tbuckley/cabot-search huggingface dataset:
<scp>BASALIT</scp> trial: double‐blind placebo‐controlled allergen immunotherapy with <scp>rB</scp>et v 1‐<scp>FV</scp> in birch‐related soya allergy
Authors: R. Treudler, A. Franke, A. Schmiedeknecht, B. Ballmer‐Weber, M. Worm, T. Werfel, U. Jappe, T. Biedermann, J. Schmitt, R. Brehler, A. Kleinheinz, J. Kleine‐Tebbe, H. Brüning, F. Ruëff, J. Ring, J. Saloga, K. Schäkel, T. Holzhauser, S. Vieths, J. C. Simon
Journal: Allergy (2016)

Conflicting results exist on the effect of allergen immunotherapy (AIT) on pollen-related food allergy. We aimed to investigate the efficacy of one-year AIT with the folding variant (FV) of recombinant (r) Bet v 1 on birch-related soya allergy.Of 138 subjects with Bet v 1 sensitization, 82 were positive at double-blind placebo-controlled food challenge (DBPCFC) with soya. A total of 56 of 82 were randomized in the ratio of 2:1 (active: placebo). Per-protocol population (PPP) had received ≥150 μg of allergen or placebo preparation.lowest observed adverse effect levels (LOAEL), postinterventional occurrence of objective signs (objS) at any dose level, sIgE/IgG4 against Bet v 1 and Gly m 4. Between-group changes were investigated (ancova, Mann-Whitney U-test, Fisher exact test).Baseline characteristics including LOAELs were comparable in both groups with objS and subjS occurring in 82% and 95% of active (n = 38) vs 78% and 83% of placebo group (n = 18). After AIT, objS occurred in 24% and 47%, respectively. LOAEL group differences showed a beneficial tendency (P = 0.081) for LOAELobjective in PPP (30 active, 15 placebo). sIgG4 raised only in active group (Bet v 1: P = 0.054, Gly m 4: P = 0.037), and no relevant changes occurred for sIgE. Only 56% of the intended sample size was recruited.For the first time, we present data on the effect of rBet v 1-FV on birch-related soya allergy. rBet v 1-FV AIT induced significant immunogenic effects. Clinical assessment showed a tendency in favour of the active group but did not reach statistical significance.
302. Combinatorial Engineering of a Receptor Footprint on AAV Serotype 4 Yields Novel Vectors
Authors: Blake H. Albright, Victoria Madigan, Lavanya Rao, John A. Chiorini, Mavis Agbandje-McKenna, Aravind Asokan
Journal: Molecular Therapy (2015)

Most AAV strains in clinical development display a broad range of cellular tropisms within the central nervous system (CNS). As such, this current panel of vectors provides several options for efficient gene expression within neurons and/or glia in the brain. However, precise therapeutic interventions will require selective targeting of distinct cell populations within the brain and other organs, such as the eye. In this regard, a select few AAV serotypes have demonstrated unique tissue tropisms following systemic or peripheral routes of administration. One such example, originally isolated from African green monkeys, is AAV4. This serotype is one of the most divergent serotypes identified to date. From a structural perspective, AAV4 has several unique surface loop topologies that are consistent with the remarkably different usage of receptors, cellular tropism and unique antigenicity displayed by this serotype. Specifically, AAV4 is known to utilize O-linked sialoglycans, or mucins, for cell surface attachment. In the current study, through a combination of structural analysis and random mutagenesis, we identified several key amino acids for further genetic manipulation. Saturation mutagenesis of key residues within a broad receptor footprint on the AAV4 capsid surface yielded a highly diverse library, which was subjected to screening as well as directed evolution in a panel of cell lines in vitro. Additional screening and directed evolution studies in vivo in the mouse CNS yielded several novel AAV4 variants that display distinct transduction profiles in the brain. Extensive in silico analyses, structural modeling, and biological characterization of the novel panel of AAV strains is currently in progress.
Targeting and anti-cancer effect of Endostatin-cytosine deaminase fusion protein
Authors: Chun-Te Chen, Chao-Kai Chou, Gabriel Hortobagyi, Mien-Chie Hung
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

360 

Endostatin, an angiogenesis inhibitor tested in multiple clinical trials, selectively targets neovascular endothelial cells, suppressing tumor growth. To enhance the therapeutic efficacy of endostatin, we fused endostatin with cytosine deaminase, which converts a prodrug 5-flucytosine into a cytotoxic 5-fluorouracil. This therapeutic strategy was developed based on the observation that the endostatin-green fluorescence protein gene and endostatin-luciferase gene selectively target to endothelial cells in vitro and to the tumor site in vivo, respectively. When we used the endostatin-cytosine deaminase fusion protein to treat s.c. grafted tumors or experimental metastasis tumors, our results showed that endostatin-cytosine deaminase treatment provided stronger tumor growth suppression and increased mean survival time of the mice compared with the treatments of endostatin alone, cytosine deaminase alone, or endostatin plus cytosine deaminase. The endostatin-cytosine deaminase protein significantly inhibited the growth of endothelial cells and preferentially induced tumor cell apoptosis.    Recently, the regulatory agency in China approved the use of endostatin as an anti-cancer agent for treating non-small cell lung cancer patients. To this regard, we also have recently generated preliminary results that show an Endo-CD fusion protein exhibited similar therapeutic efficacy to Endo-CD gene therapy in cell culture and in animal models. Considering that multiple clinical trials have been performed for endostatin protein , and it has been approved as an anti-cancer drug in China, if the Endo-CD fusion protein shows more potent anti-tumor activity in animal models than endostatin or CD alone, it may be worthwhile to move it into clinical trials.
Myc Induces Acute Myeloid Leukemia by Conferring Self-Renewal Activity to Committed Myeloid Progenitor Cells That Resist Apoptosis Via Endogenous Mcl-1.
Authors: Hui Luo, Jennifer A. Cain, AnnaLynn Molitoris, Joseph Opferman, Michael H. Tomasson
Journal: Blood (2007)
Abstract 1978: Relationship between transcription factor TWIST1 and microRNA34a in metastatic cancer cells
Authors: Md. Asaduzzaman Khan, Mousumi Tania, Chunli Wei, Junjiang Fu
Journal: Cancer Research (2015)

Abstract Background: Micro RNAs (miRNAs) are the important tools in RNA-interference (RNAi) technology, which is comparatively recent but one of the most promising bio-molecular tools for gene regulation. MiRNAs can interfere with certain genes in target specific manner, and they are being extensively investigated for cancer therapeutics. This study investigated the role of miR-34a on the expression of transcription factor TWIST1, which is involved in metastatic carcinomas. Methods: The expression of miR34a and TWIST1 was measured by quantitative polymerase chain reaction (qPCR) analysis in different cancer cell lines and breast cancer tissues. Then we have transfected the precursor and inhibitor of miR-34a into another TWIST1 rich 4T1 cancer cell, and isolated the total RNA and miRNAs for the analysis of TWIST1 expression, as well as miR-34a. Results: Initially, we have observed that miR34a is highly expressed in lower invasive MCF7 and T47D cancer cells, whereas its expression in higher invasive MDA-MB-231, MDA-MB-435 and BT-549 cancer cells is low. Oppositely, TWIST1 expression is relatively lower in MCF7 and T47D cells, but higher in MDA-MB-231, MDA-MB-435 and BT-549 cells. This inverse relationship indicated that TWIST1 might be a target of miR-34a. Interestingly transfection of miR34a precursor inhibited TWIST1 expression in 4T1 cancer cells. Conclusions: This study reports that miR-34a has reverse correlation with the high TWIST1 expression in metastatic breast cancer. Regulation of TWIST1 by miR-34a might be a potential tool in cancer diagnostics and therapeutics, especially for the treatment of metastatic cancers. Funding support: This work was supported in part by the NSFC (81172049), the Science and Technology Innovation Team of Colleges and Universities of Sichuan Province (13TD0032), the Applied Basic Research Program of Science and Technology Department of Sichuan Province (14JC0797,)and Luzhou City Special Foundation (2013LZLY-J10).Corresponding author email:fujunjiang@hotmail.com Citation Format: Md. Asaduzzaman Khan, Mousumi Tania, Chunli Wei, Junjiang Fu. Relationship between transcription factor TWIST1 and microRNA34a in metastatic cancer cells. [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 1978. doi:10.1158/1538-7445.AM2015-1978
Gene Expression Profiles for Prognosis in MGUS, Coupled with Signatures of Oncogenic Pathway Deregulation Provide a Novel Approach for Selection of Molecular Targets in Multiple Myeloma.
Authors: Ariel Anguiano, Chaitanya Acharya, Kelly Salter, Daniel McCluskey, Christina Gasperetto, Fenghuang Zhan, Madhav Dhodapkar, Joseph Nevins, Bart Barlogie, John D. Shaughnessy, Anil Potti
Journal: Blood (2007)
PTH-052 Vitamin D and other micronutrient status in patients with inflammatory bowel disease
Authors: C Raychaudhuri, A Al-Joudeh, M Srinivas, R Ellis, K D Bardhan, P J Willemse, P Basumani, B Höroldt
Journal: Gut (2010)

<h3>Introduction</h3> Low vitamin D has been reported in patients with Crohns Disease (CD). Vitamin D deficiency is associated with no-specific symptoms, has an impact on bone health. Vitamin D may also have chemoproctective and immunomodulatory effects. We assessed the Vitamin D and other micronutrient status of patients attending the IBD clinic at Rotherham. <h3>Methods</h3> 183 patients with IBD (75 Ulcerative colitis (UC), 105 CD); 80 male, 4 Asian, median age 46 (17–89) years. Patients on vitamin supplements were excluded. Measurements: vitamin D, calcium profile, CRP, FBC available for all; vitamin B12, folate, ferritin/iron studies available in 158 patients. Frequencies were compared by Fisher exact test. Patients on calcium and vitamin D or other vitamin supplements and those on medication interfering with vitamin D metabolism were excluded. Vitamin D (25HOD) categories: deficient, &lt;25 nmol/l; insufficient, 25–50 nmol/l; adequate, &gt;50 nmol/l. <h3>Results</h3> (a) 51.9% (96 patients) had suboptimal vitamin D levels (36 deficient; 60 insufficient). (b) Deficiency of vitamin D, vitamin B12, folate were common in CD than UC (22 vs 14%, 24 vs 13%; 6 vs 1%), but iron deficiency was not (12 vs 11%); none of these significant. (c) Median vitamin D levels were higher in autumn than spring, but neither deficiency nor insufficiency were significantly more common (CD p=0.25; UC p=0.51; Fischer exact test). (d) Median level were higher in men than women, but not significantly (CD p=1.0, UC p=0.70). (e) Vitamin D deficiency/insufficiency was significantly more common in patients &gt;60 years in CD but not UC (p=0.003; UC p=0.10). (F) Vitamin D deficiency/insufficiency was more common in active disease in Crohn9s but not UC, this bordered significance (p=0.05 and p=1.0). (g) No patient had a vitamin D level in the toxic range. <h3>Conclusion</h3> Suboptimal vitamin D levels are present in over 50% of patients attending our IBD clinic; deficiency in almost 20%; seasonal variation while present does not explain the high prevalence. Other micronutrient deficiencies are also frequently present. We advocate annual “vitamin check” (vitamin D, B12, folate and ferritin) for IBD patients similar to the one frequently performed for patients with coeliac disease.
579. Meganucleases as an Efficient Tool for Genome Editing
Authors: Victor V. Bartsevich, John Morris, Ginger Tomberlin, Caitlin Turner, Wendy Sharer, Michael G. Nicholson, Jeff Smith, Nag Kollu, Rachel James, Robin Armstrong, Matthew Hirsch, Derek Jantz
Journal: Molecular Therapy (2016)

The field of genome editing has exploded in recent years. However, despite being the only nuclease naturally evolved for genome editing, meganucleases have largely remained behind the scenes compared to ZFNs, TALENs, and CRISPRs due to difficulties in modifying their DNA-recognition specificity. We have developed a next-generation meganuclease platform called "ARCUS" that overcomes these production difficulties and can produce nucleases with customized activity and specificity. Unlike some other genome editing technologies, ARCUS nucleases are capable of distinguishing target sites that only differ by 1 base pair. We will present the ARCUS platform and one such example of a meganuclease engineered to distinguish the dominant P23H point mutation in the rhodopsin gene from its wild type allele for a possible gene therapy of retinitis pigmentosa
Germline and somatic DICER1 mutations in familial and sporadic liver tumors
Authors: Stefano Caruso, Julien Calderaro, Eric Letouzé, Jean-Charles Nault, Gabrielle Couchy, Anaïs Boulai, Alain Luciani, Elie-Serge Zafrani, Paulette Bioulac-Sage, Olivier Seror, Sandrine Imbeaud, Jessica Zucman-Rossi
Journal: Journal of Hepatology (2016)
78. An IND-Enabling GLP-Toxicology and Biodistribution Study Assessing Systemic rAAV9-hNAGLU Gene Delivery for Treating MPS IIIB: Genotype- and Sex-Specific Dose-Limiting Acute Liver Toxicity in Male Wild Type C57BL/6 Mice
Authors: Haiyan Fu, Aaron S. Meadows, F. Jason Duncan, Chrystal Mongomery, Kathryn Waligura, Marybeth Camboni, William G. Bremer, Christopher M. Walker, Brad Bolon, Kevin M. Flanigan, Kim L. McBride, Douglas M. McCarty
Journal: Molecular Therapy (2015)

No treatment is currently available for mucopolysaccharidosis (MPS) IIIB, a neuropathic lysosomal storage disease due to autosomal recessive defect in α-N-acetylglucosaminidase (NAGLU). In preparation for a clinical trial, we performed an IND-enabling GLP-toxicology study to assess systemic rAAV9-CMV-hNAGLU administration in wt C57BL/6 mice (6-8wk-old), at 1e14 vg/kg or 2e14 vg/kg (n=30/group, M:F=1:1). These were 2 and 4-fold higher, respectively, than our proposed clinical high dose. No adverse clinical signs were observed during the entire 6mo study duration. NAGLU activity above wt levels and vector genomes were detected in all tested CNS and somatic tissues in rAAV-treated mice through 6mo. However, acute mortality was observed in 5 male mice at 2e14 vg/kg dose on Days 6 and 8 pi. All 5 animals exhibited liver discoloration correlating with severe hepatic necrosis and vacuolation, without detectable leukocyte infiltration. At 6, 12 and 24wk pi, minimal single cell hepatocyte necrosis and/or vacuolation, and minimal cardiomyopathy were noted in a dose-dependent manner, with slight transient elevation of ALT or AST at 6wk pi. T-cell responses to AAV9 capsid and rNAGLU were detected at 6wk pi, but partially and completely diminished at 12wk pi, respectively. ELISA showed antibody responses to both AAV9 and rNAGLU in treated animals. In response to the acute mortality in the GLP-tox test, we performed a 6-wk non-GLP study mimicking the GLP-tox study conditions in male MPS IIIB and wt littermates, to further assess the approach and obtain data prior to early mortality. We treated the mice with the same batch of rAAV9-CMV-hNAGLU at the high dose, 2e14 vg/kg, and performed necropsy at 5 days and 6wk pi (n=4/group). No mortality or clinical signs were observed in either rAAV9-treated MPS IIIB or wt mice. At Day 5 pi necropsy, of 4 rAAV9-treated male wt mice, 1 exhibited liver discoloration, correlating with multifocal, periportal and midzonal hepatocyte necrosis, and 2 showed minimal single cell hepatocyte necrosis. Minimal liver damage and elevation of ALT/AST in wt mice persisted to 6wk pi. However, no abnormal changes attributed to vector treatment were detected in the liver in MPS IIIB mice. Therefore, we have identified genotype- and sex-specific dose-limiting toxicity of systemic rAAV9-hNAGLU delivery, supporting a safe profile for our proposed approach for treating MPS IIIB in patients.
536. The Viral Transduction Enhancer Vectofusin-1 Is a Nanofibrillar Peptide Capable of Increasing the Contact between Viral Vectors and Target Cells
Authors: Saliha Majdoul, Louic Vermeer, Loic Hamon, Justine Wolf, Ababacar K. Seye, Nathalie Holic, David Pastre, Daniel Stockholm, Burkhard Bechinger, Anne Galy, David Fenard
Journal: Molecular Therapy (2016)

Gene transfer into hCD34+ hematopoietic stem/progenitor cells (HSPCs) using HIV-1-based lentiviral vectors (LVs) has several therapeutic applications ranging from monogenic diseases, infectious diseases and cancer. In such therapeutic context, the gene therapy could be improved by enhancing transduction levels of target cells and by reducing the amount of LVs used on the cells for greater safety and reduced costs. We recently identified a new cationic amphipathic peptide, Vectofusin-1, with viral transduction enhancing capacity, enabling higher transduction levels with low amounts of LV. Vectofusin-1 promotes the entry of several retroviral pseudotypes into target cells when added to the culture medium and is not toxic to HSPCs. Here, we present the first insights into the mechanism of action of this new transduction enhancer. First, a viral pull down assay showed that viral particles were easily pelleted by low speed centrifugation in presence of Vectofusin-1, suggesting that this latter may form unsoluble nanofibrils, trapping lentiviral particles. Atomic force (AFM) and electron microscopy (EM) of Vectofusin-1 confirmed that this peptide is rapidly forming annular aggregates and nanofibres in culture medium. Furthermore, these fibres were shown to be auto-fluorescent in medium with high-protein content (X-Vivo20), allowing the observation of a nanofibrillar network of Vectofusin-1 using confocal microscopy. Next, Vectofusin-1 was shown to strongly interact with Congo Red, especially in presence of lentiviral particles, but labeling with Thioflavin T was inefficient, suggesting that Vectofusin-1 fibres are not amyloid-type fibrils. Structural studies by circular dichroism confirmed this result. The capacity to form nanofibrils appears to be essential for the mechanism of action of Vectofusin-1 since a defective mutant called LAH2-A4, unable to promote lentiviral transduction (Majdoul S. et al (2016) J. Biol. Chem.), was also unable to form nanofibrils. In conclusion, biophysical, nanoscopic and microscopic observations have helped us to define Vectofusin-1 as a new nanofibrillar peptide capable of enhancing lentiviral transduction of target cells in conditions well-adapted to cGMP and scalable gene therapy protocols.
Transmissible <i>Mycobacterium tuberculosis</i> Strains Share Genetic Markers and Immune Phenotypes
Authors: Hanna Nebenzahl-Guimaraes, Arjan van Laarhoven, Maha R. Farhat, Valerie A. C. M. Koeken, Jornt J. Mandemakers, Aldert Zomer, Sacha A. F. T. van Hijum, Mihai G. Netea, Megan Murray, Reinout van Crevel, Dick van Soolingen
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Successful transmission of tuberculosis depends on the interplay of human behavior, host immune responses, and Mycobacterium tuberculosis virulence factors. Previous studies have been focused on identifying host risk factors associated with increased transmission, but the contribution of specific genetic variations in mycobacterial strains themselves are still unknown.To identify mycobacterial genetic markers associated with increased transmissibility and to examine whether these markers lead to altered in vitro immune responses.Using a comprehensive tuberculosis registry (n = 10,389) and strain collection in the Netherlands, we identified a set of 100 M. tuberculosis strains either least or most likely to be transmitted after controlling for host factors. We subjected these strains to whole-genome sequencing and evolutionary convergence analysis, and we repeated this analysis in an independent validation cohort. We then performed immunological experiments to measure in vitro cytokine production and neutrophil responses to a subset of the original strains with or without the identified mutations associated with increased transmissibility.We identified the loci espE, PE-PGRS56, Rv0197, Rv2813-2814c, and Rv2815-2816c as targets of convergent evolution among transmissible strains. We validated four of these regions in an independent set of strains, and we demonstrated that mutations in these targets affected in vitro monocyte and T-cell cytokine production, neutrophil reactive oxygen species release, and apoptosis.In this study, we identified genetic markers in convergent evolution of M. tuberculosis toward enhanced transmissibility in vivo that are associated with altered immune responses in vitro.
Abstract 2726: Dysregulation of host cellular genes targeted by HPV integration contributes to HPV related cervical carcinogenesis
Authors: Ruiyang Zhang, Xiangmei Chen, Fengmin Lu
Journal: Cancer Research (2015)

Abstract The integration of HPV viral DNA into the human genome has been postulated as an important etiological event during cervical carcinogenesis. Several recent reports have indicated that this integration might cause functional dysregulation of the host cellular gene(s) involved, suggesting a possible role for such integration targeted cellular genes(ITGs) in cervical carcinogenesis. Therefore in this study, a comprehensive analysis of HPV integration events was undertaken using data collected from the scientific literature. 499 integration loci on human chromosomes were included. This systemic analysis first confirmed previous findings that the breakpointsof HPV genome are concentrated in E1, E2 and E2/E4 regions. The collected data revealed that HPV DNA preferred to integrate into intragenic regions, particularly gene-dense regions of human chromosomes. Intriguingly, the host cellular genes nearby the integration sites were found to be transcriptionally active compared to similar collection of genes picked at random locations across the human genome. Furthermore, Analysis of the integration sites in the human genome revealed that all chromosomes were represented with several integration hotspots. In addition, the ITGs identified were found to be enriched in tumor-related terms and pathways using gene ontology (GO) and KEGG analysis. Besides, functional analysis of MPPED2, one of above ITGs, demonstrated a role in blocking G1/S transition and cell proliferation retardation. Overall the results of this comprehensive analysis has implicated for the first time dysregulation of ITGs caused by viral integration as having a possible etiological involvement in cervical carcinogenesis. Citation Format: Ruiyang Zhang, Xiangmei Chen, Fengmin Lu. Dysregulation of host cellular genes targeted by HPV integration contributes to HPV related cervical carcinogenesis. [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 2726. doi:10.1158/1538-7445.AM2015-2726
Sleeve Lobectomy Is a Safe and Effective Oncologic Procedure: A Single Center Experience over Three Decades
Authors: Luis Carlos Silva Corten, Johnny Moons, James Villeneuve, Alessia Stanzi, Lieven Depypere, Hans Van Veer, Philippe Nafteux, Willy Coosemans, Herbert Decaluwé, Dirk Van Raemdonck, Paul De Leyn
Journal: Journal of Thoracic Oncology (2015)
Apoptosis Taqman Low-Density Array: Analysis of Programmed Cell Death Patway in CLL.
Authors: Agostino Cortelezzi, Umberto Gianelli, Valentina Vaira, Maria Cristina Pasquini, E. Fasoli, Antonino Neri, Lucia Nobili, Marta Lionetti, Michela Cortiana, Daniele Vincenti, Silvano Bosari, Guido Coggi, Giorgio Lambertenghi Deliliers
Journal: Blood (2007)