tbuckley/cabot-search huggingface dataset:
P09.02 Survival after re-irradiation of recurrent glioblastoma: no impact of MGMT and treatment modalities?
Authors: F. Mack, B. Baumert, R. Steffens, M. Kuhn, U. Herrlinger, M. Glas
Journal: Neuro-Oncology (2017)

PURPOSE: To determine survival after re-irradiation (re-RT) of recurrent glioblastoma and to determine the prognostic impact of MGMT methylation status, different irradiation techniques and concomitant/adjuvant drug therapy. MATERIALS/METHODS: Patients with recurrent glioblastoma who received re-RT at our institution were analyzed retrospectively for progression-free survival (PFS) and overall survival (OS). Two different regimes of radiotherapy were used: stereotactic radiotherapy (STX, radiosurgery or hypofractioned radiotherapy with 15 x 3 Gy, N=22) or 3 dimensional conformal radiotherapy (3D-CRTwith 15 x 3 Gy or 30 x 1,8 Gy, N=30). Re-RT schemes differed according to treatment volume. Results: 52 patients received re-RT for recurrent primary glioblastoma between July 2012 and May 2016. Median age was 63 years, median KPS 80% and 33 patients (64 %) received only one treatment prior re-RT. 47 patients (90%) received at least one sort of drug therapy concomitant to re-RT (alkylating chemotherapy N=27; bevacizumab N=19; bevacizumab and chemotherapy N=1). 19 tumors were MGMT methylated (37%) and 28 unmethylated (54%). 52% of all patients had only best supportive care in case of relapse after re-RT. ReRT was stopped prematurely in only 1 patient. At a median follow-up time of 74 weeks, 77% of all patients had died due to tumor progression. Median overall survival (mOS) was 32 weeks with a 6-month-OS of 59%. For MGMT methylated vs. unmethylated tumors, mOS was 37 vs. 24 weeks (p=0.180) and m-PFS was 25 vs. 19 weeks (p=0.324). The choice of concomitant therapy (bevacizumab vs. chemotherapy) had no impact on survival (mOS 32 vs. 36 weeks, p=0.993; mPFS 21 vs. 18 weeks, P=0.632). mOS for STX and 3D-CRT was 36 vs. 27 weeks (p=0.484) and mPFS was 24 vs. 19 weeks (p=0.922). CONCLUSION: After re-RT mOS was moderate with 7,4 months for patients with relapsed glioblastoma. There was no impact of MGMT promotor methylation status, the choice of concomitant therapy or type of re-RT on survival parameters in our relatively small patient cohort. Prospective studies should also take aspects of quality-of-life into account.
OS02.5 Prolonged survival of patients with recurrent medulloblastoma and atypical teratoid rhabdoid tumor treated with an antiangiogenic metronomic combination therapy
Authors: I. Slavc, A. Peyrl, A. Azizi, J. Gojo, T. Czech, M. Chocholous, D. Reisinger, K. Dieckmann, C. Haberler
Journal: Neuro-Oncology (2017)

BACKGROUND: Prognosis of patients with recurrent medulloblastoma and atypical teratoid rhabdoid tumor (ATRT) is dismal despite intensive therapy including high-dose chemotherapy with stem cell rescue. We report on 28 patients with recurrent medulloblastoma and ATRT treated with an alternative approach to conventional chemotherapy that targets neovascularisation by interfering with tumor angiogenesis at various levels. Patients and METHODS: From 11/2006 to 06/2016, 28 patients were diagnosed with recurrent embryonal tumors, 20 with a recurrent medulloblastoma (13 first, 7 multiple recurrences) and eight with recurrent ATRT (5 first, 3 multiple), three had germ line mutations. Treatment consisted of an antiangiogenic multidrug-regime including IV bevacizumab, oral thalidomide, celecoxib, fenofibrate, and etoposide alternating with cyclophosphamide, and augmented with intraventricular therapy (etoposide and liposomal cytarabine). Median age at start of antiangiogenic therapy was 10 (1–24) years for medulloblastoma and 1.5 (1–13) years for ATRT. Results: As of 11/2016, 12/20 patients with medulloblastoma are alive at a median of 25 (12–97) months after their last recurrence. 8/12 surviving patients are currently in CR for 97, 94, 93, 29, 27, 23, 19 and 18 months, five off therapy for 79, 62, 60, 22 and 18 months, three are in PR 23, 12 and 2 months after their last recurrence and one patient has stable disease 12 months after her last recurrence. 5-year-OS is 57.6 ± 13.2%. One patient died of an accident in CR 23 months after initiation of antiangiogenic therapy and one patient with a very good PR died of a septicemia seven months after his last recurrence. Two patients had prior been treated with the same antiangiogenic approach and had recurred 67 and 40 months after their last recurrence while off therapy for 36 and 21 months and both patients are in remission again, one off therapy for 18 months. 3/8 patients with ATRT are alive. Follow-up since last recurrence is 72, 27 and 24 months and all patients are off therapy for 52, 14 and 13 months. One patient died of another cause without evidence of tumor at autopsy 54 months after recurrence and while off therapy for 46 months. One surviving patient with a germ line mutation and a fourth recurrence was prior treated with the same approach albeit without intrathecal therapy. He recurred 78 months after his last recurrence while off therapy for 36 months. He is again in CR and off therapy for 13 months. Therapy is primarily outpatient, was generally well tolerated, and toxicities were manageable. CONCLUSION: The proposed antiangiogenic regimen is currently being evaluated for medulloblastomas in an international phase II protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290). The same approach seems to be also efficacious in recurrent ATRTs and warrants further evaluation.
Statistical Caution in Big Data Approaches to Transfusion Medicine Research
Authors: Nareg Roubinian, Donald Brambilla, Edward L. Murphy
Journal: JAMA Internal Medicine (2017)

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Police cannot continue to plug gaps in mental health provision, chief inspector warns
Authors: Gareth Iacobucci
Journal: BMJ (2017)

Police are increasingly relied on as the “first resort” for dealing with people with mental health conditions because of a lack of care in the community, the country’s chief inspector of constabulary has warned.

In his annual State of Policing report for England and Wales,1 Tom Winsor said that cuts to other public services were placing an “unacceptable strain” on the police and endangering public safety.

He said that police officers should not be relied on to support people who need medical care, and he called for more resources to be invested in mental health services. The government insisted that it was dealing with the issue by investing an additional …
OS09.3 Synergistic activity of NKG2D-based chimeric antigen receptor (CAR)-T cells and radiotherapy against glioma
Authors: T. Weiss, M. Weller, M. Pruschy, C. Sentman, P. Roth
Journal: Neuro-Oncology (2017)

Introduction: Glioblastoma is the most common primary brain tumor in adults and virtually always lethal despite a multimodal treatment regimen including surgery, chemotherapy and radiotherapy. Therefore, novel treatment modalities are needed. Adoptive immunotherapy with genetically engineered T cells that express a chimeric antigen receptor (CAR) to recognize and eliminate tumors in a MHC-independent manner is an emerging strategy that has led to remarkable responses in hematologic malignancies. CARs that target the natural-killer group 2-member D (NKG2D) system elegantly use the promiscuous binding properties of the NKG2D receptor that binds to several tumor-associated ligands. NKG2D-based CAR T cells have never been investigated against glioma and it is unknown if this strategy can overcome the challenges of this tumor entity and if it could even be implemented in established conventional treatment regimens. Material and Methods: CAR T cells were generated by retroviral transduction of splenocytes to express a NKG2D-based CAR (chNKG2D) or wildtype NKG2D (wtNKG2D). For in vitro studies, murine glioma cells (GL-261, SMA-560, SMA-540, SMA-407) were co-cultured with chNKG2D or wtNKG2D T cells and we assessed the cytolytic activity and cytokine production. For in vivo studies, we used GL-261 cells syngeneic to C57BL/6 mice and monitored tumor growth by magnetic resonance imaging. We tracked CAR T cells in vivo with fluorescence molecular tomography (FMT), flow cytometry and immunohistochemistry. To study the combination of radiotherapy with CAR T cells, mice received a single subtherapeutic dose of local irradiation. Results: In all murine glioma cell lines, chNKG2D T cells had a significantly higher specific cytolytic activity compared to wtNKG2D T cells. Furthermore, chNKG2D T cells produced more IFN-γ. In vivo, intravenously injected chNKG2D T cells migrated to the orthotopic tumor site, were tolerated without toxicities, prolonged the survival and cured a fraction of tumor-bearing mice. This anti-tumor effect was even more pronounced in case of intratumoral CAR T cell administration. Survivors were long-term protected against tumor re-challenge. Mechanistically, this was not the result of a classical immune memory response, but rather due to local persistence of chNKG2D T cells. Radiotherapy augmented the effect of chNKG2D T cell therapy already after a single application of a subtherapeutic dose. It promoted migration of CAR T cells to the tumor site and the effector function of NKG2D-based CAR T cells. Conclusion: We provide the first systematical preclinical assessment of NKG2D-based CAR T cells against glioma. This strategy was effective, tolerated without toxicities, conferred long-term protection and was synergistic with radiotherapy. These findings could provide a rationale to test this immunotherapeutic strategy also in human glioma patients.
THE EFFECT OF EXERCISE PRESCRIPTION ON FORCE OUTPUT AND MUSCLE ACTIVATION DURING THE NORDIC HAMSTRING EXERCISE
Authors: Rob Buhmann, Anthony Shield, Casey Sims
Journal: British Journal of Sports Medicine (2017)

Background The Nordic hamstring exercise (NHE) is employed to increase eccentric strength and reduce the risk of recurrent hamstring strain injury. Currently, the prescription of the NHE offering most benefit is unknown. Objective To assess force production, muscle activation and kinematics during two NHE prescriptions. It was hypothesized that a 5*6 repetitions protocol would yield greater average forces, smaller force drops and greater muscle activation per set compared to a 3*10 protocol. Additionally, it was hypothesised that during both protocols, peak muscle activation would occur at shorter muscle lengths than peak force. Design Randomised cross-over study. Setting Recreationally trained and sub-elite male athletes. Participants Thirteen healthy males (age 23±4 years, stature 178±6.5 cm and weight 75±17 kg). Interventions Participants performed 3*10 and 5*6 repetitions of the NHE (on separate occasions), 3 minutes rest was given between sets. Main Outcome Measurements Load cells were used to record knee flexor force, electromyography (EMG) was used to measure hamstring activation and a goniometer was used to measure knee flexion angles during each repetition. Results Average force (666.44N during 3*10 vs. 697.95N during 5*6) and force drop per set (−54.48N during 3*10 and −51.73N during 5*6) was not different between protocols. Additionally, normalised biceps femoris (87 vs. 79% of max isometric EMG during 3*10 and 5*6 respectively) and medial hamstring (111 vs. 98% of max isometric EMG during 3*10 and 5*6 respectively) EMG per set was not different between protocols. For both protocols a significant difference between the angle of peak torque and angle of peak biceps femoris EMG was observed (p&lt;.001, mean difference= 15.4, CI=13.6–17.2 degrees). Conclusions Force output and muscle activation during the NHE is not affected by prescription. Peak activation of the biceps femoris appears to occur at shorter muscle lengths than peak force, suggesting inhibition of this muscle at long lengths.
P08.35 Exosomes derived from Glioma Stem Cells (GSCs) promote cell migration, proliferation and radiation resistance in brain cancer
Authors: C. Ma, H. Nguyen, L. Paradiso, U. Putz, R. Luwor, A. Kaye, A. Morokoff
Journal: Neuro-Oncology (2017)

Introduction: Glioblastoma is the most common brain tumour with 15 month median survival due to rapid recurrence and metastasis after initial treatment. Accumulating evidences demonstrated Glioma Stem Cells (GSCs) play a vital role in tumour metastasis and therapeutic resistance but the molecular mechanism remains unclear. This study aims to identify the roles of GSCs-derived exosomes in tumour cell progression and radiation resistance to promote metastasis. Materials and Methods: Exosomes were isolated from GSCs (GSCs-Exos) by serial centrifugation. Exosomes size and morphology were confirmed using Nanosight measurement and transmission electron microscopy respectively. Differentiated glioma cell lines LN229 and U118 were utilized as recipient cell model. LN229 and U118 cells were treated with and without GSCs-Exos and their functions studied. Wound healing and spheroid migration assays were performed to detect cell migration. We also employed cell viability assay to detect cell proliferation. Colony formation assay were conducted to detect the cell survival of irradiated recipient cells after exposed to GSCs-Exos. Results: Transmission electron microscopy and Nanosight demonstrated GSCs can produce exosomes into microenvironment. Both LN229 and U118 cells increased their migratory ability in the presence of GSCs-Exos. When LN229 and U118 were exposed to GSCs-Exos, there was an increase in cell proliferation. Radiation efficacy of LN229 and U118 reduced significantly by GSCs-Exos and induced colony formation compared to differentiated glioma cells-derived exosomes. CONCLUSION: Our study showed exosomes are released by GSCs and can be taken up by differentiated glioma cells. In the presence of GSCs-Exos, differentiated glioma cells have higher proliferation and migration capacity, and acquire resistance of traditional therapeutic radiation. These results indicated GSCs-Exos play an important role in tumour progression and metastasis after conventional therapeutics. Future study will be focused on GSCs-Exos cargo content for potential prognosis biomarker identification.
The Terminology Issue for Myeloid-Derived Suppressor Cells
Authors: Rongcun Yang, Richard B.S. Roden
Journal: Cancer Research (2007)

In Response: 

In the literature, including our own ( [1][1]), diverse terms (such as Gr-1+CD11b+ myeloid cells, Gr-1+ myeloid cells, Gr-1+CD11b+ immature myeloid cells, CD11b+Gr1+CD31+myeloid progenitor, immature myeloid cells, myeloid suppressor cells, etc.) are used to describe murine Gr1+CD11b+
Characterization Of Airway Ormdl3 Expression In Human Asthma And In Relation To The Asthma Gwas Variant Rs7216389
Authors: ME Lachowicz-Scroggins, ED Gordon, C Urbanek, HJ MacLeod, S Yuan, PG Woodruff, S Ramachandran, JW Thorner, MA Seibold, JV Fahy
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Author(s): Lachowicz-Scroggins, ME; Gordon, ED; Urbanek, C; MacLeod, HJ; Yuan, S; Woodruff, PG; Ramachandran, S; Thorner, JW; Seibold, MA; Fahy, JV
P03.10 Combined immunohistochemistry for IDH1R132H, p53 and ATRX improves the molecular classification of diffuse gliomas in adults
Authors: T. Komori, M. Nitta, T. Maruyama, Y. Muragaki, T. Kawamata
Journal: Neuro-Oncology (2017)

Introduction: The updated 2016 edition of the WHO Classification of Tumor of the Central Nervous System has shifted from the traditional approach primarily based on microscopic features to that on genetic hallmarks. The classification of diffuse gliomas is now defined in accordance with their IDH and 1p/19q status. Although that shift has resulted in a more objective definition of diffuse gliomas, genetic testings, which are not always available worldwide, has become mandatory for WHO diagnosis. Immunohistochemistry (IHC) for mutant IDH1R132H and fluorescence in situ hybridization (FISH) for 1p/19q are the most popular methods, but IDH1R132H does not detect other loci and currently available probes for 1p36 and 19q13 are known to yield false positive results (about 15%). To overcome such disadvantages, we verified the utility of combined IHC for p53 and ATRX in addition to IDH1R132H, since about 90% of IDH mutated astrocytomas carry TP53 mutations followed by ATRX mutations in 80% of TP53 mutants and TP53 or ATRX mutations, which are detectable on IHC, are mutually exclusive to 1p/19q co-deletion. Materials and Methods: Archived 97 grade II-IV diffuse gliomas of adults with known 1p/19q status on FISH testing (Vysis/Abbotte DNA FISH probes, Chicago, IL) were served for study. Using Envision kit (Dako, Santa Clara, CA), IDHR132H (H09; Dianova, Hamburg, Germany), p53 (DO-7; DAKO) and ATRX (polyclonal HPA001906; Sigma-Aldrich, St. Louis, MO) were applied formalin-fixed, paraffin-embedded sections. Tumors with strongly positive nuclei > 10% of tumor cells on p53 IHC was regarded as positive (TP53 mutated) based on previous studies. Results: All ATRX-lost gliomas were 1p/19q non-deleted. Seven IDH1R132H-negative tumors were p53-positive and ATRX-lost. Six IDH1R132H-positive and ATRX-lost tumors were p53-negative. Of ATRX-intact 53 tumors, 19 tumors were p53-positive; 18 of which were 1p/19q non-deleted. Of 13 co-deleted tumors, two were IDH1R132H-negative. Conclusions: ATRX loss in gliomas was equivalent to 1p/19q non-deletion. IDH1R132H-negative, p53-positive and ATRX-lost gliomas were highly suspicious of carrying IDH mutations other than IDH1R132H. IDH1R132H-positive, ATRX-lost and p53-negative gliomas were suggested to have nonsense or frame-shift mutations of TP53. Although when IDH1R132H and p53 are negative and ATRX is intact it is difficult to predict 1p/19q status, the combined immunohistochemistry for IDH1R132H, p53 and ATRX improves the molecular classification of diffuse gliomas in daily practice.
Vitamin D levels and susceptibility to asthma, elevated IgE levels 3 and atopic dermatitis
Authors: Despoina Manoousaki, Lavinia Paternoster, Marie Standl, Miriam F Moffatt, Martin Farrall, Emmanuelle Bouzigon, David P Strachan, Florence Demenais, Mark Lathrop, William Ocm Cookson, J Brent Richards
Journal: PLoS Medicine (2017)
P01.05 Overexpression of FAT1 gene in GBM is regulated by transcription factor NFkB (RelA)
Authors: K. Chosdol, C. Srivastava, K. Irshad, H. Srinivas, Y. Gupta, C. Sarkar, A. Suri, D. K. Gupta, P. Chattopadhyay, S. Sinha
Journal: Neuro-Oncology (2017)

Introduction: Glioblastoma (GBM) is the most common and aggressive form of primary brain cancer with high tendency for local invasiveness. Hypoxia is a critical feature of glioblastoma, promoting tumor invasiveness via HIF1α. In our laboratory, we have identified the oncogenic role of ‘FAT1’ in glioma. FAT1 is a human homolog of Drosophila tumor suppressor gene ‘fat’. Increased FAT1 expression in human GBM tissue and in GBM cell lines have been observed, augmenting tumor migration/invasiveness; upregulating proinflammatory microenvironment by regulating AP1 transcriptional ­activity as well as found to be modulating HIF1a expression and activity in GBM cells. Since high expression of FAT1 has been observed in GBM and other tumors, here, we have analyzed how FAT1 expression is being regulated in glioma. Materials and Methods: Online tools like transfac, DBD etc. were used to identify potential transcription factors binding sites at the FAT1 promoter. The TCGA online dataset for GBM was analyzed for gene expression study. The expression of genes in tumor samples and GBM cell lines (U87MG and A172) was done by qPCR and Western blot analysis. The transcription regulation of FAT1 gene by NFkB (RelA) was confirmed by in vitro luciferase assay of the FAT1 promoter (5kb), 5’ deletion constructs and site directed mutagenesis of transcription factor binding site at the FAT1 promoter in U87MG cells. Chromatin-immunoprecipitation (ChIP) assay was done for analyzing the binding of endogenous RelA to FAT1 promoter. Results:In silico analysis showed multiple binding sites with high matrix score for RelA on FAT1 promoter. TCGA dataset (n=430) showed significantly higher mRNA expression of FAT1, RelA, IKBKB and RelA target genes (BCL2, MMP9 and Serpine) in GBM. A positive correlation (p<0.01) of FAT1 and BCL2 mRNA was observed in GBM tumors analyzed (n=16). We further observed increased expression of FAT1 on RelA (RelApBABE vector) overexpression and downregulation of FAT1 expression upon PDTC (NFκB inhibitor) treatment in U87MG cells, suggesting RelA having a role in regulation of endogenous FAT1 expression. Furthermore, to confirm the regulatory effect of RelA on FAT1 expression, FAT1 promoter (5kb) and multiple sequential 5’deletion constructs were analyzed by in-vitro luciferase assay. Among all constructs, 5’deletion construct containing single consensus binding site for RelA showed highest luciferase activity endogenously and on exogenous RelA overexpression in U87MG cells. Site directed mutagenesis of RelA consensus binding site decreased luciferase activities by three-fold. ChIP assay confirmed the binding of endogenous RelA on FAT1 promoter. CONCLUSION: RelA transcription factor potentially regulates FAT1 expression in GBM, which is a novel finding. This finding may be clinically relevant, helping in identifying a subset of GBMs with high FAT1 and RelA expression for molecular targeting.
Language discordance between tuberculosis patients and healthcare providers challenging universal access
Authors: Dorothy Nakiwala, Lusha Kellgren, Christian Herzmann, Ioana D. Olaru, Mike Brown, Rashida Ferrand, Palwasha Khan, Katharina Kranzer
Journal: European Respiratory Journal (2017)

We read with great interest the call for urgent action to ensure access to early diagnosis and care of tuberculosis (TB) among refugees by Dara et al . [1]. One of the five recommendations made by the European Respiratory Society and the International Union Against Tuberculosis and Lung Disease is universal access to prevention and treatment services for TB. However, universal access may be impeded by cultural and linguistic barriers [2]. These barriers are most prominent in the initial years following migration and have implications for health, and may affect both access to and quality of care [2–4]. Cultural and linguistic barriers may lead to delays in diagnosis and treatment initiation as well as difficulties in maintaining adherence and effectiveness of contact tracing. Culture and personal experience influences the way in which pain and discomfort are expressed, further complicating mutual understanding between patient and healthcare provider [2]. Language barriers are a significant problem for patients with tuberculosis in England and Scotland <http://ow.ly/DFjq309KEDT>