relationship with the previous adenocarcinoma. The patient was submitted to a bone, dural and lesion biopsy with titanium cranioplasty. Results: Histology revealed the diagnosis of metastasis of adenocarcinoma, compatible with endometrial primitive, in meningioma.The patient was studied and it was not found a primary tumor. Conclusions: Early detection of brain metastasis in endometrial carcinoma patients is very important since brain metastasis at their early stage have a better prognosis and response to the treatment. Moreover, brain-imaging studies should be considered in the routine follow-up of patients with primary endometrial carcinoma and also to search for a primary source in females with brain metastasis of unknown primary lesion.