tbuckley/cabot-search huggingface dataset:
711. Intravenous Neonatal Gene Therapy Corrects GM2 Gangliosidosis in Sandhoff Mice for Long-Term, By Using AAV Viral Vector Expressing a New Hexosaminidase Variant
Authors: Karlaina J.L. Osmon, Evan Woodley, Patrick Thompson, Katalina Ong, Subha Karumuthil-Melethil, Brian Mark, Don Mahuran, Steven J. Gray, Jagdeep S. Walia
Journal: Molecular Therapy (2015)

GM2 gangliosidosis is a group of neurodegenerative disorders, characterized by the malfunctioning Hexosaminidase A (HexA) enzyme, for which there is no treatment. HexA is composed of two similar, but non-identical subunits, the alpha and the beta, which must interact with the GM2 activator protein, a substrate-specific cofactor, to hydrolyze GM2. Mutation in either subunit (or the activator) results in the development of GM2 gangliosidosis. In these diseases, the malfunctioning protein is unable to play its role in cleaving GM2 ganglioside, whose accumulation within the neurons of the central nervous system is ultimately toxic. The resulting neuronal death induces the primary symptoms of the disease; motor impairment, seizures, and sensory impairments. The aim of this study is to observe the long-term in vivo effects of a novel treatment in a Sandhoff (beta deficient) mouse model. The treatment utilized a new Hex isoenzyme, Hex M, which functions as a homodimer in the treatment of GM2 gangliosidosis. The HexM subunit is a variant of the human Hex alpha subunit containing critical beta-components that allow it to form stable homodimers and interact with the GM2 activator protein to reduce substrate storage. Our methods include intravenous injections of the neonatal mice with a self-complementary vector (with a synthetic promoter) expressing HexM at day 0-1. We monitored one cohort for 8 weeks and another cohort long-term (>40 weeks) for biochemical, behavioural and molecular analyses. Through the enzymatic and GM2 ganglioside lipid analyses, we see that with a slight increase in enzyme activity, there is a significant increase in the clearance of GM2 gangliosides. On behavioural tests, the treated mice outperform their knockout age matched controls. While the untreated controls die before the age of 15 weeks, treated animals have survived to more than 40 weeks and are still being monitored. The molecular analyses reveal a uniform distribution of the vector between brain and spinal cord regions. In conclusion, the neonatal delivery of our newly synthesized viral vector expressing HexM to the Sandhoff mice provided long-term correction of the disease. This study will have implications not only for treatment of Sandhoff, but also Tay-Sachs disease (alpha deficiency).
DETECTION of CHROMOSOMAL 14q32 ABNORMALITIES IN B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA.
Authors: Mariangela Mura, Alessandra Trojani, Silvia Soriani, Alessandra Tedeschi, Milena Lodola, Chiara Colombo, Francesca Ricci, Enrica Morra, Marco Montillo
Journal: Blood (2009)
Abstract 733: A targetable GATA2-IGF2 axis confers aggressiveness in lethal prostate cancer
Authors: Samuel J. Vidal, Veronica Rodriguez-Bravo, Aidan Quinn, Estrelania Williams, Janis de la Iglesia-Vicente, Xiaochen Sun, Xintong Chen, Yujin Hoshida, Carlos Cordon-Cardo, Josep Domingo-Domenech
Journal: Cancer Research (2015)

Abstract Castration resistant prostate cancer (CRPC) is a significant cause of mortality worldwide. In recent years, treatment modalities that improve survival have emerged including taxane chemotherapy and second generation androgen signaling inhibitors, among others. Indeed, today the first line chemotherapeutic docetaxel as well as the second line agent cabazitaxel are mainstays of treatment. However, CRPC inexorably progresses to a chemotherapy resistant state that ultimately precedes lethality. Elucidating the molecular determinants of aggressiveness in chemotherapy resistant CRPC may therefore stimulate new therapeutic strategies that improve clinical outcomes. We used laboratory models and clinical databases to identify GATA2 as a regulator of chemotherapy resistance and tumorigenicity in this context. Whole genome expression profiling, clinical validation and genetic screening approaches revealed that GATA2 regulates a consensus signature of cancer progression associated genes. Mechanistically, direct upregulation of the growth hormone IGF2 emerged as a significant mediator of the aggressive properties regulated by GATA2. IGF2 in turn activated IGF1R and INSR as well as a downstream polykinase program. The characterization of this axis prompted a novel combination strategy whereby dual IGF1R/INSR inhibition restored the efficacy of chemotherapy and improved survival in preclinical models. These studies reveal a GATA2-IGF2 aggressiveness axis in chemotherapy resistant prostate cancer and identify a therapeutic opportunity in this challenging disease. Citation Format: Samuel J. Vidal, Veronica Rodriguez-Bravo, Aidan Quinn, Estrelania Williams, Janis de la Iglesia-Vicente, Xiaochen Sun, Xintong Chen, Yujin Hoshida, Carlos Cordon-Cardo, Josep Domingo-Domenech. A targetable GATA2-IGF2 axis confers aggressiveness in lethal prostate cancer. [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 733. doi:10.1158/1538-7445.AM2015-733
Incorporation of Alemtuzumab into Front-Line Therapy of Adult Acute Lymphoblastic Leukemia (ALL) Is Feasible: A Phase I/II Study from the Cancer and Leukemia Group B (CALGB 10102).
Authors: Wendy Stock, Daohai Yu, Ben Sanford, Gerard Lozanski, Spero Cataland, Ravi Vij, John Byrd, Bayard Powell, Meir Wetzler, Maher Albitar, Dorie Sher, Colin Edwards, Eva Hoke, Clara D. Bloomfield, Richard A. Larson
Journal: Blood (2005)
687. Development of a Safe and Effective Combinatorial Foamy Virus Vector for HIV Gene Therapy
Authors: Arun K. Nalla, Theodore Williams, Athena Lemon, Rahaf Qamou, Elizabeth Everson, Grant D. Trobridge
Journal: Molecular Therapy (2016)

The Berlin patient and successes in retroviral hematopoietic stem cell (HSC) gene therapy suggest that gene therapy may provide a functional cure for HIV. However, retroviral-HSC gene therapy has resulted in serious adverse side effects due to vector mediated genotoxicity, including leukemia. Foamy virus (FV) vectors have a promising integration profile and may be safer than retroviral vectors. FV vectors also can efficiently deliver anti-HIV transgenes that can reduce the titer of HIV-1 based lentiviral vectors. We report a novel combinatorial anti-HIV FV vector that uses a housekeeping elongation factor 1 alpha (EF1α) promoter but still potently blocks HIV infection. We first evaluated the relative potency of various previously described anti-HIV transgenes, including the C46 fusion inhibitor, the F12-Vif derivative Chim3, lens epithelium derived growth factor-integrase binding domain (LIBD) and TRIM5α-CyclophilinA fusion (TCypA) in a FV vector background. We found that C46 was the most potent anti-HIV transgene, followed by TCypA and LEDGF-IBD. Next, we hypothesized that using a less-genotoxic internal promoter to drive the transgenes would reduce vector-mediated genotoxicity. Therefore, a direct comparison was made between the efficacy of housekeeping gene promoters (EF1α and Ubiquitin C; UbC) and a highly genotoxic SFFV promoter in expressing the C46 transgene and subsequently blocking HIV replication. We observed that C46 EF1α had ~2 to 4 fold higher anti-HIV effect than C46 driven by either SFFV or UbC promoters, respectively. Based on these results, we designed a novel combinatorial FV vector expressing three anti-HIV transgenes: C46, TcypA and LIBD. The gene cassette was driven by an EF1α promoter and also has mCherry as a reporter gene (FV-E C46TLmC-W). This vector can be produced at high titer, 1.4 × 107 transducing units/ml which is critical for clinical translation. This novel combinatorial anti-HIV FV vector showed a higher potency in blocking HIV replication than C46 alone at a late time point, 21 days post HIV infection (Figure 1). An in vitro competitive survival advantage assay indicated that cells transduced with our novel combinatorial anti-HIV FV vectors are highly resistant to HIV infection compared to cells transduced with FV expressing a control EGFP reporter gene alone (FV-EG-W) (Figure 2). Further studies will be focused on the efficacy of our novel combinatorial anti-HIV FV vector in human CD34+ cells transplanted in a mouse xenotransplant in vivo model. Our goal is to develop a safe and potent combinatorial FV vector for clinical studies.
Effects of 'Cool-Down' During Exercise Recovery on Cardiopulmonary Systems in Patients With Coronary Artery Disease
Authors: Yoshiharu Koyama, Akira Koike, Takashi Yajima, Hiroshi Kano, Fumiaki Marumo, Michiaki Hiroe
Journal: Circulation (2000)

The effects of 'cool-down' during exercise recovery on cardiovascular and respiratory systems have not been fully clarified. The recovery of respiratory gasses was compared in cardiac patients after maximal exercise during which subjects either performed a cool-down or rested. Twenty-one patients (61+/-10 years) with coronary artery disease performed 2 symptom-limited incremental exercise tests on a cycle ergometer: one with a cool-down and the other without during recovery from the maximal exercise test. Expired gasses were analyzed on a breath-by-breath basis throughout the test and for 6min of recovery. Without a cool-down, the ventilatory equivalent for O2 (VE/O2) increased dramatically during recovery compared with the resting values or those of peak exercise: 44.5+/-7.7 at rest, 44.0+/-10.6 at peak exercise and 63.3+/-14.5 after 2min of recovery. End-tidal PO2 (P(ET)O2) also increased significantly during recovery. However, the overshoot phenomenon of these variables was attenuated when cool-down exercise was performed during recovery. The high ratio of VE/VO2 reflects ventilation perfusion (VA/Q) unevenness and P(ET)O2 is an index of arterial PO2. Thus, it is suggested that cool-down exercise during recovery after maximal exercise testing provides beneficial effects on the respiratory system by decreasing the VA/Q unevenness and relative hyperventilation that are observed when cool-down exercise is not performed.
506. β-Sarcoglycan Gene Transfer Prevents Muscle Fibrosis and Inflammation in an Aged LGMD2E Mouse Model
Authors: Eric R. Pozsgai, Danielle A. Griffin, Kristin N. Heller, Jerry R. Mendell, Louise R. Rodino-Klapac
Journal: Molecular Therapy (2015)

Limb-girdle muscular dystrophy type 2E (LGMD2E) results from mutations in the β-sarcoglycan (SGCB) gene causing loss of a structural protein component of the dystrophin-associated protein complex (DAPC) located at the sarcolemma. This loss results in histopathological features including chronic muscle fiber necrosis, inflammation, fat replacement and fibrosis, accompanied by deteriorating muscle strength and function. To date, no effective therapy exists to treat this debilitating disease. A suitable model for translational studies is the murine model of LGMD2E that completely lacks β-sarcoglycan (Sgcb-null mouse), and has clinical-pathological features in skeletal and cardiac muscle that replicate the human disease. Considering that a major question unanswered by gene replacement therapy is the potential efficacy of gene replacement once significant degrees of connective tissue have infiltrated dystrophic muscle, the studies described here in the β-sarcoglycan knock out mouse have particular relevance for planning future clinical trials. On the clinical side, fibrosis presents a major impasse for functional recovery. In this study, we directly addressed this question using a codon optimized human β-sarcoglycan gene (hSGCB) driven by a muscle specific tMCK promoter and the AAVrh.74 serotype (scAAVrh74.tMCK.hSGCB). We first showed restoration of expression 12 weeks post treatment following a direct intramuscular injection which was accompanied by improvements in histological parameters. Furthermore, following a clinically relevant isolated limb vascular delivery (5X10^11 vg) we found that >90% of muscle fibers expressed β-sarcoglycan in lower limb muscles. Histopathology showed a decrease in central nucleation and normalization of muscle fiber size. Immunohistochemical staining for various immune components including CD3, CD4, CD8, and macrophages showed a reduction in the numbers of immune cells following treatment. The restoration of β-sarcoglycan expression and improvement in overall histology also correlated with improvement in functional outcomes assessed by absolute and specific force generation and resistance to contraction induced injury. To measure fibrosis, quantification of picrosirius stained sections revealed a reduction of collagen deposition in TA (from 40.72 ± 1.40% to 21.22 ± 1.09%, p<0.01) and gastrocnemius (37.92 ± 1.25% to 22.90 ± 0.99%, p<0.01). Moreover, we treated an additional cohort of aged 6 month old Sgcb-null mice with extensive fibrosis already present. At 9 months >80% of muscle fibers were transduced which was accompanied by a significant reduction of fibrosis similar to what was achieved following vascular delivery in younger mice. This pre-clinical study addresses the potential for gene replacement to reverse the debilitating fibrosis, typical of many of the muscular dystrophies providing momentum for movement to a clinical gene replacement for LGMD2E.
Use of Thymoglobulin for Graft Versus Host Disease Prophylaxis Does Not Increase the Incidence of Clostridium Difficile Infection in Recipients of Allogeneic Stem Cell Transplant Recipients
Authors: Divaya Bhutani, Paul Naylor, Charles Jaiyeoba, Joseph P. Uberti, Voravit Ratanatharathorn, Abhinav Deol, Lois Ayash, Lawrence G. Lum, Sanjay Revankar, Pranatharthi Chandrasekar
Journal: Blood (2015)
PWE-079 Use of antisecretory medication after antireflux surgery for patients with gastro-oesophageal reflux disease: a systematic review of non-randomised studies
Authors: Y Yuan, N D Dattani, C Scarpignato, R H Hunt
Journal: Gut (2010)

<h3>Introduction</h3> Although antireflux surgery is effective for selected patients with gastro-oesophageal reflux disease (GERD), some patients require further antireflux medication after a variable period. We have previously reported that 14% (95%CI 9% to 20%) of patients require antisecretory medication after antireflux surgery (ARS), based on a meta-analysis of 18 RCTs.1 Since most surgical studies examining the efficacy of ARS are not randomised, we aimed to investigate the need for further ARM after ARS in recent non-randomised studies. <h3>Methods</h3> MEDLINE and EMBASE databases were searched from 2005 up to Oct 2009 for published, English-language, non-randomised studies investigating the efficacy of ARS for GERD in adults, and reporting the use of ARM after ARS. The proportions of patients using ARM after ARS were sample size weighted and pooled by applying a random-effects model using StatsDirect 2.7.2®. <h3>Result</h3> In total, 24 clinical studies met inclusion criteria with follow-up ranging from 0 to 3 months to &gt;10 years and most were single arm observational studies. Some studies reported data for more than one time point. Most surgical interventions were fundoplication, while a few studies only stated “anti-reflux surgery”. When all studies were pooled, regardless of the follow-up time point and only considering the last measured data for the same study, 20% (95% CI 13% to 28%) of patients required ARM after ARS (25 arms, n=7739). The corresponding data for the use of PPIs were 18% (11–25%, 20 arms, n=5994). When subgroup analyses were performed for different follow-up periods, the proportions of patients who required ARM after ARS were 15% (8–23%, 5 arms, n=1680), 24% (12–37%, 7 arms, n=1301), 18% (9–30%, 12 arms, n=5929), and 27% (18–37%, 5 arms, n=1447) for &lt;1 year, 1–3 years, 3–5 years, and 5–10 years, respectively. The corresponding data for the use of PPIs were 14% (6–24%, 4 arms, n=836), 36% (18%–56%, 3 arms, n=225), 12% (3–25%, 9 arms, n=3572), and 21% (15–28%, 5 arms, n=1447). <h3>Conclusion</h3> After antireflux surgery, 20% of patients still require antireflux medication in non-randomised studies, and this proportion increases with the duration of follow-up to 27% after 10 years. This figure from non-randomised studies, which is higher than that from randomised studies, is probably more representative of the unmet need in clinical practice. However, some important issues remain unanswered, including the reasons for taking ARM after ARS, and the effect of loss to follow-up in long-term observational studies. Furthermore, how best to manage reflux patients who fail surgical treatment requires further investigation.
AMN107, a Novel Aminopyrimidine Inhibitor of BCR-ABL, Has Pre-Clinical Activity Against Imatinib Mesylate-Resistant Chronic Myeloid Leukemia (CML).
Authors: Mirna Golemovic, Francis J. Giles, Miloslav Beran, Jorge Cortes, Taghi Manshouri, Hagop Kantarjian, Srdan Verstovsek
Journal: Blood (2004)
759. Reduction of HLH-like Manifestations in Murine Model of Munc13-4 Deficiency Following Lentiviral Gene Transfer into Hematopoietic Stem and Progenitor Cells
Authors: Tayebeh-Shabi Soheili, Fernando Sepulveda, Amandine Durand, Julie Rivière, Samia Martin, Geneviève de Saint Basile, Marina Cavazzana, Isabelle André-Schmutz
Journal: Molecular Therapy (2016)

Patients with mutations in UNC13D gene, coding for Munc13-4 protein, suffer from type 3 Familial hemophagocytic lymphohistiocytosis (FHL3), a life-threatening disorder of the immune system which represents 25% of all FHLs. Munc13-4 controls docking of lytic granules before they fused with the plasma membrane in cytotoxic T and NK lymphocytes and it's defect results in defective cytotoxic function of these cells. Hematopoietic stem and progenitor cell (HSPC) transplantation, which is the only curative treatment for FHL3 to date, is partially successful even when a compatible donor is available because of the important inflammatory background of patients. In this context gene therapy could be a promising therapeutic option especially for those patients without any compatible donor. In this study, we took advantages from a murine model of FHL3, the Jinx mice, to investigate the feasibility of HSPC gene therapy for this pathology. Jinx mice do not spontaneously develop clinical features of hemophagocytic lymphohistiocytosis (HLH), but do so when infected with lymphocytic choriomeningitis virus (LCMV). We generated and used a self-inactivated lentiviral vector to complement HSC from Unc13d -/- (Jinx) mice and transplanted them back into the irradiated Jinx recipients. This transplantation led to the complete reconstitution of the immune system at levels comparable to that of control mice. The recipients were then challenged with LCMV. While Jinx mice reconstituted with GFP expressing HSPC developed leukopenia, anemia and body weight loss, characteristic of HLH in this murine model, gene corrected Jinx recipients developed only mild or no HLH manifestations. This reduction in HLH manifestation correlated with a significant reduction of virus titer in the liver and serum level of IFN-g and inflammatory cytokines. All these ameliorations might be explained by the restoration of cytotoxic function of CTLs as demonstrated in an in-vitro degranulation assay. Overall, this study provides data supporting the potential of HSC gene therapy in a FHL immune dysregulation such as UNC13D deficiency.
The Natural Diterpenoid Isoforretin A Inhibits Thioredoxin-1 and Triggers Potent ROS-Mediated Antitumor Effects
Authors: Xiaoyan Sun, Weiguang Wang, Jiao Chen, Xueting Cai, Jie Yang, Yang Yang, Huaijiang Yan, Xiaolan Cheng, Juan Ye, Wuguang Lu, Chunping Hu, Handong Sun, Jianxin Pu, Peng Cao
Journal: Cancer Research (2016)

Abstract Aberrant expression of thioredoxin 1 (Trx1) plays an important role in cancer initiation and progression and has gained attention as an anticancer drug target. Here we report that the recently discovered natural diterpenoid isoforretin A (IsoA) significantly inhibits Trx1 activity and mediates anticancer effects in multiple preclinical settings. The inhibitory effect of IsoA was antagonized by free radical scavengers polyethylene glycol-catalase, polyethylene glycol superoxide dismutase, thiol-based antioxidants N-acetylcysteine and glutathione. Mass spectrometry analysis revealed that the mechanism of action was based on direct conjugation of IsoA to the Cys32/Cys35 residues of Trx1. This conjugation event attenuated reversible thiol reduction of Trx1, leading to ROS accumulation and a broader degradation of thiol redox homeostasis in cancer cells. Extending these in vitro findings, we documented that IsoA administration inhibited the growth of HepG2 tumors in a murine xenograft model of hepatocellular carcinoma. Taken together, our findings highlight IsoA as a potent bioactive inhibitor of Trx1 and a candidate anticancer natural product. Cancer Res; 77(4); 926–36. ©2016 AACR.
Anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody cixutumumab (cix) plus mTOR inhibitor temsirolimus (tem) in metastatic castration-resistant prostate cancer (mCRPC): Results of a phase I pilot study.
Authors: D. E. Rathkopf, D. C. Danila, M. J. Morris, S. F. Slovin, L. S. Borwick, L. Momen, T. Curley, G. Arauz, S. M. Larson, M. Fleisher, N. Rosen, H. I. Scher
Journal: Journal of Clinical Oncology (2011)

e15081 Background: Prostate cancer, despite a high frequency of PTEN loss and AKT/mTOR signaling, is insensitive to single agent mTOR inhibition. Relief of feedback inhibition of IGF-1R and IGF-1R signaling by Torc1 inhibitors (rapalogues) activates AKT signaling and thus may attenuate their antitumor activity. Since inhibition of IGF-1R will suppress this effect and could enhance the antitumor activity of the Torc inhibitor, a phase I/II study of cix in combination with tem for chemo-naïve patients (pts) with mCRPC was initiated in April 2010, and has completed accrual in phase I. Methods: Based on a prior phase I study of the combination in advanced solid tumors (Naing, ASCO 2009), pts with mCRPC received weekly 6 mg/kg i.v. cix and 25 mg i.v. tem. Tem was decreased if 2 or more dose limiting toxicities (DLTs) were observed in 6 pts. Radiologic evaluation was performed every 12 weeks. Correlative studies included analysis of circulating tumor cells, FDG PET, and optional FDHT PET and tumor biopsies. Results: To date, 11 pts have been enrolled and accrual to phase I is complete. Two DLTs (Gr 3 oral mucositis) were observed in cohort 1 (tem 25 mg), and 1 DLT (Gr 3 lipase) in cohort -1 (tem 20 mg). The most common adverse events at least possibly related to the study drugs included: oral mucositis (72%; 27% Gr3), diarrhea (55%; 0 Gr3), and hyperglycemia (45%; 18% Gr3). Low-grade, asymptomatic pneumonitis as determined by CT scan and/or PFTs was also seen in 7 pts (64%; 0 Gr3), which resolved following discontinuation of tem. The mTTP for the 7 evaluable pts was 32 wks (range 11-60). Notably, 2 pts elected to come off study after 6 months of weekly visits without protocol defined progression. Conclusions: Tem 20 mg in combination with cix 6 mg/kg weekly in cohort -1 has been well-tolerated to date. Since the majority of evaluable pts have remained on study past 24 wks, and in this chemo-naive population a weekly i.v. schedule is difficult to maintain, alternative dosing schedules are being discussed for the planned phase II expansion. This study has received ARRA funding and is a DOD/PCF PCCTC trial sponsored by CTEP.
Evaluation of clinical and pathological features in patients with Lynch Syndrome-related Endometrial Cancer: a single centre experience
Authors: E. Maccaroni, R. Bracci, R. Giampieri, F. Bianchi, L. Belvederesi, C. Brugiati, S. Pagliaretta, M. Del Prete, M. Pistelli, A. Pagliacci, N. Battelli, Z. Ballatore, M.G. De Lisa, A. Della Mora, S. Cascinu
Journal: Annals of Oncology (2015)