tbuckley/cabot-search huggingface dataset:
Methylation of p16 CpG islands correlated with malignant progression of gastric dysplasia in a nested case-control study
Authors: Yu Sun, Dajun Deng, Wei-Cheng You, Hua Bai, Jing Zhou, Lian Zhang, Yu-Qian Xie, Lin Shen, Jun-Ling Ma, Ji-You Li
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

889 

Background and Aims Inactivation of p16 by aberrant methylation of CpG island is a frequent event in carcinomas and precancerous lesions of various organs including stomach, which may play an important role in carcinogenesis. The aim of the present study is to investigate relationship between p16 CpG methylation and malignant progression of human gastric dysplasia based on a fellow-up endoscopic screening survey in a high-risk population. Methods Genomic DNA samples were extracted from paraffin blocks of gastric mucosal biopsies, classified as mild or moderate dysplasia histologically, both from patients who developed gastric carcinomas during 5 year’s follow-up period ( n =21) and from control subjects who did not ( n =21). The methylation status of p16 CpG islands of each sample was detected by methylation-specific polymerase chain reaction, denatured high performance liquid chromatography, and sequencing. Results Aberrant p16 CpG methylation was observed only in 5 of 21 progressive dysplasia samples, but none of 21 non-progressive ones ( p =0.024). Sequencing results confirmed that all CpG sites were methylated in the analyzed sequence from these p16 -methylated samples. Unmethylated p16 CpG island was detected in all of the samples without p16 methylation. Conclusion The present study showed firstly that p16 CpG methylation is correlated with the malignant conversion of gastric dysplasia positively. These findings suggest strongly that the p16 methylation may be a powerful biomarker for predication of malignant potential of gastric dysplasia.
OS04.1 Survival benefit associated with Gross Total Resection (GTR) in oligodendrogliomas and astrocytomas: a Surveillance, Epidemiology, and End Results Program (SEER) based analysis
Authors: A. Alattar
Journal: Neuro-Oncology (2017)

The available evidence suggests that the clinical benefits of extended surgical resection are limited for chemo-sensitive tumors, such as primary central nervous system lymphoma (PCNSL). Oligodendroglioma is generally thought to be more sensitive to chemotherapy than astrocytoma of ­comparable grades. Here, we compare the survival benefit of gross total resection (GTR) in oligodendroglioma patients relative to astrocytoma patients. Using the Surveillance, Epidemiology, and End Results Program (SEER) database, we identified 2,378 WHO grade II oligodendroglioma patients (O2) and 1,028 WHO grade III oligodendroglioma patients (O3). Surgical resection was defined as GTR, subtotal resection (STR), biopsy only, or no resection. Kaplan-Meier and multivariate Cox regression survival analysis were used to assess survival with respect to extent of resection (EOR). Cox multivariate analysis revealed that the hazard of dying from O2 and O3 was comparable between patients who underwent biopsy only (or STR) and GTR (O2: HR 1.06, 95% CI 0.73–1.53; O3: HR 1.18, 95% CI 0.80–1.72). A comprehensive search of the published literature identified eight articles without compelling evidence that GTR is associated with improved overall survival in oligodendroglioma patients. In contrast, we found that patients afflicted with WHO grade II astrocytoma (A2) benefited significantly from GTR. We identified 4,113 A2 patients in the SEER. A multivariate Cox survival analysis indicated that relative to A2 patients who underwent STR, A2 patients who underwent a GTR showed a 28.3% reduction in the hazard of death. Similar risk reductions were observed in both A2 patients age < 50 and ≥ 50. However, because of differences in the natural history of these cohorts, the relative risk reduction translated into distinct overall survival profiles. GTR in A2 patients age < 50 was associated with survival benefit of > 4 years, a finding reminiscent of anaplastic astrocytoma patients. In contrast, for A2 patients age ≥ 50, the GTR associated survival benefit was approximately 6 months, resembling that observed in glioblastoma patients. Relative to A2 patients, patients afflicted with WHO grade III astrocytoma (anaplastic astrocytoma or A3) derived greater survival benefit from GTR. We identified 2,755 A3 patients in SEER. The hazard of dying from the A3 was reduced in GTR patients by 40% relative to STR patients. For comparison, the hazard of dying from the glioblastoma was reduced in GTR patients by 24% relative to STR patients. We observed that age <50 and post-TMZ (2005–2010) independently associated with an improved survival benefit for A3 who underwent GTR. The median survival of AA patients age<50 who underwent GTR and STR in the post-TMZ era was not reached for the GTR population and 52 months for the STR population, respectively. For glioblastoma patients, the corresponding numbers for median survival were 21 and 18 months.
Neural Circuitry of Reward Prediction Error
Authors: Mitsuko Watabe-Uchida, Neir Eshel, Naoshige Uchida
Journal: Annual Review of Neuroscience (2017)

Dopamine neurons facilitate learning by calculating reward prediction error, or the difference between expected and actual reward. Despite two decades of research, it remains unclear how dopamine neurons make this calculation. Here we review studies that tackle this problem from a diverse set of approaches, from anatomy to electrophysiology to computational modeling and behavior. Several patterns emerge from this synthesis: that dopamine neurons themselves calculate reward prediction error, rather than inherit it passively from upstream regions; that they combine multiple separate and redundant inputs, which are themselves interconnected in a dense recurrent network; and that despite the complexity of inputs, the output from dopamine neurons is remarkably homogeneous and robust. The more we study this simple arithmetic computation, the knottier it appears to be, suggesting a daunting (but stimulating) path ahead for neuroscience more generally.
Bone Marrow DKK-1 Levels in Smoldering Multiple Myeloma Patients: A New Independent Risk Factor for Progression
Authors: Benedetta Dalla Palma, Valentina Marchica, Fabrizio Accardi, Daniela Guasco, Laura Notarfranchi, Federica Costa, Martina Caviola, Federica De Luca, Luisa Craviotto, Mario Pedrazzoni, Franco Aversa, Nicola Giuliani
Journal: Blood (2016)
Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species
Authors: Eugene A. Podrez, Maria Febbraio, Nader Sheibani, David Schmitt, Roy L. Silverstein, David P. Hajjar, Peter A. Cohen, William A. Frazier, Henry F. Hoff, Stanley L. Hazen
Journal: Journal of Clinical Investigation (2000)
Ovarian cancer stem cells more questions than answers
Authors: Petronella Beatrix Ottevanger
Journal: Seminars in Cancer Biology (2017)

Epithelial ovarian cancer is a highly lethal disease, which is usually diagnosed at a late stage with extensive metastases in the abdominal cavity. Ovarian cancer either develops from the ovarian surface epithelium (OSE) or from serous intra-epithelial carcinoma (STIC). Primary therapy consists of debulking surgery and platinum based chemotherapy. The success of debulking surgery depends on surgical skills but also on the gene signature of the tumour. Debulking surgery combined with first line platinum based chemotherapy, frequently leads to complete remission. However, most ovarian cancers relapse. Once the disease has relapsed, the interval between subsequent therapies decreases steadily due to rapid progression and therapy resistance. Research on therapy resistance of ovarian cancer is frequently devoted to genetic alterations in cancer cells, leading to drug inactivation, enhanced DNA repair mechanisms and intracellular pathway derangements. However the knowledge of ovarian cancer stem cells (OCSC) and the role they play in the development of cancer and therapy resistance is sparse. In this review current knowledge on the characteristics of OCSCs and the micro environmental mechanisms leading to the development or activation of OCSCs resulting in ovarian cancer is reviewed. Moreover the role of OCSC in both surgical and systemic therapy resistance and the relation with epithelial mesenchymal transformation (EMT) is discussed, as are micro-environmental signals leading to OCSC or EMT activation.
Orthogonal haplotype structure in 106 DNA repair and cell cycle control genes simplifies the search for gene-disease association
Authors: Irene M. Jones, Cynthia B. Thomas, Tina Xi, Harvey W. Mohrenweiser, David O. Nelson
Journal: Cancer Research (2004)

1484  Risk of cancer is a complex function of exposures (external and endogenous) and genetic susceptibility to these exposures. For each exposure, the function of multiple pathways may be relevant. As pathways can have dozens of genes and most genes have multiple variant single nucleotide polymorphisms (SNPs), 100s of SNPs are candidate susceptibility factors. Discerning the variants that affect function and cancer susceptibility is a major challenge. The goal of this study was identification of polymorphisms in base excision repair (BER) and antioxidant (AO) genes that affect the amount of DNA damage in untreated cells, primarily damage from oxidative metabolism, and the ability to repair damage induced by exposure to ionizing radiation (IR). Using the alkaline Comet assay we quantified single strand breaks and abasic sites in untreated cells and in cells immediately and 15 minutes after exposure to 5Gy IR, in 80 lymphoblastoid cell lines of the DNA Polymorphism Discovery Resource (DPDR). Comet distributed moment was the parameter used to quantify damage. Genotypes of the cell lines, known from extensive resequencing studies of the DPDR, included 174 variants of 34 BER genes (159 amino acid substitution SNPs and 15 SNPs in upstream ∼150bp sequences) and 17 amino acid substitution SNPs of 5 AO genes. Random Forests Regression (RFR) was used to identify SNPs that were important for predicting 2 phenotypes: endogenous (background) damage and % damage repaired 15 min after IR. Using a stringent cutoff for importance, there were 5 SNPs from 4 genes that were most influential for background damage (from greatest impact to least, POLD1 Arg19His, XRCC1 Arg399Gln, XRCC1 Val72Ala, LIG3 Arg780His, RPA4 Ala33Thr) and 7 influential SNPs for repair of IR damage (RPA4 Ala33Thr, XRCC1 Val72Ala, MPG 5 prime UTR, PNKP Pro20Ser, RAD23B Ala249Val, POLE Phe695Ile, LPO Thr105Ile). It is notable that the frequencies of these important SNPs range from 0.01 to 0.42 and that the SIFT scores of these variants independently predict an impact on protein function. In summary, RFR efficiently identified 10 out of 191 polymorphisms that help predict two phenotypes relevant to cancer risk. This study demonstrates the ability to use heuristic machine learning techniques to identify functionally important genetic variation by analyzing relationships between phenotypes and complex genotypes. This work was performed under the auspices of the U.S. Department of Energy by the University of California, Lawrence Livermore National Laboratory under Contract No. W-7405-Eng-48.
PROTECTIVE VENTILATION WITH CO2-REMOVAL TECHNIQUE IN PATIENTS WITH ARDS
Authors: Pierpaolo Terragni, Luciana Mascia, R. Urbino, G. Rosboch, M. Basso, A. Birocco, L. Cochelli, C. Degiovanni, M. Nicosia, Vito Marco Ranieri
Journal: Intensive Care Medicine (2007)
P16.04 Practical application of intraoperative tractography on awake brain surgery
Authors: C. de Quintana Schmidt, A. Leidinger, B. Gomez, E. Granell, O. Gallego, J. Craven, L. Salgado, M. Rico, J. Aibar, J. Molet
Journal: Neuro-Oncology (2017)

Introduction: Tractography is a radiological technique which allows a non-invasive understanding of subcortical brain fiber tracts. It is a helpfull technique for presurgical planning and the study of tumoral lesions and their anatomical relationship with adjacent fibers. However, there is an open debate on inter-observer variability, limits in lesion with edema for example, ultimate precision, and its practical benefit during surgery. In our study we analyze the practical benefit of intraoperative tractography in awake brain surgery Materials and methods: Prospective study using intraoperative tractography on awake surgery patients at Sant Pau Hospital. Follow up started in 2014 until present day. We compare awake patient surgeries with and without the use of intraoperative tractography after the acquisition of a navigation system that allowed us to apply this technique. Studied variables: surgical time with awake patient in minutes (using the asleep-awake-asleep technique), pain (VAS scale), anxiety (0-10), degree of collaboration (0-10 being 10 maximum punctuation) and percentage of complete resection. Results: N= 36 patients. 25 male (69,4%) and 11 female (30,6%). Mean age: 53,8 (33-75) years. Awake surgery with intraoperative tractography was performed on 19 patients [52,8% IC95% 36,5-69,1%]. On 17 patients, this technique was no available [47,2% IC95% 30,9-63,5%]. Mean surgical time on the tractography group was of 93,6 minutes, versus 119,8 minutes for those awake patient surgery without the use of this tool. Mean surgical time reduction was of 26,1 minutes [IC95% 9,3-43 minutes] (p=0.004). The mean degree of patient collaboration scored 7,4 when using intraoperative tractography, versus 6,8 when not, mean pain scores were of 2,6 versus 3 and mean anxiety score of 3,3 versus 3,2 (p=0.403, p=0.394 y p=0.889 respectively). 73,7% of the patients operated with intraoperative tractography had total resections, against 52,9% for those without this tool. (p=0.299). Conclusions: Intraoperative tractography aids the surgeon reducing the duration of awake patient surgeries, although there is no statistically significant repercussion on intraoperative anxiety or pain scores, nor on the degree of collaboration during the procedure. It seems that a higher rate of full resections is obtained when using intraoperative tractography, despite no statistical significance.
Seasonal determinants of access to care: implications for measles outbreak risk in Madagascar
Authors: C Jessica E Metcalf, Keitly Mensah, Amy P Wesolowski, Amy K Winter, B Ramamonjiharisoa, Saki Takahashi, A Randriamanantena, Richter Razafindratsimandresy, Jean-Michel Heraud
Journal: The Lancet (2017)
Critical Issues for the Translation of Cardioprotection
Authors: Gerd Heusch
Journal: Circulation Research (2017)

The translation from numerous successful animal experiments on cardioprotection beyond that by reperfusion to clinical practice has to date been disappointing. Animal experiments often use reductionist approaches and are mostly performed in young and healthy animals which lack the risk factors, comorbidities, and comedications which are characteristics of patients suffering an acute myocardial infarction or undergoing cardiovascular surgery. Conceptually, it is still unclear by how much the time window for successful reperfusion is extended by preconditioning, and how long the duration of ischemia can be so that adjunct cardioprotection by postconditioning at reperfusion still protects. Experimental studies addressing long-term effects of adjunct cardioprotection beyond infarct size reduction, that is, on repair, remodeling, and mortality, are lacking. Technically, reproducibility and robustness of experimental studies are often limited. Grave faults in design and conduct of clinical trials have also substantially contributed to the failure of translation of cardioprotection to clinical practice. Cardiovascular surgery with ischemic cardioplegic arrest is only a surrogate of acute myocardial infarction and confounded by the choice of anesthesia, hypothermia, cardioplegia, and traumatic myocardial injury. Trials in patients with acute myocardial infarction have been performed on agents/interventions with no or inconsistent previous animal data and in patients who had either some reperfusion already at admission or were reperfused too late to expect any myocardial salvage. Of greatest concern is the lack of adequate phase II dosing and timing studies when rushing from promising proof-of-concept trials with surrogate end points such as infarct size to larger clinical outcome trials. Future trials must focus on interventions/agents with robust preclinical evidence, have solid phase II dosing and timing data, and recruit patients who have truly a chance to benefit from adjunct cardioprotection.
Whole Genome 250K SNP Array Allows for Detection of Previously Unidentified Lesions in Chromosome 5 in Patients with MDS.
Authors: Lukasz P. Gondek, Abdo Haddad, Mikkael A. Sekeres, Yasuhito Nannya, Seishi Ogawa, Alan F. List, Jaroslaw P. Maciejewski
Journal: Blood (2006)
Genotype-outcome correlations in pediatric AML: the impact of a monosomal karyotype in trial AML-BFM 2004
Authors: M Rasche, C von Neuhoff, M Dworzak, J-P Bourquin, J Bradtke, G Göhring, G Escherich, G Fleischhack, N Graf, B Gruhn, O A Haas, T Klingebiel, B Kremens, T Lehrnbecher, A von Stackelberg, J Tchinda, Z Zemanova, C Thiede, N von Neuhoff, M Zimmermann, U Creutzig, D Reinhardt
Journal: Leukemia (2017)

We conducted a cytogenetic analysis of 642 children with de novo acute myeloid leukemia (AML) treated on the AML-Berlin-Frankfurt-Münster (BFM) 04 protocol to determine the prognostic value of specific chromosomal aberrations including monosomal (MK+), complex (CK+) and hypodiploid (HK+) karyotypes, individually and in combination. Multivariate regression analysis identified in particular MK+ (n=22) as a new independent risk factor for poor event-free survival (EFS 23±9% vs 53±2% for all other patients, P=0.0003), even after exclusion of four patients with monosomy 7 (EFS 28±11%, P=0.0081). CK+ patients without MK had a better prognosis (n=47, EFS 47±8%, P=0.46) than those with MK+ (n=12, EFS 25±13%, P=0.024). HK+ (n=37, EFS 44±8% for total cohort, P=0.3) influenced outcome only when t(8;21) patients were excluded (remaining n=16, EFS 9±8%, P<0.0001). An extremely poor outcome was observed for MK+/HK+ patients (n=10, EFS 10±10%, P<0.0001). Finally, isolated trisomy 8 was also associated with low EFS (n=16, EFS 25±11%, P=0.0091). In conclusion, monosomal karyotype is a strong and independent predictor for high-risk pediatric AML. In addition, isolated trisomy 8 and hypodiploidy without t(8;21) coincide with dismal outcome. These results have important implications for risk stratification and should be further validated in independent pediatric cohorts.
OS06.7 PI-3Kγ inhibition suppresses glioblastoma tumorigenicity through disruption of an IL11-STAT3-MYC signaling axis between microglia and glioblastoma
Authors: J. Li, M. Kaneda, K. Patel, J. Wang, J. Akers, V. Ramakrishnan, T. Jiang, B. Carter, J. Varner, C. Chen
Journal: Neuro-Oncology (2017)

While mutations in isocitrate dehydrogenase (IDH) gene are associated with favorable prognosis in glioblastoma patients, the biologic basis for favorable survival in patients with wild-type IDH (wtIDH) glioblastoma remains poorly understood. We identified that an inflammatory gene signature whose expression inversely correlated with patient survival in three independent, wtIDH glioblastoma cohorts (The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and REMEBRANDT). Systematic analysis of the inflammatory infiltrates of the glioblastoma microenvironment revealed microglia as the predominant cell type driving this survival association. The pro-tumorgenic effects of microglia can be recapitulated using conditioned media derived from microglia. We cross-referenced proteomic profile of microglia conditioned media with the TCGA and the CGGA to identify constituent soluble factors with survival association and identified IL11. In both clinical datasets, increased IL11 expression was associated with shortened survival. Moreover, IL11 expression closely correlated with the survival-associated inflammatory signature in both TCGA and CGGA glioblastomas. IL11 mRNA and protein expression are elevated in clinical glioblastoma specimen relative to the surrounding cerebrum. Analysis of samples secured from three unrelated patients revealed that IL11 expression was largely found in the microglia fraction. In vitro and in vivo experiments demonstrate that IL11 was necessary and sufficient for enhancement of glioblastoma tumorigenicity. Microglia released IL11 induced activation of a STAT3-MYC signaling axis in glioblastoma cells, which ultimately lead to up-regulation of genes required for glioblastoma tumorigenicity, including OLIG2, SOX2, and POU3F2. PI3Kγ activation in myeloid-derived cells, including microglia, is essential for its trafficking into the tumor microenvironment. We hypothesized that PI3Kγ inhibition or inactivation should impede microglia trafficking to the glioblastoma microenvironment and suppress tumorigenicity. Supporting our hypothesis, treatment with the PI3Kγ, TG100-115, suppressed glioblastoma tumorigenicity in vivo by reduced microglia density and IL11 release in the glioblastoma microenvironment. These effects were recapitulated when murine glioblastoma GL261 were implanted into p110γ-/- mice. Importantly, ectopic expression IL11 in GL261 reversed the tumor-suppressive effect of TG100-115. The anti-glioblastoma effects of TG100-115 were enhanced by temozolomide, the standard of care chemotherapy for glioblastoma. These results suggest microglia is a mediator of clinical glioblastoma survival and disruption of microglia-glioblastoma interaction as potential therapeutic strategy.
Searching for Happiness
Authors: Andrea Ferrari, Paola Gaggiotti, Matteo Silva, Laura Veneroni, Chiara Magni, Stefano Signoroni, Michela Casanova, Roberto Luksch, Monica Terenziani, Filippo Spreafico, Cristina Meazza, Carlo Alfredo Clerici, Maura Massimino
Journal: Journal of Clinical Oncology (2017)
P10.20 Retrospective analyses of clinical characteristics of diffuse midline glioma
Authors: K. Miyashita, H. Sabit
Journal: Neuro-Oncology (2017)

Introduction: Glioma arising from midline structures with mutation of Histone H3-K27M (H3- K27M) was newly added as “diffuse midline glioma, H3 K27M-mutant” in 2016 WHO classification. This study is retrospective analyses of the clinical characteristic of diffuse midline glioma. METHODS: Twenty cases of astrocytoma arising from midline structures (thalamus, pons, and spinal cord) treated in our department from 1991 to November 2016 were included. The mutations of H3-K27M and IDH were evaluated by immunohistochemical staining. We divided the series of the cases in diffuse midline glioma, H3 K27M-mutant (Group A) and others (Group B). We compared age, sex, IDH mutation and overall survival (OS) between the groups. Results: Clinical characteristics of each groups were as follows: Group A(8 cases, Male: Female= 5:3, Age 25-65, median 25y/o)and Group B (12 cases, Male: Female=10:2, Age 7-82, median 52.5y/o. No cases had IDH mutation. Tumor grade of each group was as follows: Group A (II:2, III:1, IV:5) and Group B (I:1, II:2, III:2, IV:5). OS was 6- 79.9month (median 25.7) and 5.7- 34.9 month (median 26.6) in Group A and B, ­respectively. As for OS, there was no significant differences between each group. Conclusions: About half of gliomas arising from midline structures were possesses H3- K27M and satisfied the criteria of diffuse midline glioma. No significant clinical differences were observed in diffuse midline glioma and other gliomas occurred at midline structures.