tbuckley/cabot-search huggingface dataset:
677. Stabilizing the rAAV Vector Genome Increases AAV Vector Transduction Efficiency
Authors: Katie A. Pokiniewski, Andrea R. Moore, Biao Dong, Qizhao Wang, Weidong Xiao
Journal: Molecular Therapy (2015)

It has been determined that AAV vector efficiency decreases due to the following mechanisms: ineffective endocytosis, endosomal degradation, inefficient trafficking, and the need to convert from a single-stranded AAV genome to a transcriptional active double-stranded form. Administering rAAV vectors in conjunction with a drug that can enhance vector transduction may overcome some of these cellular barriers encountered during infection as well as help stabilize the genome. Here we discovered that Cidofovir(CDV), a monophosphate nucleotide analogue that competitively inhibits the incorporation of deoxycytidine triphosphate into viral DNA via viral DNA polymerase, is able to increase single-stranded rAAV transgene expression in the nucleus by 2 to 9 fold, depending on the cell type and concentration. This increase has been consistently observed in 16095, HelaS3, and Hek293 cells with little toxicity to the cells. However, there is less than a two-fold increase with Cidofovir treatment when using self-complementary AAV vectors(scAAV), suggesting that CDV might enhance conversion of the AAV genome from single to double stranded form. These observations were confirmed using two different serotypes, AAV2 and AAV8, in vitro indicating that the mechanism of enhancement is not serotype dependent. Southern Blot analysis along with real-time PCR demonstrated that Cidofovir treatment in HelaS3 cells increases viral DNA accumulation 24 hours post-infection compared to PBS treated cells. Cells pretreated with CDV then infected with rAAV revealed no difference in the amount of vector present between 0 and 2 hrs post infection, suggesting CDV does not enhance viral entry. However, cytoplasmic and nuclear fractions of HelaS3 cells pretreated with CDV or PBS demonstrated that CDV pretreatment enhances viral accumulation of rAAV vectors in both the cytoplasm and nucleus 24 hours post-infection. In vivo, Hemophilia A BALB/c(BALB/c-HA) mice were treated with CDV prior to infection with a rAAV containing the fVIII Human Light chain(LC) gene. It showed that CDV treatment enhanced the amount of LC antigen when compared to control group. Approximately two fold increase was observed up to fourteen weeks post-injection. These results demonstrate that CDV treatment can enhance and sustain rAAV levels in vivo. CDV has already been approved by the Food and Drug Administration (FDA) for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome (AIDS). The effects of CDV on small DNA viruses that lack their own viral DNA polymerase, like AAV, have not been documented. The use of drugs like Cidofovir can greatly contribute to the understanding of rAAV trafficking and eventually lead the development of novel strategies to increase overall efficiency of AAV transduction.
Comparison of Multiple Myeloma Donor Patient Samples and Derived Cell Lines Identifies a Confirmed Hyperdiploid Myeloma Cell Line and Demonstrates Remarkable Genetic Similarity Between Cell Lines and Patient Samples
Authors: Jonathan J Keats, Bonnie K. Arendt, Esteban Braggio, Michael Barrett, Tammy Price-Troska, Rafael Fonseca, P. Leif Bergsagel, Diane F. Jelinek
Journal: Blood (2008)
A Phase Ib Trial of Romidepsin in Association with CHOP in Patients with Peripheral T-Cell Lymphoma (PTCL): The Ro-CHOP Study
Authors: Jehan Dupuis, Rene-Olivier Casasnovas, Herve Ghesquieres, Franck Morschhauser, Herve Tilly, Catherine Thieblemont, Vincent Ribrag, Bertrand Coiffier
Journal: Blood (2012)
Clinical and Immunological Results Of a Phase I/IIa Study Of Allogeneic Dendritic Cell (DC) Vaccination, An “off The shelf” Treatment To Prevent Or Delay Relapse In Elderly Patients With Acute Myeloid Leukemia
Authors: Arjan A van de Loosdrecht, Sandra van Wetering, Saskia Santegoeds, Satwinder Kaur Singh, Malika Koppes, Anthony Hall, Ada M. Kruisbeek, Tanja D. de Gruijl, Gert J. Ossenkoppele
Journal: Blood (2013)
P176 Diagnosing asthma in children using spirometry: evidence from a birth cohort study
Authors: CS Murray, P Foden, LA Lowe, H Durrington, A Custovic, A Simpson
Journal: Thorax (2016)

<h3>Background</h3> NICE draft guidance for the diagnosis of childhood asthma proposes algorithms based on four tests of lung function (FEV1/FVC ratio, bronchodilator reversibility [BDR], FeNO, PEFR variability); a minimum of two tests must be positive to make a diagnosis. For FEV1/FVC ratio, the proposed cut-off for a positive test is &lt;70%, or the lower limit of normal (LLN), which is neither defined nor widely available. In this algorithm, spirometry is the first-line investigation, and children with FEV1/FVC &gt; 70% are not offered BDR. However, the diagnostic test accuracy for FEV1/FVC and BDR is unknown. Within the setting of a population-based birth cohort we investigated the value of FEV1/FVC and BDR in diagnosing asthma. <h3>Methods</h3> We assessed study participants at clinical follow-up at age 16 years using validated questionnaires and lung function measurement. Spirometry was measured according to ATS/ERS guidelines. Using the Asthma UK reference equations, we calculated LLN for FEV1/FVC. BDR was considered positive if FEV1 increased by &gt;12% following administration of 400 mg of salbutamol. Current asthma was defined as all three of: (1) doctor-diagnosed asthma ever, (2) wheezing in the previous 12 months and (3) current use of asthma treatment. We assigned children negative to all three features as a non-asthmatic control group. <h3>Results</h3> Spirometry was available for 630 children (325 boys, age range 13.1–16.9 years), of whom 74 (11.7%) had current asthma and 403 were assigned as non-asthmatic controls. FEV1/FVC was significantly lower among asthmatics (84.1% <i>vs.</i> 89.2%, p &lt; 0.001, Figure 1). Ten children (1.6%) had FEV1/FVC &lt;70% (two in asthma group). Discriminative ability of FEV1/FVC &lt; 70% was poor (Receiver operating characteristic curve, AUC = 0.70; sensitivity = 2.7% [2/74], specificity = 98.8% [398/403]). For the calculated FEV1/FVC LLN (74.8% for boys, 78.2% for girls), 28 children (4.4%) had FEV1/FVC&lt;LLN (11 in asthma group). Discriminative ability of FEV1/FVC&lt;LLN was poor (sensitivity 14.9% [11/74]; specificity 97.0% [391/403]). BDR was positive in 54 children (8.7%), of whom 12 had asthma. Discriminative ability of BDR was poor (AUC = 0.64, sensitivity = 16.2% [12/74], specificity = 93.5% [373/399]). Combining these two tests did not result in a better diagnostic accuracy (sensitivity = 2.7%, specificity = 99.0%). <h3>Conclusions</h3> FEV1/FVC &lt; 70% or &lt;LLN, and BDR &gt; 12% have a poor diagnostic accuracy as tests for childhood asthma.
487. Therapeutic Genome Editing by Combined Viral and Non-Viral Delivery of CRISPR System Components to the Mouse Liver
Authors: Hao Yin
Journal: Molecular Therapy (2016)

The CRISPR(clustered regularly interspersed short palindromic repeats)/Cas9 system has emerged as a transforming genome editing tool. Cas9/sgRNA recognizes the protospacer-adjacent motif (PAM) sequence and a complementary 20 nucleotide genomic sequence and induces double stranded DNA breaks (DSBs), which are repaired by error-prone non-homologous end-joining (NHEJ) or precise homology-directed repair (HDR). CRISPR/Cas9 genome editing has been applied to correct disease-causing mutations in mouse zygotes and human cell lines, but delivery to adult mammalian organs to correct genetic disease genes has not been reported prior to our study. The liver disease hereditary tyrosinemia type I is a particularly suitable model for gene repair-based therapy because the repaired hepatocytes will expand and repopulate the liver. In tyrosinemia patients, mutation of fumarylacetoacetate hydrolase (FAH), the last enzyme catalyzing the tyrosine catabolic pathway, leads to accumulation of toxic metabolites and severe liver damage. The Fahmut/mut mouse model is caused by a G->A point mutation in the last nucleotide of exon 8. This causes splicing skipping of exon 8 and truncated Fah messenger RNA (mRNA). These mice can be treated with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), an inhibitor of an enzyme upstream of FAH, to prevent toxin accumulation in hepatocytes. In our first proof-of-concept study, we demonstrate CRISPR/Cas9-mediated correction of a Fah mutation in hepatocytes in a mouse model of the human disease hereditary tyrosinemia. Delivery of components of the CRISPR/Cas9 system by hydrodynamic injection resulted in initial expression of the wild-type Fah protein in ~1/250 liver cells. Expansion of Fah-positive hepatocytes rescued the body weight loss phenotype. Our study indicates that for the first time CRISPR/Cas9-mediated genome editing is possible in adult animals and has potential for correction of human genetic diseases. The combination of Cas9, guide RNA and repair template DNA can induce precise gene editing and the correction of genetic diseases in adult mammals. However, clinical implementation of this technology requires safe and effective delivery of all of these components into the nuclei of the target tissue. Here in our second study, we combined lipid nanoparticle—mediated delivery of Cas9 mRNA with adeno-associated viruses encoding a sgRNA and a repair template to induce repair of a disease gene in adult animals. We applied our delivery strategy to a mouse model of human hereditary tyrosinemia and show that the treatment generated Fah-positive hepatocytes by correcting the causative Fah splicing mutation. Treatment rescued disease symptoms such as weight loss and liver damage. The efficiency of correction was >6% of hepatocytes after a single application, suggesting potential utility of Cas9-based therapeutic genome editing for a range of diseases.
Prevalence and Patterns of Cytomegalovirus (CMV) Reactivation In Adult Acute Lymphoblastic Leukemia Patients on Chemotherapy: Single Center Experience
Authors: Seema Gulia, Manju Sengar, Uma Dangi, Hari Menon, Sanjay Biswas, Rohini Kelkar, Reena Nair
Journal: Blood (2011)
The Genetic Architecture of Major Depressive Disorder in Han Chinese Women
Authors: Roseann E. Peterson, Na Cai, Tim B. Bigdeli, Yihan Li, Mark Reimers, Anna Nikulova, Bradley T. Webb, Silviu-Alin Bacanu, Brien P. Riley, Jonathan Flint, Kenneth S. Kendler
Journal: JAMA Psychiatry (2016)

Despite the moderate, well-demonstrated heritability of major depressive disorder (MDD), there has been limited success in identifying replicable genetic risk loci, suggesting a complex genetic architecture. Research is needed to quantify the relative contribution of classes of genetic variation across the genome to inform future genetic studies of MDD.To apply aggregate genetic risk methods to clarify the genetic architecture of MDD by estimating and partitioning heritability by chromosome, minor allele frequency, and functional annotations and to test for enrichment of rare deleterious variants.The CONVERGE (China, Oxford, and Virginia Commonwealth University Experimental Research on Genetic Epidemiology) study collected data on 5278 patients with recurrent MDD from 58 provincial mental health centers and psychiatric departments of general medical hospitals in 45 cities and 23 provinces of China. Screened controls (n = 5196) were recruited from a range of locations, including general hospitals and local community centers. Data were collected from August 1, 2008, to October 31, 2012.Genetic risk for liability to recurrent MDD was partitioned using sparse whole-genome sequencing.In aggregate, common single-nucleotide polymorphisms (SNPs) explained between 20% and 29% of the variance in MDD risk, and the heritability in MDD explained by each chromosome was proportional to its length (r = 0.680; P = .0003), supporting a common polygenic etiology. Partitioning heritability by minor allele frequency indicated that the variance explained was distributed across the allelic frequency spectrum, although relatively common SNPs accounted for a disproportionate fraction of risk. Partitioning by genic annotation indicated a greater contribution of SNPs in protein-coding regions and within 3'-UTR regions of genes. Enrichment of SNPs associated with DNase I-hypersensitive sites was also found in many tissue types, including brain tissue. Examining burden scores from singleton exonic SNPs predicted to be deleterious indicated that cases had significantly more mutations than controls (odds ratio, 1.009; 95% CI, 1.003-1.014; P = .003), including those occurring in genes expressed in the brain (odds ratio, 1.011; 95% CI, 1.003-1.018; P = .004) and within nuclear-encoded genes with mitochondrial gene products (odds ratio, 1.075; 95% CI, 1.018-1.135; P = .009).Results support a complex etiology for MDD and highlight the value of analyzing components of heritability to clarify genetic architecture.
Long-term safety/tolerability of lanreotide autogel/depot (LAN) treatment for metastatic intestinal and pancreatic neuroendocrine tumours (NETs): Final results of the CLARINET open-label extension (OLE)
Authors: M. Caplin, M. Pavel, J.C. Cwikła, A. Phan, M. Raderer, E. Sedláčková, G. Cadiot, E. Wolin, J. Capdevila, L. Wall, G. Rindi, N. Liyanage, S. Braun, P. Ruszniewski
Journal: Annals of Oncology (2016)
367. A Dopamine Gene Therapy for Advanced PD: 4 Years Phase I/II Clinical Update
Authors: Stéphane Palfi, Jean Marc Gurruchaga, Scott Gs Ralph, Colin Watts, Philip Buttery, Helene Lepetit, James Miskin, Gaetane Gouello, Sonia Lavisse, Gilles Fenelon, Claire Thiriez, Pierre Brugières, Roger Barker, Philippe Hantraye, Kyriacos Mitrophanous
Journal: Molecular Therapy (2016)

Parkinson's disease (PD) is a neurodegenerative condition that results in a progressive degeneration of dopaminergic neurons. The dopamine (DA) precursor L-Dopa and dopamine agonists provide the primary standard of care and demonstrate good therapeutic benefit in the early stages of disease. However, their long term use is associated with severe motor side effects that are at least partially caused by the fluctuating nature of dopaminergic stimulation that arises from oral drug administration. As such, a therapy that provides a more continuous and local supply of dopamine to the site of pathology provides a potential approach for the development of new therapeutic strategies. ProSavin® is a gene therapy product that utilises a lentiviral vector to transfer three genes that are critical for de novo dopamine biosynthesis in the striatum, that is depleted of dopamine in PD. Fifteen advanced PD patients have received ProSavin® in three dose cohorts. ProSavin® has been demonstrated to be safe and well tolerated at all doses evaluated to date. No serious adverse events related to the study drug or surgical procedures were observed. All patients demonstrated improvement over baseline at both 6 and 12 months, which were sustained in some patients up to four years. Patients in the highest dose cohort demonstrated the greatest improvement in motor scores, a reduction in requirement for oral dopaminergic medication, and evidences of DA production by PET imaging. In summary, ProSavin® was safe and well tolerated in advanced PD patients. To increase the dose of ProSavin® by administering more vectors is not desirable due to physical constraints. Therefore we have generated OXB-102, an improved version of ProSavin®, that expresses the same enzymes but with an increased DA production per genetically modified cell. An update on OXB-102 will be presented.
Sixty seconds on . . . New Year resolutions
Authors: Nigel Hawkes
Journal: BMJ (2016)

Not really. I follow Oscar Wilde: “Their origin is pure vanity. Their result is absolutely nil.”

Possibly, but the psychological literature isn’t terribly encouraging. One study showed that 22% of people who made them admitted failure after only a week, 40% at a month, 50% at three months, and 81% after two years. Most likely the real figures were even …
Abstract LB-201: Functional role for tumor heterogeneity: Paracrine signaling between tumor subclones of mouse SCLC promotes metastasis
Authors: Min Chul Kwon, Natalie Proost, Kate Sutherland, John Zevenhoven, Anton Berns
Journal: Cancer Research (2015)

Abstract Tumor heterogeneity might not only lead to pools of cells with a different resistance profile to therapy, the heterogeneity can also create a unique tumor-microenvironment. Earlier we have shown that clonal evolution in mouse SCLC can result in subclones with either neuro-endocrine (NE) and non-NE features. Co-grafting of such subclones endow the NE tumor cells with metastatic potential. To address the underlying mechanism we conducted a series of in vivo graft experiments and found that non-cell autonomous paracrine signaling is required in the subcutaneously grafted tumor to permit dissemination. The expression of transcription factor Pea3 in NE cells was identified as a functional downstream target of this paracrine interaction between the tumor subclones. Fgf2 secreted by non-NE subclones causes the expression of Pea3 in the NE cells through activation of Mapk pathway thereby temporarily potentiating its invasive capacity and facilitating intravasation into the circulation. These findings reveal a cooperating role of tumor cell subclones in mouse SCLC. Our data indicate that inhibition of the Fgf2/Mapk/Pea3 axis might be exploited to impair growth and metastatic spread of SCLC. Given the similarity in phenotypic tumor cell heterogenenity and signaling aberrations between mouse and human SCLC, inhibition of this signaling axis is therefore worth exploring in human SCLC. Citation Format: Min Chul Kwon, Natalie Proost, Kate Sutherland, John Zevenhoven, Anton Berns. Functional role for tumor heterogeneity: Paracrine signaling between tumor subclones of mouse SCLC promotes metastasis. [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-201. doi:10.1158/1538-7445.AM2015-LB-201
Molecular Structure and Biological Activity of NPP-4, An Endothelial Cell Surface Pyrophosphatase/ Phosphodiesterase That Stimulates Platelet Aggregation and Secretion Via Liberation of ADP Upon Hydrolysis of Diadenosine Triphosphate
Authors: Deborah L. Ornstein, Ronald Albright, William C. Chang, Donna Robert, Wenxiang Cao, Enrique De La Cruz, Demetrios Braddock
Journal: Blood (2011)
Prognostic Value Of Red Blood Cell and Platelet Transfusion In Elderly Patients With Aggressive Lymphoma Receiving First Line Immunochemotherapy: An Analysis Of The Lysa LNH 03-6B Study
Authors: Richard Delarue, Herve Tilly, Gilles Andre Salles, Catherine Thieblemont, Serge Bologna, Herve Ghesquieres, Olivier Hermine, Corinne Haioun, Andre Bosly
Journal: Blood (2013)
388. Wide-Scale Gene Transfer of Amyotrophic Lateral Sclerosis Related Proteins To Adult Rats
Authors: Kasey L. Jackson, Robert D. Dayton, Ronald L. Klein
Journal: Molecular Therapy (2015)

Wide-scale gene transfer to the central nervous system (CNS) has been achieved in the past few years by way of a peripheral route of administration. This may be relevant to gene therapy considering that a one-time peripheral treatment can penetrate the CNS and affect CNS function long-term. We have used the wide-scale approach to study a disease of the spinal cord, amyotrophic lateral sclerosis (ALS). TDP-43 and FUS are RNA-binding proteins involved in the genetics and pathology of ALS and frontotemporal lobar degeneration (FTLD). Most cases of ALS, including sporadic, non-familial ALS, harbor TDP-43 pathology. TDP-43 was previously expressed in the spinal cord among other tissues after an intravenous delivery of AAV9 to neonatal rats. An adult onset model would be more relevant to ALS and more amenable for sequential gene therapy or pharmacological interventions. In this study, we attempted to induce motor paralysis relevant to ALS in adult rats by expressing TDP-43 or FUS. Several AAV vectors encoding GFP were tested for optimization, AAV8, 9, and 10. The vectors were applied via tail vein to young rats (6 weeks old) at an equal per kg vector dose. Gene transfer in the adult rat CNS was feasible and highly neuron-selective as observed in the spinal cord and the cerebellum with all AAVs tested. When TDP-43 or FUS were individually expressed in adults with AAV9, both proteins caused severe immobilization within 4 weeks, and in the case of FUS, there was physical atrophy. With refinement, this approach could yield an appropriate platform for studying the mechanisms and molecular therapy of ALS and FTLD.
Comparison of Out-of-Pocket Costs for Patients (pts) with Hodgkin’s Disease (HD), Indolent Non-Hodgkin’s Lymphoma (INHL) and Aggressive Non-Hodgkin’s Lymphoma (ANHL).
Authors: Kathryn McCaffrey, Matthew Fisher, Lucie Kutikova, Lee Bowman, Andrew Evens, Leo Gordon, Heather Auto, Charles Bennett
Journal: Blood (2005)
RTHP-25. SUPERIOR PROGNOSTIC VALUE OF CUMULATIVE INTRACRANIAL TUMOR VOLUME (CITV) RELATIVE TO LARGEST INTRACRANIAL TUMOR VOLUME (LITV) FOR STEREOTACTIC RADIOSURGERY TREATED BRAIN METASTASIS PATIENTS
Authors: Clark Chen, Brian Hirshman, Bayard Wilson, Mir Amaan, James Proudfoot, Takao Koiso, Osamu Nagano, Toru Serizawa, Masaaki Yamamoto
Journal: Neuro-Oncology (2016)

Two intracranial tumor volume variables have been shown to prognosticate survival of stereotactic radiosurgery (SRS) treated brain metastasis (BM): the largest intracranial tumor volume (LITV) and the cumulative intracranial tumor volume (CITV). We compared LITV and CITV in terms of their one-year survival prognostication using the Scored Index for Radiosurgery (SIR) model that included age, Karnofsky Performance Score (KPS), status of extracranial disease and the number of brain metastasis as prognostic variables. Models were compared using established statistical measures, including the Net Reclassification Index (NRI>0) and Integrated Discrimination Improvement (IDI). The analysis was performed in two independent cohorts, each consisting of ~3,000 patients. In both cohorts, replacement of LITV with CITV in the SIR model improved the model’s ability to predict one-year survival. In the first cohort, the CITV model showed a Net Reclassification Index (NRI>0) improvement 0.2574 (95% CI 0.1890-0.3257) and Integrated Discrimination Improvement (IDI) of 0.0088 (95% CI 0.0057 - 0.0119) relative to the LITV model. In the second cohort, the CITV model showed a NRI>0 of 0.2604 (95% CI 0.1796 - 0.3411) and IDI of 0.0051 (95% CI 0.0029 - 0.0073) relative to the LITV model. After accounting for age, KPS, status of extracranial disease, and the number of brain metastasis, CITV offer superior prognostic value relative to LITV for SRS-treated BM patients in two independent cohorts that summed to ~6,000 patients.
High Mortality In Extreme Hyperleukocytosis In Pediatric Acute Myeloid Leukemia: A Report From the Children's Oncology Group.
Authors: Lillian Sung, Todd A. Alonzo, Robert B. Gerbing, Richard Aplenc, Soheil Meshinchi, Laura Burden, Susana C. Raimondi, Betsy A. Hirsch, Samir Kahwash, Amy Heerema-McKenney, Laura Winter, Kathleen Glick, Patti Byron, Tanya Wallas, Franklin O. Smith, Alan S. Gamis
Journal: Blood (2010)