tbuckley/cabot-search huggingface dataset:
Epigenomic and transcriptomic approaches in the post-genomic era: path to novel targets for diagnosis and therapy of the ischaemic heart? Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart
Authors: Cinzia Perrino, Albert-Laszló Barabási, Gianluigi Condorelli, Sean Michael Davidson, Leon De Windt, Stefanie Dimmeler, Felix Benedikt Engel, Derek John Hausenloy, Joseph Addison Hill, Linda Wilhelmina Van Laake, Sandrine Lecour, Jonathan Leor, Rosalinda Madonna, Manuel Mayr, Fabrice Prunier, Joost Petrus Geradus Sluijter, Rainer Schulz, Thomas Thum, Kirsti Ytrehus, Péter Ferdinandy
Journal: Cardiovascular Research (2017)

Despite advances in myocardial reperfusion therapies, acute myocardial ischaemia/reperfusion injury and consequent ischaemic heart failure represent the number one cause of morbidity and mortality in industrialized societies. Although different therapeutic interventions have been shown beneficial in preclinical settings, an effective cardioprotective or regenerative therapy has yet to be successfully introduced in the clinical arena. Given the complex pathophysiology of the ischaemic heart, large scale, unbiased, global approaches capable of identifying multiple branches of the signalling networks activated in the ischaemic/reperfused heart might be more successful in the search for novel diagnostic or therapeutic targets. High-throughput techniques allow high-resolution, genome-wide investigation of genetic variants, epigenetic modifications, and associated gene expression profiles. Platforms such as proteomics and metabolomics (not described here in detail) also offer simultaneous readouts of hundreds of proteins and metabolites. Isolated omics analyses usually provide Big Data requiring large data storage, advanced computational resources and complex bioinformatics tools. The possibility of integrating different omics approaches gives new hope to better understand the molecular circuitry activated by myocardial ischaemia, putting it in the context of the human 'diseasome'. Since modifications of cardiac gene expression have been consistently linked to pathophysiology of the ischaemic heart, the integration of epigenomic and transcriptomic data seems a promising approach to identify crucial disease networks. Thus, the scope of this Position Paper will be to highlight potentials and limitations of these approaches, and to provide recommendations to optimize the search for novel diagnostic or therapeutic targets for acute ischaemia/reperfusion injury and ischaemic heart failure in the post-genomic era.
Abstract 271: Nos1ap Alters Qtc Intervals Upon Overexpression in Mice
Authors: Tatjana Williams, Daniel Oppelt, Anahi Paula Arias-Loza, Marco Abesser, Joachim Schmitt, Kai Schuh, Oliver Ritter
Journal: Circulation Research (2015)

Rationale: The QT interval duration (QTc) reflects cardiac depolarization. It may predispose individuals to ventricular tachycardia and sudden cardiac death if prolonged (long QTc), shortened (short QTc) or otherwise unregularly. Whole-genome association studies have linked genetic variations in the neuronal nitric oxide synthase adapter protein NOS1AP to variations in QTc intervals and sudden cardiac death. Hypothesis: We hypothesize NOS1AP functions as an L-type-Ca2+ channel modulator via its interaction with the neuronal nitric oxide synthase NOS1. Therefore, alterations in myocardial NOS1AP expression should temper with QTc intervals and increase susceptibility to rhythm disorders. Methods and results: We generated conditional double transgenic mice by crossbreeding pTRE-6xHN-Nos1AP animals with α-MHC-tTA mice; NOS1AP expression is therefore restricted to cardiomyocytes and under control of doxycycline (Tet-Off system). Double transgenic animals were investigated with the main focus upon electrical alterations. Heart rates were similar in NOS1AP overexpressing and non-induced animals. Atrial programmed stimulation repeatedly caused atrial tachycardia, while ventricular programmed stimulation caused VT in NOS1AP overexpressing mice. There was a clear decrease of QTc intervals in NOS1AP overexpressing mice paralleld by a significantly reduced survival (only 56% after 12 weeks vs 100% in non-induced mice. Induced QTc alterations and accompanied deaths subsided upon readministration of doxycycline. We also investigated the functional effect of the human SNP rs16847548 (T/C). We found that this SNP decreased NOS1AP transcriptional activity in vitro and therefore suggest this leads to a decrease in NOS1AP expression in humans. Conclusion: Myocardial overexpression of NOS1AP leads to short QTc syndrome with increased susceptibility to atrial and ventricular rhythm disorders and cardiac death. SNP rs16847548 in NOS1AP resulted in less NOS1AP promoter activity in vitro which could explain the alteration in QTc intervals. In summary, not only mutations in ion channels themselves but also genetic alterations in the expression of ion channel modulators such as NOS1AP, have an impact on QTc intervals.
P10.05 Establishment of team work awake craniotomy: clinical experience in Taiwan
Authors: P. Chen, W. Chang, Y. Chao, C. Toh, K. Wei
Journal: Neuro-Oncology (2017)

Introduction: Awake craniotomy provides the opportunity to maximize both extent of resection and preservation of neurological function. Serial preoperative and postoperative neurobehavial evaluation, magnetic resonance image examination and intraoperative task investigation need multidisciplinary experts to cooperate. Materials and Methods: From 2013, we gradually establish our team for awake craniotomy. Patient who had brain tumor with the symptom of aphasia or hemiparesis and are willing to cooperate would be entered the protocol of awake craniotomy. Patients would receive complete preoperative neurobehavial examination by psychologists and speech therapists and magnetic resonance image included diffuse tensor image. During operation, Patients went through asleep-awake-asleep anesthetic techniques. Direct electric stimulation was used for both cortical and subcortical mapping. Navigation included information of lesion and important fiber tract guided the direction of excision. Rehabilitation doctor performed the tasks and decided the positive response caused by stimulation or excisional procedure. After operation, post-operative image and neurobehavial examination would be performed within one week, 3 months, 6 months and one year later Results: We scheduled awake craniotomy on almost every Tuesday. In recent 89 patients who received awake craniotomy, Twenty-five participants with recurrent tumor underwent the operation. Seven patients received twice and one patient received three times of awake craniotomy. Two patients had controllable intraoperative seizure attack. Early termination of awake status was found in two patients due to general discomfort. Patients with modest preoperative performance status still benefit from the operation. Neurobehavioral functions improved over time and some specific feature correlate to certain aspect of quality of life. The grading of tumor and the extension of resection influence the recovery of neurobehavioral functions and progression free survival considerably. Conclusions: Awake craniotomy is a feasible and effective way to improve not only patient`s survival rate but also quality of life. A team with neurosurgeon, rehabilitation doctor, speech therapist, psychologist, anesthesiologist, nurses and other specialist is important to improve the quality of clinical care for patient who received awake craniotomy. This study is supported by Chang Gung Memorial Hospital with grant number: CMRPG3D0243
P09.44 One year with Optune in Austria: First report on clinical experiences
Authors: D. Pinggera, J. Kerschbaumer
Journal: Neuro-Oncology (2017)

Objective: Tumor Treating Fields (TTFields) consist of intermediate frequency alternating electric fields that are delivered through 4 transducer arrays, directly placed on the shaved scalp. Optune TTF treatment is an established, non-invasive antimitotic therapy for patients with newly diagnosed or recurrent glioblastoma (GBM). Treatment efficacy was evaluated in the EF-14 trial, showing significant improvement of both, overall and progression free survival. This is the first report on clinical experiences with Optune in Austria (Start: February 2016, N=11 patients). All patients received a prescription in our department, the only certified TTF treatment center in Austria. Results: We treated newly diagnosed (N=8) and recurrent GBM patients (N=3). Our patient population included female (N=4) and male (N=7) patients with a mean age of 42 years (range 17-69 years) at the date of prescription. The mean treatment time was 3.4 months (range 2 weeks - 6 months). The disease was rated stable in 5 patients with a mean compliance rate of 82.06% daily. Three patients (27 %) showed progressive disease, one with a surgically resectable recurrence, the other patient with a diffuse progression of the disease. With regards to the side effects we were faced with mild to moderate skin irritation (RTOG 0-1) in 2 patients, but those could be treated by the use of local steroid application and did not cause significant treatment interruption in all but one patient. We noticed that patients need approximately 4 weeks to get used to the therapy. We perform regular follow-up visits including evaluation of patient compliance. With regards to the compliance rate and due to the patient’s feedback we were able to show that patients mostly accept this new treatment approach. Conclusion: TTF is generally an accepted and efficacious treatment for GBM. The promising results of the preterm analysis of EF-14 were recently confirmed in the final analysis. Our experiences with TTF are widely positive with great acceptance by the patients, however, the short treatment time does not allow reliable outcome analysis.
P01.04 AMPK activation and glycolysis inhibition protect neural cells from glucose and oxygen restriction
Authors: L. Barialai
Journal: Neuro-Oncology (2017)

The serine/threonine kinase mTOR is a central regulator of cell growth and metabolism. It integrates various growth inhibitory signals such as depletion of glucose, amino acids, ATP and oxygen leading to adaption to these starvation conditions. Inhibition of the mammalian target of rapamycin (mTOR) protects glioma cells from hypoxia-induced cell death by sustaining cellular energy levels. AMP-activated protein kinase (AMPK) indirectly inhibits mTOR complex 1 (mTORC1) and is activated by an increase of the AMP/ATP ratio. This causes initiation of adaptive programs leading to inhibition of anabolic pathways and increasing ATP synthesis. Acetyl-CoA carboxylase (ACC) is one of the AMPK target proteins and is deactivated via phosphorylation. So far, it has been shown that activation of AMPK via the direct activator A-769662 in human glioma cells decreases glucose consumption and lactate production and protects glioma cells from hypoxia-induced cell death as well as from glucose deprivation. The competitive glycolysis inhibitor 2-desoxy-d-glucose (2DG) causes a decrease in ATP levels inducing phosphorylation of AMPK and hence its activation. We tested whether these results could be transferred to non-malignant cells. Here we investigated the effects of AMPK activation via A-769662 and 2DG in the immortalized astrocytic cell line SVG as a model for neural cells in our paradigm of hypoxia-induced cell death. We found that A-769662 and 2DG induced phosphorylation of AMPK and ACC in astrocytes comparable to the situation in glioma cells. This resulted in mTOR inhibition and following decrease of phosphorylation of the mTORC1 target ribosomal protein S6, a translational regulator. Treatment with the AMPK activators led to decreased glucose consumption and lactate production. Furthermore it induced an increase in oxygen consumption. This indicates a more efficient glucose utilization through oxidative phosphorylation. Hypoxia-induced cell death was significantly decreased by A-769662 and 2DG. However in contrast to malignant glioma cells, 2DG did not show any toxicity in astrocytes under normoxic conditions. In conclusion, activation of AMPK via A-769662 and 2DG protected astrocytes from glucose and oxygen deprivation. Glycolysis inhibition did not result in toxicity in astrocytes in contrast to glioma cells. Thus, these results establish potential avenues for neuroprotective and tumor specific intervention strategies.
Tumor suppressor p53 transcriptionally regulates Bak expression in pancreatic cancer
Authors: Tawnya L. Bowles, Melinda M. Mortenson, Joseph M. Galante, Michael G. Schlieman, Subbulakshmi Virudachalam, Richard J. Bold
Journal: Cancer Research (2006)

4976  Introduction: The threshold for induction of the mitochondrial apoptosis pathway is determined by the relative balance of pro- and anti-apoptotic members of the Bcl-2 family. Underexpression of pro-apoptotic proteins or relative overexpression of anti-apoptotic proteins may result in apoptotic resistance in cancer cells. We have previously shown that Bak, a pro-apoptotic member of the Bcl-2 family, is underexpressed in pancreatic cancer. The mechanisms of Bak gene regulation are not clearly defined. Tumor suppressor p53 has been show to upregulate Bax gene expression through direct transcriptional transactivation. We identified two putative p53 transcriptional sites in the Bak promoter with homology to consensus p53-binding motifs. We hypothesize that p53 regulates the transcription of Bak through binding at these motifs. Methods: The human pancreatic cancer cell lines BxPC-3 (wildtype p53) and MIA-PaCa-2 (mutant p53) were used for all experiments. Bak mRNA and protein levels were determined by RT-PCR and Western blotting, respectively. To demonstrate binding of p53 to the putative sites in the Bak promoter, electromobility shift assays were performed. A Bak promoter/luciferase reporter was also constructed to functionally evaluate Bak gene promoter function. The effect of site-directed mutagenesis of the putative p53 sites was performed and the effect examined in both cell lines. Finally, the effect of restoration of wildtype-p53 in the MIA-PaCa-2 cell line (mutant p53) on Bak transcription was determined. Results: Bak RNA and protein levels were higher in BxPC-3 (wildtype p53) than MIA-PaCa-2 (mutant p53). Gel-shifted products to the putative p53 sites in the Bak promoter was demonstrated in BxPC-3, but not MIA-PaCa-2. Mutation of the putative p53 sites eliminated the gel shift product and reduced promoter activity in the promoter/luciferase construct in BxPC-3, but had no effect in MIA-PaCa-2. Conclusions: Tumor suppressor p53 transcriptionally regulates the pro-apoptotic protein Bak in pancreatic cancer. Loss of functional p53, a common event in pancreatic cancer, may result in suppression of Bak transcription. Therapy targeted at transcriptionally increasing Bak may be a novel method of therapy to increase pro-apoptotic protein content and therefore restore apoptotic sensitivity in pancreatic cancer.
P14.21 Can vascular risk factors influence number of brain metastases?
Authors: B. Berk, S. Nagel, R. Kortmann, K. Hoffmann, C. Gaudino, C. Seidel
Journal: Neuro-Oncology (2017)

BACKGROUND: Up to 30-40% of patients with solid tumors develop cerebral metastases. Number of cerebral metastases is relevant for treatment and prognosis. However, factors that determine number of metastases are not well defined. Distribution of metastases is influenced by blood vessels and cerebral small vessel disease can reduce number of metastases. Aim of this pilot study was to analyze the influence of vascular risk factors (arterial hypertension, diabetes mellitus, smoking, hypercholesterolemia) and of peripheral arterial occlusive disease (PAOD) on number of brain metastases. METHODS: 200 patients with pre-therapeutic 3D-brain MRI and available clinical data were analyzed retrospectively. Number of metastases (NoM) was compared between patients with/without vascular risk factors (vasRF). Results: Patients with PAOD had significant less brain metastases than patients without PAOD (NoM=4.43 vs. 6.02, p=0.043), no other single vasRF conferred a significant effect on NoM. NoM differed significantly between different tumor entities. CONCLUSION: Presence of PAOD showed some effect on number of brain metastases implying that tumor-independent vascular factors can influence brain metastasation.
P06.11 ENPP3 overexpression in astrocytomas
Authors: J. Werner, G. Röhn
Journal: Neuro-Oncology (2017)

Objective: The ENPP (ectonucleotide pyrophosphatase/phosphodiesterase) ectoenzymes 1, 2 and 3 are type II transmembrane proteins with ATPase and ATP pyrophosphatase activities. ENPP3 (CD203c) is an activation marker for mast cells and basophils. In addition, it is regularly expressed in both uterus and prostate. First publications indicate a role of ENPP3 in glial tumors. The expression has been shown in both rat glial precursor cells and in human glioma cell lines. The exposure to N-ethyl-N-nitrosurea (EtNU) causes an overexpression of ENPP3 in neuroectodermal tumors originated from glial precursor cells in rats. A recent study demonstrated high ENPP3 expression in clear renal cell carcinoma and tumor growth inhibition was noticed via antibody-drug conjugates. The goal of this study was to evaluate whether ENPP3 is expressed on low- and high-grade gliomas. In order to assess the further value of targeting ENPP3 only patient tissue and no cell-line was used for this study. Methods: Quantitative real-time PCR was performed with Cycler Rotor Gene Q and the Rotor-Gene SYBR Green using two primers with different target locations. SDHA was used as a housekeeping gene. Data analysis was performed with Graphpad Prism 7. Statistical tests used: Kruskal-Wallis for ANOVA and Mann-Whitney U for two-taled t-tests. Expression levels are displayed in mean values and standard error of the mean (SEM). In addition, immunostaining was performed with a primary antibody from Biolegend (ABIN2661579) and with Diaminobenzidine. Results: Fresh frozen samples of 50 patients (10 control brain tissue, 10 grade II astrocytomas, 10 anaplastic astrocytomas, 10 secondary- and 10 primary-glioblastomas (GBM)). Both primers detected a significantly higher level of ENPP3 in astrocytomas compared to control brain tissue (Primer A: 0.51 ± 0.09 vs. 0.15 ± 0.04, p=0.0045; Primer B: 1.13 ± 0.32 vs. 0.37 ± 0.14, p=0.0216), whereas primary GBM did not show elevation in comparison to control brain tissue (Primer A: 0.144 ± 0.016 vs. 0.15 ± 0.04; Primer B: 0.476 ± 0.104 vs. 0.37 ± 0.14). The expression levels of primary and secondary GBMs did not differ significantly. Immunostaining mainly showed positive staining in astrocytomas, while GBM exhibited little positive staining only. Conclusion: To the best of our knowledge, this is the ﬁrst study to prove ENPP3 expression on glioma patient-samples. Low-grade gliomas have significantly higher ENPP3 expression than control brain tissue. Unlike most cell surface molecules, ENPP3 shows stronger expression in low-grade glioma compared to glioblastoma. This finding could play a role for immunotargeting ENPP3 in gliomas.
P10.16 Novalis radiosurgery for brainstem diffuse midline gliomas in children and adults; A single-institution’s experience
Authors: C. Lee, C. Choi
Journal: Neuro-Oncology (2017)

AIM: We evaluate the treatment outcomes of Novalis radiosurgery with chemotherapy in children and adults with brainstem diffuse midline gliomas and review the literature. METHODS: Thirty-three patients (18 children, 15 adults) with brainstem diffuse midline gliomas treated with Novalis radiosurgery and chemotherapy were retrospectively evaluated. The median ages of the children and adults were 8 years (range: 3-16 years) and 41 years (range: 28-65 years), respectively. A histological diagnosis was obtained in 8 patients. The median total radiation dose was 45 Gy (range: 21-60 Gy including 4 booster radiosurgery patients) with a single fraction size of 1.8-4.0 Gy. Chemotherapy with temozolomide or other alkylating agent was administered concurrently or post-radiosurgery in 15 patients.Results: Tumor progression within 6months after Novalis radiosurgery occurred in 10 patients (8 children and 2 adults). Tumor progression after 6months occurred in 16 patients (8 children and 8 adults). Two child and 1 adults survived without tumor progression. Two adult patients died with other cause without tumor progression. Five adult patients survived with booster Novalis radiosurgery or chemotherapy after tumor progression. The median progression free survival/overall survival times for children and adults were 14.5/14.5 and 20.5/44.0 months, respectively. CONCLUSION: In this study, the prognosis of children with BSGs was considerably poorer than that of adults, and our results are consistent with those of previous studies. Efforts with chemo-immunotherapy should be made to improve the survival outcomes of patients with brainstem diffuse midline gliomas, especially in children. Booster radiosurgery was also effective in adult patients.
Preeclampsia and Hypertension
Authors: Nisha I. Parikh, Juan Gonzalez
Journal: JAMA Internal Medicine (2017)

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Single-Lineage Bone Marrow Failure Driven By 2 Novel PI3KCD Mutations
Authors: Maurizio Miano, Francesca Fioredda, Alice Grossi, Enrico Cappelli, Elena Palmisani, Maura Faraci, Tiziana Lanza, Paola Terranova, Michaela Calvillo, Concetta Micalizzi, Edoardo Lanino, Filomena Pierri, Stefano Giardino, Isabella Ceccherini, Carlo Dufour
Journal: Blood (2016)