tbuckley/cabot-search huggingface dataset:
244. Development and Qualification of Assays for Human Embryonic Stem Cell (hESC)-Derived Cardiomyocytes Intended for Clinical Use
Authors: Jennil Patel, Wei Dang, Aparna Krishnan, Derek Kong, David Hsu, Larry Couture
Journal: Molecular Therapy (2016)

Stem cell therapy holds the promise for numerous degenerative diseases and injuries. Human embryonic stem cells (hESCs) are the starting cell population for many of these potential therapies since they are capable of seemingly indefinite proliferation in the pluripotent state and have the ability to differentiate into all cell types found in the adult. It is vital that the cellular therapeutics derived from these highly proliferative cells are well characterized prior to clinical use and the assays used to characterize these cellular products are well developed. 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 early phase clinical studies. We have developed a systematic approach to characterize hESC-derived cell products using well developed technologies such as real-time quantitative polymerase chain reaction (RT-qPCR) and flow cytometry. We have standardized the development and qualification of each assay which involves the selection and banking of positive and negative controls, selection and banking of critical reagents, determination of assay conditions, qualification of assay, generation of assay qualification report and standard operating procedure (SOP). In addition, we have established a general guideline to assist the selection of appropriate markers for different products. Here we describe the application of this systematic approach to develop and qualify identity and purity assays for hESC-derived cardiomyocytes produced through hESC differentiation procedure in suspension culture. Selection of markers for the characterization of cardiomyocyte products will be discussed, and development and qualification of the assays will be reported.
Intensive Chemotherapy Is Not Recommended for Patients with AML or High-Risk MDS Aged over 60 Years with Complex Karyotype Anomalies.
Authors: Sabine Knipp, Barbara Hildebrandt, Aristoteles A.N. Giagounidis, Guido Kobbe, Rainer Haas, Carlo Aul, Norbert Gattermann, Ulrich Germing
Journal: Blood (2004)
Double-guidewire technique in difficult biliary cannulation for the prevention of post-ERCP pancreatitis: a systematic review and meta-analysis
Authors: Frances Tse, Yuhong Yuan, Paul Moayyedi, Grigorios Leontiadis, Alan Barkun
Journal: Endoscopy (2016)

<b>Background and study aims</b> Difficult cannulation is a risk factor for pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP). The double-guidewire technique (DGT) may improve cannulation success and reduce the risk of post-ERCP pancreatitis (PEP) in patients with difficult cannulation. This systematic review compared the DGT with persistent conventional cannulation or other advanced techniques in patients with difficult cannulation. <b>Patients and Methods</b> CENTRAL, MEDLINE, EMBASE, and CINAHL databases and DDW and UEGW abstracts up to March 2016 were searched for randomized controlled trials (RCTs) comparing DGT with persistent conventional cannulation or other advanced techniques (precut, pancreatic duct [PD] stenting). The primary outcome was PEP. Secondary outcomes included severity of PEP, successful cannulation of the common bile duct (CBD) with the randomized technique, overall CBD cannulation success, and ERCP-related complications. <b>Results</b> 7 RCTs (577 patients) were included. Use of the DGT significantly increased PEP compared to other endoscopic techniques (risk ratio [RR] 1.98, 95 % confidence interval [95 %CI] 1.14 – 3.42). There was no significant difference in CBD cannulation success with the randomized technique (RR 1.04, 95 %CI 0.87 – 1.24) or in overall cannulation success (RR 1.04, 95 %CI 0.91 – 1.18) between DGT and other techniques. There was also no significant difference in the risk of other ERCP-related complications (bleeding, perforation, cholangitis, and mortality). The results were robust in sensitivity analyses. <b>Conclusions</b> In patients with difficult cannulation, sole use of the DGT appears to increase the risk of PEP without any superiority in achieving biliary cannulation compared to other techniques. PD stenting may reduce the risk of PEP when the DGT is used. The influence of co-intervention in the form of per-procedural nonsteroidal anti-inflammatory drug (NSAID) administration is unclear.
Comorbidity Index (CI) in Autologous Hematopoietic Cell Transplantation (HCT) for Malignant Diseases: Validation of the HCT-CI
Authors: Marcelo C. Pasquini, Brent R. Logan, Vincent T Ho, Philip L. McCarthy, Kenneth R. Cooke, J. Douglas Rizzo, Xiaochun Zhu, Mohamed L. Sorror
Journal: Blood (2012)
Photopheresis in HIV-1 Infected Patients Utilizing (Benzoporphyrin Derivative Verteporfin/BPD-MA) and Light.
Authors: Zale P. Bernstein, Thomas Dougherty, Sandra Gollnick, Stanley Schwartz, Supriya Mahajan, James Kepner, Adam Sumlin, Carleton Stewart, Paul Wallace, Harold Walder, Bernard Poiesz
Journal: Blood (2007)
719. Combination of ICOS and 4-1BB in a Third Generation CAR Exhibits Enhanced T Cell Persistence and Increased Antitumor Effect
Authors: Sonia Guedan, Prachi Patel, Shannon E. McGettigan, Avery D. Posey, Omkar Kawalekar, John Scholler, Brian Keith, Carl H. June
Journal: Molecular Therapy (2015)

T cell persistence is likely to promote long-term antitumor effects after adoptive T cell transfer; however, T cells expressing chimeric antigen receptors (CARs) have not persisted well in patients with solid tumors in trials reported to date. Here, we hypothesized that CD4+ and CD8+ T cells may need distinct costimulation signals to persist. To test this hypothesis, we compared the in vivo antitumor effects and persistence of combined CD4+ and CD8+ T cells redirected with CARs containing different costimulatory domains (CD28, 4-1BB or ICOS). Using multiple mouse tumor models, we demonstrate that the ICOS intracellular domain enhanced the in vivo persistence of CAR-expressing CD4+ T cells. Persistence of CD8+ T cells was highly dependent on the intracellular domain used to redirect CD4+ T cells; specifically, CD4+ T cells expressing an ICOS-based CAR significantly increased the persistence of CD8+ T cells expressing either CD28- or 4-1BB-based CARs. We further demonstrate that the combination of ICOS and 4-1BB in a third generation CAR (ICOSBBz) is more effective at eliminating large pancreatic tumors than either 4-1BB or ICOS alone. T cells redirected with ICOSBBz showed a less differentiated phenotype with superior proliferation and in vivo persistence. These results indicate that ICOSBBz-based CARs are promising therapeutics for clinical testing.
Abstract 4107: CCR9/CCL25 mediates epithelial-mesenchymal transition in prostate cancer
Authors: Patrick P. Carriere, Hina Mir, Neeraj Kapur, Rajesh Singh, Guru Sonpavde, James W. Lillard, Shailesh Singh
Journal: Cancer Research (2015)

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men, despite the treatment options offered in the clinics. Hence, it is important to further elucidate the molecular mechanisms of PCa progression in order to design more effective treatment strategies. PCa metastasis is a multi-step process that involves epithelial-mesenchymal transition (EMT), during which stationary epithelial cancer cells adopt a mesenchymal phenotype that better suits for survival and motility. We have previously shown that CCR9-expressing PCa cells migrate to and invade distal secondary sites under the influence of chemokine CCL25, its natural ligand. However, the precise molecular mechanisms facilitating EMT in PCa are still not fully understood. Here, we investigated the biological significance of CCR9/CCL25 signaling in inducing EMT in PCa. Modulation of several EMT markers was assessed by western blot and real time qPCR in metastatic PCa cell lines, with or without CCL25 activation. Our results show that following CCL25 stimulation, CCR9 signaling differentially modulates expression of the EMT markers E-cadherin and N-Cadherin in PCa cells, as compared to untreated controls. These findings suggest that the CCR9-CCL25 axis plays an important role in mediating EMT in PCa, thereby increasing the ability of PCa cells to metastasize. Citation Format: Patrick P. Carriere, Hina Mir, Neeraj Kapur, Rajesh Singh, Guru Sonpavde, James W. Lillard, Shailesh Singh. CCR9/CCL25 mediates epithelial-mesenchymal transition in prostate cancer. [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 4107. doi:10.1158/1538-7445.AM2015-4107
559. Spell Checking Nature: A Therapeutic Use of the CRISPR/Cas9 System in Duchenne Muscular Dystrophy
Authors: Daria Wojtal, Dwi U. Kemaladewi, Zeenat Malam, Sarah Abdullah, Elzbieta Hyatt, Victoria Huang, Vincent Mouly, Thomas Voit, Francesco Muntoni, Evgueni A. Ivakine, Ronald D. Cohn
Journal: Molecular Therapy (2015)

Recently the high precision genome-modifying technology, originated from a prokaryotic defense mechanism called the Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) system, has been harnessed as a tool for programmable, high precision gene modification in eukaryotes. Thus far it has been shown to be highly effective in inactivating genes, however little is known about the gene editing and regulation capabilities of this system. As a proof of concept we utilized CRISPR/Cas9 system to study three different therapeutic approaches for Duchenne Muscular Dystrophy (DMD), a devastating X-linked neuromuscular disorder. The first approach is aimed at approximately 26% of patients that have point mutations in DMD gene. Here we used gene editing to correct DMD E2035X, a pathogenic mutation in DMD patient myoblasts by designing short RNA sequences complementary to the locus called guides, paired with the Streptococcus pyogenes Cas9. We were able to generate targeted double stranded DNA breaks that were corrected through homology directed repair using single stranded oligos carrying the corrected DNA sequence. Other pathogenic DMD mutations are duplications, which are found in approximately 13% of DMD patients. Utilizing a modified CRISPR strategy that involves a double nuclease approach we deleted a 145 kb (Exons 18-30) duplication and restored dystrophin expression in patient cells. Furthermore, as an universal, mutation-independent treatment approach, we have also utilized a third modified CRISPR system to upregulate utrophin expression to compensate for the loss of dystrophin. In DMD patient myoblasts, we utilized S.pyogenes Cas9, fused to transcriptional activator VP160 to target utrophin promoter. We demonstrated 2.5-5 fold utrophin upregulation resulting in increased expression of β-dystroglycan, providing evidence for functional significance of this strategy. Lastly, in order to determine if this tool is of potential clinical significance, we have began to interrogate CRISPR/Cas9 system in dystrophin-deficient mdx mouse. We have developed strategies for the delivery of CRISPR machinery via rAAV with the goal to achieve dystrophin editing and utrophin upregulation simultaneously in vivo. Taken together, our proof of concept studies provide insights into the potentially far-reaching impact of the therapeutic benefits of the CRISPR system that can be adapted to target a variety of mutations in DMD.
PWE-034 Evidence against intramacrophage replication of Crohn's disease<i>E coli</i>being dependent on an anaerobic environment within the phagolysosome: lack of efficacy for metronidazole
Authors: P P Knight, B J Campbell, J M Rhodes
Journal: Gut (2010)

<h3>Introduction</h3> <i>Escherichia coli</i> isolates from colonic Crohn9s disease (CD) tissue have previously been demonstrated to replicate within J774-A1 macrophages, and to be sensitive to antibiotics such as ciprofloxacin, trimethoprim, tetracycline and rifampicin. It has been hypothesised that <i>E coli</i> internalised into macrophage vesicles may utilise anaerobic metabolism and become susceptible to the effect of metronidazole, an anaerobe specific antibiotic. Our aim was to evaluate efficacy of metronidazole used at Cmax (maximal plasma concentration achievable with standard dosing) on replication of CD colonic <i>E coli</i> isolate (HM605) within macrophages in-vitro, both as a single agent and in combination with ciprofloxacin <h3>Methods</h3> Murine macrophages (J774-A1) in culture were infected with CD <i>E coli</i> isolate HM605 for 2 h, to allow bacterial internalisation, followed by removal of extracellular bacteria by gentamicin (20 μg/ml) treatment for 1 h. Macrophages were incubated for a further 3 h in either the absence of antibiotics or in the presence of metronidazole (20 μg/ml) orciprofloxacin (4 μg/ml), alone or in combination. Cells were then lysed and internalised bacteria enumerated by overnight growth on LB agar. <h3>Results</h3> CD <i>E coli</i> HM605 survived and replicated 6.95-fold following gentamicin treatment. Following ciprofloxacin treatment alone, only 503±455 cfu were present within macrophages compared with 36 355±16 696 cfu in "no antibiotic" controls (p&lt;0.001). Ciprofloxacin plus metronidazole resulted in low intramacrophage growth (240±196 cfu, p&lt;0.001) unlike metronidazole alone (6.990±7.016, p=0.206), but with the combination not producing significantly enhanced killing when compared with ciprofloxacin alone (p=0.85). <h3>Conclusion</h3> Metronidazole confers no additional effect to ciprofloxacin in intramacrophage killing of CD <i>E coli</i> HM605 in vitro.
The Immunomodulatory Role of Lenalidomide on Prevnar® Responses in Patients with Relapsed Multiple Myeloma: A Comprehensive Analysis of the Immune Response
Authors: Kimberly Ann Noonan, Anna Ferguson, Carol A. Huff, Amy Emerling, Stephanie Mgebroff, Rose Wilson, Robert D. Knight, Ivan M. Borrello
Journal: Blood (2008)
Abstract 1446: Induction of epithelial-to-mesenchymal transition (EMT) by SL-15 knockdown contributes to anoikis resistance in human colorectal cancer metastases
Authors: Soo Young Jun, Hyun-Soo Cho, Jeong-Ju Lee, Jun-Ho Ahn, Ji-Yong Yoon, Jae-Hye Lee, Min Hyuk Choi, Nam-Soon Kim
Journal: Cancer Research (2015)

Abstract Purpose of the study: Metastasis or systemic dissemination of cancer cells into secondary organs is responsible for 90% of cancer-related fatalities. Our team previously screened out SL-15 as therapeutic target of gastric cancer through the analysis of gene expression profiling. In this study, we investigated the roles of human SL-15 in colorectal cancer (CRC) metastasis. Experimental procedures: SL-15 levels of metastatic liver CRC tissues and of primary CRC tissues as well as of adjacent nontumour tissues were compared using quantitative RT-PCR. Transwell and wound healing methods were used to determine the migration/invasion abilities of CRC cells. Flow cytometery analysis was performed to measure the apoptotic ratio as well as the levels of E-cadherin/p53/SL-15. Confocal observation and Western blot analysis were used for studying the underlying mechanisms of small interfering RNA against SL-15 (siSL-15)-induced CRC metastasis. Results: The level of SL-15 was higher in the order of metastatic liver CRC tissues, primary CRC tissues and then the adjacent nontumor tissues. siSL-15 significantly induced the migration/invasion of CRC cells that was almost entirely suppressed by the co-expression of SL-15. Importantly, the application of siSL-15 contributes to anoikis resistance of CRC cells via the upregulation of zinc finger E-box-binding homeobox 1 (ZEB1) in stem-like subtype CRC cells and intestinal trefoil factor (ITF) in goblet- like subtype CRC cells by the inhibition of glycogen synthase kinase 3 β (GSK3β) and of β-catenin degradation, thereby leading to downregulation of E-cadherin as well as p53 degradation. Importantly, the interactions among SL-15/p53/GSK3β that were dissociated upon the application of siSL-15 were determined. Conclusions: SL-15 is more highly up-regulated in metastatic liver CRC cancer than in primary CRC cancer and the adjacent nontumor tissue: SL-15 knockdown contributes to anoikis resistance of CRC cells and CRC metastasis via inducing epithelial-to-mesenchymal transition as well as p53 degradation due to the dissociation of SL-15 with GSK3β and p53. Citation Format: Soo Young Jun, Hyun-Soo Cho, Jeong-Ju Lee, Jun-Ho Ahn, Ji-Yong Yoon, Jae-Hye Lee, Min Hyuk Choi, Nam-Soon Kim. Induction of epithelial-to-mesenchymal transition (EMT) by SL-15 knockdown contributes to anoikis resistance in human colorectal cancer metastases. [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 1446. doi:10.1158/1538-7445.AM2015-1446
The EULAR points to consider for health professionals undertaking musculoskeletal ultrasound for rheumatic and musculoskeletal diseases
Authors: Heidi J Siddle, Peter Mandl, Daniel Aletaha, Thea P Vliet Vlieland, Marina Backhaus, Patricia Cornell, Maria-Antonietta D'Agostino, Karen Ellegaard, Annamaria Iagnocco, Bente Jakobsen, Tiina Jasinski, Nina H Kildal, Michaela Lehner, Ingrid Möller, Gabriela M Supp, Philip O'Connor, Anthony C Redmond, Esperanza Naredo, Richard J Wakefield
Journal: Annals of the Rheumatic Diseases (2016)

Musculoskeletal ultrasound has evolved into an important clinical decision-making tool by assisting in the diagnosis of inflammatory arthritis, monitoring disease activity and therapeutic response, and guiding interventions.1–7 The role of the non-medical health professional has advanced, with many undertaking training and using musculoskeletal ultrasound to improve patient care and in doing so, increasing their scope of practice. Health professionals with clinical expertise and experience using ultrasound are also providing training for colleagues and medical clinicians.

As previously described among rheumatologists,8 ,9 the use of musculoskeletal ultrasound and training undertaken varies significantly between different professional groups and across Europe. Guidelines to support training for rheumatologists have been formulated10 but currently there are no recommendations to support the education and training needs of non-medical health professionals using musculoskeletal ultrasound.

A European League Against Rheumatism (EULAR) task force was established to reach a consensus on the role of, and education and training needs of health professionals undertaking musculoskeletal ultrasound for the management of people with …
99. Construction and Evaluation of Recombinant AAV Vectors for Central Nervous System Gene Delivery
Authors: Diego Sucunza, Jose Diego Pignataro, Esperenza Lopez-Franco, Alberto Jose Rico, Lucia Vanrell, Iria Gonzalez, Elvira Roda, Africa Vales, Jose Luis Lanciego, Gloria Gonzalez-Aseguinolaza
Journal: Molecular Therapy (2016)

The Adeno-associated virus (AAV) have become a highly promising tool for research and clinical applications in the Central Nervous System (CNS). Here we used the reporter gene EGFP under the transcriptional control of five minimal promoters (MinP) that show efficient and specific expression in neurons or astrocyte in vitro. We also describe the extent of viral spread, transduction efficiency and cell type specificity of each promoter into the mouse striatum using the AAV serotype 8 (AAV8). Robust and specific neuronal EGFP expression was observed with the BM88 (88pb) and B2RN (170bp) MinPs, both in vivo and in vitro. Cell typing with immunofluorescence confirmed the efficient AAV8 gene expression into the striatal neurons. Furthermore, we detected axonal transport of the EGFP protein when using these promoters. Additionally, two variants of the minimal human GFAP promoter (<600bp) were evaluated to analyze the role of a 75bp segment (D region) spanning bp -132 to -57 with respect to the RNA start site, in the control of the transgene expression. A reduction on the transcriptional activity was observed in vivo when the region was eliminated. In addition, a minimal murine GFAP promoter (581bp) was generated that exhibited mostly glial expression; however, we also observed EGFP expression in other type of cells like microglia. In summary, we have developed a set of AAV vectors designed for SNC specific cell type expression using minimal promoters to drive gene expression when the size of the inserts matters.
658. Increasing Fetal Hemoglobin Expression With TALEN Induced Small Deletions in Peripheral Blood Stem Cells
Authors: Christopher T. Lux, Andrew M. Scharenberg, Brandon K. Hadland
Journal: Molecular Therapy (2015)

Hemoglobinopathies are common and morbid inherited conditions caused by mutations in hemoglobin genes that generate pathologic globin molecules or reduced expression of wild type hemoglobin. A subset of individuals with hemoglobinopathy-associated beta globin mutations have a mild clinical phenotype and are found to carry additional disease modifying mutations including small deletions or point mutations that induce fetal hemoglobin expression. This condition is referred to as hereditary persistence of fetal hemoglobin. Recent progress in the arenas of gene editing and hematopoietic stem cell (HSC) expansion has raised the possibility of treating hemoglobinopathies through direct modification of genes in HSCs to increase the expression of fetal hemoglobin in the erythroid lineage. To date, most attempts to induce fetal hemoglobin have targeted the expression of transcription factors implicated in regulation of fetal hemoglobin production, such as Bcl11a, an approach which could lead to unintended and potentially deleterious effects on cellular phenotype. Here, we are evaluating the application of mRNA transfection of TALENs to directly modify transcription factor binding sites within the hemoglobin locus in HSCs to achieve efficient, stable expression of fetal hemoglobin. We have designed TALENs to induce small deletions in the beta hemoglobin promoter at the binding site of KLF1, postulated to play a role in localizing the active chromatin hub to and preferentially expressing adult beta hemoglobin, as well as other globin locus target regions implicated in the regulation of fetal hemoglobin production. By combining TALEN-mediated gene modification with novel HSC expansion approaches involving the recently described small molecule UM729, we hope to realize both efficient HSC modification and expansion with a sufficient level of fetal hemoglobin production in erythrocytes to achieve a functional cure for a wide range of beta hemoglobinopathies.
Preference for subcutaneous or intravenous administration of rituximab among patients with untreated CD20+ diffuse large B-cell lymphoma or follicular lymphoma: results from a prospective, randomized, open-label, crossover study (PrefMab)
Authors: M. Rummel, T.M. Kim, F. Aversa, W. Brugger, E. Capochiani, C. Plenteda, F. Re, P. Trask, S. Osborne, R. Smith, A. Grigg
Journal: Annals of Oncology (2016)
Single and Multiple Oral Doses of LGD-4665, a Small Molecule Thrombopoietin Receptor Agonist, Increase Platelet Counts in Healthy Male Subjects
Authors: Zofia E. Dziewanowska, Richard M. Matsumoto, J.K. Zhang, Kristine Schindler, Gordon Loewen, James P. Doherty, Jolene K. Berg, Barbara Newberry
Journal: Blood (2007)