tbuckley/cabot-search huggingface dataset:
Abstract 1559: Progranulin A9D mutation functionally leads to the cytoplasm retardation of angiogenin
Authors: Jinghao Sheng, Yongdui Chen, Siqi Li, Haojie Dong, Guangdi Chen, Zhengping Xu
Journal: Cancer Research (2015)

Abstract Neurodegenerative diseases are progressive neurological disorders with selective neuron loss in particular regions of brain, including frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and many others. Gene defects have been recognized as a prominent factor in the etiology and pathogenesis of neurodegenerative diseases. To date, hundreds of genetic variants that located in dozens of genes have been associated with susceptibility to various neurodegenerative diseases. Among them, more than 60 mutations in progranulin (PGRN) have been reported in FTLD, AD, ALS and PD. One of the mutations in PGRN gene exon 1 introduces a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (PGRN A9D), and results in cytoplasmic mis-sorting of this protein. However, the mechanism of actions of this mis-sorting remains elusive. To address this issue, we first examined the subcellular distribution of PGRN with A9D mutation in human neuronal-like cells (SH-SY5Y). The results have shown that PGRN A9D mutation failed to undergo maturation and accumulated in the stress granules. Interestingly, this mutation also induces redistribution of cellular angiogenin (ANG), a stress response factor and neurodegenerative diseases related protein, from nuclear to cytoplasm. PGRN was also directly interacted with ANG in stress granules. Furthermore, the cytoplasmic retardation of ANG by PGRN A9D mutation abolished ANG-enhanced rRNA transcription and cell survival. Taken together, these results indicate that PGRN with A9D mutation changed localization of ANG as well as cell growth and survival, suggesting that PGRN and ANG act in concert to regulate the progress of neurodegenerative diseases. Citation Format: Jinghao Sheng, Yongdui Chen, Siqi Li, Haojie Dong, Guangdi Chen, Zhengping Xu. Progranulin A9D mutation functionally leads to the cytoplasm retardation of angiogenin. [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 1559. doi:10.1158/1538-7445.AM2015-1559
A Randomized Phase 2 Study of Sapacitabine, An Oral Nucleoside Analogue, in Older Patients with Myelodysplastic Syndrome (MDS) Refractory to Hypomethylating Agents.
Authors: Guillermo Garcia-Manero, Selina Luger, Parameswaran Venugopal, Lori J. Maness, Meir Wetzler, Jessica Altman, David F. Claxton, Stephen Strickland, Stefan Faderl, Judy Chiao, Hagop M. Kantarjian
Journal: Blood (2009)
The prognostic significance of serum levels of tumour necrosis factor- alpha and interleukin-6 and their association with cachexia in patients with prostate cancer
Authors: V. Michalaki, K. Syrigos, M. Odontiadis, J. Waxman
Journal: Journal of Clinical Oncology (2004)

4743 Background: The complex syndrome of cancer cachexia is multifactorial in origin and several cytokines may be involved in its aetiology. The present study was undertaken to evaluate the relationship between serum tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and cachexia in patients with prostate cancer (CaP), and their prognostic significance. Methods: The levels of TNF-α and IL-6 were determined in serum samples from 26 patients with organ-confined CaP, from 54 patients with advanced or metastatic CaP and from 38 controls. High sensitive commercially available (ELISA) assays were used to determine cytokine levels. Serum IL-6 and TNF-α levels were correlated with serum albumin levels, hemoglobin levels, body mass index, clinicopathological variables and patient survival. The prognostic significance of the above parameters was assessed using univariate and multivariate Cox's proportional hazards model analyses. Results: Weight loss more than 10% over a 3–6 month period was seen in 7 of 54 patients (13%) with advanced CaP. The median levels of TNF-α and IL-6 were significantly elevated in cachectic patients with advanced prostate cancer (9.3 pg/ml and 6.7 pg/ml respectively) compared with patients with localized disease (1.3 pg/ml, and 1.9 pg/ml p< .001), or healthy subjects. The serum albumin levels, hemoglobin levels, and body mass index of the patients with elevated serum TNF-α and IL-6 levels were significantly lower (p< 0.001) than the corresponding values in patients with very low levels of both cytokines. TNF-α levels correlated with IL-6 levels, but there was no correlation between PSA levels and cytokine levels. With a median follow-up of 48 months, patients with elevated serum levels of both cytokines and cachexia had a significantly higher mortality rate (p < 0.05) than those with undetectable serum levels. Conclusions: These results suggest that TNF-α and IL-6 levels were correlated with significant cachexia and related to survival in patients with advanced prostate cancer, and could provide potential targets for the treatment of cancer cachexia. No significant financial relationships to disclose.
DDIS-11. MOLECULAR MECHANISMS OF DIANHYDROGALACTITOL (VAL-083) IN OVERCOMING CHEMO-RESISTANCE IN GLIOBLASTOMA
Authors: Beibei Zhai, Anna Golebiewska, Anne Steino, Jeffrey Bacha, Dennis Brown, Simone Niclou, Mads Daugaard
Journal: Neuro-Oncology (2016)

Glioblastoma (GBM) is the most aggressive malignant brain cancer. The heterogeneous nature of GBM tumors and highly chemoresistant cancer stem-cells (CSCs) comprise significant clinical challenges. Most GBM tumors express O6-methylguanine-DNA-methyltransferase (MGMT) causing intrinsic chemoresistance to temozolomide and CCNU. Even tumors initially responsive to temozolomide, often recur with deficient DNA mismatch repair system (MMR) leading to acquired chemoresistance to temozolomide. Alteration in p53, particularly gain-of-function mutations, are correlated with poor prognoses in GBM, potentially by increasing MGMT-expression and temozolomide-resistance. Second-line treatment with bevacizumab, while successfully inducing intra-tumor hypoxia, has not improved overall survival. This is possibly due to GBM CSCs rapidly adapting to hypoxia by upregulating glucose-uptake and increasing invasiveness. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent that readily crosses the blood-brain barrier, accumulates in brain tumor tissue and has demonstrated activity against GBM in prior NCI-sponsored clinical trials. VAL-083 induces interstrand cross-links at guanine-N7 causing DNA double-strand breaks and cell-death. VAL-083 is equally active against GBM CSCs and non-CSCs, and the activity is MGMT-independent and appears minimally dependent on wild-type p53, in vitro. A Phase I/II clinical trial studying VAL-083 in recurrent GBM, after temozolomide and bevacizumab failure, suggested potential of VAL-083 to offer clinically meaningful survival benefits. Here we report a distinct mechanism-of-action of VAL-083, showing that VAL-083 leads to irreversible S-phase cell-cycle arrest, activation of the homologous recombination pathway and ensuing cell-death, through mechanisms independent of MGMT and MMR. We used biochemical and microscopic analyses of DNA repair markers to investigate the VAL-083-induced DNA damage response in cancer-cells harbouring wild-type or mutated MMR-proteins and p53. We furthermore investigated the cytotoxic activity of VAL-083 against GBM cancer-cells under normoxia vs. hypoxia. Our results demonstrate a distinct anti-cancer mechanism for VAL-083. At the meeting we will present further results clarifying VAL-083’s potential to overcome chemoresistance in the treatment of GBM.
Abstract 14360: Ratiometric and Allometric Relations Between Left Atrial Dimension and Measures of Body Size: the EchoNoRMAL Collaboration
Authors: Giovanni de Simone, Ernst R Rietzschel, Iana Simova, Liza Thomas, Raffaele Izzo, Havard Dalen, FD Richard Hobbs, Arnold C Ng, Christopher M Triggs, Katrina K Poppe, Gillian A Whalley
Journal: Circulation (2013)

Normalization for body size is an accepted method to compare cardiovascular parameters among subjects with differing body shape. As largely demonstrated for LV mass, normalization should take into ...
E-learning resources in Myanmar
Authors: Espen Bjertness, Thein Thein Htay, Nay Soe Maung, Zaw Wai Soe, Saw Sanda Aye, Ole Petter Ottersen, Tippawan Liabsuetrakul, Per Grøttum, Magnus Hovland, Mahmood Amiry-Moghaddam
Journal: The Lancet (2016)
Comparasion Between Nilotinib and Dasatinib as Second-Line Therapy for Patients with Chronic Myeloid Leukemia: A Single Center Retrospective Study.
Authors: Clarisse Lobo, Carla Boquimpani, Tania Silva Madeira, Patricia Wendling, Claudia Maximo, Carlos Bernardo Lima, Elias Atta, Renata DE SOUZA Cravo
Journal: Blood (2010)
Long-Term Anti-Leukemic Activity of Ponatinib in Patients with Philadelphia Chromosome-Positive Leukemia: Updated Results from an Ongoing Phase 1 Study
Authors: Michael W Deininger, Jorge E. Cortes, Hagop M. Kantarjian, Neil Shah, Dale Bixby, Michael J. Mauro, Ian W. Flinn, Thomas O'Hare, Simin Hu, David J. Dorer, Victor M. Rivera, Tim Clackson, Christopher D. Turner, Frank G Haluska, Brian J. Druker, Moshe Talpaz
Journal: Blood (2012)
Reduced Intensity Conditioning with Fludarabine/Busulfan 6.4mg/Kg Results In High Donor Chimerism and Low Toxicity In Both Related and Unrelated Allo-SCT for Hematologic Malignancies.
Authors: Steven C Goldstein, Selina M. Luger, Noelle Frey, Alexander Perl, Edward A Stadtmauer, Donald Tsai, Alison Loren, Sunita Nasta, Elizabeth Hexner, Ran Reshef, Jacqueline Smith, Joanne Hinkle, Pavel Vassilev, Michael J Vozniak, David L. Porter
Journal: Blood (2010)
706. Non-Invasive Intranasal Administration of AAV9-Iduronidase Prevents Emergence of Neurologic Disease and Neurocognitive Dysfunction in a Murine Model of Mucopolysaccharidosis Type I
Authors: Lalitha Belur, Megan Buckvold, Kelly Podetz-Pedersen, Maureen Riedl, Lucy Vulchanova, Leah R. Hanson, Karen Kozarsky, William H. Frey, Walter C. Low, Carolyn Fairbanks, R. Scott McIvor
Journal: Molecular Therapy (2015)

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive storage disease caused by deficiency of alpha-L-iduronidase (IDUA), resulting in accumulation of glycosaminoglycans (GAGs). In the severe form of the disease (Hurler syndrome), death results by age 10. Current treatments for this disease include hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). However, ERT is ineffective in treating CNS disease due to the inability of lysosomal enzymes to traverse the blood-brain barrier, and while there is neurologic benefit to HSCT the procedure is associated with significant morbidity and mortality. We have taken a novel approach to treat neurologic disease associated with Hurler syndrome, using intranasal administration of an IDUA-encoding AAV9 vector. A CAGS regulated AAV9-IDUA vector was infused intranasally into adult mice (2-3 months of age) that had been immunotolerized at birth with Aldurazyme to prevent anti-IDUA immune response. Mice sacrificed at 3 months post-infusion exhibited IDUA enzyme activity levels that were 100-fold that of wild type in the olfactory bulb, with wild type levels of enzyme restored in all other parts of the brain. Intranasal treatment with AAV9-IDUA also resulted in clearance of tissue GAG storage materials in all parts of the brain. QPCR analysis of vector genomes indicated only background levels in all portions of the brain. There was strong IDUA immunofluorescence staining of tissue sections observed in the nasal epithelium and olfactory bulb but there was no evidence for the presence of transduced cells in other portions of the brain. This indicates that clearing of storage materials most likely occurred as a result of enzyme diffusion from the olfactory bulb and the nasal epithelium into deeper areas of the brain. At 6 months of age, intranasally treated animals along with age-matched heterozygote and IDUA-deficient control animals were subjected to neurocognitive testing using the Barnes maze. Unaffected heterozygote animals exhibited improved performance in this test while MPS I mice displayed a deficit in locating the escape. Remarkably, MPS I mice treated intranasally with AAV9-IDUA exhibited behavior similar to the heterozygote controls, demonstrating prevention of the neurocognitive deficit seen in the untreated MPS I animals. There was no significant difference between heterozygote animals and treated animals, while latency to escape was significantly different between these two groups and MPS I deficient animals (P<0.001). This novel, non-invasive strategy for intranasal AAVIDUA administration could potentially be used to treat CNS manifestations of several disorders, including lysosomal storage diseases.
474. Consequences of Infusion Time on Efficiency of Intravenous Delivery of Vector Genomes to the Liver
Authors: Jonathan B. Rosenberg, Bishnu P. De, Lucy Quach, Carol Russo, Stephen M. Kaminsky, Dolan Sondhi, Ronald G. Crystal
Journal: Molecular Therapy (2016)

Based on the knowledge that, when administered intravenously (IV), 90% of adeno-associated virus (AAV) gene transfer vectors are transferred to the liver, the IV route has become the standard for gene therapy applications directed toward genetic modification of liver cells. To achieve maximum transfer of vector genomes to the liver, most attention has been focused on AAV serotype and dose, but little focus has been directed toward whether differences could be achieved by varying the timing of IV vector administration. To assess this variable, we administered rh. 10 serotype AAV vectors intravenously to rodents using 2 variables: (1) single vs multiple administrations; and (2) length of time of infusion. To assess single vs multiple administration, mouse cohorts (C57Bl/6 males, n=5/group) were administered AAVrh.10hα1AT, encoding for human α1-antitrypsin (α1AT), IV at 1012 genome copies (gc)/kg, 4×1012 gc/kg and a 3rd cohort receiving the 1012 gc/kg dose on 4 consecutive days. Mice were bled at 4, 14, 28, and 112 days post-administration. Serum human αlAT levels showed the expected dose response. Mice administered 1012 gc/kg daily for 4 days had αlAT serum levels below those achieved by the single dose 4×1012 gc/kg group (day 112, p<0.001), but mice administered 4 days consecutively at 1012 gc/kg had significantly higher levels of serum α1AT levels than that of a single administration at the same 1012 gc/kg dose (day 112, p<0.0003). This could be an advantage when dosing for a single administration is limited by volume, vector concentration, or total dose. To assess whether single administration of the same dose over different times would achieve different levels of transfer of vector genomes to the liver, rats (Fischer 344 males) were administered IV AAVrh. 10hFXN (an AAVrh. 10 vector coding for the human frataxin cDNA), with a fixed volume (1 ml) over 1 min, 30 min, 4 hr and 24 hr, each infusion time tested at 3 doses (1011, 1012, and 1013 gc/kg). Rats were sacrificed after 7 days and liver vector genome levels evaluated by quantitative PCR. There was a dose-dependent increase in vector genomes in the liver for all infusion times (p<0.0001). However, there were no differences observed in vector genome copies in the liver between any of the 4 different rates of vector infusion, i.e., there was no advantage to administration over different lengths of times (p>0.1, for all time comparisons in each dosage group). We conclude that, at least in rodents, the use of multiple daily injections influences the expression patterns of the targeted gene; however, the rate of infusion does not appear to be a critical parameter for the design of intravenous infusion for targeting AAV vectors to liver.
Clinical implications of PET-negative residual disease at the completion of chemotherapy for diffuse large B-cell Lymphoma.
Authors: B. S. Dabaja, J. Phan, L. Medeiros, H. Chuang, L. Fayad, F. Hagemeister, F. D. Shihadeh, P. Allen, M. A. Rodriguez
Journal: Journal of Clinical Oncology (2011)

e18516 Background: To evaluate potential differences in overall survival (OS) and progression-free survival (PFS) according to PET and CT disease status at completion of chemotherapy for patients with diffuse large B-cell lymphoma. Methods: Subjects were 303 patients with histologically confirmed DLBCL treated between January 2001 and December 2007; no patient received radiation therapy. We evaluated: age, sex, Ann Arbor stage, bulky disease, International Prognostic Index score, Ki-67 expression, PET standardized uptake values (SUVs), disease status after chemotherapy and at last follow-up. Results: Median age was 61 years; 149 men; 81 (27%) had stage I-II, 242 (73%) stage III-IV. A total of 248 patients (82%) completed 6-8 cycles of doxorubicin-based therapy. On multivariate analysis, both OS and PFS were significantly influenced by: the presence of PET negative residual mass on CT at completion of therapy (P < 0.001 for OS and P < 0.001 for PFS); number of cycles and type of chemotherapy (P < 0.001 for OS and P< 0.001 for PFS); Combined presence (p=0.01 for OS and P=0.003 for PFS) of high Ki 67, high PET SUV, and bulky disease; and IPI score (P = 0.001 for OS and P < 0.001 for PFS). Same factors remained significant when replacing response to therapy with size (> 2cm) or number of residual sites (p<0.0001 OS and p<0.0001 PFS). Conclusions: Presence of a residual mass on CT at the completion of chemotherapy has both prognostic and predictive value in patients with DLBCL. These patients should be considered for biopsy and further consolidative therapy
483. In Vivo DMD Gene Editing in Muscles and Muscle Stem Cells of Dystrophic Mice
Authors: Mohammadsharif Tabebordbar, Kexian Zhu, Jason Cheng, Jeffrey Widrick, Winston Yan, Ru Xiao, Luk Vandenberghe, Feng Zhang, Amy Wagers
Journal: Molecular Therapy (2016)

Duchenne muscular dystrophy (DMD) is a X-linked genetic disorder that arises from frame-disrupting mutations in the DMD gene, encoding DYSTROPHIN. Lack of DYSTROPHIN expression destabilizes muscle fiber membranes, increases susceptibility to contraction-induced injury and drives muscle degeneration. Removing one or more exons from the mutated transcript can produce an in-frame mRNA and a truncated but still functional protein. In this study, we develop and test a direct gene editing strategy to recover DYSTROPHIN expression in the mdx mouse model of DMD. Coupling clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 endonucleases delivered via adeno-associated virus (AAV) with paired guide RNAs flanking the mutated Dmd exon 23, we demonstrate precise excision of intervening DNA and restoration of Dystrophin reading frame and protein expression in vivo in both skeletal and cardiac muscles following local or systemic delivery. DYSTROPHIN expression in AAV Dmd-CRISPR treated mdx mice was sufficient to partially recover functional deficiencies of dystrophic muscle. Finally, we demonstrate in vivo targeting of the mdx mutation in endogenous muscle stem cells, suggesting that AAV-CRISPR may provide a means to support ongoing repair of dystrophic fibers with corrected muscle precursors. This study provides proof-of-concept evidence supporting the feasibility and efficacy of in vivo genome editing to correct frame-disrupting mutations in DMD.
Development and Evaluation of the Clinical Utility of a Next Generation Sequencing (NGS) Tool for Myeloid Disorders
Authors: Angela Hamblin, Adam Burns, Christopher Tham, Ruth Clifford, Pauline Robbe, Adele Timbs, Joanne Mason, Helene Dreau, Andreas Weller, Puthen Jithesh, Olivia Fox, Melody Tabiner, Adam Mead, Andrew Peniket, Paresh Vyas, Shirley Henderson, Anna Schuh
Journal: Blood (2014)
Abstract 2258: Myc drives Pten/ p53-deficient proliferation and metastasis due to Il6-secretion and Akt-suppression via Phlpp2
Authors: Dawid G. Nowak, Hyejin Cho, Tali Herzka, Victoria M.Y. Wang, Serif Senturk, Daniel V. DeMarco, David Ding, Christof Fellmann, Tumas Beinortas, David Kleinman, Kaitlin Watrud, Muhan Chen, John E. Wilkinson, Mireia Castillo-Martin, Carlos Cordon-Cardo, Brian D. Robinson, Lloyd C. Trotman
Journal: Cancer Research (2015)

Abstract The sporadic transition from indolent to metastatic disease is a hallmark of prostate cancer (PC) and frequently involves deletion of PTEN and TP53. We recently recapitulated metastasis of Pten/ Trp53-mutant PC in mouse using the RapidCaP system and surprisingly, we found that it is driven by Myc, rather than Akt activation. Here, we show that cell-cell communication by Il6 drives this Akt-Myc switch through activation of the Akt-inactivating phosphatase Phlpp2. Primary cells revealed that loss of Pten/ Trp53 triggers secretion of the Il6 cytokine when these genes are deleted together, but not separately. Il6 then communicates a downstream program of Stat3-mediated Myc activation, which drives cell proliferation. Abrogation of Myc activity by Myc inhibition with the JQ1 bromodomain inhibitor, Myc-RNAi, and Myc-CRISPR/ Cas9 approaches inhibited proliferation. We validated these findings in vivo, where peak proliferation in Pten/ Trp53 mutant primary and metastatic PC did not correlate with activated Akt, but with Stat3/ Myc activation instead. Most notably, we found that Myc strongly activates the Akt phosphatase Phlpp2 in primary cells and RapidCaP metastasis, and showed genetically that Phlpp2 is essential for dictating proliferation and Myc-mediated suppression of Akt. Collectively, our data reveal competition between two proto-oncogenes: Myc and Akt, which ensnarls the Phlpp2 gene to facilitate Myc-driven metastasis. Citation Format: Dawid G. Nowak, Hyejin Cho, Tali Herzka, Victoria M.Y. Wang, Serif Senturk, Daniel V. DeMarco, David Ding, Christof Fellmann, Tumas Beinortas, David Kleinman, Kaitlin Watrud, Muhan Chen, John E. Wilkinson, Mireia Castillo-Martin, Carlos Cordon-Cardo, Brian D. Robinson, Lloyd C. Trotman. Myc drives Pten/ p53-deficient proliferation and metastasis due to Il6-secretion and Akt-suppression via Phlpp2. [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 2258. doi:10.1158/1538-7445.AM2015-2258