tbuckley/cabot-search huggingface dataset:
Influence of Different Genetic Alterations On the Engraftment Capacity and Serial Transplantation Efficiency of AML Patient-Derived Bone Marrow and Peripheral Blood Cells in NSG Mice
Authors: Julia Schüler, Peter Haas, Kerstin Klingner, Björn W. Hackanson, Heinz-Herbert Fiebig, Michael Lübbert
Journal: Blood (2012)
Why would anyone want to believe in Big Gods? [Open Peer Commentary]
Authors: I.A. Brazil, M. Farias
Journal: Behavioral and Brain Sciences (2016)

We suggest an alternative explanation for the emergence of Big Gods that places less emphasis on the role of cognitive tendencies and selection of prosocial cultural variants. Instead, we argue that the fundamental motivation to reduce uncertainty and increase long-term predictability provides a better account for the rise of Big moralizing Gods in a complex and heavily regulated social environment.
566. Targeted Lentiviral Vector Integration Mediated by the AAV Rep78 Protein
Authors: Pingjuan Li, Jizhong Zou, Michael T. Morreale, Michael P. Marino, Jakob Reiser
Journal: Molecular Therapy (2016)

Our goal is to improve the safety of lentiviral vectors by shifting their integration preference to genomic "safe harbor" sites where therapeutic transgenes can integrate and function in a predictable manner. To do this, we have generated integrase-defective LV vectors (IDLVs) capable of inserting transgene sequences at predetermined genomic sites through homologous recombination (HR). To increase the frequency of HR, we employ genome editing approaches involving site-specific nucleases. A major drawback of this approach is safety concerns caused by inadvertent double strand breaks (DSBs) and non-homologous end-joining (NHEJ) events at unintended genomic (off target) sites. To bypass this risk, we are pursuing site-specific nucleases that do not involve DSBs as a potentially safer class of DNA-modifying agents for site-specific integration of transgenes in human cells. The sequence and strand-specific endonucleases Rep78 and Rep68 encoded by adeno-associated virus (AAV) have previously been reported to stimulate HR of plasmids bearing homology arms corresponding to the AAVS1 safe harbor locus on chromosome 19. We tested the integration efficiency of IDLVs containing short homology arms corresponding to the AAVS1 locus mediated by an engineered version of the AAV2-derived Rep78 protein in HEK293 cells. We compared the integration efficiency of IDLVs mediated by the Rep78 protein to that of an AAVS1-specific zinc finger nuclease (ZFN). Furthermore, we explored the potential of IDLV donor vectors for targeted integration mediated by Rep78 in human induced pluripotent stem cells (hiPSCs). The results obtained indicate that in the presence of the Rep78 protein, the integration efficiency of IDLVs was up to 8.3 fold higher compared to cells treated with the donor vector alone. Moreover, the efficiency of site-specific targeting mediated by Rep78 was higher than that of the AAVS1-specific ZFN. We also showed that Rep78 can successfully direct integration of IDLVs at the AAVS1 locus in hiPSCs. We anticipate that the approach used may ultimately contribute to the reduction of risks associated with LV vectors.
Cocaine-Levamisole Thrombovasculopathy: A Report From the Southern Network On Adverse Reactions (SONAR) Project
Authors: Charles Bennett, Irene Dy, Peter Wiernik, Jennie Buchanan, Richard Dart, Brian Edlin, Erin Gilbert, Priya Mahindra, Alanna Murday, Zaina Parvez Qureshi
Journal: Blood (2012)
The Impact of Early Molecular Response in Event Free Survival in Patients with Chronic Myeloid Leukemia Treated with Imatinib
Authors: Laura Fogliatto, Marcelo Eduardo Zanella Capra, Mariza Shaan, Tito Vanelli Costa, Mayde Seadi Torriani, Luis Carlos Zanandrea Contin, Raquel Breunig, Katia Fassina, Mario Sérgio Fernandes, Denise Almeida, Marco Antônio Schilling, Tânia Hellwig, Tiago Daltoe, Adriana Zardo, Mariangela Moschen, Moema Nene, Juarez Fontoura Silveira, Tahiane Brum Soares, Liane Esteves Daudt, João Friedrisch, Lucia Silla
Journal: Blood (2014)
MRI appearance does not change in the first 7 days after acute hamstring injury—a prospective study
Authors: Arnlaug Wangensteen, Roald Bahr, Robbart Van Linschoten, Emad Almusa, Rodney Whiteley, Erik Witvrouw, Johannes L Tol
Journal: British Journal of Sports Medicine (2016)

The optimal timing of MRI following acute hamstring injury is not known and is mainly based on expert opinions.To describe the day-to-day changes in the extent of oedema and investigate the optimal timing for detection of fibre disruption on MRI following acute hamstring injuries.Prospective, descriptive study.We performed standardised MRI (1.5T) ≤1 day after injury in male athletes with acute hamstring injury. If initial MRI revealed positive signs of injury (increased signal intensity on fluid sensitive sequences), consecutive MRIs were obtained daily throughout the subsequent week (ie, 7 times). The MRI parameters (day 1-7) were scored by a single radiologist using a standardised scoring form. The day-to-day changes in the extent of oedema (distance from tuber, craniocaudal length, mediolateral width and anteroposterior depth) and the presence and extent of fibre disruption (tear) were assessed with descriptive statistics and repeated measures using analysis of variance of log-transformed data. The overall main effect for time was reported with a significance level set at p<0.05.13 out of 132 male athletes assessed for eligibility between January 2014 and December 2015 were included. 1 dropped out, while 12 (31 years, range 20-49) completed the study; 11 had 7 MRI scans each and one had 5 MRI scans performed. There were no significant day-to-day changes for any of the extent of oedema measures (p values ranging from 0.12 to 0.81). Fibre disruption (tear), present in 5 of the athletes, was detectable from day 1, with small and insignificant day-to-day changes (p values ranging from 0.45 to 0.95).We observed insignificant day-to-day changes in the extent of oedema throughout the first week following acute hamstring injury. Fibre disruption (tear) was detectable from the first day after injury. These findings indicate that MRI can be performed on any day during the first week following an acute (hamstring) muscle injury.
Abstract 5440: Novel PD-1 blockade bioassay to assess therapeutic antibodies in PD-1 and PD-L1 immunotherapy programs
Authors: Zhi-Jie Jey Cheng, Natasha Karassina, Jamison Grailer, Jim Hartnett, Frank Fan, Mei Cong
Journal: Cancer Research (2015)

Abstract Programmed death receptor-1 (PD-1) and its ligand (PD-L1) are among the few important immunotherapy targets for cancer. Current PD1 assays measure cell proliferation or cytokine production in primary T cells which are tedious, have high assay variation and small assay window. To enable quantitative potency measurement for key anti-PD-1 drugs in the market or in clinical trials such as pembrolizumab and nivolumab, as well as anti-PD-L1 drugs in clinical trials such as MPDL3280A and BMS-936559, here we report the development of a robust bioluminescent cell-based PD1 blockade bioassay. For this, we built a PD-1 effector cells in Jurkat cells which stably express human PD-1 and a NFAT-RE-luciferase reporter, and a PD-L1 positive artificial Antigen Presenting Cells (PD-L1+ aAPC) in CHO-K1 cells which stably express PD-L1 and an engineered TCR activator. Once these two cell types were co-cultivated, transcriptional activation of NFAT pathway in PD-1 effector cells, mediated by binding of TCR complex with TCR activator in PD-L1+ aAPC, is significantly suppressed by PD-1/PD-L1 engagement. This inhibition can then be specifically reversed by co-incubation of PD-1 or PD-L1 blocking antibodies in dose-dependent manner, but not by the antibody for other immune checkpoint receptors such as anti-CTLA4 ipilimumab. We further developed both PD-1 effector cells and PD-L1+ aAPC in Thaw-and-Use format so the cells can be plated for assay without the need of cell culture. The resultant PD-1 assay using Thaw-and-Use cells brings the benefit of convenience, low day-to-day variation, and easy lab-to-lab assay transfer. We demonstrate the assay is able to measure relative potency for antibody biologics, and also can detect potency changes for stressed antibody samples. In summary, the reporter-based PD-1 blockade assay provides a valuable tool for both drug screening and characterization in early drug discovery, and lot release and stability study in drug manufacture for therapeutic antibody drug candidates in PD-1 and PD-L1 immunotherapy programs. Citation Format: Zhi-Jie Jey Cheng, Natasha Karassina, Jamison Grailer, Jim Hartnett, Frank Fan, Mei Cong. Novel PD-1 blockade bioassay to assess therapeutic antibodies in PD-1 and PD-L1 immunotherapy programs. [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 5440. doi:10.1158/1538-7445.AM2015-5440
心筋細胞でAkt/MAPキナーゼとp70 S6キナーゼ経路を経由するホスファチジルイノシトール‐3‐キナーゼによる生存シグナルおよび肥大シグナルの伝達
Authors: Oh H, Kunasada K, Matsui H, Yamauchi-Takihara K
Journal: Circulation (1998)
347. Tagging FKRP and LARGE by CRISPR/Cas9 for Monitoring Expression and Localization
Authors: Anthony R. Blaeser, Pei Lu, Qi Long Lu
Journal: Molecular Therapy (2015)

Limb-girdle muscular dystrophy type 2I is caused by mutations in the gene for fukutin-related protein (FKRP). This protein is a putative glycosyltransferase shown to play an important role in the addition of glycans to the muscle membrane protein alpha-dystroglycan (α-DG). The glycosylation of α-DG is accomplished through the function of more than 17 putative and known glycosylatransferases including LARGE, which, when overexpressed, has been shown to compensate for the loss of function in FKRP and Fukutin. However, the exact localization of the endogenous proteins is unknown and no reliable antibody is available for monitoring the changes of their expression. The use of CRISPR/Cas9 for gene editing has been growing in populatiry as a method for introducing mutations into endogenous proteins or as a way of introducing specific sequences, such as a reporter gene. Here we present the use of the CRISPR/Cas9 gene editing system for the addition of a GFP tag to endogenous FKRP and LARGE for the identification of localization as well as to act as a marker for examining changes in expression as a results of treatment with specific compounds. We have applied several techniques to determine the effectiveness of the CRISPR/Cas9 system and encountered many different barriers. The results of these experiments provide valuable information in understanding the role of FKRP in α-DG glycosylation as well as new ways of examining the effects of experimental therapies targeting this glycosylation. With the new knowledge and methods obtained it will be easier to eventually move into in vivo studies to examine their effects in an animal model.
Busulfan Exposure Decrease CCyR Rate On Imatinib Therapy - Impact On Recent Pretreatment
Authors: Irina Dyagil, Elza Lomaia, Kudrat Abdulkadirov, Elena Goryunova, Natalia Lazorko, Ekaterina Romanova, Eugenia Sbityakova, Alla Abdulkadirova, Irina Martinkevich, Vera Udalieva, Elena Usacheva, Irina Zotova, Vasiliy Shuvaev, Elena Machulaitene, Ekaterina Poznyak, Maria Ivanova, Natalia Ilina, Elena Koryagina, Tatiana Shneider, Svetlana Stepanova, Irina Dmitrenko, Natalia Babkina, Tatiana Perekhrestenko, Zvenyslava Masliak, Andrey Zaritskey
Journal: Blood (2011)
173. Insulin B9-23 LV-Driven Expression in Hepatocytes Combined With Suboptimal Dose of Anti-CD3 mAb Cures Type 1 Diabetes in NOD Mice
Authors: Andrea Annoni, Fabio Russo, Alessio Cantore, Luigi Naldini, Maria Grazia Roncarolo
Journal: Molecular Therapy (2015)

Type 1 diabetes (T1D) is an autoimmune disease resulting in complete destruction of insulin-producing pancreatic β cells. In T1D in human and in the non-obese diabetic (NOD) mouse, the spontaneous murine model of T1D, auto-reactive T cells target islet-associated antigens. Induction of antigen (Ag)-specific tolerance could cure Type 1 Diabetes (T1D) but it has not been achieved yet. We previously showed that lentiviral vector (LV)-mediated gene expression in hepatocytes induces active tolerance toward the encoded-Ag. Systemic administration of a single dose of Integrase competent (IC) or integrase defective (ID) LV.ET.InsB9-23.142T, enabling stable and transient expression of InsB9-23 in hepatocytes, respectively, arrests β cell destruction in NOD mice at advanced pre-diabetic stage by generating InsB9-23-specific FoxP3+ T regulatory cells (Tregs). In the present study we tested the efficacy of hepatocytes-directed LV.ET. InsB9-23.142T gene transfer in protecting from disease progression at later stages and in reversing T1D. Treatment with LV.ET.InsB9-23.142T in NOD mice with glucose levels ranging from 200mg/mL to 250mg/mL blocked T1D progression in only 27% of the mice. Co-expression of the late auto-Ags-derived epitopes GAD206-220 and IGRP195-214 in hepatocytes did not improve the efficacy of LV.ET.InsB9-23.142T treatment. LV.ET.InsB9-23.142T treatment in diabetic NOD mice with blood glucose levels ranging from 250mg/mL to 300mg/mL did not result in reversion to normoglycemic levels in any of the treated mice. We next combined InsB9-23 gene transfer with anti-CD3 monoclonal antibody (mAb) treatment. Treatment with anti-CD3 mAb at optimal doses is able per se to reverse T1D in NOD mice. Therefore, we tested decreasing doses of anti-CD3 mAb in diabetic NOD mice with blood glucose levels ranging from 250mg/mL to 300mg/mL to identify the sub-optimal dose unable to revert T1D. We found that a single administration of anti-CD3 mAb at 5μg instead of 10μg results was not effective. This sub-optimal dose of anti-CD3 mAb (1X 5μg) was administered together with LV.ET.InsB9-23.142T to NOD mice with blood glucose levels ranging from 250mg/mL to 300mg/mL. Results showed T1D reversal in 75% of ICLV-treated and 40% of the IDLV-treated mice. These data indicate that the LV.ET. InsB9-23.142T treatment combined with sub-optimal anti-CD3 mAb treatment is able to reverse overt diabetes.
Phase I Exploratory Study of IV Formulation of Panobinostat in Combination with Bortezomib in Relapsed/Refractory Multiple Myeloma Patients: Effect On Serum PTH and Gene Expression Profiling (GEP) Studies
Authors: Maurizio Zangari, Tamara Berno, Giampaolo Talamo, Xin Zhan, Wen Zhou, He Wang, Ye Yang, Jiliang Xia, Yi Zhou, Karen Pena, Leanne Lujan, Jessica Kohan, Mohamed E Salama, Fenghuang Zhan
Journal: Blood (2012)
Autologous Transplantation for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Achieves Outcomes Similar to Allogeneic Transplantation - Results of CALGB 10001 (Alliance)
Authors: Meir Wetzler, Dorothy Watson, Wendy Stock, Kouros Owzar, Gregory Koval, Eva Hoke, John M McCarty, William Blum, Bayard L. Powell, Guido Marcucci, Clara D Bloomfield, Charles Linker, Richard A. Larson
Journal: Blood (2012)
Abstract LB-210: Telomerase activation by genomic rearrangements in high-risk neuroblastoma
Authors: Martin Peifer, Frederik Roels, Falk Hertwig, Roopika Menon, Andrea Kraemer, Reinhard Buettner, Sven Perner, Alexander Schramm, Johannes H. Schulte, Frank Westermann, Roman K. Thomas, Matthias Fischer
Journal: Cancer Research (2015)

Abstract Neuroblastoma is a malignant pediatric tumor of the sympathetic nervous system. While roughly half of these tumors regress spontaneously or are cured by limited therapy, high-risk neuroblastomas have an unfavorable clinical course, despite intensive multimodal treatment. The genetic basis of the various clinical subtypes of the disease has remained largely elusive. To gain a better understanding of the genetic events that may drive neuroblastoma tumorigenesis, we here performed whole-genome sequencing of 42 primary neuroblastomas (high-risk, n = 25; low-risk, n = 17). We identified genomic rearrangements affecting chromosome 5p15.22 in a 50 kb region centromeric of the human telomerase reverse transcriptase gene (TERT) in 8 tumors. The rearrangements occurred only in high-risk neuroblastomas (8/25, 32%) in mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumor type. In an Independent validation cohort of 14 high-risk neuroblastomas, we detected rearrangements of the TERT locus in 4 additional samples. The structure of the rearrangements varied greatly, including balanced translocations, low-level copy number gains, focal amplifications and chromothripsis. Independent of the copy number at this region, all alterations consistently induced massive transcriptional up-regulation of TERT and of three additional genes located in close proximity to the chromosomal breakpoint. By contrast, MYCN-amplified tumors showed only up-regulation of TERT itself, suggesting that both MYCN amplification and TERT rearrangements converge on TERT activation. Supporting a functional role of TERT, both MYCN-amplified neuroblastoma cell lines and cell lines bearing TERT rearrangements exhibited elevated TERT expression and enzymatic telomerase activity in comparison to cell lines without these aberrations. Our findings show that remodeling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma, and places telomerase activation in the center of transformation in a large fraction of these tumors. More broadly, our findings provide a mechanistic basis for molecular diagnosis and therapy of this deadly pediatric tumor entity. Citation Format: Martin Peifer, Frederik Roels, Falk Hertwig, Roopika Menon, Andrea Kraemer, Reinhard Buettner, Sven Perner, Alexander Schramm, Johannes H. Schulte, Frank Westermann, Roman K. Thomas, Matthias Fischer. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. [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-210. doi:10.1158/1538-7445.AM2015-LB-210
Amiodarone-Induced Thyroid Dysfunction and Ventricular Tachyarrhythmias During Long-Term Therapy in Japan.
Authors: Tsuyoshi Shiga, Michi Wakaumi, Naoki Matsuda, Morio Shoda, Nobuhisa Hagiwara, Kanji Sato, Hiroshi Kasanuki
Journal: Circulation (2001)

In 232 Japanese patients receiving long-term amiodarone therapy for life-threatening ventricular tachyarrhythmias, hyperthyroidism and hypothyroidism developed in 29 patients (12.5%) and 25 patients (10.8%), respectively. In patients with hyperthyroidism, the recurrence of sustained ventricular tachycardia was significantly higher with thyrotoxicosis than in the euthyroid period (31% vs 3%, p<0.01). Holter monitoring showed that the average heart rate and ventricular premature complexes significantly increased with hyperthyroidism. On the other hand, there was no increase in the recurrence of ventricular tachyarrhythmia with hypothyroidism. There was no change in the dose or the plasma concentration of amiodarone or desethylamiodarone in the euthyroid period or when hyperthyroidism or hypothyroidism manifested. It is important to monitor for arrhythmia when hyperthyroidism develops during amiodarone therapy.
Randomized Phase II Trial on Primary Chemotherapy with High-Dose Methotrexate Alone or Associated with High-Dose Cytarabine for Patients with Primary CNS Lymphoma (IELSG #20 Trial): Tolerability, Activity and Event-Free Survival Analysis
Authors: Andres JM Ferreri, Michele Reni, Marco Foppoli, Maurizio Martelli, Marina Siakantaris, Maurizio Frezzato, Maria Giuseppina Cabras, Alberto Fabbri, Gaetano Corazzelli, Fiorella Ilariucci, Giuseppe Rossi, Riccardo Soffietti, Caterina Stelitano, Daniele Vallisa, Francesco Zaja, Marta Gelemur, Gian Marco Aondio, Giuseppe Avvisati, Monica Balzarotti, Alba Brandes, Maria Joao Costa, Henry Gomez, Attilio Guarini, Graziella Pinotti, Luigi Rigacci, Catrina Uhlmann, Maria Angelopoulou, Maria Tirindelli, Virginia Naso, Alberto Franzin, Nicoletta Anzalone, Maurilio Ponzoni, Emanuele Zucca, Federico Caligaris- Cappio, Franco Cavalli
Journal: Blood (2008)
PTU-041 The use of cyclosporin a in acute severe ulcerative colitis: long-term outcomes
Authors: L M Sharkey, F Bredin, A Nightingale, M Parkes
Journal: Gut (2010)

<h3>Introduction</h3> Cyclosporin A (CyA), a potent suppressor of T lymphocyte reponses, has been used to treat steroid-refractory acute flares of ulcerative colitis (UC) since the early 1990s as an alternative to colectomy. We present the Cambridge data regarding response rates andlong-term colectomy-free survival following use of CyA in this context. <h3>Methods</h3> From our inflammatory bowel disease database we extracted details of all patients receiving CyA for UC between January 2000 and July 2009. 44 patients had received CyA, 37 for acute flares refractory to intravenous corticosteroid therapy. Hospital records were unavailable for two patients and two received this treatment twice, hence 37 episodes of CyA use in 35 patients were analysed. <h3>Results</h3> 24 patients were male; aged 17–72 years. On admission 20 patients were on prednisolone (10–60 mg); three were established on immunomodulator therapy (five others had started &lt;3 weeks prior to admission) and seven were on no treatment. CyA was started a median of 8 days after admission with most patients (31/37) receiving CyA orally from outset at a starting dose of 4.5–8.3 mg/kg daily (the patient receiving 4.5 mg/kg was pregnant). Doses were adjusted to achieve a level of 150–250 μg/l. The other six received intravenous CyA at 2–5 mg/kg (5/6 were treated before 2004), and were changed to oral CyA 2–8 days after starting. Of the 35 patients who received CyA for acute UC, 15 have undergone colectomy during median follow-up of 46 months. 11/15 surgeries were carried out due to lack of response in the acute phase after mean 6.1 days (range 2–12) of CyA. 20/24 patients who responded and were discharged on CyA have not required colectomy. The other four patients underwent colectomy 3–8 months post discharge. All patients were monitored by our IBD nurses, with weekly drug levels while on CyA. 15 side effects in 12 patients included headache (11%), paraesthesia and hypertension (8.5%) each. The latter, as well as renal impairment (5.7%) were treated with dose reduction. 5.7% of patients complained of tremors and one patient (2.8%) developed neutropaenia on combination CyA and azathioprine. As per our protocol, 84.6% (22/26 episodes) were started on a thiopurine at a mean of 6.8 weeks post-discharge from hospital (range 0–34 weeks) once the oral prednisolone dose was below 15 mg. <h3>Conclusion</h3> Most UC patients requiring CyA received this orally with good tolerability and safety. Of patients who responded in the acute setting and were discharged on cyclosporine 83% have avoided colectomy. We attribute this success to close patient monitoring by our IBD nurses, and careful management of the wean over from CyA to azathioprine. Our data suggest that in those who respond CyA does not simply “delay the inevitable colectomy”.