tbuckley/cabot-search huggingface dataset:
143. Off-Target Analysis of a rAAV-U7snRNA Vector Used for the Treatment of Duchenne Patients By Exon Skipping
Authors: Claire Domenger, Aurélie Lardenois, Marine Allais, Virginie François, Marie Montus, Laurent Servais, Thomas Voit, Philippe Moullier, Caroline Le Guiner
Journal: Molecular Therapy (2015)

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder affecting 1 male in 5000 and caused by mutations in the gene encoding for the Dystrophin protein. So far, there are no strongly effective treatments but gene-based therapies are currently being developed. Among them, the selective removal by exon skipping of exons flanking an out-of frame mutation in the dystrophin messenger can result in shorter in-frame transcripts that are translated into functionally active Dystrophin. Exon skipping can be achieved using modified U7-small nuclear RNA (snRNA) in which a therapeutic antisense oligonucleotide (AO) is cloned. Such optimized U7snRNA, called U7.OPT, can be packaged in recombinant vectors derived from Adeno-Associated Virus (rAAV), allowing a long-lasting repair of the dystrophin messenger after one single administration. We recently published the high ability of a rAAV8.U7.OPT vector to transduce the skeletal muscle but also the liver and restore the open reading frame of the dystrophin transcript in GRMD dogs muscles injected in one forelimb. We are now moving forward to a phase I/II clinical trial in DMD patients treatable by skipping of the exon 53 of the dystrophin messenger. Because an abundant presence of the therapeutic U7.OPT RNA can in theory lead to partial hybridization to non-targeted messenger(s) with unwanted side effects, we looked for possible off-target events. Primary human myotubes and hepatocytes, untransduced or transduced with our clinical rAAV.U7.OPT vector, served as our in vitro model system. The skipping of exon 53 of the human dystrophin messenger upon vector transduction was validated. In silico analysis using the miRanda algorithm identified some gene candidates expressed in liver and muscle, i.e. messengers which could be the target of our dystrophin-specific AO. Three of them were analyzed by RT-PCR and RTqPCR and showed not detectable exon skipping events or differential expression. Other candidates are currently analyzed. Simultaneously, further investigation included a full transcriptomic analysis by RNA sequencing comparing the samples obtained from untransduced vs transduced primary cells. Preliminary results revealed differential gene expression patterns between the two types of samples. We are now exploring the respective impact of the rAAV transduction itself vs the AO effect per se to finally identity potential off-target events. The complete data will be presented and discussed in the context of our future clinical trial in DMD patients. This project is supported by AFM (Association Francaise contre les Myopathies) and ADNA (Advanced Diagnostics for New Therapeutic Approaches), a program dedicated to personalized medicine, coordinated by Institut Merieux and supported by research and innovation aid from the French public agency, BpiFrance.
Investigator-Initiated Phase 2 Trial of Rituximab in Adult Japanese Patients with Treatment-Resistant Acquired Thrombotic Thrombocytopenic Purpura
Authors: Yoshitaka Miyakawa, Kazunori Imada, Tatsuo Ichinohe, Yusuke Yamane, Kenji Nishio, Takayuki Abe, Yoshihiro Fujimura, Yasunori Ueda, Masanori Matsumoto, Shinichiro Okamoto
Journal: Blood (2015)
Hyper-CVAD plus nelarabine in the treatment of newly diagnosed patients with T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LL).
Authors: A. Al-Ameri, D. A. Thomas, F. Ravandi, S. M. O'Brien, H. Kantarjian, G. Borthakur, T. M. Kadia, M. Kelly, R. Garris, S. Faderl
Journal: Journal of Clinical Oncology (2011)

6554
Chronic Pain Is An Independent Predictor of Lower 6 Minute Walk Distance In Patients with Sickle Cell Disease: Results From Walk-PHaSST Study
Authors: Lakshmanan Krishnamurti, Ruchika Goel, Oswaldo Castro, Robyn J. Barst, Erika Berman Rosenzweig, Vandana Sachdev, Roberto F. Machado, Simon Gibbs, Jane A Little, Dean E. Schraufnagel, Reda E. Girgis, Claudia R. Morris, David B. Badesch, Sophie Lanzkron, Jonathan C. Goldsmith, Victor R. Gordeuk, Gregory J. Kato, Mark Gladwin, Kathryn Hassell
Journal: Blood (2010)
Bortezomib-Based Chemotherapy Regimens Can Inmprove The Complete Remission In Newly Diagnosed Multiple Myeloma Patients With Bcl-2 and Survivin Overexpression
Authors: Zeng Wen, Huang Lifang, Yicheng Zhang, Sun Hanying, Liu Wenli, Meng Fankai, Zhou Jianfeng
Journal: Blood (2013)
Acute Myeloid Leukemia with Myelodysplasia-Related Changes (MRC) Did Not Show Inferior Outcomes Compared to Those without MRC,
Authors: Jee Hyun Kong, Hyun Ae Jung, Hee Kyung Ahn, Silvia Park, Hee-Jin Kim, Kihyun Kim, Jun Ho Jang, Seok Jin Kim, Won Seog Kim, Mark Lee, Chul Jung
Journal: Blood (2011)
Survival analysis of stage IV NSCLC patients treated by the Brazilian public health system compared with patients treated at a research center in the same institution.
Authors: C. H. Barrios, M. Debiasi, A. P. Fay, L. S. Viola, L. Zamprogna, J. M. Mesa
Journal: Journal of Clinical Oncology (2011)

e16525 Background: Treatment of metastatic lung cancer has improved significantly over the last 2 decades. Unfortunately, many of the new treatments are expensive and inaccessible to most patients (pts) in developing countries. This study aims to compare the survival of advanced NSCLC in 2 different populations treated in the same institution in Brazil: public health system (BPHS) vs. research center (RC). Methods: This is an observational study comparing the survival of pts treated by the BPHS with pts enrolled in research protocols at an oncology RC of the same institution. Inclusion criteria were: diagnosis of NSCLC, stage IV and PS 0-2. All patients who met the inclusion criteria in the oncology service BPHS registry were enrolled (from April/2007 to April/2010). Routine chemotherapy in these pts was platinum based with VP-16, Taxanes, Gemcitabine or Vinorelbine. Patients engaged in any first line clinical trial for metastatic NSCLC in our RC from November/2004 to May/2010 were also analyzed. Data was censored on December/2010. Survival data was obtained using the Kaplan-Meier method. A Cox-Proportional Hazards Ratio model was performed for adjustment of potential confounders. Results: The BPHS group had 41 pts and the RC group had 66 pts. Median survival in the BPHS group was 5.00 mo versus 10.00 mo in the RC group (p = 0.01). The hazard ratio for mortality in the RC group was 0.60 (95%CI, 0.37 – 0.95; p =0.03), adjusted for age, sex, skin color, smoking, PS and histology. Conclusions: This analysis entails the possibility of significant biases related to patient selection and other potential confounding factors (e.g. Hawthorne effect). However, our results show an impressive difference in the survival of pts treated by the national standard pattern of care (BPHS) with that of pts participating in randomized clinical trials. The suggestion is that in developing countries, participation in clinical research should be stimulated as it represents an invaluable opportunity for pts unable to receive state of the art care to improve their survival. New studies addressing this issue should be performed.
Comparison of Two Mycophenolate Mofetil Dosing Regimens Following Hematopoietic Cell Transplantation (HCT).
Authors: Pamala A. Jacobson, Sheiren Farag El-Massah, John Rogosheske, Amber Kerr, Janel Boyle-Long, Todd DeFor, Cathryn Jennisen, Claudio Brunstein, John E. Wagner, Marcie Tomblyn, Daniel Weisdorf
Journal: Blood (2008)
Nordic Mantle Cell Lymphoma (MCL) Project: Preemptive Rituximab Treatment of Molecular Relapse Following Autotransplant Can Reinduce Molecular Remission and Prolonged Disease-Free Survival.
Authors: Christian H. Geisler, Erkki Elonen, Arne Kolstad, Anna Laurell, Lone B. Pedersen, Niels S. Andersen, Mats Jerkeman, Marie Nordstrom, Grethe F. Lauritzen, Elisabeth Ralfkiaer, Maans Akerman, Christer Sundstrom, Ruth Langholm, Marja-Liisa Karjalainen-Lindsberg, Outti Kuittinen, Mikael Eriksson
Journal: Blood (2005)
PWE-039 Lymphogranuloma venereum proctitis masquerading as inflammatory bowel disease in 12 homosexual men
Authors: R Srirajaskanthan, S Soni, S Lucas, S Alexander, J White, T Wong
Journal: Gut (2010)

<h3>Introduction</h3> Lymphogranuloma venereum (LGV) is a recognised cause of proctitis which can be difficult to distinguish clinically and histologically from inflammatory bowel disease (IBD). The condition was first described in 2004, following an outbreak in The Netherlands. Lymphogranuloma venereum (LGV) proctitis is caused by L1, L2 and L3 serovars of CT and has evaded detection in recent decades in developed countries. <h3>Aim</h3> We describe a case series of LGV proctitis seen among HIV-positive men who have sex with men (MSM) who underwent endoscopy and biopsy and were diagnosed provisionally with IBD. <h3>Methods</h3> A retrospective study was performed in an inner London hospital. Clinical data were collated from confirmed or suspected cases of LGV proctitis where endoscopy and biopsy had been performed as part of the investigation of clinical symptoms. LGV was confirmed by the detection of LGV-specific DNA from rectal swab specimens, with supportive evidence from Chlamydia serology. Stored histological specimens from rectal biopsies were analysed retrospectively for LGV-specific DNA with the use of molecular techniques. <h3>Results</h3> All 12 cases were in HIV positive homosexual men, median age 41.5 years (range 27–55). In all twelve cases of LGV proctitis rectal biopsies had been obtained. All patients were symptomatic at the time of endoscopy and endoscopic features of proctitis were present in 10 of 12 cases. Mucosal ulceration, cryptitis, crypt abscesses and granulomas were common histological findings but crypt distortion, where seen, was usually mild: in most cases these findings were attributed initially to IBD. All cases were reviewed in gastroenterology or colorectal surgical clinics, where provisional diagnosis of IBD or non-specific proctitis were made. Eight patients were commenced on courses of metronidazole or 5-aminosalicylates. Two patients were given courses of prednisolone. Extraction of LGV-specific DNA from rectal biopsy specimens enabled confirmation of three cases of suspected LGV. <h3>Conclusion</h3> During the recent epidemic of LGV proctitis among UK MSM, it has become apparent that the clinical, endoscopic and histological features of the infection may closely resemble IBD and this may obscure the diagnosis. Relevant clinicians and pathologists should be alerted to the current epidemiology and clinical features of LGV in the UK.
695. Splice-Correction of X-Linked Agammaglobulinemia in a Human BAC-Transgenic Mouse Model Using Oligonucleotides
Authors: Burcu Bestas, Pedro M.D. Moreno, Emelie K.M. Blomberg, Dara K. Mohammad, Karin E. Lundin, Robert Månsson, Anna Berglöf, Jesper Wengel, Edvard C.I. Smith
Journal: Molecular Therapy (2015)

The inherited immunodeficiency, X-linked agammaglobulinemia (XLA), is caused by mutations in the BTK gene, and results in a B-lineage developmental block. We have recently assessed the treatment potential of splice-correcting oligonucleotides (SCOs) targeting a mutated BTK transcript, which contains a pseudo-exon (Bestas et al., J. Clin Invest 124: 4067, 2014). In order to study the potential of SCOs, we engineered a novel, Bacterial Artificial Chromosome (BAC)-transgenic mouse carrying a mutated human BTK gene, originally found in an XLA family. In order to avoid any influence of mouse endogenous Btk protein, we bred the BAC-transgenic mice onto a Btk knockout background. In this model it was possible to correct the defect both in pro-B-cells in vitro, and also in mature B-cells, as demonstrated by the injection of SCOs in vivo. The corrected mRNA gave rise to a functional BTK protein. As a final proof-of-concept we were also able to correct the defect in primary patient cells. In this study we used different nucleotide chemistries, 2'-O-methyl, locked nucleic acid (LNA) and morpholino chemistries. We have now included also other nucleotide chemistries in order to make comparative studies. This is to our knowledge the first time that a lymphocyte defect, caused by abnormal splicing, has been corrected in vivo using a splice-correction approach.
High Incidence of Fatty Liver and Insulin Resistance in Long-Term Adult Survivors of Childhood Stem Cell Transplantation Recipients.
Authors: Yuichiro Tomita, Hiroyuki Ishiguro, Hiromi Hyoudou, Tsuyoshi Sinagawa, Yukiharu Yasuda, Takashi Shimizu, Tsuyoshi Morimoto, Osamu Shinohara, Hiromasa Yabe, Kiyoshi Ando, Shunichi Kato
Journal: Blood (2007)
Clarithromycin (Biaxin®), Low Dose Thalidomide and Dexamethasone (BLT-D) in Newly Diagnosed and Previously Treated African American Patients with Multiple Myeloma: A Retrospective, Single Institution Experience.
Authors: Jack Jacoub, Joao L. Ascensao, Boyer James, Thomas O’Connor, Reema Batra, Harish P. Dave, Geraldine P. Schechter
Journal: Blood (2005)
Flt3 Ligand Negatively Regulates In Vitro Migration, Intracellular Signaling Activated by SDF-1α/CXCR4 and In Vivo Homing of Hematopoietic Progenitor Cells.
Authors: Seiji Fukuda, Hal E. Broxmeyer, Louis M. Pelus
Journal: Blood (2004)
Abstract P254: Protein Kinase C Binding Protein 1 Inhibits Hypoxia-Inducible Factor 1 Action in the Heart
Authors: Chad B Walton, David Veal, Chrisy Mafnas, Keith A MacCannell, Cynthia D Anderson, Ralph V Shohet
Journal: Circulation Research (2011)

The response to hypoxia in tissues is regulated by the heterodimeric transcription factor hypoxia inducible factor-1 (HIF-1). We have investigated the transcriptional effects of hypoxia-inducible factor 1 alpha (HIF-1α) in the heart by expressing an oxygen-stable form of HIF-1α in cardiac myocytes of transgenic mice. The result in most cases is regulation of an expected panoply of genes that restore homeostasis during hypoxia, with corresponding phenotypic changes including contractile dysfunction and increased capillary density. In mice that do not show this phenotype, the mRNA for protein kinase c binding protein 1 isoform 2 (PRKCBP1) was much more abundant, as was the protein, and chromatin immunoprecipitation shows a predominant binding of HIF to the promoter of this gene. Sequencing of the promoter region of the PRKCBP1 gene from the two phenotypes revealed an unexpected 480 bp insert in the HIF-resistant animals containing two canonical HIF binding sites. The protein co-immunoprecipitates with HIF and inhibits HIF transcriptional activity in cell culture. In FVB mice, that contain the promoter insert, PRKCBP is induced by ischemia and co-localizes with HIF in the infarct region. It may be responsible for the greater susceptibility of this strain to heart failure after infarction. We have confirmed with genetic, transcriptional, biochemical, and physiological data that Prkcbp1 inhibits HIF activity through direct interaction, in a mechanism mediated by transcriptional control.
Synergistic Activity of Co-Treatment with PIM1 Kinase Inhibitor SGI-1776 and Histone Deacetylase Inhibitor Panobinostat or Heat Shock Protein 90 Inhibitor AUY922 against Human CML and Myeloproliferative Neoplasm (MPN) Cells.
Authors: Warren C. Fiskus, Kathleen M. Buckley, Rekha Rao, Yongchao Wang, Atul Joshi, Daniel G. Chong, Anand Jillella, Celalettin Ustun, Peter Atajada, Cornelia Quadt, Kapil N. Bhalla
Journal: Blood (2009)
170. PhaseRx mRNA Technology Platform Uses SMARTT Polymer Technology ® to Target and Deliver mRNA to the Liver and Treat a Urea Cycle Disorder in a Mouse Disease Model
Authors: Mary Prieve, Allen Li, Alex Baturevych, Eric Bell, Teri Blevins, Anna Galperin, Pierrot Harvie, Jean-Rene Ella Menye, Sean Monahan, Amber Paschal, Maher Qabar, Debashish Roy, Matt Waldheim, Mike Houston
Journal: Molecular Therapy (2016)

Messenger RNA (mRNA) is a promising alternative in both the viral and non-viral DNA-based gene delivery fields. Current viral vectors for gene therapy are associated with serious safety concerns and nonviral vectors are limited by low gene transfer efficiency. mRNA gene expression in the liver can be used for treatment of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes expressed solely or predominantly in the liver. SMARTT Polymer Technology® has been developed into a robust platform for RNA therapeutics. Optimization of the mRNA technology platform has led to stepwise improvements in mRNA delivery to the liver using GalNAc targeted polymers. We demonstrated a 5,000-fold improvement in activity over our first generation delivery system. Urea cycle disorders result from single gene mutations that lead to deficiency in one of the six enzymes in the urea cycle pathway. This deficiency can trigger elevated blood ammonia levels, also known as hyperammonemia, a life-threatening illness that leads to brain damage, coma or even death in humans. The deficient protein is intracellular and IV protein therapeutics are ineffective. Liver transplantation is the only cure for urea cycle disorders but is limited by the shortage of donors and complications associated with rejection and infection of the transplant. There is a dire need for new treatment options. Using the mRNA technology platform, we have demonstrated preclinical proof of concept in a urea cycle disorder mouse disease model. Treatment with therapeutic mRNA shows normalization of blood ammonia levels in hyperammonemic mice. Therapeutic mRNA expression is detected in the liver after a single mRNA dose with good duration of expression. The treatment was well tolerated, with no toxicities associated with both single and multiple dosing regimens. This mRNA technology platform provides a significant opportunity for the treatment of urea cycle disorders and other orphan liver diseases.
PTH-090 Prevalence of IgA deficiency in patients with type 1 diabetes and the effect on detection of coeliac disease: are NICE guidelines appropriate?
Authors: J S Leeds, A D Hopper, W Egner, G Wilde, S Tesfaye, M Hadjivassiliou, D S Sanders
Journal: Gut (2010)

<h3>Introduction</h3> Immunoglobulin A (IgA) deficiency has a population prevalence of 1 in 500–700 individuals. IgA deficiency has been associated with coeliac disease (CD) leading to false negative serological testing. For this reason, NICE have recommended that IgA testing is necessary when case-finding for CD. Scott <i>et al</i> previously modelled the cost-effectiveness of additional IgA measurement on the predictive value of CD screening and found it to be ineffective and unnecessary in improving test predictive outcomes using Fagan9s nomogram at 1 in 50 prevalence. The relationship of IgA deficiency with other autoimmune conditions such as Type 1 diabetes (T1DM) has been poorly quantified. The aim of this study was to assess the prevalence and presenting symptoms of IgA deficiency as defined by levels undetectable by current immunoassay platforms in patients with T1DM and CD. <h3>Methods</h3> We recruited patients with T1DM (n=1000), CD (n=234) and controls who were volunteers from primary care (n=1200). All patients were assessed for CD using antigliadin antibodies (IgA and IgG), IgA endomysial antibodies and IgA anti-tissue transglutaminase antibodies and total IgA levels. IgA deficiency was defined as a total IgA level &lt;0.2 g/l. In each cohort the prevalence of IgA deficiency was calculated and compared. The effect of IgA deficiency on the detection rate of CD was estimated by comparing with duodenal biopsy results. <h3>Results</h3> The prevalence of IgA deficiency in each group was 10/1000 (1%) in those with T1DM, 2/1200 in population control (0.17%) and 4/234 (1.71%) in those with CD. Lack of detectable IgA was more common in both the T1DM group (p=0.015) and the CD group (p=0.008) compared to controls. There was no significant difference in prevalence of IgA deficiency between CD and T1DM (p=0.32). In the T1DM group 33/1000 had CD of which only 1 had IgA deficiency leading to an antibody negative presentation. In the population controls both IgA deficient individuals had normal duodenal biopsies and no relevant symptoms. In the CD group 3 individuals had positive IgG antigliadin antibodies at presentation and all had relevant symptoms. <h3>Conclusion</h3> IgA deficiency is confirmed to be more common in both Type 1 diabetes and coeliac disease compared to population controls at 1 in 100 and 1 in 50 cases. Despite this very few individuals with IgA deficiency alone appear to have underlying villous atrophy on biopsy and therefore contrary to NICE recommendations this strategy may not be cost effective. Few if any IgA deficient patients are likely to be missed if IgA measurement was not made routinely—as most appeared to be asymptomatic.
Trends in Marijuana Use Among Pregnant and Nonpregnant Reproductive-Aged Women, 2002-2014
Authors: Qiana L. Brown, Aaron L. Sarvet, Dvora Shmulewitz, Silvia S. Martins, Melanie M. Wall, Deborah S. Hasin
Journal: JAMA (2016)

Wilson M. Compton, MD, MPE; Beth Han, MD, PhD, MPH; Arthur Hughes, MS; Christopher M. Jones, PharmD, MPH; Carlos Blanco, MD, PhD
Rapid Visual Screening and Programmable Subtype Classification of Ebola Virus Biomarkers
Authors: Mustafa Balcioglu, Muhit Rana, Mustafa Salih Hizir, Neil M. Robertson, Kashfia Haque, Mehmet V. Yigit
Journal: Advanced Healthcare Materials (2016)

The massive outbreaks of the highly transmissible and lethal Ebola virus disease were caused by infection with one of the Ebolavirus species. It is vital to develop cost‐effective, highly sensitive and selective multitarget biosensing platforms that allow for both the detection and phenotyping. Here, a highly programmable, cost‐efficient and multianalyte sensing approach is reported that enables visual detection and differentiation of conserved oligonucleotide regions of all Ebolavirus subtypes known to infect human primates. This approach enables the detection of as little as 400 amols (24 × 10 6 molecules) of target sequences with the naked eye. Furthermore, the detection assay can be used to classify four virus biomarkers using a single nanoprobe template. This can be achieved by using different combinations of short single stranded initiator molecules, referred to as programming units, which also enable the simultaneous and rapid identification of the four biomarkers in 16 different combinations. The results of 16 × 5 array studies illustrate that the system is extremely selective with no false‐positive or false‐negative. Finally, the target strands in liquid biopsy mimics prepared from urine specimens are also able to be identified and classified.