tbuckley/cabot-search huggingface dataset:
Long-Term Follow-up of Therapy-Related MDS and AML Patients Treated with Allogeneic Hematopoietic Cell Transplantation Reveals Substantial 10 Year Survival and Comparably Low Treatment-Related Mortality
Authors: Björn Hackanson, Claudia Schmoor, Hartmut Bertz, Reinhard Marks, Ralph Wäsch, Robert Zeiser, Jürgen Finke
Journal: Blood (2014)
280. Combination of Low-Dose Gene Therapy and Monthly Enzyme Replacement Therapy Improves the Phenotype of a Mouse Model of Lysosomal Storage Disease
Authors: Rita Ferla, Marialuisa Alliegro, Edoardo Nusco, Pamela Claudiani, Alberto Auricchio
Journal: Molecular Therapy (2015)

Enzyme replacement therapy (ERT) is the current standard of care for Mucopolysaccharidosis type VI (MPS VI) that is caused by deficiency of arylsulfatase B (ARSB), which results in widespread accumulation and excretion of toxic glycosaminoglycans (GAGs). However, ERT is associated with inconvenient multiple and costly administrations and fails to ameliorate cardiac, visual and bone abnormalities. To overcome ERT limitations, we developed a successful gene therapy approach based on a single administration of AAV2/8 that targets liver of MPS VI animal models. Importantly, we showed that a single systemic administration of AAV2/8 at high doses (2×10e12 gc/kg) is at least as effective as the current ERT therapeutic regimen based on weekly infusions of recombinant human ARSB (rhARSB). If this translates to humans, gene therapy could replace ERT for MPS VI. However, the administration of high doses of AAV2/8 requires a challenging and costly production process, and results in cell-mediated immune responses that eliminate transduced hepatocytes. Similarly, weekly ERT infusions are costly and require high patient compliance. We therefore evaluated in a mouse model of MPS VI whether the combination of low doses of AAV2/8 at 6×10e11 or 2×10e11 gc/kg with a rarified ERT schedule (1mg/kg once a month) may be as effective as the single treatments at high doses or frequent regimen. Significant increase of ARSB activity was found in liver of all treated mice. Detectable but low activity was variably observed in spleen and kidney and was associated with significant reduction of tissue GAGs, regardless of treatment and ARSB activity levels, similarly to what observed in mice treated with high doses of AAV2/8 or weekly ERT. This supports previous data indicating that low enzymatic levels improve MPS VI visceral phenotype. Evaluation of GAG storage in myocardium and heart valves is in progress. Urinary GAG, which are a sensitive biomarker of systemic clearance of lysosomal storage and, thus of therapeutic efficacy, are slightly reduced in mice treated with either monthly ERT or 2×10e11 gc/kg of AAV2/8. The reduction is more consistent at 6×10e11 gc/kg. Importantly, urinary GAG decreased more in mice receiving the combined therapy than in those receiving single treatments. In particular, urinary GAG reduction in mice treated with both 6×10e11 gc/kg of AAV2/8 and monthly ERT was comparable to that obtained following administration of either high doses of AAV2/8, i.e 2×10e12 gc/kg, or weekly ERT. The data collected so far show similar efficacy between low-dose gene therapy combined with rarified ERT and the corresponding single treatments at high doses or frequent regimen. This should increase the safety and reduce the risks and costs associated with both therapeutic approaches.
Hypothermia for Neuroprotection in Convulsive Status Epilepticus
Authors: Stephane Legriel, Virginie Lemiale, Maleka Schenck, Jonathan Chelly, Virginie Laurent, Fabrice Daviaud, Mohamed Srairi, Aicha Hamdi, Guillaume Geri, Thomas Rossignol, Julia Hilly-Ginoux, Julie Boisramé-Helms, Benjamin Louart, Isabelle Malissin, Nicolas Mongardon, Benjamin Planquette, Marina Thirion, Sybille Merceron, Emmanuel Canet, Fernando Pico, Yves-Roger Tran-Dinh, Jean-Pierre Bedos, Elie Azoulay, Matthieu Resche-Rigon, Alain Cariou
Journal: New England Journal of Medicine (2016)

Convulsive status epilepticus often results in permanent neurologic impairment. We evaluated the effect of induced hypothermia on neurologic outcomes in patients with convulsive status epilepticus.In a multicenter trial, we randomly assigned 270 critically ill patients with convulsive status epilepticus who were receiving mechanical ventilation to hypothermia (32 to 34°C for 24 hours) in addition to standard care or to standard care alone; 268 patients were included in the analysis. The primary outcome was a good functional outcome at 90 days, defined as a Glasgow Outcome Scale (GOS) score of 5 (range, 1 to 5, with 1 representing death and 5 representing no or minimal neurologic deficit). The main secondary outcomes were mortality at 90 days, progression to electroencephalographically (EEG) confirmed status epilepticus, refractory status epilepticus on day 1, "super-refractory" status epilepticus (resistant to general anesthesia), and functional sequelae on day 90.A GOS score of 5 occurred in 67 of 138 patients (49%) in the hypothermia group and in 56 of 130 (43%) in the control group (adjusted common odds ratio, 1.22; 95% confidence interval [CI], 0.75 to 1.99; P=0.43). The rate of progression to EEG-confirmed status epilepticus on the first day was lower in the hypothermia group than in the control group (11% vs. 22%; odds ratio, 0.40; 95% CI, 0.20 to 0.79; P=0.009), but there were no significant differences between groups in the other secondary outcomes. Adverse events were more frequent in the hypothermia group than in the control group.In this trial, induced hypothermia added to standard care was not associated with significantly better 90-day outcomes than standard care alone in patients with convulsive status epilepticus. (Funded by the French Ministry of Health; HYBERNATUS ClinicalTrials.gov number, NCT01359332 .).
Continuing Reduction in Level of Residual Disease after 4 Years in Patients with CML in Chronic Phase Responding to First-Line Imatinib (IM) in the IRIS Study.
Authors: John M. Goldman, Timothy Hughes, Jerry Radich, Susan Branford, Andreas Hochhaus, Charlene So, Insa Gathmann, Elisabeth Wehrle, Jaspal Kaeda
Journal: Blood (2005)
Obesity and the Transformation of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma: A Population-Based Cohort Study
Authors: Su-Hsin Chang, Suhong Luo, Theodore S. Thomas, Katiuscia K. O’Brian, Graham A. Colditz, Nils P. Carlsson, Kenneth R. Carson
Journal: JNCI Journal of the National Cancer Institute (2016)

Multiple myeloma (MM) is one of the most common hematologic malignancies in the United States and is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). This study investigates the role of obesity in the progression of MGUS to MM.A retrospective identified cohort of patients in the US Veterans Health Administration database diagnosed with MGUS between October 1, 1999, and December 31, 2009, was followed through August 6, 2013. Patient-level clinical data were reviewed to verify MM diagnosis, if any. Survival analyses utilizing interval-censored data were used to investigate the risk of progression of MGUS to MM. Statistical tests were two-sided.The analytic cohort consisted of 7878 MGUS patients with a median follow-up of 68 months. Within the cohort, 39.8% were overweight and 33.8% were obese; 64.1% were of white race. During follow-up, 329 MGUS patients (4.2%) progressed to MM: 72 (3.5%) normal-weight patients (median follow-up = 61.9 months), 144 (4.6%) overweight patients (median follow-up = 69.1 months), and 113 (4.3%) obese patients (median follow-up = 70.6 months). In the multivariable analysis, overweight (hazard ratio [HR] = 1.55, 95% confidence interval [CI] = 1.16 to 2.06) and obesity (HR = 1.98, 95% CI = 1.47 to 2.68) were associated with an increased risk of transformation of MGUS to MM. Moreover, black race was associated with a higher risk of MM (HR = 1.98, 95% CI = 1.55 to 2.54).Obesity and black race are risk factors for transformation of MGUS to MM. Future clinical trials should examine whether weight loss is a way to prevent the progression to MM in MGUS patients.
467. Consistency of Research Grade Lentiviral Vector Manufacturing Over 60 Batches
Authors: Wesley C. Gorman, Pranali Buch, Hannah Maheno, Michael Kuczewski, Nolan Sutherland, Logan Trimble, J. Dominic Mancini, Mark D. Angelino, Maria Mercedes Segura, Robert H. Kutner
Journal: Molecular Therapy (2015)

Lentiviral vectors (LV) have shown to be efficient gene transfer vehicles in a growing list of gene therapy applications and are currently being evaluated in clinical trials. bluebird bio has developed a GMP manufacturing process for large-scale production of third generation VSV-G pseudotyped HIV-1 based lentiviral vectors to support such trials. To cope with the increased demand for researchgrade LV material for preclinical testing, a mirror small-scale manufacturing model is used at bluebird bio to generate LV batches at scales ranging between 2 and 10L. The manufacturing process is based on the transient transfection of adherent HEK 293T cells with packaging and envelope plasmids along with a transfer plasmid coding for a gene of interest. Harvested supernatants are subsequently concentrated and purified using a combination of membrane filtration and chromatography steps. Analytical data obtained over 60 batches of LV manufactured using this process indicates that it consistently delivers high quality vector preparations with an infectious titer > 1E+08 TU/mL and a particle/infectious ratio between 100-500, emphasizing the robustness of the process design. Process yields typically range between 30 and 60 %, according to both infectious particle determinations using the HOS cell titer assay and total particle determinations as assessed by p24 ELISA. A linear correlation between harvested supernatant LV titers and final product LV titers is observed. This process is used to generate LV preparations to support ALD, β-Thalassemia, Sickle Cell Disease and CAR-T programs.
Low Doses of Thalidomide (Thal) in Low Risk MDS with Transfusion-Dependant Anemia: The GFM THAL-SMD-200 Trial.
Authors: J. Tamburini, C. Elie, D. Vassilief, M.C. Quarre, O. Beyne-Rauzy, M. Gardembas, A. Aouba, C. Berthou, L. Sanhes, A. Guerci, A. Stamatoullas, F. Bauduer, J.J. Sotto, L. Legros, S. Vaultier, P. Fenaux, F. Dreyfus, D. Bouscary
Journal: Blood (2006)
Toll-Like Receptors 2 and 4 Mediate the Capacity of Human Bone Marrow-Derived Mesenchymal Stem Cells to Support the Proliferation and Differentiation of CD34+ Cells In a Non-Synergistic Way.
Authors: Xingbing Wang, Qiansong Cheng, Jian Wang, Liang Xia, Xuhan Zhang, Kaiyang Ding, Zimin Sun
Journal: Blood (2010)
Reliability of periodontal diagnostic tools for monitoring peri‐implant health and disease
Authors: Pierluigi Coli, Véronique Christiaens, Lars Sennerby, Hugo De Bruyn
Journal: Periodontology 2000 (2016)

Abstract The prevalence, causes and consequences of crestal bone loss at dental implants are a matter of debate. In recent years, a high prevalence of peri‐implant soft‐tissue inflammation, associated with peri‐implant bone loss, has been reported and the need for treatments similar to those offered for natural teeth affected by periodontitis has been proposed. This suggestion is based on the assumption that periodontal indices, such as probing pocket depth and bleeding on probing, are reliable indicators of the peri‐implant tissue conditions and good predictors of future bone loss. However, based on a critical review of the literature in the present paper, it is concluded that periodontal indices are not reliable either for identifying peri‐implant disease or for predicting future risk for peri‐implant crestal bone loss and implant failure. The long‐term experiences with dental implants, presented in the literature, indicate that the presence of bleeding on probing, probing pocket depths much larger than 4 mm and some bone loss seem to reflect, in most instances, normal conditions of well‐functioning dental implants, bearing in mind that healing of dental implants is the result of a foreign body reaction with the formation of scar tissue. Therefore, the use of probing pocket depth and bleeding on probing assessments may lead to over‐diagnosis and possibly to over‐treatment of assumed biofilm‐mediated peri‐implantitis lesions. It is the opinion of the authors of this review that a treatment should only be initiated when a clinical problem is present based on patient's symptoms (discomfort, pain), the presence of swelling, redness and pus, and significant crestal bone loss over time (as verified with radiographs). The treatment should aim at resolving the infection, which could include removal of the implant.
A Phase II Trial of Bexarotene, a Retinoid X Receptor Agonist, in Non-M3 Acute Myeloid Leukemia
Authors: Donald E. Tsai, Melissa Potuzak, Anthony Mato, Alison Wakoff Loren, David Porter, Edward A. Stadtmauer, Steven Goldstein, Alexander Perl, Cezary Swider, Adam Bagg, Emile Youssef, Selina Luger
Journal: Blood (2008)
Abstract 3015: BCL10 is a novel DNA damage response factor whose expression inversely correlates with the clinical outcome of breast invasive ductal carcinoma
Authors: Min Zhu, Hongchang Zhao, Xingzhi Xu
Journal: Cancer Research (2015)

Abstract Timely and properly cellular response to DNA damage is essential for maintenance of genome stability and integrity. B-cell lymphoma/leukemia 10 (BCL10) facilitates ubiquitination of NEMO in the cytosol, activating NFκB signaling. Translocation and/or point mutations of BCL10 associate with mucosa-associated lymphoid tissue lymphomas and other malignancies. We recently found that BCL10 in nucleus is enriched onto the DNA damage sites in an ATM- and RNF8-dependent manner, and ATM-dependent phosphorylation and RNF8-dependent ubiquitination of BCL10 confers UBC13 to RNF8/RNF168 to regulate ubiquitination-mediated DSB signaling and repair. In this report, we further found that inhibition of BCL10 expression compromised RNF168 dimerization and RNF168-dependent histone H2A ubiquitination. Immunohistochemistry staining analysis revealed that BCL10 expression status inversely correlates with prognosis in 339 cases of breast invasive ductal carcinoma with a median follow up of 60 months (range, 3-127 months). Taken together, our results demonstrated that BCL10 is a novel DDR factor with a potential role as a biomarker in breast cancer therapy. Note: This abstract was not presented at the meeting. Citation Format: Min Zhu, Hongchang Zhao, Xingzhi Xu. BCL10 is a novel DNA damage response factor whose expression inversely correlates with the clinical outcome of breast invasive ductal carcinoma. [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 3015. doi:10.1158/1538-7445.AM2015-3015
Abstract B37: Mesothelin-targeted immunotoxin RG7787 (LMB-100) preferentially depletes secreted proteins and short-lived intracellular proteins to augment tumor cell killing by taxanes
Authors: Christine Alewine, Rebekah Landsman, Michael Rudloff, Emily Kolyvas, Jinqiu Chen, Ira Pastan
Journal: Cancer Research (2016)

Abstract Mesothelin (MSLN) is a cell surface antigen expressed by a number of solid tumors including most pancreatic adenocarcinomas. RG7787 is a MSLN-targeted immunotoxin that is entering clinical testing for patients with advanced pancreatic cancer. RG7787 binds to MSLN on the cancer cell surface through a high affinity Fab and delivers a modified Pseudomonas exotoxin A (PE) payload into the cell cytosol. PE induces apoptosis by catalyzing the irreversible modification and inactivation of elongation factor-2 (EF-2), halting protein synthesis. This is a novel mechanism of action which produces synergistic tumor killing in combination with nab-paclitaxel in preclinical mouse models and in cell culture. Our goal is to understand the mechanism of this interaction. We have previously demonstrated that taxane does not increase delivery of RG7787 to tumors grown in mice and that taxane does not augment protein synthesis inhibition caused by RG7787. We hypothesized that RG7787 should deplete levels of secreted proteins and short-lived intracellular proteins and that insufficiencies of these factors may enhance taxane-mediated killing. To examine the effect of RG7787 on the pancreatic cancer secretome, we treated pancreatic cancer cells grown in culture or mice bearing tumor xenografts with RG7787 and used ELISA to examine levels of secreted proteins in conditioned medium and interstitial tumor fluid. We found that RG7787 treatment causes dose-dependent decreases in secreted proteins even at non-lethal doses. To demonstrate proof of principle that short-lived proteins are preferentially depleted, we created a reporter cell line co-expressing both GFP and a destabilized fluorescent Cherry protein (Cherry-PEST). We found that treatment with RG7787 reduced the levels of Cherry-PEST but not GFP in a dose-dependent fashion confirming our hypothesis. Consistent with this, we found that levels of the short-lived Bcl-2 family survival factor Mcl-1 are reduced in cells treated with the combination of RG7787 and taxane compared to taxane treatment alone. We conclude that RG7787 depletion of Mcl-1 primes cells for killing by taxane. We are now testing the combination of RG7787 (LMB-100) with nab-paclitaxel in a Phase IB/II trial for patients with pancreatic cancer. Citation Format: Christine Alewine, Rebekah Landsman, Michael Rudloff, Emily Kolyvas, Jinqiu Chen, Ira Pastan.{Authors}. Mesothelin-targeted immunotoxin RG7787 (LMB-100) preferentially depletes secreted proteins and short-lived intracellular proteins to augment tumor cell killing by taxanes. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B37.
607. Gene Therapy Delivering Anti-inflammatory Viral Proteins for Ocular Inflammation
Authors: Cristhian J. Ildefonso, Henrique Jaime, Qiuhong Li, Masmudur M. Rahman, Grant McFadden, Alfred S. Lewin
Journal: Molecular Therapy (2015)

Inflammation in the retina is a contributing factor in ocular diseases such as uveitis, diabetic retinopathy, and dry-age related macular degeneration (AMD). The M013 protein from the myxoma virus has been shown to interfere with both the inflammasome and NF-kB signaling, modulating the synthesis and secretion of the proinflammatory cytokine interleukin-1β (IL-1β). Our goal is to develop adeno-associated virus (AAV) vectors that can deliver viral anti-inflammatory genes into the retina to decrease inflammation. Stably transduced cells expressing the TatM013 protein were generated using lentiviral vectors. Inflammasome activation was induced with either LPS or 4-hydroxynonenal and IL-1β concentration was measured by ELISA. Expression and secretion of sGFP-TatM013 was observed in transfected HEK293T cells by fluorescent microscopy and western blot. The anti-inflammatory effect of TatM013 was evaluated in an Endotoxin Induced Uveitis (EIU) animal model by the intravitreal injection of C57BL/6J mice with AAV2 viral particles delivering either sGFP-TatM013 or GFP followed by injection of LPS one month thereafter. Expression was determined by fluorescence fundoscopy and anti-inflammatory effect was measured by counting the number of infiltrative cells present in the vitreous in H&E stained paraffin sections of enucleated eyes. The expression of TatM013 reduced the induced IL-1β secretion in stable cells. Cellular distribution of sGFP-TatM013 was punctuate compared to GFP in transfected cells. The secretion and cleavage of the sGFP-TatM013 construct was inferred by detection of the fused sGFP-TatM013 protein in the cell lysate and the free form of sGFP in the conditioned media. A reduction in the concentration of secreted induced IL-1β was observed in cells exposed to conditioned media from sGFP-TatM013 transfected HEK293T cells. The quantity of infiltrative cells in the vitreous was significantly lower in the eyes injected with sGFP-TatM013 than with GFP injected eyes in the EIU mouse model. The expression of TatM013 inhibits the induced secretion of IL-1β in vitro. The expression of a secretable and cell penetrating TatM013 in the retina reduces the inflammatory response in the EIU mouse model. We are also developing other anti-inflammatory viral proteins that can be delivered by AAV vectors. Our vectors could be a potential therapy for diseases with an inflammatory component such as uveitis.
MiR-21 expression as prognostic biomarker in extrahepatic but not intrahepatic radically resected cholangiocarcinomas
Authors: I. Garajová, G. Brandi, G. Biasco, M. Deserti, S. Tavolari, A. Palloni, L. Verlicchi, T. Le Large, D. Di Piazza, E. Giovannetti
Journal: Annals of Oncology (2015)
Abstract 1295: Role of glycine N-methyltransferase in the regulation of T cell responses in experimental autoimmune encephalomyelitis
Authors: Chung-Hsien Li, Ming-Hong Lin, Yen-Fu Chen, Shih-Han Chu, Pang-Hsien Tu, Cheng-Chieh Fang, Chia-Hung Yen, Peir-In Liang, Jason C. Huang, Yu-Chia Su, Huey-Kang Sytwu, Yi-Ming A. Chen
Journal: Cancer Research (2015)

Abstract Glycine N-methyltransferase (GNMT) is known for its function as a tumor suppressor gene. Since 100% of female Gnmt−/− mice developed hepatocellular carcinoma, we hypothesized that Gnmt−/− mice may have defective immune surveillance. In this study, we examined the immune modulation of GNMT in T cell responses using experimental autoimmune encephalomyelitis (EAE). The results showed that EAE severity was significantly reduced in Gnmt−/− mice. Pathological examination of the spinal cords revealed that Gnmt−/- mice had significantly lower level of mononuclear cell infiltration and demyelination than the wild-type mice. In addition, quantitative real-time PCR showed that expression levels of pro-inflammatory cytokines, including IFN-gamma and IL-17A, were much lower in the spinal cord of Gnmt−/- than in that of wild-type mice. Accordingly, myelin oligodendrocyte glycoprotein (MOG)-specific T cell proliferation and induction of T helper (Th) 1 and Th17 cells were markedly suppressed in MOG35-55 induced Gnmt−/- mice. Moreover, the amount of regulatory T cells was significantly increased in these mice. When the T cell receptor was stimulated, the proliferative capacity and the activation status of mTOR-associated downstream signaling were significantly decreased in GNMT−/- CD4+ T cells via an IL-2 and CD25-independent manner. Moreover, GNMT deficiency enhanced the differentiation of regulatory T cells without affecting the differentiation of Th1 and Th17 cells. Furthermore, the severity of EAE in mice adoptive transferred with GNMT-deficient CD4+ T cells was much milder than in those with wild-type CD4+ T cells. In summary, our findings suggest that GNMT is involved in the pathogenesis of EAE and plays a crucial role in the regulation of CD4+ T cell functions. Citation Format: Chung-Hsien Li, Ming-Hong Lin, Yen-Fu Chen, Shih-Han Chu, Pang-Hsien Tu, Cheng-Chieh Fang, Chia-Hung Yen, Peir-In Liang, Jason C. Huang, Yu-Chia Su, Huey-Kang Sytwu, Yi-Ming A. Chen. Role of glycine N-methyltransferase in the regulation of T cell responses in experimental autoimmune encephalomyelitis. [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 1295. doi:10.1158/1538-7445.AM2015-1295