tbuckley/cabot-search huggingface dataset:
74. The Mechanism of Hepatotoxicity from IV Administration of High Dose VSV
Authors: Lianwen Zhang, Michael Steele, Marshall B. Behrens, Mark J. Federspiel, Stephen J. Russell, Kah Whye Peng
Journal: Molecular Therapy (2015)

Vesicular Stomatitis Virus (VSV) is a potent replication competent oncolytic virus (OV). Most individuals do not have pre-existing anti-VSV antibodies, making VSV an ideal OV for treatment of disseminated cancer. To tailor the virus for systemic use, VSV-IFNb-NIS was attenuated through genetic modification to encode interferon beta which restricts virus replication in nontransformed cells and a sodium iodide symporter (NIS) reporter gene to enable real time noninvasive imaging of the sites of virus infection in patients. Preclinical studies in mice show that, in contrast to expectations, dose limiting toxicity was hepatotoxicity, not neurotoxicity. To investigate the mechanism(s) underlying VSV induced hepatotoxicity, we first sought to determine if liver damage was due to interactions with viral particles or required virus infection. C57BL/6 mice were given saline, 109 TCID50 VSV-mIFNb-NIS or equivalent amounts of inactivated VSV-mIFNb-NIS intravenously. There was a significant increase in ALT and AST at 24h while no significant change was found in the animals receiving inactivated VSV. Studies with adenoviruses showed that Ad-induced hepatotoxicity was attenuated by depletion of macrophages in the liver and spleen using clodronate liposomes. Our studies in clodronate treated C57BL/6 mice showed even higher levels of ALT and AST enzymes in the blood with significantly increased cell damage in the liver and spleen by 24h if mice were given 109 VSV-IFNb-NIS. In contrast, ALT/AST levels did not change significantly in mice given heat inactivated VSV (104 infectious units but the same number of viral particles as the 109 stock). Similar data were also observed in Balb/c mice. In conclusion, our studies indicate that dose limiting toxicity from IV administration of high dose (4×1010 TCID50/kg) VSV-mIFNb-NIS in a mouse is not neurotoxicity, but hepatotoxicity. The mechanism of the hepatotoxicity is direct infection and killing of hepatocytes by live virus, and not due to the interaction of viral particles with macrophages and Kupffer cells. Hence, in contrast to adenovirus dosing (viral particles/kg), our data suggest that VSV dosing should be calibrated in units of infectious virus (TCID50/kg) and not numbers of viral particles per test subject.
406. The MDX/UTR +/- Mouse Is a Superior Mouse Model for Duchenne Muscular Dystrophy
Authors: Thais B. Lessa, Chady H. Hakim, Carlos E. Ambrósio, Dongsheng Duan
Journal: Molecular Therapy (2015)

Duchenne Muscular Dystrophy (DMD) is a severe muscle wasting disease caused by the absence of the dystrophin protein. Dystrophin, the core component of the dystrophin-associated glycoprotein complex, is responsible in stabilizing the sarcolemma during muscle contraction and relaxation. In the absence of dystrophin, muscle becomes fragile and susceptible to damage. This results in progressive muscle degeneration and replacement with fibrotic tissue. The mdx mouse is the most commonly used animal model for DMD. However, it is also considered a poor model because it cannot reproduce the severe dystrophic phenotype seen in patients. Genetic elimination of utrophin, an autosomal homolog of dystrophin, yields a symptomatic double knockout (dko) model. Unfortunately, human patients do not have utrophin deficiency. An utrophin heterozygous mdx (mdx/utrn+/-) mouse would theoretically be a better model should it show more severe muscle dysfunction than the mdx mouse. To test this hypothesis, we systematically examined diaphragm disease in 2-m-old sex-matched mdx and mdx/utm+/-mice. Compared to the mdx mouse, the mdx/utrn+/-mouse displayed more defective histological changes. Importantly, muscle force and passive property were significantly more compromised in the mdx/utrn+/-mouse. Collectively, our data demonstrated for the first time that the mdx/utrn+/-mouse represent a better DMD model at both morphological and physiological levels.
661. Assay Development and Qualification for Human Embryonic Stem Cell (hESC)-Derived Cardiomyocytes Intended for Clinical Studies
Authors: Derek Kong, Wei Dang, Aparna Krishnan, Heather Javier, Jennil Patel, David Hsu, Larry A. Couture
Journal: Molecular Therapy (2015)

Human embryonic stem cell (hESC)-derived cellular products have been considered as promising candidates for cell replacement therapy for multiple degenerative diseases. At the Center of Biomedicine and Genetics (CBG), we have manufactured under cGMP numerous hESC-differentiated products including neuron stem cells (NSC), neuronal progenitor cells (NPC), retinal pigment epithelium (RPE) cells, dopaminergic neurons and cardiomyocytes intended for pre-clinical and clinical studies. Specifically, cardiomyocytes are produced through hESC differentiation procedure utilizing adherent and notably suspension culture systems.
543. In Vivo Beta-Cell-Targeted Gene Editing by AAV Vectors
Authors: Salma G. Morsy, Jason Tonne, Yaxi Zhu, Paul Belmonte, Yasuhiro Ikeda
Journal: Molecular Therapy (2016)

The CRISPR/Cas9 and guide RNA system has emerged as a promising genome editing platform, due to its simplicity, versatility and efficiency, compared to prior techniques for genome modification. Although the original Cas9 gene is too long to be packaged by AAV vectors, Dr. Zhang and colleagues have identified a shorter Cas9 protein from S. aureus (saCas9), which allows generation of a single AAV vector carrying both saCas9 and a guide RNA. Previously, we and others have demonstrated that AAV serotypes 8 and 9-based vectors are highly pancreas-tropic. Our long-term goal is to develop efficient beta-cell- and acinar-cell-targeted gene editing systems based on the AAV-saCas9 system. We first assessed on-target effects of the AAV-saCas-gRNA vector system in vitro. We generated two GFP sequence-targeted gRNA vectors, and tested their genome editing effects using two HT1080 cell lines carrying a single copy of GFP. Infection of HT1080 lines with an multiplicity of infection (MOI) of 2×104 resulted in 40-55% GFP knockout by two AAV-gRNA constructs. Gene editing efficiency was comparable in two HT1080 lines, and dose-dependent. Consecutive, multiple high-dose infections for 3 days achieved up to 80% GFP knockdown. To test whether a subset of cells are more resistant to the AAV-saCas9-mediated genome editing, we sorted the remaining 20% of GFP-positive cells and re-infected recovered GFP-positive cells with the two saCas9 vectors. Our data showed those cells were equally permissive to the saCas9 vectors, when compared to their parental line. To assess the off-target effects of the AAV-saCas9-gRNA system, we compared the exome sequences of the vector-treated cells. Our preliminary result identified multiple off-target deletions upon AAV-saCas9 treatments. We are currently analyzing whether those off-target effects were due to their similarity to the GFP targeting gRNA sequences, or independent from the gRNA sequences. We then tested the feasibility of the AAV-saCas9-gRNA vector system for beta-cell-targeted gene editing in vivo. We generated AAV8 vectors carrying Pdx1-targeting gRNA, with saCas9 driven by CMV promoter. Single intraperitoneal injection of AAV saCas9 vectors led to efficient knockout of Pdx1 expression in the pancreatic beta-cells. To limit potential off-target effects, we need to restrict saCas9 expression in beta-cells. However, our original beta-cell targeted vectors carry a relatively long, 1.1kb insulin promoter sequence. We therefore optimized the insulin promoter sequence and determined the minimum, essential promoter sequence, which facilitates robust transgene expression with high tissue-specificity. We are in the process of testing the AAV-saCas9-gRNA vectors with the optimized insulin promoter sequence for in vivo beta-cell gene editing.
Understanding the Full Effect of the Changing Legal Status of Marijuana on Youth
Authors: Alain Joffe
Journal: JAMA Pediatrics (2016)

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Optimising bone health in the young male athlete
Authors: Adam S Tenforde, Aurelia Nattiv, Kathryn Ackerman, Michelle T Barrack, Michael Fredericson
Journal: British Journal of Sports Medicine (2016)

Sports participation provides many health benefits to young athletes of both sexes. However, a subset of male athletes may suffer from unrecognised low bone density and impaired skeletal health, predisposing them to an increased risk of fracture. The effects of delayed diagnosis and inappropriate treatment of low bone density among male athletes may have severe consequences in future longevity in sport as well as long-term bone health. It has been well described that low energy availability alters the neuroendocrine axis, resulting in menstrual dysfunction, low bone mineral density (BMD) and increased risk for bone stress injury (BSI) in female athletes.1 ,2 However, male athletes may also experience an analogous process that parallels the female athlete triad (Triad).3 As childhood and adolescence represent a critical time for accruing peak bone mass, identifying modifiable risk factors for impaired skeletal health is important to ensure the long-term health in athletes of both sexes.

Similar to female athletes,4 there appear to be cumulative risk factors for low BMD (Z-scores <−1.0) in the young male athlete. A prior investigation in 42 male runners identified BMI ≤17.5 kg/m2 and a belief that being thinner leads to faster running performances as risk factors for having lower BMD.5 Risk factors in the young male athlete obtained from anthropometric measures and self-report questionnaires include low body weight (<85% expected weight), stress fracture history, average …
Quality of Evidence Underlying the American Heart Association/American College of Cardiology/Heart Rhythm Society Guidelines on the Management of Atrial Fibrillation
Authors: Adam S. Barnett, William R. Lewis, Michael E. Field, Gregg C. Fonarow, Bernard J. Gersh, Richard L. Page, Hugh Calkins, Benjamin A. Steinberg, Eric D. Peterson, Jonathan P. Piccini
Journal: JAMA Cardiology (2016)

The joint American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) guidelines on the management of atrial fibrillation (AF) are used extensively to guide patient care.To describe the evidence base and changes over time in the AHA/ACC/HRS guidelines on AF with respect to the distribution of recommendations across classes of recommendations and levels of evidence.Data from the AHA/ACC/HRS guidelines on AF from 2001, 2006, 2011, and 2014 were abstracted. A total of 437 recommendations were included.The number of recommendations and distribution of classes of recommendation (I, II, and III) and levels of evidence (A, B, and C) were determined for each guideline edition. Changes in recommendation class and level of evidence were analyzed using the 2001 and 2014 guidelines.From 2001 to 2014, the total number of AF recommendations increased from 95 to 113. Numerically, there was a nonsignificant increase in the use of level of evidence B (30.5% to 39.8%; P = .17) and a nonsignificant decrease in the use of level of evidence C (60.0% to 51.3%; P = .21), with limited changes in the use of level A evidence (8.4% to 8.8%; P = .92). In the 2014 guideline document, 10 of 113 (8.8%) recommendations were supported by level of evidence A, whereas 58 of 113 (51.3%) were supported by level of evidence C. Most recommendations were equally split among class I (49/113; 43.4%) and class IIa/IIb (49/113; 43.4%), with the minority (15/113; 13.3%) assigned as class III. Most class I recommendations were supported by level of evidence C (29/49; 59.2%), whereas only 6 of 49 (12.2%) were supported by level of evidence A. No rate control category recommendations were supported by level of evidence A.Some aspects of the quality of evidence underlying AHA/ACC/HRS AF guidelines have improved over time. However, the use of level of evidence A remains low and has not increased since 2001. These findings highlight the need for focused and pragmatic randomized studies on the clinical management of AF.
Right ventricular perforation by tunneled hemodialysis catheter
Authors: Lucas V. Assis, Edna R.S. Pereira, Cinara B. Sá, Israel Guimarães-Neto, João B. Masson-Silva, Thalita O. Matos, Flaubert R.S. Santos, Marina A.O.O. Neiva, Brenno N.S.S. Conde
Journal: Kidney International (2016)
Relevant Discordance Between 68Ga-DOTATATE and 68Ga-DOTANOC in SDHB-Related Metastatic Paraganglioma
Authors: Ingo Janssen, Katherine I. Wolf, Chan H. Chui, Corina M. Millo, Karel Pacak
Journal: Clinical Nuclear Medicine (2016)

Pheochromocytomas/paragangliomas are somatostatin receptor 2-overexpressing tumors. Ga-DOTA-peptide imaging has recently shown excellent results in the detection of metastatic lesions in these tumors. However, currently used Ga-DOTA peptides show different somatostatin receptor affinities. Here, we report the remarkable differences in a patient who was imaged with Ga-DOTANOC and Ga-DOTATATE PET/CT within a 7-month period. The patient presented with a nearly negative Ga-DOTANOC PET/CT scan, whereas on Ga-DOTATATE PET/CT, multiple highly positive lesions were identified.
Abstract 3229: Distinct types of cetuximab resistant KRAS mutant of colorectal cancer revealed by an integrated sensitivity assay
Authors: Takahiro Tashiro, Hiroaki Okuyama, Hiroko Endo, Kenji Kawada, Masayuki Ohue, Yoshiharu Sakai, Masahiro Inoue
Journal: Cancer Research (2015)

Abstract Purpose: Cetuximab, an anti-EGFR antibody, is clinically used in colorectal cancer (CRC) patients. Several clinical trials revealed that KRAS mutant is resistant to cetuximab. As KRAS is one of the downstream molecules in EGFR pathway, KRAS mutants are thought to be resistant to cetuximab due to the constitutive activation of downstream signaling, although mechanism of resistance in KRAS-mutant CRC remains to be elusive. We developed a primary culture system, CTOS method, by which cancer cells are prepared and cultured from patient tumors, maintaining histological and molecular characteristics of original tumors (Kondo 2011 PNAS). CTOS method can be applied to patient tumors as well as mouse xenografts. In this study, we performed integrated sensitivity assays by in vivo/in vitro CTOS sensitivity assay, and CTOS signaling assay in order to investigate characteristics of KRAS mutant CRC cells. Methods: Nine CTOS lines (3 KRAS-wild type, and 6 KRAS-mutant) were analyzed. For in vivo sensitivity assay, growth suppression by cetuximab was evaluated in mouse xenografts derived from CTOSs. CTOSs were classified into three groups according to the response (Regression: tumors became smaller than initial size; Intermediate; tumors became smaller than untreated control but bigger than initial size; Progression: no effect). For in vitro sensitivity assay, growth suppression by cetuximab was evaluated in CTOSs. For signaling analysis, CTOSs were treated with EGF and/or cetuximab, and phosphorylation of EGFR, AKT, and ERK were evaluated. Results: Regression in vivo was found in the tumors originated only from KRAS-wt (2/3). KRAS-mutant CTOSs were able to be clearly divided into two groups. Type I (2 CTOSs) showed Progression in vivo, no response in vitro, and no response in signaling assay. Even the phosphorylation of EGFR was not inhibited by cetuximab treatment. On the other hand, Type II (4 COTSs) showed Intermediate in vivo, moderate response in vitro, and variable responses in signaling assay. ERK phosphorylation was inhibited by cetuximab treatment in all 4 CTOSs. Conclusions: Using integrated in vivo and in vitro assays, KRAS mutant was able to be divided into two distinct groups according to the response to cetuximab. Resistant mechanism of KRAS mutant rather than MAPK pathway activation can be studied in this integrated assay system. Citation Format: Takahiro Tashiro, Hiroaki Okuyama, Hiroko Endo, Kenji Kawada, Masayuki Ohue, Yoshiharu Sakai, Masahiro Inoue. Distinct types of cetuximab resistant KRAS mutant of colorectal cancer revealed by an integrated sensitivity assay. [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 3229. doi:10.1158/1538-7445.AM2015-3229
Phase I Study of Elotuzumab (HuLuc63) in Phase I Study of Elotuzumab (HuLuc63) in Relapsed/Refractory Multiple Myeloma
Authors: Jeffrey A. Zonder, Seema Singhal, William Bensinger, Ann Mohrbacher, Mohamad A. Hussein, Nikhil C. Munshi, Ingrid Caras, Anil Singhal, Frits van Rhee
Journal: Blood (2008)
Abstract LB-254: High-throughput drug matrix screen with SMAC (second mitochondria-derived activator of caspases)-mimetic birinapant in high-grade serous ovarian cancer cell lines identifies synergism
Authors: Kristen Bunch, Ian Goldlust, Craig Thomas, Lidia Hernandez, Rajarshi Guha, Christina Annunziata
Journal: Cancer Research (2015)

Abstract Background: Inhibitors of apoptosis (IAPs) are attractive anti-cancer therapeutic targets as a mechanism to sensitize cancer cells to apoptosis. IAPs are overexpressed in ovarian cancer and portend a poor prognosis. SMAC- mimetics are IAP antagonists that have shown in vitro and in vivo antitumor activity in ovarian cancer, but preclinical and clinical studies suggest SMAC mimetics may be more effective in combination therapies. Methods: Birinapant (B) was initially screened in combination with each of 1,912 compounds using an automated acoustic drug dispensation system in 6×6 matrices. Seventy compounds were chosen from the initial screen, based on synergistic characteristics, and verified in 10×10 matrices. The most clinically rational drug combinations with B were further evaluated in 8 high-grade serous ovarian cancer cell lines (CAOV3, CAOV4, OV-90, OVCAR4, OVCAR5, OVCAR8, PEO1, PEO4), focusing on 3 synergistic (docetaxel, panobinostat, volasertib) and 2 antagonistic combinations (cisplatin, olaparib) for exploration of mechanism. Combination index was determined using Compusyn software. Results: Specific classes of drugs were identified to have synergism with B, including taxanes, HDAC inhibitors, and PLK1 inhibitors, while platinum agents and PARP inhibitors were found to be antagonistic. Four of the 8 cell lines were sensitive to B. Caspase-Glo 3/7 assay was performed in B-sensitive cell lines and confirmed increased caspase-3 activity in the combination treatments. Ongoing studies include genomic analysis, mechanistic interrogation, and in vivo xenograft studies. Conclusions: B is a promising novel therapy for use in combination treatment for ovarian, fallopian tube, or primary peritoneal cancers. Our findings provide insight on optimal therapies to combine with B, and constitute a foundation for further evaluation of predictive and pharmacodynamic biomarkers to select the patient population most likely to respond to this targeted therapeutic approach. Citation Format: Kristen Bunch, Ian Goldlust, Craig Thomas, Lidia Hernandez, Rajarshi Guha, Christina Annunziata. High-throughput drug matrix screen with SMAC (second mitochondria-derived activator of caspases)-mimetic birinapant in high-grade serous ovarian cancer cell lines identifies synergism. [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 LB-254. doi:10.1158/1538-7445.AM2015-LB-254
Flow Cytometric FLT3 Expression in Acute Leukaemias Is of Diagnostic Value but Does Not Correlate with ITD / D835Y Mutation Status.
Authors: Colin Ridler, Matthew Smith, Tim Milne, Fatema Ebrahim, Marion Macey, T. A. Lister, Jude Fitzgibbon, Jamie D. Cavenagh, Samir G. Agrawal
Journal: Blood (2004)
Abstract 3375: Can prostate cancer derived neuromodulators regulate intratumoral axonogenesis
Authors: Dmitriy W. Gutkin, Galina V. Shurin, Michael R. Shurin, Anton A. Keskinov
Journal: Cancer Research (2015)

Abstract Well-developed angiolymphatic network in solid malignant tumors has been proven as an important requirement for tumor growth and progression. However, the level of innervation of the tumor mass is not a well-known factor in tumor development and spreading. Several mechanisms may be responsible for activation and inhibition of neural elements in the tumor microenvironment, including numerous neurotrophic factors (NF) that have axon attractive and axon repellent properties. We have examined 40 cases of human prostate adenocarcinoma by immunohistochemical stains, highlighting neural elements (S-100, PGP9.5, neurofilament) and blood vessels (CD31, CD34). The result revealed that while blood vessels were abundant in the tumor tissue, the neural structures were very scarce compared to benign prostate tissue. Next, in a model system, cell-free supernatants from TRAMP C2 and RM-1murine prostate cancer cell lines were added to the murine neuron cultures, and morphology of the neurons was analyzed by assessing the number of cells with neurites, the number of neuritis per cell, and the lengths of neurites. The data showed that tumor-conditioned media of TRAMP-C2 and RM-1 cells significantly inhibit the neurite growth in mouse neuron cultures. Analysis of gene expression in murine prostatic adenocarcinoma by RT-PCR revealed expression of Semaphorin 4A, Semaphorin 3F, Ephrin A1, Ephrin B2, and Slit2. Finally, the transfection of murine prostate cancer cells with Ephrin 1A and Slit2 siRNAs has prevented their neuron-inhibiting effect. Together, our results suggest that prostate carcinoma cells express NF factors that may inhibit neurite growth and lead to down-regulated innervation of tumor mass. The role of this phenomenon in tumor growth and metastatic potential is under investigation. Citation Format: Dmitriy W. Gutkin, Galina V. Shurin, Michael R. Shurin, Anton A. Keskinov. Can prostate cancer derived neuromodulators regulate intratumoral axonogenesis. [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 3375. doi:10.1158/1538-7445.AM2015-3375