tbuckley/cabot-search huggingface dataset:
P03.24 Downregulation of SMARCB1/INI1 expression in atypical chordomas is associated with upregulation of SMARCB1 regulators miR-671-5p and miR-193a-5p
Authors: M. C. Sharma, P. B. Malgulwar
Journal: Neuro-Oncology (2017)

Introduction: Atypical chordomas are relatively rare tumors which arise from the skull base and vertebral column. More frequent in childhood as compared to adults, they are more aggressive with higher incidence of metastasis and a dismal prognosis. Microscopically, they demonstrate atypical or poorly differentiated histology. Recent reports suggest that loss of SMARCB1/INI1/SNF5, a member of the ATP-dependent SWI/SNF chromatin-remodelling complex, is associated with aggressive behavior in a subset of chordomas. However, cause of loss/inactivation of SMARCB1 expression remains elusive, with discrepant results obtained between gene mutation and protein expression. MicroRNAs (miRNAs) are a class of noncoding RNAs that post-transcriptionally down-regulate gene expression through mechanisms of translational repression and mRNA destabilization. They play specific roles in cell proliferation, differentiation and apoptosis. Recent reports suggest that loss of SMARCB1/INI1 expression is regulated by miRNAs viz. miR-206, miR-381, miR-671-5p and miR-193a-5p. We aimed to investigate the expression of these miRNAs in atypical chordomas and correlate the findings with INI1 protein loss. Methods: In this retrospective study, 12 cases of atypical chordomas diagnosed during a period of 11 years (2006–2016) were retrieved from the archives of the Department of Pathology, AIIMS. Immunohistochemistry for INI1, Fluorescence-in-situ-hybridization for 22q chromosomal region, and mutation analysis for all 9 exons of SMARCB1 were performed. RNA isolation, qRT-PCR for miRNA and mRNA quantification and Pathway analysis using KEGG were performed. Results: Among the 5 miRNAs analyzed, 4 miRNAs were found to be differentially regulated (downregulated: miR-206; upregulated: miR-381-5p, miR-671-5p and miR-193a-5p) in cases (p<0.05) as compared to control. Notably, miR-671-5p and miR-193a-5p were found to be significantly upregulated in SMARCB1/INI1 immunonegative cases. Pathway analysis for miR-671-5p and miR-193a-5p demonstrated that TGF-β pathway (5 genes SMAD7, ACVR1, ACVR2A, ACVR2B, SP1) was significantly targeted by these miRNAs (p=0.005) and TGF-β1 mRNA levels showed positive correlation with miR-671-5p (R2=0.65, p=0.042) and miR-193a-5p (R2=0.70, p=0.019). Further, expression of TGF-β1 mRNA was significantly upregulated in SMARCB1/INI1 immunonegative cases (p=0.024). Conclusion: We report for the first time the upregulation of miR-671-5p and miR-193a-5p in SMARCB1/INI1 immunonegative atypical chordomas, with upregulation of TGF-β pathway. TGFβ signaling inhibition is an emerging strategy for cancer therapy and is a potential therapeutic target in atypical chordomas. Additionally, the present study highlights the fundamental role of miRNA mediated epigenetic and post-translational modifications in the pathogenesis and progression of chordomas.
OS06.5 YAP is essential for glioblastoma proliferation and survival in vitro and in vivo
Authors: A. J. Gogos, H. Zhu, K. Drummond, A. P. Morokoff, A. H. Kaye, A. W. Burgess
Journal: Neuro-Oncology (2017)

Introduction: Despite improved understanding of the genomic basis of glioma, the prognosis for patients with glioblastoma multiforme (GBM) remains dismal. Targeting glioma stem cell signalling pathways may provide novel therapeutic opportunities. Yes-associated protein (YAP) is downstream of the Hippo pathway and is a key regulator of organogenesis and an emerging oncogene. It is a transcriptional co-factor active in stem cell niches that promotes proliferation and migration and inhibits apoptosis and differentiation. There is mounting evidence that YAP is important in many solid malignancies, however its role in GBM is poorly understood. Methods: Mutation, copy number, gene expression and clinical data from the Cancer Genome Atlas glioma datasets were downloaded analysed in R. For in vitro experiments, two YAP specific lentiviral, doxycycline inducible shRNA vectors were utilised, as was a scramble control. YAP knockdown models were generated in two established GBM cell lines and two patient derived gliomasphere lines with variable baseline YAP expression. Knockdown was confirmed using Western blot and qPCR. Functional domains assayed included proliferation, migration and colony formation. Signalling network activation will be assessed by RNA-Seq. Luciferase expressing human glioblastoma cells were stereotactically implanted into the right frontal lobe of five week old Balb/c nu/nu mice. Once tumours were detectible, YAP was knocked down by feeding a random subsample of mice doxycycline. Results: YAP expression is elevated in GBM when compared with normal brain or lower grade gliomas (p<0.01). High YAP expression was associated with worse median survival for grade II (7.3 vs 9.8 years, p<0.01) and grade III tumours (1.9 vs 5.2 years (p<0.001), but not for patients with GBM (14 vs 14 months (p=NS). YAP overexpression was not explained by upstream mutations or copy number alterations of Hippo components. In vitro YAP knockdown resulted in up to 93% reduction in glioma cell proliferation at 7 days (p < 0.01). YAP knockdown cells would never reach full confluence despite extended culture duration. Migration was reduced by more than 90% (p<0.01), as was colony forming ability (p<0.05). These effects were noted in all cell lines examined, regardless of baseline YAP expression. In vivo YAP knockdown resulted in a 100 fold decrease in tumour size, as measured by luminescence (p<0.01). After two weeks of treatment, 72% of YAP knockdown tumours were no longer detectable on imaging. CONCLUSION: Genetic disruption of YAP signalling results in significantly impaired glioma cellular proliferation and altered morphology in vitro, and dramatic tumour reduction in vivo. This suggests YAP is essential to glioblastoma survival and is a promising therapeutic target.
P04.12 Different optimal cutoff values for metabolic uptake depending on the metabolic tumor volume of 11C-methionine PET/CT on recurrent metastatic brain tumors
Authors: T. Y. Jung, S. Jung, K. S. Moon, W. Y. Jang, S. H. Lim, K. S. Park, J. J. Min, H. S. Bum, I. Y. Kim, S. Y. Kwon
Journal: Neuro-Oncology (2017)

Purpose: 11C-methionine positron emission tomography-computed tomography (MET-PET) has been used to diagnose recurrent metastatic brain tumors. Because the spatial resolution of MET-PET is low, a partial volume effect may decrease the diagnostic value in small lesions. Therefore, we evaluated the predictive value of metabolic uptake for tumor recurrence after gamma knife radiosurgery (GKR), depending on metabolic tumor volume. Material and Methods: From November 2008 to June 2015, 48 patients with metastatic brain tumors received 77 MET-PET examinations for differential diagnosis between recurrence and radiation necrosis. Recurrence (n=51) was diagnosed in cases of histological confirmation or tumor control after repeated GKR over 4 months. Radiation necrosis (n=26) was diagnosed in cases of stable or reduced volume without treatment for 4 months. Cases with mass enlargement with/without treatment were excluded. On MET-PET images, the metabolic uptake (T/N ratio) was estimated as the ratio of maximal MET uptake of the lesion to that of the contralateral normal gray matter, and metabolic tumor volume (MTV) was volume over 1.3× the mean MET uptake of the contralateral normal cortex. The predictive value of the T/N ratio was evaluated depending on the pathology, magnetic resonance enhanced volume (MRV), and MTV. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff values for the differential diagnosis. Results: The mean T/N ratio was 2.26 (± 1.12) for recurrent lesions and 1.44 (± 0.21) for radiation necrosis (p = 0.0001). The area under the ROC curve (AUC) was 0.790, and a T/N ratio greater than 1.60 provided 75.3% diagnostic accuracy with 71.2% sensitivity and 80.8% specificity. Small cell lung carcinoma showed the best diagnostic value compared to other pathologies (AUC: 1.0, optimal cutoff value: 1.38). Lesions with MTV ≥ 4 cm3 and MRV ≥ 2 cm3 represented greater diagnostic value and higher optimal cutoff value compared to smaller lesions. Different MTV-corrected optimal cutoff values (MTV < 1 cm3: 1.35, MTV ≥ 1 cm3: 1.6) showed 79.2% diagnostic accuracy compared to a cutoff value of 1.6 (p = 0.031). Conclusions: MET uptake showed lower diagnostic accuracy for smaller lesions, which had a lower optimal cutoff value for diagnosis. Different optimal cutoff values for MET uptake should be considered according to the MTV to increase diagnostic accuracy. *This research was supported by Basic Science Research Pro-gram through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2014R1A1A1004469).
Abstract 54: Probenecid Improves Myocardial Function in an Ischemic Heart Disease Murine Model
Authors: Nathan Robbins, Sheryl E Koch, Min Jiang, Michael Tranter, Xiaoping Ren, W Keith Jones, Jack Rubinstein
Journal: Circulation Research (2012)

Introduction Probenecid, previously used for the treatment of gout, is a transient receptor potential vanilloid 2 (TRPV2) agonist. We have found TRPV2 in murine cardiomyocytes and when stimulated by probenecid, results in a positive inotropic response through Ca 2+ influx independent of β-adrenergic signaling. Our hypothesis is that probenecid will increase contractility without affecting cell survival. Methods We studied the role of probenecid as a positive inotrope in a mouse model of ischemic heart disease. We administered probenecid via intraperitoneal injections (100mg/kg) before and after ischemia/reperfusion injury (I/R) and orally via treated water (100mg/kg daily for 4 weeks), using saline injections and untreated water as respective controls. Ischemia was induced by a 45 minute ligation of the LAD followed by reperfusion and all mice were followed serially via echocardiography. We also evaluated the effects of probenecid on HL-1 cell apoptosis by conducting cell viability assays. Results Treatment with probenecid before I/R had no effect on subsequent infarct size (51.6±3.71% vs. 53.4±1.54%;P=NS). However, post-I/R probenecid caused an increase in ejection fraction (EF) of 10.9±1.98% in mice with initial EF between 40-50% (n=6; P&lt;0.01) and 7.28±1.63% in mice with higher initial EF (50-60%) (n=6; p&lt;0.01). Echocardiographic analysis of mice with oral probenecid after I/R demonstrated higher EF and smaller diastolic volume (47.19±2.29%; 79.57mL±1.63; n=6) compared to untreated mice (43.67±2.91%; 89.05mL±5.67; n=6). Cell viability assays showed high concentrations of probenecid had minimal effect on cell viability (88.6±6.2% of control) whereas treatment with high concentrations of isoproterenol (10mM) greatly decreased cell viability (6.7±0.1% of control). Conclusions These experiments demonstrate 1) probenecid increases myocardial contractility at baseline and significantly more so after I/R injury; 2) probenecid therapy improves function when used chronically; 3) the increase in contractility is not associated with either increased infarct size in vivo or apoptosis in vitro. Thus, unlike other positive inotropes, such as isoproterenol, probenecid increases contractility without resulting in significant cell death.
The Management of Antiplatelet and Antithrombotic Regimens in Patients With Mechanical Valves Undergoing Percutaneous Coronary Intervention
Authors: Cian P. McCarthy, Subodh Verma, Deepak L. Bhatt
Journal: JAMA Cardiology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Comprehensive Genetic Interrogation of Circulating Multiple Myeloma Cells at Single Cell Resolution
Authors: Jens G Lohr, Sora Kim, Joshua Gould, Birgit Knoechel, Yotam Drier, Daniel Gray, Nicole Birrer, Bang Wong, Gavin Ha, Cheng-Zhong Zhang, Guangwu Guo, Matthew Meyerson, Andrew Yee, Jesse Boehm, Noopur Raje, Todd R. Golub
Journal: Blood (2016)
Interleukin-6 increases resistance to anti-androgen therapy via TIF2
Authors: Siting Feng, Soo Lee, Allen Gao
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

697 

Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a critical role in the development and progression of prostate cancer. The levels of IL-6 in serum are significantly elevated in many men with advanced, hormone-refractory prostate cancer. Numerous studies have suggested the role of IL-6 in the growth and androgen responsiveness of prostate cancer cells in vitro and in vivo . To study the role of IL-6 in prostate cancer cells in response to androgen deprivation therapy, series of lower and higher passages of LNCaP cell sublines were generated by a long-term exposure of LNCaP cells in IL-6 containing culture media. The higher passages of LNCaP cells treated with IL-6 are more resistant to bicalutamide treatment compared to parental LNCaP cells. To understand the mechanisms of IL-6 mediated resistance to bicalutamide treatment, we compared the expression of coactivator TIF2 expression in IL-6 treated LNCaP cells and parental LNCaP cells. The levels of TIF2 in IL-6 treated LNCaP cells were found significantly higher than the parental LNCaP cells. Down regulation of TIF2 expression via siRNA in IL-6 treated LNCaP cells decreased resistance of these cells to bicalutamide treatment; while over expression TIF2 in the parental LNCaP cells increased resistance of these cells to bicalutamide treatment. Collectively, these results suggest that overexpression of IL-6 increases prostate cancer cells resistance to bicalutamide treatment via overexpression of TIF2.
Response by Vilahur et al to Letters Regarding Article, “Protective Effects of Ticagrelor on Myocardial Injury After Infarction”
Authors: Gemma Vilahur, Manuel Gutiérrez, Laura Casani, Lourdes Varela, Antoni Capdevila, Guillem Pons-Lladó, Francesc Carreras, Leif Carlsson, Alberto Hidalgo, Lina Badimon
Journal: Circulation (2017)
Use of Montelukast to Reduce Infusion Reactions in an Early Access Treatment Protocol of Daratumumab in United States Patients with Relapsed or Refractory Multiple Myeloma
Authors: Ajai Chari, Tomer M Mark, Amrita Krishnan, Keith Stockerl-Goldstein, Saad Z Usmani, Anil Londhe, Delores Etheredge, Hollee Parros, Sarah Fleming, Baolian Liu, Scott Freeman, Jon Ukropec, Thomas Lin, Ajay K Nooka
Journal: Blood (2016)
Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial
Authors: Kay-Tee Khaw, Alistair W Stewart, Debbie Waayer, Carlene M M Lawes, Les Toop, Carlos A Camargo, Robert Scragg
Journal: The Lancet Diabetes & Endocrinology (2017)
Attenuation of tumor angiogenesis in murine melanoma model using liposomal formulation of Coenzyme Q10
Authors: Indushekhar Persaud, Niven R. Narain, Winston Woan, Kathryn J. Russell, Lindsey H. Malik, Carlos A. Ricotti, Jie Li, George Elgart, Sung L. Hsia
Journal: Cancer Research (2006)

977  Angiogenesis is a major focus for cancer therapy and has been a focus for drug development. Our prior data have demonstrated in vitro administration of Q10 restores the apoptotic potential in melanoma and squamous carcinoma cells, without adversely affecting normal epithelial cells. Through western blot analysis we have shown the reduction of Bcl-2, an anti-apopotic protein, in melanoma without a significant effect on normal fibroblast. In addition, we induce human melanoma tumors (derived from Skmel-28 cells) in nude athymic mice and applied a Q10 liposomal topical formulation for 30 days. Subsequently, the subjects were sacrificed and the tumors were excised, weighed, and processed for histological analysis. The treatment tumors showed an average of 53.2% reduction in tumor mass compared to the control. Moreover, histological analysis of the treatment group showed a significant reduction in the structural integrity of tumor vasculature. Further investigation will entail the examination of Q10 effect on mitochondrial mediated pathways for the reduction of angiogenic factors. In addition, apoptotic markers with a relation to angiogenesis will be examine to provide supporting evidence for this phenomenon. Taken together, our data suggests a potential for the use of a topical application of Q10 for the treatment of cutaneous malignancies.
Annular Flaccid Pustules on the Trunk
Authors: Dimitra Kiritsi, Melika Hoch, Johannes S. Kern
Journal: JAMA Dermatology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
P09.04 Glioblastoma unique aspects dictate the ways to overcome the two causes of resistance to current therapy and find future effective treatments in the trunk-branch era
Authors: E. Brognaro
Journal: Neuro-Oncology (2017)

Glioblastoma multiforme is a solid tumor with unique characteristics due to its organ of origin and its development modalities. The brain is very sensitive to oxygen and glucose deprivation and it is the only organ that cannot be neither entirely removed nor transplanted. Furthermore, many radiological, clinical and surgical clues and recent indirect experimental evidence indicates that the microinfiltration of the whole brain parenchyma occurs in very early stages of tumor bulk growth or likely even before. As a consequence, the primary glioblastoma is the only tumor where the malignant (i.e. infiltrating the organ of origin) and deadly (i.e. leading cause to patient’s death) phases coincide. Moreover, only in glioblastoma there are three stages of development (one pre-hypoxic and two post-hypoxic) in relation to the oxygen tension. Glioblastoma is characterized by phenotypic diversity, intratumor heterogeneity and treatment failure with 14-15 months median overall survival in optimally treated patients. This is due to the two causes of resistance to current therapeutic strategies. The first is the process of bottleneck selection in the tumor mass or in its residues of those subclones, invariably present due to the complex and multifacted intratumor heterogeneity, with particular features to resist and survive therapy which will emerge, expand and give rise to a new bulk. The second, as indicated by radiological, clinical and surgical clues and by the indirect experimental proof from recent genetic analysis of distant recurrences, is the presence of quiescent founder cancer stem cells (CSCs) which have microinfiltrated the entire brain parenchyma at the very beginning of glioblastoma development or probably even before the growth of the primary tumor bulk. These founder CSCs have subsequently exited the cell-cycle and settled dormant in G0 state in perivascular parenchymal niches in the whole brain protected by their properties, the niche-microenvironment and the blood-brain barrier. Recent studies have provided evidence that cancer stem cells, recently named “units of selection”, are those cells that drive tumor growth and progression through a trunk-branch evolution pattern. As fundamental units of trunk-branch tumor evolutionary development and as unique cells which can survive for a long time in a quiescent status in specialized niches, CSCs are unambiguously those cells which must be targeted by future innovative therapies. The latter, to be effective, must identify the exclusive CSCs properties related to their impaired asymmetrical division and or to driver lesions of the founder CSC without pre-existing mutations in minority subclones and not by-passed by alternative mechanisms or pathways and or exclusive markers used by the founder CSCs to settle quiescent (involving mechanisms of adhesion, anchorage and cell-cycle arrest) in the perivascular parenchymal niches.