tbuckley/cabot-search huggingface dataset:
ATPS-63OSMOTIC SWELLING REGULATES TUMOR GROWTH AND DRUG UPTAKE IN HUMAN GLIOBLASTOMA
Authors: Shirin Iikhanizadeh, Yekaterina Miroshnikova, Aaron Frantz, Wen Zhu, Aurora Idilli, David Quigley, John Lakins, Sergey Magnitsky, Joanna Phillips, David James, Mitchel Berger, Daniele Arosio, Dandan Sun, Valerie Weaver, William Weiss, Anders Persson
Journal: Neuro-Oncology (2015)

BACKGROUND: High interstitial fluid pressure (IFP) represents a barrier for drug uptake in human GBM, the most common primary brain tumor. Fluid accumulation and high cell density compress tumors and promote osmotic swelling of tumor cells. Although studies have clarified the role of tumor vasculature, it remains unclear whether osmotic swelling of cancer cells regulates tumor growth and drug uptake. METHODS: To address this, we used human GBM tumorspheres and xenografts. We developed methodology to measure IFP in GBM xenografts and mechanical compression in 3D-cultures. Fluorescent-based sensors were used to measure cell volume and chloride levels. To reduce IFP and osmotic swelling in GBM cells, we established exogenous or endogenous induction of antisecretory factor (AF), known to be safe in patients, reduces elevated intracranial pressure in rodents, and lowers IFP in subcutaneous solid tumors. RESULTS: Intriguingly, our data demonstrate that elevated pressure drives proliferation of GBM tumorspheres. Transcriptional profiling showed that increased compression regulates genes involved in translation and ion transport. AF peptide completely blocked compression-induced proliferation and transcriptional changes. We found that AF targeted the sodium-potassium-chloride channel (NKCC1), more potently than the NKCC1 inhibitor bumetanide, and prevented restoration of cell volume and chloride permeability under hyperosmotic conditions. AF therapy effectively reduced tumor growth, increased drug uptake, and extended survival in GBM xenografts, effects that were mediated through lowering of IFP, reduced cell volume, and inhibition of NKCC1 activity. CONCLUSIONS: We find that elevated IFP in human GBMs maintains osmotic swelling in tumor cells as a second barrier for drug uptake. Our results further show that elevated pressure is a driver of proliferation, survival, and translational control. AF therapy represents a novel approach to inhibit NKCC1 activity and osmotic swelling in human GBMs, leading to reduced tumor growth and increased drug uptake, ultimately improving the outcome for this disease.
Risk Factors for Coarctation of the Aorta on Prenatal Ultrasound
Authors: Alessandra Familiari, Maddalena Morlando, Asma Khalil, Sven-Erik Sonesson, Carolina Scala, Giuseppe Rizzo, Gelsomina Del Sordo, Chiara Vassallo, Maria Elena Flacco, Lamberto Manzoli, Antonio Lanzone, Giovanni Scambia, Ganesh Acharya, Francesco D’Antonio
Journal: Circulation (2016)

Prenatal diagnosis of coarctation of the aorta (CoA) is still challenging and affected by high rates of false-positive diagnoses. The aim of this study was to ascertain the strength of association and to quantify the diagnostic accuracy of different ultrasound signs in predicting CoA prenatally.Medline, Embase, CINAHL, and Cochrane databases were searched. Random-effects and hierarchical summary receiver operating characteristic model meta-analyses were used to analyze the data.Seven hundred ninety-four articles were identified, and 12 (922 fetuses at risk for CoA) articles were included. Mean mitral valve diameter z score was lower (P<0.001) and the mean tricuspid valve diameter z score was higher in fetuses with CoA than in those without CoA (P=0.01). Mean aortic valve diameter z score was lower in fetuses with CoA than in healthy fetuses (P≤0.001), but the ascending aorta diameter, expressed as z score or millimeters, was similar between groups (P=0.07 and 0.47, respectively). Mean aortic isthmus diameter z scores measured either in sagittal (P=0.02) or in 3-vessel trachea view (P<0.001) were lower in fetuses with CoA. Conversely, the mean pulmonary artery diameter z score, the right/left ventricular and pulmonary artery/ascending aorta diameter ratios were higher (P<0.001, P=0.02, and P=0.02, respectively) in fetuses with CoA in comparison with controls, although aortic isthmus/arterial duct diameter ratio was lower in fetuses with CoA than in those without CoA (P<0.001). The presence of coarctation shelf and aortic arch hypoplasia were more common in fetuses with CoA than in controls (odds ratio, 26.0; 95% confidence interval, 4.42-153; P<0.001 and odds ratio, 38.2; 95% confidence interval, 3.01-486; P=0.005), whereas persistent left superior vena cava (P=0.85), ventricular septal defect (P=0.12), and bicuspid aortic valve (P=0.14) did not carry an increased risk for this anomaly. Multiparametric diagnostic models integrating different ultrasound signs for the detection of CoA were associated with an increased detection rate.The detection rate of CoA may improve when a multiple-criteria prediction model is adopted. Further large multicenter studies sharing the same imaging protocols are needed to develop objective models for risk assessment in these fetuses.
14. Next Generation AAV Vectors for Limiting Systemic Leakage and Improving Safety Following CNS Administration
Authors: Giridhar Murlidharan, Lavanya Rao, Dan Wang, Travis Corriher, Kyung Seok-Oh, Guangping Gao, R. Jude Samulski, Alice F. Tarantal, Aravind Asokan
Journal: Molecular Therapy (2015)

Intracranial or intrathecal administration of certain AAV vectors for CNS gene transfer is accompanied with systemic leakage into off-target organs such as the liver and spleen. Both preclinical and clinical studies have highlighted potential concerns related to high vector dose-related immunotoxicity and more recently, hepatic genotoxicity in mouse models. In order to address these potential safety issues and reduce the effective dose required to achieve efficient transgene expression in the CNS, we have rationally engineered next generation AAV vectors that show robust CNS spread and efficient transduction, while demonstrating minimal leakage into the systemic circulation. Direct CNS administration or intrathecal infusion of AAV9 results in highly efficient gene expression in neuronal and glial cellular populations in neonatal and adult mice in vivo. However, AAV9 vectors are also disseminated into the blood circulation accompanied by broad vector biodistribution and reporter gene expression in the heart, liver, spleen and kidney. CNS-to-liver and CNS-to-spleen ratios of vector genome copy numbers ranging from 0.3 to 1 were observed. A prototype, engineered AAV strain demonstrated similar potential for spread and high transduction efficiency in neonatal and adult mice. However, transgene expression was primarily restricted to neurons and virtually no leakage into systemic organs was observed regardless of CNS injection route. Preliminary studies in rhesus macaques also confirm the ability of the engineered AAV strain to spread and globally transduce the primate brain. Additional biodistribution data from rodent and primate models is forthcoming. These studies provide a roadmap for addressing clinical gene therapy challenges through continued vector development and confirm that natural AAV isolates are excellent platforms for building next generation vectors with robust transduction efficiency and improved safety profiles.
Array CGH Analysis of Nodal T-Cell Lymphomas: Identification of Genomic Alterations Specific to Angioimmunoblastic and Unspecified Subtypes, and Correlation with Transcriptomic Data.
Authors: Laurence de Leval, David Rickman, Emilie Thomas, Louis Huang, Aurélien de Reynies, Françoise Berger, Thierry Molina, Josette Brière, Luc Xerri, Christian Gisselbrecht, Philippe Gaulard
Journal: Blood (2007)
Targeting Acute Myeloid Leukemia Stem Cells by MUC1-C Subunit Inhibition
Authors: Dina Stroopinsky, Jacalyn Rosenblatt, Keisuke Ito, Li Yin, Hasan Rajabi, Baldev Vasir, Turner Kufe, Brett Glotzbecker, Katarina Luptakova, Heidi Mills, Robin Joyce, Dimitrios Tzachanis, Vassiliki A Boussiotis, James Levine, Ilene Galinsky, Richard Stone, Pier Paolo Pandolfi, Donald Kufe, David Avigan
Journal: Blood (2010)
Targeting therapies influence survival of refractory patients with advanced lung adenocarcinoma: A phase II randomized trial.
Authors: K. Zarogoulidis, E. Boutsikou, T. Kontakiotis, P. Zarogoulidis, E. Eleftheriadou, L. Sacas, G. Galaktidou
Journal: Journal of Clinical Oncology (2011)

7599 Background: Several attempts were undertaken in order to improve outcome of the standard platinum based chemotherapy by adding new targeting therapies. Methods: 174 patients with lung adenocarcinoma (stage IV) received chemotherapy 6 cycles of carboplatin AUC = 5.5 + docetaxel 100 mg /m2 After the second cycle of chemotherapy patients are randomized in 4 Groups: Group A 44/174 (contol group) received only the above chemotherapy, Group B 44/174 received CT + erlotinib 150mg/day per os, Group C 44/174 received CT + bevacizumab 7.5 mg / kgr* IV . Group D 42/174 received CT + a combination of Erlotinib + bevacizumab (same dose as group B and C) Groups B, C and D after chemotherapy completion continued the above targeting therapies till disease progression Results: A statistically significant survival benefit was observed only with Breslow test among the 4 investigated groups (p= 0.031) (median survival (95% CI) in days, [450 (390-510) , 495 (343-647), 574 (503-645), 663 (633-693)] respectively. Patents with stable or progressive disease after the 2nd chemotherapy in group C and D, had a statistically significant survival benefit compared with group A and B. (p < 0.001 Log Rank test). Conclusions: In our study the addition of bevazizumabe in platinol/docetaxel combination improved survival in patients with extensive lung adenocarcinoma. This benefit was more prominent in patients with stable and progressive disease after 2 cycles of chemotherapy.
422. In a Suicide Gene Therapy Approach to Cancer, γ-Irradiation Can Completely Abolish the Bystander Effect of the PA-STK Ovarian Tumour Cell Line Due to Its Radiation Sensitivity, Resulting in Necrotic Cell Death
Authors: Jehad Zweiri, Bernard Souberbielle, Farzin Farzaneh
Journal: Molecular Therapy (2015)

The effect of irradiation on HSV-TK-expressing tumour cells and their bystander killing has been examined. The data presented shows that the irradiation substantially reduced the ability of PA-STK ovarian cells to induce the bystander killing of unmodified tumour cells. PA-STK cells were found to be very sensitive to irradiation and appeared to die too rapidly (even after a low dose of 500-rad) to enable metabolic conversion of GCV to its phosphorylated products, and/or fail to form gap-junctions with their neighbouring cells. Characterisation of tumour cell death showed that PA-STK cells undergo picnosis (a form of necrosis) after irradiation. In contrast, the TK-modified human and mouse mesothelioma cells were found to retain their in vitro bystander killing effect after irradiation. These results suggest that PA-STK cells are not suitable for clinical trials if the cells need to be lethally irradiated before in vivo use. However, the human mesothelioma cell line CRL-5830-TK appears to retain its bystander killing potential after lethal irradiation. In clinical trials, it may therefore be a suitable vehicle for HSV-TK suicide gene therapy for mesothelioma. The low IC50 of GCV in these cells (about 1μμ) makes them particularly attractive.
NK cell dysregulation in metastatic melanoma.
Authors: I. P. Silva, A. Gallois, S. Jimenez-Baranda, E. Godefroy, I. Osman, N. Bhardwaj
Journal: Journal of Clinical Oncology (2011)

e21078 Background: The adaptive immune response is compromised in metastatic melanoma (MM), however little is known about the protective innate immune mechanisms including Natural Killer (NK) cells. NK cells can eliminate tumor cells through cytotoxicity and enhance adaptive immunity through the production of cytokines such as IFN-gamma. We propose that NK cell dysfunction may contribute towards melanoma progression. The aim of this study was to evaluate NK cell phenotype and correlate it with their function in MM subjects. Methods: We purified NK cells from the PBMCs of 10 MM donors (MD) and 10 healthy donors (HD) controls. They were analyzed for the percentage of NK cells (CD3-CD56+) and their subsets (CD56bright/CD16- - cytokine producers; CD56dim/CD16+ - cytotoxic; CD56bright/CD16+; CD56dim/CD16). These NK cells were characterized in terms of: cytotoxicity (perforin expression), cytokine production (IFN-g), activating receptors (NKp44 and NKp30) and immunoinhibitory receptors (PD-1) by flow cytometry, prior and after 24h stimulation with IL2, IL12 and IL15. Results: In unstimulated conditions, the cytotoxic subset (CD56dim/CD16+) was the most frequent (70%) in HD NK cells; in MD NK cells, the cytotoxic subset corresponded to only 40% while an as yet uncharacterized subset (CD56dim/CD16-) was the most frequent (60%). After stimulation, the cytotoxic subset decreased in both HD and MD NK cells; in HD there was an increase of the cytokine producers’ subset from 5% to 30%, while in MD the CD56dim/CD16- subset increased to almost 90%. When functionally characterized, MD NK cells decreased perforin levels after stimulation (from 75% to 50%), differently from HD NK cells. The production of IFN-g was higher in HD NK cells (25%) than in MD NK cells (15%) following stimulation. Finally, NKp44 was decreased in MD NK cells (10%), when compared to HD NK cells (25%) and PD1 was increased in MD NK cells (30%), when compared to HD NK cells (15%). Conclusions: NK cells from MM patients have significant changes in functionality (cytotoxicity and IFN-g) and in the expression of immunoinhibitory and activating receptors. Those changes suggest that these anti-tumor innate immune cells are dysregulated, contributing to an impaired immunosurveillance in MM.
Deletion of Rac2 inhibits Proliferation of Chronic Myelogenous Leukemia (CML) Stems Cells and Progenitors (HSC/P) In Vivo and Promotes Survival of Scl/p210-BCR-ABL Mice.
Authors: Amitava Sengupta, Jorden Arnett, Susan Dunn, Jose Cancelas
Journal: Blood (2009)
Abstract 4718: Inositol polyphosphate 4-phosphatase II activates PI3K/SGK3 signaling to promote proliferation of human melanoma cells
Authors: Chen Chen Jiang, Meng Na Chi, Su Tang Guo, James S. Wilmott, Xiang Yun Guo, Xu Guang Yan, Chun Yan Wang, Xiao Ying Liu, Lei Jin, Hsin-Yi Tseng, Amanda Croft, Hubert Hondermarck, Tao Liu, Richard A. Scolyer, Xu Dong Zhang
Journal: Cancer Research (2015)

Abstract Inositol polyphosphate 4-phosphatase type II (INPP4B) inhibits phosphatidylinositol 3-kinase (PI3K)/Akt signaling and is emerging as a tumor suppressor in a variety of tissues. Here we report that, conversely, it functions as an oncogenic regulator in human melanoma through activating PI3K/SGK3 signaling. While it was upregulated in a subset of melanomas, knockdown of INPP4B inhibited melanoma cell proliferation in vitro, and retarded melanoma growth in a xenograft model. In contrast, overexpression of INPP4B resulted in increased proliferation and anchorage-independent growth of melanocytes. Strikingly, INPP4B did not impinge on activation of Akt in melanocytic cells. Instead, it promoted PI3K/SGK3 signaling, in that INPP4B knockdown inhibited, whereas overexpression of INPP4B enhanced, activation of SGK3. Indeed, the effect of INPP4B on melanocytic cell proliferation was due to enhanced activation of SGK3, as co-introduction of an active form of SGK3 rescued melanocytes and melanoma cells from inhibition of proliferation triggered by INPP4B knockdown, and knockdown of SGK3 abolished enhancement in cell proliferation resulting from INPP4B overexpression. Upregulation of INPP4B appeared largely due to downregulation of microRNA-494 (miR-494) and/or miR-599 as a result of gene copy number reduction in melanoma cells. Collectively, these results reveal that INPP4B upregulation mediated by loss of miR-494 and/or miR-599 promotes melanoma cell proliferation through activation of PI3K/SGK3 signaling, and suggest that the role of INPP4B in the pathogenesis of cancers of different origins needs to be defined discretely. Citation Format: Chen Chen Jiang, Meng Na Chi, Su Tang Guo, James S. Wilmott, Xiang Yun Guo, Xu Guang Yan, Chun Yan Wang, Xiao Ying Liu, Lei Jin, Hsin-Yi Tseng, Amanda Croft, Hubert Hondermarck, Tao Liu, Richard A. Scolyer, Xu Dong Zhang. Inositol polyphosphate 4-phosphatase II activates PI3K/SGK3 signaling to promote proliferation of human melanoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4718. doi:10.1158/1538-7445.AM2015-4718
The Endocannabinoid 2-Arachidonoylglycerol Regulates Platelet Function.
Authors: Samantha Baldassarri, Alessandra Bertoni, Paolo Lova, Stefania Reineri, Chiara Sarasso, Manuela Zanfa, Elena Sanna, Mauro Maccarrone, Mauro Torti, Fabiola Sinigaglia
Journal: Blood (2006)
Ask1 regulates murine platelet granule secretion, thromboxane A2 generation, and thrombus formation
Authors: Meghna U. Naik, Pravin Patel, Randall Derstine, Ramya Turaga, Xi Chen, Kalyan Golla, Keith B. Neeves, Hidenori Ichijo, Ulhas P. Naik
Journal: Blood (2016)
PML-RARA-associated cooperating mutations belong to a transcriptional network that is deregulated in myeloid leukemias
Authors: C Ronchini, A Brozzi, L Riva, L Luzi, A M Gruszka, G E M Melloni, E Scanziani, G Dharmalingam, M Mutarelli, V Belcastro, S Lavorgna, V Rossi, O Spinelli, A Biondi, A Rambaldi, F Lo-Coco, D di Bernardo, P G Pelicci
Journal: Leukemia (2016)
<i>Aggregatibacter actinomycetemcomitans</i> –induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis
Authors: Maximilian F. Konig, Loreto Abusleme, Jesper Reinholdt, Robert J. Palmer, Ricardo P. Teles, Kevon Sampson, Antony Rosen, Peter A. Nigrovic, Jeremy Sokolove, Jon T. Giles, Niki M. Moutsopoulos, Felipe Andrade
Journal: Science Translational Medicine (2016)

Aggregatibacter actinomycetemcomitans generates citrullinated autoantigens involved in rheumatoid arthritis through its pore-forming toxin leukotoxin A.
The impact of frontline risk-adapted strategy on the overall survival (OS) of patients with newly diagnosed multiple myeloma (MM): A population study in Singapore (SG).
Authors: D. C. Tan, K. H. Ong, L. P. Koh, S. S. Wong, M. T. Khin, L. H. Lee, Y. T. Goh, W. J. Chng
Journal: Journal of Clinical Oncology (2011)

8081 Background: MM is clinically heterogeneous and risk stratification is vital for prognostication and informing treatment. We evaluate the survivaldata of MM patients (pts) managed in SG, overall, and with respect to treatment eras before (era 1) and after (era 2) the incorporation of bortezomib (BTZ) as frontline therapy for high-risk MM. Methods: From the consolidated database of 3 main tertiary centers treating MM, we study the OS impact of risk-adapted approach on 483 consecutive and previously untreated MM pts from 2000 to 2009. Most relapsing pts had access to BTZ from 2004, but from 2006, BTZ became incorporated in the frontline for high-risk pts (defined by presence any adverse factors: ISS stage 3, karyotypic deletion 13 or non-hyperdiploidy, or deletion 17p, t(4;14) or t(14;16) on interphase-FISH). Disease response was assessed after induction treatment and after transplantation for non-transplanted and transplanted pts respectively. Landmark analysis at 1 year was used for comparing survival outcomes of different response groups. Results: Pts and disease characteristics were comparable between the 2 eras. At a median follow-up of 1.5 years, 0% and 26% of pts had received frontline BTZ, while 24% and 21% received BTZ at relapse in eras 1 (n=262) and 2 (n=221) respectively. Overall, ISS, cytogenetics, age (> 60 years), presenting platelet count (≤ 140 x 109/L) and eventual response attained were discriminating of the OS (median= 4.7 years) on univariate analyses. The median OS for era 1 and 2 were 4.2 years (95% CI, 2.8-5.6) and not reached respectively (p=0.02). On Cox regression multivariate analysis stratified by era, a non-hyperdiploid karyotype was the single most significant adverse prognostic factor in era 1 (HR 2.1, 95% CI, 1.1-4.3, p=0.03), while attainment of ≥VGPR superceeded all baseline parameters as the most significant prognosticator in era 2 (HR 0.06, 95% CI, 0.02-0.2, p<0.001). Conclusions: Our study suggests that BTZ in frontline combination, rather than sequential use may be better able to overcome adverse risk factors. Upfront risk-adapted strategy may be vital for optimizing healthcare resources.
PO08ACCOUNTING FOR THE DOSE-VOLUME PARADOX IN STEREOTACTIC RADIOSURGERY OF BRAIN METASTASES:VOLUME STANDARDISED LINEAR QUADRATIC AND LINEAR QUADRATIC CUBIC TUMOUR CONTROL PROBABILITY MODELS AS AUDIT TOOLS
Authors: H. Benghiat, P. Sanghera, M. Cook, R. Simmons, G. Heyes, D. Spooner, G. Cruickshank, A. Hartley
Journal: Neuro-Oncology (2015)

INTRODUCTION: Comparison of local control rates at 12 months (LC) for brain metastases (BM) treated with stereotactic radiosurgery (SRS) is hindered by the dose-volume paradox wherein larger metastases may receive lower doses. This phenomenon will have a significant effect on differences in LC between centres, some treating small asymptomatic metastases. Linear quadratic (LQ) or linear quadratic cubic (LQC) tumour control probability (TCP) models are proposed as audit tools to assist such comparisons. METHOD: Series were identified reporting LC by volume of BM. The parameters of the LQ and LQC models α/β, α and DL were derived by adjusting these variables to achieve the highest correlation between the observed rate of LC and the modelled TCP for variable clonogen density (CD) 107-109 cm-1. The models obtained were then tested on a series of 48 brain metastases treated with single fraction SRS in a single centre using the surface dose and volume of individual metastases. RESULTS: 8 single fraction series with sufficient LC data were identified. Parameters derived for the models for CD 107 and 109 respectively were LQ α/β = 16.7,15.7 Gray (Gy); α = 0.49, 0.59 Gy-1; LQC α/β = 10.3, 9.6 Gy; α = 0.43, 0.52 Gy-1 and DL 26.2, 26.3 Gy. All 4 models gave a similar TCP at 12 months for the test population, e.g. LQ CD 107 gives TCP of 0.58 (95% CI 0.47-0.69) predicting LC in the test population between 47 and 69% compared to the observed LC of 60% (95% CI 46-74%). CONCLUSION: The models presented may assist in the comparison of LC between series with variable volumetric case mix. However, modification to correct for histological heterogeneity would help to refine these models.
Deletion 17p in Unselected Newly Diagnosed Symptomatic Patients with Multiple Myeloma
Authors: Efstathios Kastritis, Evangelos Terpos, Maria Gkotzamanidou, Maria Roussou, Maria Gavriatopoulou, Magdalini Migkou, Evangelos Eleutherakis-Papaiakovou, Dimitrios Christoulas, Dimitra Gika, Meletios Athanasios Dimopoulos
Journal: Blood (2011)
Vitamin D pathway modulation in Caucasian case series of healthy women and breast cancer patients
Authors: L. Mercatali, N. Masalu, A. Bongiovanni, A. Pangan, R. Tedaldi, E. Scarpi, F. La Manna, C. Liverani, C. Spadazzi, T. Ibrahim, D. Amadori, P. Serra
Journal: Annals of Oncology (2015)
Identification of Target Gene at 2p15 Amplification in DLBCL Using Contig Array CGH.
Authors: Noriko Fukuhara, Hiroyuki Tagawa, Yasuhiro Kameoka, Yumiko Kasugai, Sivasundaram Karnan, Yasuo Morishima, Shigeo Nakamura, Masao Seto
Journal: Blood (2005)