tbuckley/cabot-search huggingface dataset:
538. Transient Non-Viral RNA Delivery Mediated by a Lentiviral Particle
Authors: Pascale Bouillé, Régis Gayon, Alexandra Iché, Christine Duthoit, Lucille Lamouroux, Jean-Christophe Pagès
Journal: Molecular Therapy (2016)

Safe and efficient gene therapies including gene-targeting technologies are very challenging but very promising approaches nowadays. The scientific and clinical communities have been working for a long time together to encounter substantial clinical advances they have made possible thanks to numerous improvements in cell culture and gene transfer methods. Opportunities to improve gene transfer into primary or stem cells involve a better design of the vectors used. Such improvements must lead to an increase of the transduction efficiency including the percentage of positive cells, as well as a better level and duration of expression, cell phenotype preservation and the number of genes delivered.. Lentiviral vectors have seen their use largely increased in clinical protocols over the past few years but safety concerns have been highlighted. First, the permanent genetic modification remains a focus of significant regulatory oversight and even integrase- or reverse transcriptase-deficient lentiviral vectors leads to residual integration events. Moreover, all the gene-editing technologies entail a "hit-and-run" mechanism that requires only a transient expression of the nuclease complex. In parallel, mRNA delivery is a versatile, flexible, and safe mean for protein therapies but chemical or electroporation-based transfection protocols are known to induce cell toxicity and phenotype modifications of the target cells. Here, we describe a new chimeric lentiviral platform that allows mRNA delivery into the target cells without any genomic signature. The respective properties of the MS2 bacteriophage and the lentiviral vectors have been combined to build a non-integrative packaging system in which the wild type HIV packaging sequence is replaced by the MS2 stem-loop repeats and the MS2 Coat sequence is inserted into the NucleoCapsid sequence. The resulting lentiviral particle is able to deliver a non-viral RNA into the cytoplasm of target cells, directly available for protein translation. Transduction of immortalized cells but also of T cells and HSC with these RNA lentiviral particles (RLP) shows an efficient, fast and transient expression of both reporters and functional proteins such as genome editing enzymes. Particles structure and functionality, cell transduction and characterization of such engineered cells have been compared with those obtained with an integrative lentiviral vector. Particularly by recruiting the RNA independently of dimerization with more than four molecules per particles, RLPs allow the cotransfer of different species of RNA into target cells. This new delivery system is a great candidate handle the safe and clinically suitable delivery of the editing machinery, which can transiently act without inducing cellular toxicity or immunogenicity.
Evaluation of the Myocilin Mutation Gln368Stop Demonstrates Reduced Penetrance for Glaucoma in European Populations
Authors: Abhishek Nag, Han Lu, Matthew Arno, Adriana I. Iglesias, Pieter Bonnemaijer, Linda Broer, Andre G. Uitterlinden, Caroline C.W. Klaver, Cornelia van Duijn, Pirro G. Hysi, Christopher J. Hammond
Journal: Ophthalmology (2016)
554. Serotype Comparison of AAV Transduction in Adipose-Derived Stem Cells
Authors: Priyanka Sharma, Sunishka M. Wimalawansa, Gregory C. Gould, R. Michael Johnson, Katherine J. D.A. Excoffon
Journal: Molecular Therapy (2016)

Adipose-derived stem cells (ASC) demonstrate promising results in the treatment of many diseases. However, it is unlikely that a simple infusion of cells will provide the full range of desired treatment results. Transient genetic modification of ASC to turn them into drug-eluting depots is likely to enhance their reparative characteristics and accelerate healing. We hypothesized that adeno-associated virus (AAV), an approved gene therapy vector that has never been associated with disease, has several ideal characteristics needed for creating drug-eluting ASC. The most common recombinant AAV vectors were tested for transduction and duration of gene expression. rAAV5 demonstrated both the highest and longest term expression. The glycosylation profile of ASC was determined and we show that rAAV5 transduction requires plasma membrane associated sialic acid. Future studies will focus on rAAV5 as the vector of choice to deliver disease specific genes to drive biological drug delivery, engraftment, and disease correction.
Access to essential medicines for children with cancer: a joint SIOP-CCI position statement
Authors: Avram Denburg, Brijesh Arora, Ramandeep Singh Arora, Carmen Auste, Poonam Bagai, Ronald Barr, Julia Challinor, Tim Eden, Edith Grynzspancholc, Ruth Hoffman, Michael Link
Journal: The Lancet Oncology (2016)
Evaluation of the efficacy and the safety of lanreotide autogel 120 mg on tumor growth stabilization in patients with progressive neuroendocrine tumors (NETs) who are not eligible to surgery or chemotherapy.
Authors: M. Martin-Richard, V. Alonso, M. Marmol, D. E. Castellano, E. Fonseca, A. Velasco, J. L. Garcia, F. Rivera, A. Galan, M. Quindos, I. Maetsu, P. Martinez de Prado, J. Sastre, M. Llanos, C. Pericay, A. Segura, J. Arenas, E. Pineda, P. Maisonobe, B. Massuti
Journal: Journal of Clinical Oncology (2011)

e14660 Background: Somatostatin analogs (SSTAs) are the treatment of choice for hormonal symptoms associated with NETs. Clinical studies have suggested stabilization or, in rare cases, partial response in the tumour mass. In a population of documented progressive NETs no data of antitumoral activity of SSTAs analogs given as sole treatment has been presented. We undertook a phase II trial (NCT0032646) to evaluate the efficacy of lanreotide Autogel 120mg on tumour growth stabilisation in patients with documented progressive NETs. Methods: Thirty patients from 17 Spanish hospitals with advanced and/or metastatic well-differentiated NETs progressive within the last 6 months were treated with lanreotide Autogel 120 mg every 28 days until progression. Treatment with SSTA during the previous 6 months was an exclusion criterion. No patients received chemotherapy (CT) or interferon (IFN) during the 4 weeks before study inclusion. Radiologic evaluation was performed every 3 cycles. Primary endpoint was progression-free survival (PFS) per central blind review. Clinical baseline characteristics were: Age median: 63y (40-78), M/F (50%/50%), Median time since diagnosis 5.5y (0.2-22.2), ECOG 0/1/2: 63%/30%/7% Foregut/Midgut/Unknown: 47%/40%/13%; Ki index: median 2.0 (1-20); Functioning/Non Funct. (63%/37%); Previous treatment: CT/ IFN/SSTAs (33%/23%/20%) Results: Median PFS (95% CI) was 12.9 months (7.9-16.5) both in ITT and PP populations. Best tumour responses were: 4%PR/89%SD/7% PD. Ki 67 index was the most likely prognostic factor for PFS (HR 1.17; p= 0.017). Discontinuation of treatment because of adverse events (AE) occurred in one patient. Only one severe related AE was detected (aerophagia). No impairment in EORTC QLQ-C30 for the whole group was detected during treatment. Conclusions: In this study, the sole treatment with lanreotide Autogel 120 mg in progressive NET patients provides a median PFS > 12 months with a very low toxicity. This apparent tumoral control effect should be confirmed in a phase III ongoing trial (Clarinet, NCT00842348). Acknowledgment: Study sponsored by IPSEN.
Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
Authors: None The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group
Journal: JAMA (2002)

Antihypertensive therapy is well established to reduce hypertension-related morbidity and mortality, but the optimal first-step therapy is unknown.To determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease (CHD) or other cardiovascular disease (CVD) events vs treatment with a diuretic.The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, active-controlled clinical trial conducted from February 1994 through March 2002.A total of 33 357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor from 623 North American centers.Participants were randomly assigned to receive chlorthalidone, 12.5 to 25 mg/d (n = 15 255); amlodipine, 2.5 to 10 mg/d (n = 9048); or lisinopril, 10 to 40 mg/d (n = 9054) for planned follow-up of approximately 4 to 8 years.The primary outcome was combined fatal CHD or nonfatal myocardial infarction, analyzed by intent-to-treat. Secondary outcomes were all-cause mortality, stroke, combined CHD (primary outcome, coronary revascularization, or angina with hospitalization), and combined CVD (combined CHD, stroke, treated angina without hospitalization, heart failure [HF], and peripheral arterial disease).Mean follow-up was 4.9 years. The primary outcome occurred in 2956 participants, with no difference between treatments. Compared with chlorthalidone (6-year rate, 11.5%), the relative risks (RRs) were 0.98 (95% CI, 0.90-1.07) for amlodipine (6-year rate, 11.3%) and 0.99 (95% CI, 0.91-1.08) for lisinopril (6-year rate, 11.4%). Likewise, all-cause mortality did not differ between groups. Five-year systolic blood pressures were significantly higher in the amlodipine (0.8 mm Hg, P =.03) and lisinopril (2 mm Hg, P<.001) groups compared with chlorthalidone, and 5-year diastolic blood pressure was significantly lower with amlodipine (0.8 mm Hg, P<.001). For amlodipine vs chlorthalidone, secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine (10.2% vs 7.7%; RR, 1.38; 95% CI, 1.25-1.52). For lisinopril vs chlorthalidone, lisinopril had higher 6-year rates of combined CVD (33.3% vs 30.9%; RR, 1.10; 95% CI, 1.05-1.16); stroke (6.3% vs 5.6%; RR, 1.15; 95% CI, 1.02-1.30); and HF (8.7% vs 7.7%; RR, 1.19; 95% CI, 1.07-1.31).Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.
Mechanisms of Acquired Drug Resistance to the HDAC6 Selective Inhibitor Ricolinostat Reveals Rational Drug-Drug Combination with Ibrutinib
Authors: Jennifer E. Amengual, Sathyen A. Prabhu, Maximilian Lombardo, Kelly Zullo, Paul M. Johannet, Yulissa Gonzalez, Luigi Scotto, Xavier Jirau Serrano, Ying Wei, Jimmy Duong, Renu Nandakumar, Serge Cremers, Akanksha Verma, Olivier Elemento, Owen A. O'Connor
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Pan-class I/II histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform-selective HDAC inhibitors are emerging as potentially more targeted agents. ACY-1215 (ricolinostat) is a first-in-class selective HDAC6 inhibitor. To better understand the discrete function of HDAC6 and its role in lymphoma, we developed a lymphoma cell line resistant to ACY-1215. Experimental Design: The diffuse large B-cell lymphoma cell line OCI-Ly10 was exposed to increasing concentrations of ACY-1215 over an extended period of time, leading to the development of a resistant cell line. Gene expression profiling (GEP) was performed to investigate differentially expressed genes. Combination studies of ACY-1215 and ibrutinib were performed in cell lines, primary human lymphoma tissue, and a xenograft mouse model. Results: Systematic incremental increases in drug exposure led to the development of distinct resistant cell lines with IC50 values 10- to 20-fold greater than that for parental lines. GEP revealed upregulation of MAPK10, HELIOS, HDAC9, and FYN, as well as downregulation of SH3BP5 and LCK. Gene-set enrichment analysis (GSEA) revealed modulation of the BTK pathway. Ibrutinib was found to be synergistic with ACY-1215 in cell lines as well as in 3 primary patient samples of lymphoma. In vivo confirmation of antitumor synergy was demonstrated with a xenograft of DLBCL. Conclusions: The development of this ACY-1215–resistant cell line has provided valuable insights into the mechanistic role of HDAC6 in lymphoma and offered a novel method to identify rational synergistic drug combinations. Translation of these findings to the clinic is underway. Clin Cancer Res; 23(12); 3084–96. ©2016 AACR.
Hypoxia Increases Repopulating Ability of Myelodysplastic Syndrome Bone Marrow Cells
Authors: Erico Masala, Francesca Buchi, Serena Pillozzi, Ana Valencia-Martinez, Tommaso Rondelli, Antonella Gozzini, Alessandro Sanna, Alberto Bosi, Persio Dello Sbarba, Valeria Santini
Journal: Blood (2015)
Phase II study of topotecan and bevacizumab in advanced refractory non-small cell lung cancer (NSCLC).
Authors: S. F. Powell, A. Beitinjaneh, R. L. Bliss, R. A. Kratzke, J. W. Leach, A. Dudek
Journal: Journal of Clinical Oncology (2011)

7563 Background: Bevacizumab in combination with carboplatin and paclitaxel improves survival of patients with NSCLC in a first-line setting. We hypothesized that non-cross-resistant, second-line salvage therapy with the topoisomerase 1 inhibitor, topotecan, in combination with bevacizumab would have activity in NSCLC. Methods: Forty-two patients were enrolled between 10/2006-9/2010. Patients received topotecan 4.0 mg/m2 on days 1, 8 and 15 and bevacizumab 10 mg/kg on days 1 and 15 as IV infusions. Treatment was repeated every 28 days in the absence of disease progression or unacceptable toxicity. Eligibility criteria included age older than 18 years, ECOG PS of 0-1, and adequate organ function. Patients with treated brain metastases were permitted to enter this study. Response assessment (using RECIST) was performed every two cycles. Primary endpoint of this study was progression-free survival (PFS). Results: Forty-two patients were enrolled in the study. Median age was 60.6 years (range = 36-81). Patients had a median of 3 prior treatment regimens (range 1-7), and 93% had prior platinum therapy. The primary objective of PFS was 238 days (95% CI, 117-332 days). Overall survival (OS) was 345 days (95% CI, 213-464 days). Response rates were as follows: 14.3% partial response (PR), 54.8% stable disease (SD), 28.6% progressive disease (PD). Grade 3 hematologic toxicities seen in participants included thrombocytopenia (16.7%), neutropenia (9.5 %), and anemia (4.8%). There was no grade 4 or higher hematologic toxicities. Only one toxic death, due to pulmonary hemorrhage, occurred during the study. The only grade 4 toxicity was a pulmonary embolism in one patient. Grade 3 non-hematologic adverse events were minimal (<8%) and included: hyperglycemia, bone pain, gastroesophageal reflux, diarrhea, infection, shortness of breath, bowel obstruction, DVT, abdominal pain, pseudogout, and SVC thrombosis. Conclusions: The combination of bevacizumab and topotecan as a salvage therapy for metastatic NSCLC appears to be well tolerated and provides significant progression-free survival. A randomized trial should be performed to compare this combination with other NSCLC regimens.
Abstract 281: Virotherapy with a Semliki Forest virus-based vector encoding IL-12 synergizes with PD-1/PD-L1 blockade
Authors: José I. Quetglas, Sara Labiano, M. Ángela Aznar, Elixabet Bolaños, Arantza Azpilicueta, Inmaculada Rodríguez, Erkuden Casales, Alfonso Rodríguez, Cristian Smerdou, Ignacio Melero
Journal: Cancer Research (2015)

Abstract Virotherapy and checkpoint inhibitors can be combined for the treatment of cancer with complementarity and potential for synergistic effects. We have developed a cytolytic but non-replicative viral vector system based on Semliki Forest virus that encodes IL-12 (SFV-IL-12). Following direct intratumoral injection, infected cells release transgenic IL-12, die and elicit an inflammatory response triggered by both abundantly copied viral RNA and IL-12. In difficult to treat mouse cancer models, such as those derived from MC38 and bilateral B16-OVA, SFV-IL-12 synergized with an anti-PD-1 monoclonal antibody (mAb) to induce tumor regression and prolong survival. Similar synergistic effects were attained upon PD-L1 blockade. Combined SFV-IL-12 + anti-PD-1 mAb treatment only marginally increased the elicited CTL response over SFV-IL-12 as a single agent, at least when measured by in vivo killing assays. In contrast, we observed that SFV-IL-12 treatment induced expression of PD-L1 on tumor cells in an IFNγ-dependent fashion. PD-L1-mediated adaptive resistance thereby provides a mechanistic explanation of the observed synergistic effects achieved by the SFV-IL-12 + anti-PD-1 mAb combination. Citation Format: José I. Quetglas, Sara Labiano, M. Ángela Aznar, Elixabet Bolaños, Arantza Azpilicueta, Inmaculada Rodríguez, Erkuden Casales, Alfonso Rodríguez, Cristian Smerdou, Ignacio Melero. Virotherapy with a Semliki Forest virus-based vector encoding IL-12 synergizes with PD-1/PD-L1 blockade. [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 281. doi:10.1158/1538-7445.AM2015-281
Response to: ‘Autoinflammatory disease damage index (ADDI): a possible newborn also in hidradenitis suppurativa daily practice’ by Damiani <i>et al</i>
Authors: Kim V Annink, Nienke M ter Haar, Joost Frenkel
Journal: Annals of the Rheumatic Diseases (2017)

Response to: 'Autoinflammatory disease damage index (ADDI): a possible newborn also in hidradenitis suppurativa daily practice' by Damiani et alWe thank Dr Damiani et al 1 for their interesting letter about the utility of the autoinflammatory disease damage index (ADDI) in patients with hidradenitis suppurativa (HS), as a response to our recently published article 'The development of the autoinflammatory disease damage index'. 2 It is important to investigate whether the ADDI is also useful for other autoinflammatory diseases.However, we need to consider that the ADDI is developed and will be validated for familial Mediterranean fever, cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic fever syndrome and mevalonate kinase deficiency only.The selection of items was based on an intensive literature search and consensus procedure, to make sure all (and only) relevant items for these four diseases were covered. 2 HS-specific damage, such as disfiguring scars, will not be measured by the ADDI, although this damage might have an important influence on the patients' daily life. 3 As mentioned in the letter, prospective validation of the ADDI in patients with HS is essential before it can be used in the daily practice.We are looking forward to these results.
Iron and Isocitrate Calibrate Erythropoietin Responsiveness of Erythroid Progenitors Via Aconitase Tuning of Protein Kinase C Activity.
Authors: Grant C. Bullock, Lorrie L Delehanty, Anne-Laure Talbot, Sara Gonias, Wing-Hang Tong, Tracey Rouault, Jason Chruma, Adam Goldfarb
Journal: Blood (2009)
Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma: A Phase 2 Study Update
Authors: Ranjana H. Advani, Andrei R. Shustov, Pauline Brice, Nancy L. Bartlett, Joseph D. Rosenblatt, Tim Illidge, Jeffrey Matous, Radhakrishnan Ramchandren, Michelle A. Fanale, Joseph M. Connors, Yin Yang, Dana A. Kennedy, Barbara Pro
Journal: Blood (2011)
579. Combinatorial RNA Interference Therapy Prevents Selection of Pre-Existing HBV Variants in Human Liver Chimeric Mice
Authors: Mi-Hua Tao, Yao-Ming Shih, Cheng-Pu Sun, Ping-Yi Wu
Journal: Molecular Therapy (2015)

BACKGROUND & AIMS: Selection of drug-resistant viral variants is a major cause of treatment failure in chronic hepatitis B virus (HBV) infection. We previously identified a highly potent shRNA, S1, which, when delivered by an adeno-associated viral vector, effectively inhibits HBV replication in HBV transgenic mice. Here, we investigated the impact of a pre-existing shRNA-resistant HBV variant on the efficacy of shRNA therapy and propose the use of combination shRNA therapy to prevent viral escape. METHODS: We applied the "PICKY" software to systemically screen the HBV genome, then used hydrodynamic transfection and HBV transgenic mice to identify additional highly potent shRNAs for use, together with S1, as combination therapy. Human liver chimeric mice were infected with a mixture of wild-type and T472C HBV, a S1-resistant HBV variant, then viral dynamics were monitored during treatment with a single or combined shRNAs. RESULTS: We identified five highly potent shRNAs that reduced serum HBV DNA levels by 900- to 8,500-fold in HBV transgenic mice. In HBV-infected human liver chimeric mice, the presence of T472C mutant compromised the therapeutic efficacy of S1 and resulted in replacement of wild-type HBV by T472C HBV. In contrast, combinatorial therapy using S1 and P28, one of five potent shRNAs, markedly reduced titers for both wild-type and T472C HBV Interestingly, treatment with P28 alone led to the emergence of escape mutants with mutations in the P28 target region. CONCLUSIONS: The presence of viral quasispecies in HBV patients might compromise efficacy of RNAi therapy by selecting shRNA-resistant HBVs. Combinatorial RNAi therapy can minimize the escape of resistant HBV mutants.
Mabthera (Rituximab) in the Treatment of 34 Adult Patients with Refractory Autoimmune Hemolytic Anemia (AIHA).
Authors: JRafael Cabrera, F. Javier Penalver, Isabel Millan, Alberto Alvarez-Larran, Jose L. Diez-Martin, Laura Gallur, Isidro Jarque
Journal: Blood (2004)
PTU-052 Liver fibrosis in patients on long-term methotrexate therapy: correlation of serological markers and transient elastography: Abstract PTU-052
Authors: I Barnova, A Bray, S Shetty, C Kennedy, F Gordon, R Przemioslo
Journal: Gut (2010)

<h3>Introduction</h3> Long-term use of Methotrexate (MTX) therapy carries a risk of hepatic fibrosis. Liver biopsy is the gold standard in assessing hepatic fibrosis in patients treated with MTX. Procollagen lll aminopeptide (P3NP) assessment can reduce the number of liver biopsies but has a poor predictive value. Transient elastography (TE) is an indirect assessment of liver fibrosis using liver stiffness indices. The positive predictive value (PPV) of TE for F1/F0 disease is 0.95, for F2/F3 is 0.88 and F4 is 0.95 compared to liver biopsy and P3NP is a comparison to these findings. We studied patients taking long-term MTX and compared liver fibrosis indices using P3NP and TE. <h3>Methods</h3> Patients taking long-term MTX therapy were recruited from two centres. Participants were divided into three groups: Dermatology, Rheumatology and IBD. All patients had TE and P3NP levels taken at the same time. The results of TE and P3NP levels were compared. <h3>Results</h3> We collected samples from 79 patients: 24 Dermatology, 42 Rheumatology and 13 IBD patients. The results are shown in Abstract 052, the correlation was best achieved in patients with IBD (r=0.92). The dermatology and rheumatology group showed very similar values of correlation in spite of the fact that the average cumulative dose of dermatology patients was almost doubled. The correlation coefficient of P3NP and TE was 0.667 in dermatology patients and 0.62 in rheumatology patients. <h3>Conclusion</h3> The correlation coefficient of P3NP and TE readings was 0.71 in all patients. The best correlation was in patients with IBD. It is likely that P3NP levels are not a satisfactory standard to compare to and liver biopsy comparison would be more robust. In all cases more abnormal high P3NP values were obtained compared to TE in patients who had no clinical and radiological evidence of high-grade fibrosis. These data suggest a better correlation between TE and liver fibrosis stage. Second, there was no significant difference in liver fibrosis results between dermatology and rheumatology group of patients.