tbuckley/cabot-search huggingface dataset:
P10.03 Immunological differences between patient-matched normal-derived and GBM-derived pericytes
Authors: J Macapagal, A Brooks, P Schweder, E Mee, R Faull, T I H Park, M Dragunow
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma Multiforme (GBM) is the most aggressive, fatal, yet most common form of brain malignancy in adults. Despite advances in immune-based treatments for other modes of cancer, GBM remains a challenge due to its ability to dampen immune responses via mechanisms not yet fully understood. With a median survival time of only 15 months following diagnosis, there is a strong push to find new targets for therapy. The microenvironment comprises a mixture of malignant tumour cells, stroma, blood vessels and infiltrating inflammatory cells. Despite advances in understanding the contribution of these cells in establishing an anti-inflammatory microenvironment, the contribution of pericytes, an important neurovascular mural cell that forms the blood-brain barrier, has been inadequately studied. Therefore, we investigated the differences in immune profile between patient-matched non-neoplastic brain- and GBM-derived pericytes under basal and induced conditions. MATERIAL AND METHODS Primary patient-matched non-neoplastic brain and GBM tumour derived pericytes were isolated from specimens excised from consenting patients undergoing GBM surgical resection at Auckland City Hospital. Pericytes were treated with inflammatory cytokines including IL-1β, IFN-γ, TNFα and TGFβ for up to 24 hours. Inflammatory profile changes were probed for using fluorescent immunocytochemistry, qRT-PCR and spectral flow cytometry. Media was also collected for secretome analysis via cytometric bead array. RESULTS GBM pericytes show decreased expression of CX3CL1, both basally and following IL-1β treatment, via qRT-PCR and CBA. In contrast, increased gene expression and secretion of IL-6 and IL-8 by GBM pericytes were observed. GBM pericytes also basally express CD90 and anti-inflammatory molecule PD-L1 compared to their normal counterparts. In terms of activated pathways, basal SMAD2/3 activation is increased in GBM pericytes, while also showing greater activation following treatment with IL-1β, IFN-γ but not TNFα. C/EBPδ is activated and translocated following inflammatory stimulation; however, shows localised expression within the cytoplasm only observed in GBM pericytes. CONCLUSION This immunological screen of GBM pericytes highlights them as key players in the establishment of the tumour microenvironment. With data suggesting the activation of pathways such as the SMAD2/3 pathway in an unconventional manner, it suggests the potential for pericytes to manipulate pathways towards a more immunosuppressive outcome. Further immune characterisation of such cells is required to fully understand how they might contribute to the immunosuppressive nature of GBM.
Retinal stem cell transplantation: Balancing safety and potential
Authors: Mandeep S. Singh, Susanna S. Park, Thomas A. Albini, M. Valeria Canto-Soler, Henry Klassen, Robert E. MacLaren, Masayo Takahashi, Aaron Nagiel, Steven D. Schwartz, Kapil Bharti
Journal: Progress in Retinal and Eye Research (2019)

Stem cell transplantation holds great promise as a potential treatment for currently incurable retinal degenerative diseases that cause poor vision and blindness. Recently, safety data have emerged from several Phase I/II clinical trials of retinal stem cell transplantation. These clinical trials, usually run in partnership with academic institutions, are based on sound preclinical studies and are focused on patient safety. However, reports of serious adverse events arising from cell therapy in other poorly regulated centers have now emerged in the lay and scientific press. While progress in stem cell research for blindness has been greeted with great enthusiasm by patients, scientists, doctors and industry alike, these adverse events have raised concerns about the safety of retinal stem cell transplantation and whether patients are truly protected from undue harm. The aim of this review is to summarize and appraise the safety of human retinal stem cell transplantation in the context of its potential to be developed into an effective treatment for retinal degenerative diseases.
Dementia in China: epidemiology, clinical management, and research advances
Authors: Longfei Jia, Meina Quan, Yue Fu, Tan Zhao, Yan Li, Cuibai Wei, Yi Tang, Qi Qin, Fen Wang, Yuchen Qiao, Shengliang Shi, Yan-Jiang Wang, Yifeng Du, Jiewen Zhang, Junjian Zhang, Benyan Luo, Qiumin Qu, Chunkui Zhou, Serge Gauthier, Jianping Jia
Journal: The Lancet Neurology (2019)
P14.103 Patterns of diffuse glioma progression
Authors: G L Kobyakov, A Belyashova, Y Trunin, O Absalyamova, K Lodygina, N Kobiakov
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND According to WHO 2016 Classification, all gliomas are considered potentially malignant. Earlier it was thought that the ultimate goal for treatment is local control of tumor growth: maximal surgical resection with subsequent local radiotherapy +/- chemotherapy. Disease progression was primarily linked only to local relapse. In the recent years, different progression patterns of diffuse glioma were identified: from distant growth into an anatomically unrelated area far from primary lesion, to bone metastases and even to visceral organ metastases. MATERIAL AND METHODS In this study we analyzed glioblastoma progression patterns in a cohort of 170 patients, who received radiation therapy as one of the treatment options for local relapse in Burdenko Neurosuregry Institute. All patients had a first relapse of glioblastoma at the age of 16 to 74 years old, 72 patients were female and 98 male. All patients initially underwent surgery and local radiotherapy (in combination with temozolomide) for a solitary supratentorial lesion of glioblastoma. Various methods of radiotherapy (including radiosurgery and hypofractionated radiation therapy) were used as one of the treatment options for recurrent tumor. One of our aims was to evaluate glioblastoma progression patterns in this cohort. RESULTS Comparing neuroimaging data at the time of tumor progression with initial MRI we found that in 127 of 170 patients disease progression was identified anatomically close to the primary tumor site, i.e. disease progressed as a local relapse. Recurrent lesions without obvious anatomical relation to primary site were identified in 33 patients (19.4%); in particular, 7 patients had a lesion in contralateral hemisphere, one patient had spinal subarachnoid dissemination. A combination of local and distant tumor progression was identified in 10 of these 33 patients. CONCLUSION We identified the following progression patterns for diffuse glioma based to these data and previous clinical experience: (a) local brain relapse - anatomically close to the primary lesion; (b) brain and spinal subarachnoid spread; (c) distant relapse - anatomically unrelated to primary tumor (can be both in ipsilateral or contralateral brain hemisphere); (d) local tumor progression as infiltration of soft tissues of the head and cranial bones; (e) regional lymph node metastases; (f) distant metastases - skeletal bone metastases and/or visceral organ metastases. Naturally, different combinations of these diffuse malignant glioma progression patterns are possible. A quite high incidence and differences between diffuse glioma progression patterns require a more thorough evaluation both because of treatment strategies as well as to understand the origins of glial tumors (e.g. Why in some cases of complete remission at the primary tumor site there is tumor progression in contralateral hemisphere?)
Individual Assignment of Adult Diffuse Gliomas into the EM/PM Molecular Subtypes Using a TaqMan Low-Density Array
Authors: Jiuyi Li, Yang Xue, Anna Wenger, Yingyu Sun, Zheng Wang, Chuanbao Zhang, Yunqiu Zhang, Boglarka Fekete, Bertil Rydenhag, Asgeir Store Jakola, Tao Jiang, Helena Carén, Xiaolong Fan
Journal: Clinical Cancer Research (2019)

We aimed to develop a diagnostic platform to capture the transcriptomic resemblance of individual adult diffuse gliomas of WHO grades II to IV to neural development and the genomic signature associated with glioma progression.Based on the EM/PM classification scheme, we designed a RT-PCR-based TaqMan low-density array (TLDA) containing 44 classifier and 4 reference genes. Samples of a training dataset (GSE48865), characterized by RNA-sequencing, were utilized to optimize the TLDA design and to develop a support vector machine (SVM)-based prediction model. Complemented with Sanger sequencing for IDH1/2, and low coverage whole genome sequencing (WGS), the TLDA and SVM prediction model were tested in a validation (31 gliomas) and a test (121 gliomas) dataset.Independent of morphologically defined subtypes and grades, gliomas can be individually assigned into the EM and PM glioma subtypes with the respective areas under ROC curves at 0.86 and 0.85 in the validation dataset. The EM gliomas showed a medium overall survival (OS) of 15.6 months, whereas the medium OS for PM gliomas was not reached (HR = 3.55; 95% confidence interval, 1.96-6.45). The EM and PM gliomas showed distinct patterns of genomic alterations, with IDH mutation and 1p19q codeletion in the PM gliomas and gain of chromosome 7/loss of chromosome 10 in the EM gliomas. Extensive chromosomal abnormalities marked the progression of PM gliomas.The integration of EM/PM subtyping, IDH sequencing, and low coverage WGS may improve the risk stratification and selection of treatment regimens for patients with glioma.
Mitochondrial Morphology Controls Hematopoietic Stem Cell Self-Renewal and Confers Them Divisional Memory
Authors: Ashwini S. Hinge, Jingyi He, Eucabeth Mose, Jose Javier, James Bartram, Ellen Fjellman, Hiromi Sesaki, H Leighton Grimes, Nathan Salomonis, Marie-Dominique Filippi, PhD
Journal: Blood (2017)
New Hope for Patients with Major Depressive Disorder?
Authors: Emil F. Coccaro
Journal: New England Journal of Medicine (2019)

Major depressive disorder is a serious mental health condition that affects up to 16% of people in the United States during their lifetimes and about 7% of the U.S. population in a given year.1 In addition, patients with major depressive disorder have an outsized risk of suicidal behavior. Approximately 60% of patients with major depressive disorder have a response to currently marketed antidepressant agents. However, many other patients do not have a response and are considered to have treatment-resistant depression. Reasons for treatment resistance include the clinical and biologic heterogeneity of the disorder and the likelihood that no single mechanism . . .
P11.14 The addition of hyperbaric oxygen to the treatment of T98G glioblastoma cell cultures with selected CK2 inhibitor TDB enhances its anti-tumour effect
Authors: E Pucko, R Ostrowski, M Zielinska, E Matyja
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive glial neoplasm characterized by infiltrative cell growth in adults. The current standard of care for high-grade glioma patients includes surgery, radiotherapy and chemotherapy using temozolomide and other alkylating agents. Despite this, median survival of the patients with GBM is less than two years. One of the main factors related to the progression of neoplastic cells is hyperactivity of protein kinases, including CK2 kinase and a high level of tumor hypoxia, both of which also contribute to tumour resistance to treatment. Our previous study indicated that some CK2 inhibitors exhibit anti-proliferative effect on glioma cells. The aim of this study was to examine whether HBO may enhance the anti-tumour efficacy of 1-(β-D-2’-deoxyribofuranosyl)-4,5,6,7-tetrabromo-1H-benzimidazole (TDB) - CK2 inhibitor, under combination HBO/TDB therapy. MATERIAL AND METHODS Studies were performed on human glioblastoma T98G cell line (ATCC). Cells were cultured in MEM medium supplemented with 1-(β-D-2’-deoxyribofuranosyl)-4,5,6,7-tetrabromo-1H-benzimidazole in concentrations of 0.1 μM; 1 μM, 25 μM, 50 μM, 75μM, 100 μM. Cultures were sustained in various oxygen conditions: normoxia for 24 and 48 hours or1 hour of hyperbaric oxygen (HBO, 97,5% O2/2,5% CO2, pressure of 2 ATA) followed by 23 hours of normoxia (21% O2/5% CO2/78% N2). Control groups included the cultures sustained in normoxia conditions. The viability of glioma cell lines was established at 24 and 48 hours post TDB treatment by Cell Titer 96®A Queous One Solution Cell Proliferation Assay. RESULTS The study evidenced that TDB inhibited the viability of neoplastic cells at a concentration of 75 μM after 24 and 48 hours. Administration of hyperbaric oxygen alone also caused a reduction in viability of glioblastoma cells. The cytotoxic effect of the tested CK2 inhibitor was significantly enhanced when tested compound was combined with HBO. What’s more, under the influence of hyperbaric oxygen, TDB significantly reduced the viability of tumor cells already at a concentration of 25 μM after 24 hours. CONCLUSIONS Hyperbaric oxygen administration significantly reduces the viability of T98G line cells and increases their sensitivity to the tested CK2 kinase inhibitor. The beneficial cytotoxic effect of TDB/HBO can be obtained at lower concentrations of the tested compound and after shorter exposure time as compared to its administration without HBO. Acknowledgement: The research was supported by the Foundation for the Development of Diagnostic and Therapy, Warsaw
P03.06 Cavernous malformations of the brainstem: radiosurgical management with gamma knife
Authors: K Abdel Karim, A M El-Shehaby, W A Reda, R M Emad Eldin, A Nabeel, S Tawadros, P Khalil
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND About 20% of intracranial cavernous malformations (CM) occur in the brainstem. The greatest risk of brainstem CM is hemorrhage which can be devastating and even fatal in this location. The optimal management for these lesions would naturally be microsurgical resection. However, surgery in this location is associated with significant morbidity and mortality. Gamma knife radiosurgery provides a safer alternative. The purpose of this study is to investigate the efficacy of gamma knife radiosurgery for brainstem CM in preventing bleeding, as well as, assess safety with regards to radiation-induced complications. Additionally, we aimed to evaluate the feasibility and safety of volume-staged gamma knife radiosurgery for larger CM in the brainstem. MATERIAL AND METHODS Between September 2007 and August 2017, 48 patients with brainstem CM were treated by gamma knife. Thirty-two patients were available for follow up of at least one year. A total of 33 lesions were treated (one patient had two brainstem CM). Twenty-eight patients had at least one hemorrhagic event before radiosurgery. The patients underwent 40 gamma knife sessions. These included 28 single sessions (including two sessions for same patient for 2 different lesions in pons). Five patients had volume-staged gamma knife treatments due to the large size of the CM. The median total CM volume/lesion was 0.8 cc (0.1–30.4 cc), while the median target volume/session was 1 cc (0.1–11.5 cc). The median prescription dose was 12 Gy (10–14 Gy). RESULTS The mean follow up after treatment was 40 months (12–95 months). The annual hemorrhage rate (AHR) before gamma knife radiosurgery was 25.5%. After treatment there were a total of 5 hemorrhagic events with an overall AHR of 4.5%. Three hemorrhagic events occurred in the first 2 years after treatment with an AHR of 2.7% and 2 events more than 2 years after treatment with an AHR of 2.2%. No hemorrhagic events occurred among the patients treated by volume-staged radiosurgery. Clinical improvement was observed in 15 (46.9%) patients. Temporary adverse radiation events developed in 6 patients (19%). CONCLUSION Gamma knife radiosurgery provides an effective and safe treatment alternative to surgery for brainstem CM. Volume-staged gamma knife radiosurgery for brainstem CM appears to be a viable option for larger CM.
P11.02 Hypothermia effect on glioblastoma cell viability, proliferation and migration
Authors: C Fulbert, C Gaude, E Sulpice, S Chabardès, D Ratel
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma is the most common and aggressive primary brain tumor in adults. In spite of intensive treatment, patients have a poor prognosis with a median survival of 14–16 months. After surgical resection followed by postoperative chemoradiation (combined temozolomide treatment and radiotherapy), tumor recurs in the resection margin for more than 90% of patients. This recurrence results from the activation of residual glioblastoma cells beyond the resection cavity by therapy-induced injuries. To handle this issue, we propose therapeutic hypothermia as an adjuvant treatment, in order to place the resection margin in a state of hibernation. In fact, hypothermia was introduced as a promising therapeutic approach in various medical applications like cardiac arrest and pharmaco-resistant epilepsy. Only a few in vitro studies explored the effects of hypothermia on cancer cells and showed promising results. The aim of our work is to investigate the effects of hypothermia on glioblastoma cell proliferation and migration, two key cellular processes involved in cancer progression. MATERIAL AND METHODS We performed in vitro experiments on glioblastoma cell lines with different p53 status and various growth rates. For exploring the therapeutic potential of both mild and moderate hypothermia, we studied their impact on cell viability, proliferation and migration. We also performed cell cycle analysis by quantitation of DNA content using flow cytometry. RESULTS Results were similar for all glioblastoma cell lines, and demonstrated that cells were extremely sensitive to hypothermia. We showed that both mild and moderate hypothermia induced significant changes on glioblastoma cell lines behavior with a strong inhibition of cell proliferation and migration. Moderate hypothermia also affected glioblastoma cell viability and modified their distribution into the cell cycle phases. CONCLUSION Our results were comparable in all glioblastoma cell lines tested, demonstrating a consistent and universal effect of hypothermia. We showed that hypothermia significantly inhibits cell proliferation and migration, which are key processes involved in tumor growth. Proliferation arrest could be explained by the accumulation of cells in the G2/M phase of the cell cycle. Together, these results support hypothermia as a promising adjuvant therapy for glioblastoma patients. Indeed, combined with current treatments, moderate hypothermia applied at the resection margin could prevent tumor recurrence after surgical resection. There is a crucial need to propose innovative glioblastoma treatments, and hypothermia appears as a promising therapeutic way. SUPPORT This work received financial support through grants from the Groupement des Entreprises Françaises de Lutte contre le Cancer (GEFLUC Grenoble - Dauphiné - Savoie) and the Fonds de dotation Clinatec.
N95 Respirators vs Medical Masks for Preventing Influenza Among Health Care Personnel
Authors: Lewis J. Radonovich, Michael S. Simberkoff, Mary T. Bessesen, Alexandria C. Brown, Derek A. T. Cummings, Charlotte A. Gaydos, Jenna G. Los, Amanda E. Krosche, Cynthia L. Gibert, Geoffrey J. Gorse, Ann-Christine Nyquist, Nicholas G. Reich, Maria C. Rodriguez-Barradas, Connie Savor Price, Trish M. Perl
Journal: JAMA (2019)

Clinical studies have been inconclusive about the effectiveness of N95 respirators and medical masks in preventing health care personnel (HCP) from acquiring workplace viral respiratory infections.To compare the effect of N95 respirators vs medical masks for prevention of influenza and other viral respiratory infections among HCP.A cluster randomized pragmatic effectiveness study conducted at 137 outpatient study sites at 7 US medical centers between September 2011 and May 2015, with final follow-up in June 2016. Each year for 4 years, during the 12-week period of peak viral respiratory illness, pairs of outpatient sites (clusters) within each center were matched and randomly assigned to the N95 respirator or medical mask groups.Overall, 1993 participants in 189 clusters were randomly assigned to wear N95 respirators (2512 HCP-seasons of observation) and 2058 in 191 clusters were randomly assigned to wear medical masks (2668 HCP-seasons) when near patients with respiratory illness.The primary outcome was the incidence of laboratory-confirmed influenza. Secondary outcomes included incidence of acute respiratory illness, laboratory-detected respiratory infections, laboratory-confirmed respiratory illness, and influenzalike illness. Adherence to interventions was assessed.Among 2862 randomized participants (mean [SD] age, 43 [11.5] years; 2369 [82.8%]) women), 2371 completed the study and accounted for 5180 HCP-seasons. There were 207 laboratory-confirmed influenza infection events (8.2% of HCP-seasons) in the N95 respirator group and 193 (7.2% of HCP-seasons) in the medical mask group (difference, 1.0%, [95% CI, -0.5% to 2.5%]; P = .18) (adjusted odds ratio [OR], 1.18 [95% CI, 0.95-1.45]). There were 1556 acute respiratory illness events in the respirator group vs 1711 in the mask group (difference, -21.9 per 1000 HCP-seasons [95% CI, -48.2 to 4.4]; P = .10); 679 laboratory-detected respiratory infections in the respirator group vs 745 in the mask group (difference, -8.9 per 1000 HCP-seasons, [95% CI, -33.3 to 15.4]; P = .47); 371 laboratory-confirmed respiratory illness events in the respirator group vs 417 in the mask group (difference, -8.6 per 1000 HCP-seasons [95% CI, -28.2 to 10.9]; P = .39); and 128 influenzalike illness events in the respirator group vs 166 in the mask group (difference, -11.3 per 1000 HCP-seasons [95% CI, -23.8 to 1.3]; P = .08). In the respirator group, 89.4% of participants reported "always" or "sometimes" wearing their assigned devices vs 90.2% in the mask group.Among outpatient health care personnel, N95 respirators vs medical masks as worn by participants in this trial resulted in no significant difference in the incidence of laboratory-confirmed influenza.ClinicalTrials.gov Identifier: NCT01249625.