tbuckley/cabot-search huggingface dataset:
468. GLP-Compliant Non-Clinical Safety and Biodistribution of a Recombinant AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI
Authors: Rita Ferla, Jean-Brice Marteau, Severine Pouillot, Karen Kozarsky, James Brown, Stefania Galimberti, Maria Grazia Valsecchi, Vincent Zuliani, Alberto Auricchio
Journal: Molecular Therapy (2016)

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disorder caused by deficiency of the enzyme arylsulfatase B (ARSB), which results in widespread accumulation and excretion of toxic glycosaminoglycans. We recently developed a successful gene therapy approach based on a single systemic administration of AAV2/8 that targets liver of MPS VI animal models. In view of a gene therapy clinical trial for MPS VI, we performed GLP-compliant non-clinical studies to assess the safety and biodistribution of AAV2/8. TBG. hARSB, a recombinant AAV2/8 vector encoding human ARSB (hARSB) under the control of the thyroxine-binding globulin promoter (TBG). We used transgenic C57/BL6-TgARSBC91S mice that overexpress an inactive hARSB C91S mutant and are thus immune tolerant to hARSB. Mice were treated with either AAV2/8.TBG. hARSB or the vehicle alone, as control. Toxicity was evaluated on day 15 (D15) and 180 (D180) after systemic injection of 2×1013 gc/kg, which is 10X the highest dose proposed for the clinical study [20males(M)+20females(F)/treatment/timepoint]. No mortality, abnormal clinical signs and alteration in body weight, body temperature and food intake were observed through the study. Similarly, no clinically relevant changes in blood chemistry and hematology were found in treated mice compared to controls. Histopathology revealed thyroid epithelial hypertrophy in AAV-treated mice. AAV2/8.TBG. hARSB biodistribution and expression was evaluated on D15 and D180 at the dose of 2×1012 gc/kg, which is 1X the highest dose proposed for the clinical study (5M+5F/treatment/timepoint). Although vector DNA was present in all organs on D15, it was sequestered mainly in liver at levels at least 3 logs higher than those found in other organs. Vector DNA declined on D180, but remained high in liver. Accordingly, hARSB was mainly expressed stably in liver, supporting TBG tissue specificity. Vector DNA was found in gonads of both sexes at 3 logs lower than in liver. A robust reduction of vector DNA was observed on D180. A supportive study conducted in male rabbits showed that vector shedding in semen was only transient, which suggests that the risk of inadvertent germline transmission of AAV2/8. TBG.hARSB is minimal at least in male animals. An in situ hybridization study is ongoing in ovaries to elucidate AAV localization. Finally, AAV DNA was only transiently present in plasma, urine and stools of mice (up to D37, D2 and D14, respectively), which minimizes the potential risk associated with transmission to third parties and/or the environment. In conclusion, these studies show a safe profile of intravenous administrations of AAV2/8. TBG.hARSB and pave the way for the phase I/II clinical trial.
Survival Advantage with Comparable Complete Chimerism Patterns in Reduced Toxicity Treosulfan-Based Vs Reduced Intensity Busulfan-Based Conditinioning Regimen in AML/MDS Patients Undergoing Allogeneic Haematopoietic Cell Transplantation
Authors: Ioannis Batsis, Ioanna Sakellari, Apostolia Papalexandri, Despina Mallouri, Sofia Charalampidou, Maria Kaliou, Achilleas Afisidis, Eleni Gavriilaki, Varnavas C Constantinou, Evangelia Yannaki, Panayotis Kaloyannidis, Chrysa Apostolou, Damianos Sotiropoulos, Chrysanthi Vadikolia, Christos Smias, Achilles Anagnostopoulos
Journal: Blood (2015)
Abstract 594: AGT mutations as a prognosis factor in patients with astrocytoma
Authors: Talia Wegman-Ostrosky, Ernesto Soto-Reyes, Silvia Vidal-Millan, Sonia Mejia, José Sánchez-Corona, Luis A. Herrera
Journal: Cancer Research (2015)

Abstract Background: Astrocytomas are the most common and lethal brain tumors. The median survival of patients is 15 months. The study of genetic alterations may help to understand the mechanisms of development and behavior of the disease and thus understand the risk factors and prognostic factors. AGT gene and its peptide derivatives, are involved in cell proliferation and neoangiogenesis and resistance to apoptosis, hence the pathogenesis of astrocytomas. Objective: To identify somatic and germinal AGT gene variations in from patients with astrocytoma. Material and methods: 155 randomly selected files from patients diagnosed with astrocytoma between 2008-2014 were revised to determined clinical prognosis factor in Mexican population. In 25 patients, the molecular analysis of the whole codification region, 5´UTR and 3´UTR of the gene AGT was done in tumors biopsy and blood. Each amplified region had a depth of minimum 1500x. IonReporter software was utilize to analyze the genetic variants and using Integrative Genomic Viewer we confirmed that each variant had a Phred higher than 25. Genotypic frequencies were compared with HapMapMex. Results The clinical variants associated with prognosis were age (OR 0.01 IC 95% 1.02-1.07, p = 0.000), Grade IV (OR 17.11, IC 95% 1.89-132.13 p = 0.011), location of tumor (OR 1.17, IC 1.2-6.3, p = 0.016), total resection (OR = .186, IC 95% .098-.622, p = 0.003, Karnofsky (OR = .05, IC 95% 0.024-0.24, p = 0.003), motor deficiency (OR = 3.5, IC = 1.1-10.5, p = 0.025). In blood were found 11 genetic variants. rs4049, rs2148582, rs699, rs4762 and rs1926723 were associated with risk of tumor in the codominant model. rs5050 (- A20C) was statistically associated with the prognosis (OR 10.8, IC 1.16-100.51 p = 0.036). These variant it is part of a haplotype related to low expression of angiotensinogen. In biopsies of 2 patients missense mutations were found p.Arg477His in one patient and Gly226Ala -Pro165Ser in another one. Conclusion: In 8% of the tumors samples new somatic mutations were found. The genetic variant rs5050 of AGT is a prognosis biomarker in patients with astrocytoma. Citation Format: Talia Wegman-Ostrosky, Ernesto Soto-Reyes, Silvia Vidal-Millan, Sonia Mejia, José Sánchez-Corona, Luis A. Herrera. AGT mutations as a prognosis factor in patients with astrocytoma. [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 594. doi:10.1158/1538-7445.AM2015-594
Glycosylphosphatidylinositol (GPI) Protein-Negative Population of Leukemic Cells in Patients with De Novo Acute Leukemia.
Authors: Hideyoshi Noji, Tsutomu Shichishima, Masatoshi Okamoto, Kazuhiko Ikeda, Akiko Nakamura, Yukio Maruyama
Journal: Blood (2005)
Laparoscopy to Predict the Result of Primary Cytoreductive Surgery in Patients With Advanced Ovarian Cancer: A Randomized Controlled Trial
Authors: Marianne J. Rutten, Hannah S. van Meurs, Roelien van de Vrie, Katja N. Gaarenstroom, Christiana A. Naaktgeboren, Toon van Gorp, Henk G. Ter Brugge, Ward Hofhuis, Henk W.R. Schreuder, Henriette J.G. Arts, Petra L.M. Zusterzeel, Johanna M.A. Pijnenborg, Maarten van Haaften, Guus Fons, Mirjam J.A. Engelen, Erik A. Boss, M. Caroline Vos, Kees G. Gerestein, Eltjo M.J. Schutter, Brent C. Opmeer, Anje M. Spijkerboer, Patrick M.M. Bossuyt, Ben Willem Mol, Gemma G. Kenter, Marrije R. Buist
Journal: Journal of Clinical Oncology (2017)

Purpose To investigate whether initial diagnostic laparoscopy can prevent futile primary cytoreductive surgery (PCS) by identifying patients with advanced-stage ovarian cancer in whom &gt; 1 cm of residual disease will be left after PCS. Patients and Methods This multicenter, randomized controlled trial was undertaken within eight gynecologic cancer centers in the Netherlands. Patients with suspected advanced-stage ovarian cancer who qualified for PCS were eligible. Participating patients were randomly assigned to either laparoscopy or PCS. Laparoscopy was used to guide selection of primary treatment: either primary surgery or neoadjuvant chemotherapy followed by interval surgery. The primary outcome was futile laparotomy, defined as a PCS with residual disease of &gt; 1 cm. Primary analyses were performed according to the intention-to-treat principle. Results Between May 2011 and February 2015, 201 participants were included, of whom 102 were assigned to diagnostic laparoscopy and 99 to primary surgery. In the laparoscopy group, 63 (62%) of 102 patients underwent PCS versus 93 (94%) of 99 patients in the primary surgery group. Futile laparotomy occurred in 10 (10%) of 102 patients in the laparoscopy group versus 39 (39%) of 99 patients in the primary surgery group (relative risk, 0.25; 95% CI, 0.13 to 0.47; P &lt; .001). In the laparoscopy group, three (3%) of 102 patients underwent both primary and interval surgery compared with 28 (28%) of 99 patients in the primary surgery group ( P &lt; .001). Conclusion Diagnostic laparoscopy reduced the number of futile laparotomies in patients with suspected advanced-stage ovarian cancer. In women with a plan for PCS, these data suggest that performance of diagnostic laparoscopy first is reasonable and that if cytoreduction to &lt; 1 cm of residual disease seems feasible, to proceed with PCS.
Health Literacy: application of the principles in the context of ASMN-IRCCS and AUSL Reggio Emilia
Authors: L. Mangone, L. Scarabelli, G. Prati, F. Giovanardi, D. Pezzuolo, E. Gervasi, F. Gazzotti, V. Bedogni, L. Scaltriti
Journal: Annals of Oncology (2015)
Abstract A06: Identification of tumor-specific antibodies using phage display selections on pancreatic ductal organoids
Authors: Tobiloba E. Oni, Carmelita Bautista, Bryce Nelson, David A. Tuveson
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a five year survival rate at 6%. The high mortality of this disease is associated with its late diagnosis. Developing accurate means of early detection will allow for curative surgery and significantly improve patient outcomes. Monoclonal antibodies against tumor-associated neoepitopes are promising tools for identifying novel biomarkers due to their exquisite specificity. To generate antibodies specific to pancreatic tumor cells, we have adapted previously established screening methods with synthetic phage displayed Fab libraries to the pancreatic ductal organoid system, a recently developed ex vivo platform for culturing both normal and malignant pancreatic tissue. This antibody screen employs negative selection of Fabs binding normal organoids to eliminate those cell surface markers elevated during normal ductal cell proliferation, a state similar to the proliferation observed in the pancreas during inflammatory conditions. This is significant because the ability of novel biomarkers to accurately detect pancreatic cancer depends on their capacity to distinguish PDAC from benign diseases of the pancreas. Using this method, we have isolated five unique Fabs that preferentially bind cell surface antigens on tumor but not normal organoids derived from human PDAC and non-diseased patients respectively. Characterization of the cognate antigens of these antibodies and validation of their binding to human tissue are ongoing. We demonstrate that pancreatic ductal organoids provide a systematic platform to screen antibody libraries for the discovery of biomarkers specific to the neoplastic state. Citation Format: Tobiloba E. Oni, Carmelita Bautista, Bryce Nelson, David A. Tuveson.{Authors}. Identification of tumor-specific antibodies using phage display selections on pancreatic ductal organoids. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A06.
638. Expression-Targeted Cancer Gene Therapy Using pran to Drive Caspase 3 Expression
Authors: Xuguang Chen, W.T. Godbey
Journal: Molecular Therapy (2015)

Finding specific yet strong DNA control elements is the key component of securing the safety and efficacy of expression-targeted gene therapy treatments. One of barriers which limits the therapeutic success of the technology is that cancer-specific promoters, even through possessing excellent selectivity, are most often not strong enough. As a result, there remains a great need for identifying and developing cancer-specific promoters with targetable and robust activity. Based on a top-down algorithm, a panel of promoter candidates with both excellent specificity and strength was identified. Among those candidates, we found that the promoter of RAS-related Nuclear protein (pran) yielded excellent gene expression levels in cancer cell lines of breast, prostate, and ovarian origin, but was significantly less active in normal cells. The transfection efficacy of plasmids encoding the green fluorescent protein (GFP), driven by the pran was up to 99.8% that of reporter plasmids driven by pcmv-driven positive controls. When compared to GFP-encoding plasmids driven by the human telomerase reverse transcriptase promoter (which is under investigation in clinical trials), pran yielded reporter intensities between 5- and 15-fold greater. In terms of targeting efficiency, GFP expression was highly restricted in normal cells, with no differences observed between pran and a promoterless control vector. The pran was next used to drive the expression of a bioactive exon – a constitutively active form of caspase 3, which induces apoptosis in expressing cells. Morphologic observations and viability assays both confirmed toxic effects of the delivered plasmids in cancer cells, with little, if any, effect in normal cells. Apoptosis was confirmed by caspase 3 detection assays. Cell viability was reduced by up to 60% after one treatment. Multiple treatments, however, are feasible with non-viral gene delivery vectors, and are under investigation in an in vivo model of transitional cell carcinoma.
PO11IN VITRO HUMAN, SPHEROID, CO-CULTURE MODEL FOR PRECLINICAL ASSESSMENT OF DIRECT APPLICATION THERAPEUTICS TO PAEDIATRIC BRAIN TUMOURS
Authors: Delyan P. Ivanov, Terry L. Parker, David A. Walker, Cameron Alexander, Marianne B. Ashford, Paul R. Gellert, Martin C. Garnett
Journal: Neuro-Oncology (2015)

INTRODUCTION: Spheroid co-cultures of brain tumours and human foetal brain tissue hold promise as physiologically-relevant in vitro models with high predictive potential. Apart from modelling tumour-host interactions, the human foetal tissue serves as a control comparing cytotoxicity and neurotoxicity. Previous co-culture models have suffered from spheroid-size variability, required manual sorting and offered limited quantitation capabilities. We describe a high-throughput platform yielding reproducible co-cultures amenable to automation, quantification and screening. METHOD: The human medulloblastoma cell line UW228-3 and foetal brain tissue were marked with two cytoplasmic, fluorescent dyes (CDCFDASE, Celltrace Violet) and seeded simultaneously in 96-well ultra-low-attachment plates. Tumour and normal cells formed reproducible (d = 600 µm, CV% = 10%), single co-culture spheroids in each well. After three days, the spheroids were exposed to the cytotoxic drug etoposide (0.3-100 µM) for 48h, followed by a 48h drug-free phase. The viability of each cell type was quantified using flow cytometry and multiphoton microscopy. RESULTS: Both dyes were retained in the mixed cultures facilitating normal and tumour tissue recognition and dose-response curve computation. Despite seeding as a mix, tumour and normal cells organised in two opposing poles in the co-cultures, with a main tumour mass and some tumour cells invading the normal tissue. Etoposide levels of 10 µM were found to maximise toxicity to tumours (6.5%viability), while normal tissue viability was 40%. CONCLUSION: The reproducible platform and universal compatibility of the marking procedure make this model transferable to other tumour types and primary tissues.
Future Directions of Geriatric Trauma Care
Authors: Erika L. Rangel
Journal: JAMA Surgery (2016)

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 Surgery 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 Surgery journal
The PI3 Kinase δ Inhibitor, CAL-101 (GS-1101), Inhibits Chronic Lymphocytic Leukemia (CLL) Cell Survival in Endothelial and Marrow Stromal Cell Co-Cultures.
Authors: Stefania Fiorcari, Wells S Brown, Bradley W McIntyre, Susan O'Brien, Mariela Sivina, Julia Hoellenriegel, William G. Wierda, Michael J Keating, Roberto Marasca, Brian J. Lannutti, Zeev Estrov, Jan A. Burger
Journal: Blood (2011)
PO32GENE CO-EXPRESSION NETWORK ANALYSIS REVEALS UNIQUE MOLECULAR CHARACTERISTICS GOVERNING THE MARGINS OF GLIOBLASTOMA
Authors: Anbarasu Lourdusamy, Stuart Smith, Richard Grundy, Ruman Rahman
Journal: Neuro-Oncology (2015)

INTRODUCTION: Glioblastoma (GBM) is the most common malignant brain tumor in adults with a poor outcome due to recurrence from residual disease. Tumour cell invasion into brain parenchyma is likely a major contributor to multimodal treatment failure. Understanding the mechanisms that govern invasion will permit the identification of molecular targets that are functionally important for recurrence disease progression. METHOD: We analysed RNA-sequencing data consisting of tissues within the contrast-enhancing (CE) region, core (C) and non-enhancing (NE) margins of tumors from 27 GBM, and 17 normal brain (NB) samples. To identify NE-specific alterations in transcriptome organization, we conducted a genome-wide gene co-expression network analysis. RESULTS: Twenty modules of co-expressed genes were identified and revealed that expression patterns of NE are more similar to NB than CE for the majority of the modules. Two discrete modules (M1 and M2) were significantly associated with NE and are highly enriched with oligodendocyte (M1: 13 genes, FDR < 3.11 × 10–09; M2: 36 genes, FDR < 2.63 × 10–32) and white matter-associated (M1: 8 genes, FDR < 1.16 × 10–09; M2: 10 genes, FDR < 1.01 × 10–05) genes. M1 was enriched for integrin mediated signalling (DOCK1, FUT8, GAB2), vacuole organization (MAN2A1, PSEN1, TFEB), and platelet activation (RHOG, TGFB3). In contrast, M2 was enriched for lipid biosynthetic processes (GPAT2, GPD1, PIP4K2A, UGT8), ion transport (BEST1, SGK2, SGK3, TMC6), and cell shape regulation (ERMN, FGD4, S100B, SEMA4D). CONCLUSION: Unique molecular GBM abnormalities i implicate transcriptional dysregulation of distinct biological processes that are associated with invasion.
Brief Report: Late‐Onset Cryopyrin‐Associated Periodic Syndrome Due to Myeloid‐Restricted Somatic <i>NLRP3</i> Mosaicism
Authors: Anna Mensa‐Vilaro, María Teresa Bosque, Giuliana Magri, Yoshitaka Honda, Helios Martínez‐Banaclocha, Marta Casorran‐Berges, Jordi Sintes, Eva González‐Roca, Estibaliz Ruiz‐Ortiz, Toshio Heike, Juan J. Martínez‐Garcia, Alberto Baroja‐Mazo, Andrea Cerutti, Ryuta Nishikomori, Jordi Yagüe, Pablo Pelegrín, Concha Delgado‐Beltran, Juan I. Aróstegui
Journal: Arthritis & Rheumatology (2016)

Gain-of-function NLRP3 mutations cause cryopyrin-associated periodic syndrome (CAPS), with gene mosaicism playing a relevant role in the pathogenesis. This study was undertaken to characterize the genetic cause underlying late-onset but otherwise typical CAPS.We studied a 64-year-old patient who presented with recurrent episodes of urticaria-like rash, fever, conjunctivitis, and oligoarthritis at age 56 years. DNA was extracted from both unfractionated blood and isolated leukocyte and CD34+ subpopulations. Genetic studies were performed using both the Sanger method of DNA sequencing and next-generation sequencing (NGS) methods. In vitro and ex vivo analyses were performed to determine the consequences that the presence of the variant have in the normal structure or function of the protein of the detected variant.NGS analyses revealed the novel p.Gln636Glu NLRP3 variant in unfractionated blood, with an allele frequency (18.4%) compatible with gene mosaicism. Sanger sequence chromatograms revealed a small peak corresponding to the variant allele. Amplicon-based deep sequencing revealed somatic NLRP3 mosaicism restricted to myeloid cells (31.8% in monocytes, 24.6% in neutrophils, and 11.2% in circulating CD34+ common myeloid progenitor cells) and its complete absence in lymphoid cells. Functional analyses confirmed the gain-of-function behavior of the gene variant and hyperactivity of the NLRP3 inflammasome in the patient. Treatment with anakinra resulted in good control of the disease.We identified the novel gain-of-function p.Gln636Glu NLRP3 mutation, which was detected as a somatic mutation restricted to myeloid cells, as the cause of late-onset but otherwise typical CAPS. Our results expand the diversity of CAPS toward milder phenotypes than previously reported, including those starting during adulthood.
Square root sign of left ventricular diastolic pressure curve in atrial septal defect.
Authors: Yoshio Kita, Yuzo Hirota, Takaharu Saito, Gen Shimizu, Kiyotaka Kaku, Keishiro Kawamura
Journal: Circulation (1990)

The square root (dip and plateau) sign was observed in 7 of 21 adult patients with atrial septal defect (ASD). This study evaluated left ventricular (LV) diastolic filling dynamics and hemodynamic findings in 7 patients (Group 1) with, and 14 patients (Group 2) without the square root sign; 10 normal subjects (Group 3) served as controls. No significant differences were observed in LV end-diastolic and end-systolic volumes, ejection fraction, or left to right shunt. In Group 1, 77% of LV filling was completed in the first half of diastole; this percentage was 49% and 53% in Groups 2 and 3, respectively (both p less than 0.01 versus Group 1). Early diastolic filling velocity (at 20% of diastole) in Group 1 was significantly greater, and late diastolic filling velocity (at 80% and 90% of diastole) was reduced in Group 1 compared to those in Groups 2 and 3 (all p less than 0.05). The average values for right and left ventricular end-diastolic pressures were significantly higher in Group 1 (11 +/- 2 and 10 +/- 4 mmHg, p less than 0.05) than Group 2 (7 +/- 2 and 7 +/- 2 mmHg, p less than 0.05). It is suggested that a constrictive pathophysiology due to 4 chambers interaction or right ventricular constraint may play a role in the genesis of the square root sign in ASD.
SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation
Authors: Xiaofeng Wang, Ryan S Lee, Burak H Alver, Jeffrey R Haswell, Su Wang, Jakub Mieczkowski, Yotam Drier, Shawn M Gillespie, Tenley C Archer, Jennifer N Wu, Evgeni P Tzvetkov, Emma C Troisi, Scott L Pomeroy, Jaclyn A Biegel, Michael Y Tolstorukov, Bradley E Bernstein, Peter J Park, Charles W M Roberts
Journal: Nature Genetics (2016)
Two-Year Analysis of Efficacy and Safety of Deferasirox (Exjade®) Treatment in Myelodysplastic Syndrome Patients Enrolled in the US03 Study.
Authors: Alan F. List, Maria R. Baer, David P. Steensma, Azra Raza, Jason Esposito, Noelia Martinez-Lopez, Carole Paley, John Feigert, Emmanuel C. Besa
Journal: Blood (2009)