tbuckley/cabot-search huggingface dataset:
11. Gene Therapy Mediated Increase in dATP Improves Cardiac Performance in Models of Systolic Heart Failure
Authors: Farid Moussavi-Harami, Maria V. Razumova, Yuanhua Cheng, Guy Odom, Sam Teichman, Jil Tardiff, Stephen D. Hauschka, Jeffrey S. Chamberlain, Charles M. Murry, Michael Regnier
Journal: Molecular Therapy (2015)

Heart Failure results in more deaths and hospitalizations than almost any other single cause. We are exploring gene therapy treatment strategies that increase 2 deoxy-adenosine triphosphate (dATP) levels via cardiac specific expression of ribonucleotide reductase (RNR) in heart muscle. dATP is produced by RNR. In vitro studies show it increases the magnitude & rate of contraction in rodent, pig & failing human heart muscle without altering calcium handling or slowing relaxation. RNR expression in heart muscle increases intracellular dATP, cardiomyocyte contraction & cardiac performance in rodents. To do this we ligated a cDNA encoding both human RNR subunits to miniaturized cardiac specific enhancer/promoter portions of human cardiac troponin T and packaged the therapeutic "BB-R12" gene in AAV6. In the current study expanded the types of heart failure treated by BB-R12 by testing the effect of dATP on contractile function in a transgenic mouse model of familial dilated cardiomyopathy (DCM). These mice carry and phenocopy a missense mutation (D230N) in alpha-tropomyosin (Tm) that was identified in two DCM family cohorts that exhibit progressive ventricular dilation and loss of systolic function. We measured the effect of dATP on the Ca2+ sensitivity of force in demembranated trabeculae from young adult D230N & WT mice (3 mice & 8-10 trabeculae per group). pCa50 was decreased (lower Ca2+ sensitivity) for D230N Tm (5.47±0.01) compared to WT (5.59±0 0.03) mice, and substituting dATP for ATP rescued this defect (5.55±0.03). dATP also increased isometric force ~20% at pCa=5.8, the approximate level of intracellular Ca2+ seen in a cardiomyocyte twitch. We also measured force and the kinetics of activation & relaxation of isolated myofibrils. Force at pCa=5.6 decreased from 85±14 mN/mm2 in WT myofibrils to 52±7 mN/mm2 (p<0.05) in D230N Tm myofibrils. Importantly, the force deficit was improved to 72±14 mN/mm2 (p=0.47) with dATP. Similarly, the activation rate decreased in D230N Tm myofibrils (1.6±0.2 s-1) vs. WT mice (3.5±0.3 s-1), and this was partially corrected by dATP (2.5±0.4 s-1). dATP also corrected alterations in the early, slow relaxation phase of myofibrils from D230N Tm mice. In ongoing studies, we are systemically injecting 4-6 week old D230N Tm mice with AAV6-BB-R12 to determine how this affects cardiac function acutely, as well as the time course of reduced systolic function, progressive ventricular dilation & wall remodeling. In related studies, we found AAV6-BB-R12 rescues cardiac function in an infarcted pig heart failure model. These studies assess the ability of BB-R12 to acutely treat diseased hearts and act as a preventative agent in progressive heart failure.
The Association of Fludarabin, Oral Busulfan and Thymoglobulin Prior to Matched-Related Allo-SCT Allows for High Long Term Outcome for Both Patients with Myeloid or Lymphoid Malignancies and Reveals the Impact of CD34+ Graft Cell Dose On Cgvhd and Outcome: Long Term Analysis of a Homogenous Cohort of 100 Consecutive Patients.
Authors: Didier Blaise, Laure Farnaut, Benjamin Esterni, Catherine Faucher, Sabine Furst, Jean El Cheikh, Patrick Ladaique, Norbert Vey, Reda Bouabdallah, Anne Marie Stoppa, Claude Lemarie, Boris Calmels, Luca Castagna, Mohamad Mohty, Christian Chabannon
Journal: Blood (2009)
PTU-060 Primary sclerosing cholangitis post liver transplantation—the impact of inflammatory bowel disease
Authors: D Joshi, I Bjarnason, J O'Grady, A Belgaumkar, M Heneghan, A Suddle, V Aluvihare, J Wendon, M Rela, N Heaton, K Agarwal
Journal: Gut (2010)

<h3>Introduction</h3> An association between PSC and IBD is well recognised. Patients with PSC are increasingly and successfully treated by liver transplantation (LT), but the post LT course of IBD remains ill-defined. <h3>Methods</h3> A retrospective cohort study was performed to define the post transplant course of all adult (&gt;18 years) patients who had undergone LT for PSC at Kings College Hospital (Oct 1990-Aug 2009). Comparison populations of IBD/PSC and PSC were analysed. <h3>Results</h3> 110 patients (72% male) with PSC underwent LT (mean age 47±11). 74 (67%) patients had concurrent IBD (IBD/PSC) and 36 had PSC alone (PSC). In the IBD/PSC group 67 pts (91%) had UC (&gt;90% pan-colonic disease). A further six patients (5%) were diagnosed with UC post LT. In the IBD/PSC group, mean duration of IBD was longer compared to the duration of PSC pre-LT (104.7±136.7 vs 25±40.3, p=0.0001). 13% had undergone pan-proctocolectomy and 18% were not on any medications. Patient survival post LT was similar at 1 and 5 years (91% and 87% PSC vs 96% and 88% IBD/PSC). Graft survival was also similar between both groups although an increased incidence of HAT (six cases) was noted in the IBD/PSC group. Thrombotic events were increased in IBD/PSC (12 cases vs 1 case). 31 patients had a flare of IBD (mean time to flare 34 months±28). IBD free survival at 5 years was 50% in the IBD/PSC group. Mean time (months) to recurrence of PSC was similar between the two groups (65±36 vs 65±8). On univariate analysis predictors of graft survival included active colitis pre-LT (OR 16, 95% CI 3 to 94, p=0.02), immunosuppression (OR 6, 1.3 to 29, p=0.02), HAT (OR 6, 1.6 to 24, p=0.007) and pre-LT colectomy conferred a graft survival benefit (OR 5.6, 1.8 to 17.8, p=0.003). Smoking pre-LT was a predictor of recurrence of IBD post LT (OR 14, 2 to 75, p=0.003). Only 54 patients in the IBD/PSC group (72%) had documented evidence of annual colonoscopy post LT. 36% of patients (8/75) required colectomy in the IBD/PSC group; six for severe disease and two for de-novo neoplasia. A higher rate of neoplasia was seen in the IBD/PSC group (70% vs 30%). Duration of PSC pre-LT was predictive of rPSC (OR 1.03, 1.01 to 1.05, p=0.002). Multivariate analysis: only active colitis was a predictor of graft survival (OR 14, 2 to 100, p=0.01). <h3>Conclusion</h3> Patient survival post LT for PSC with or without IBD appeared similar. Patients with IBD/PSC are at increased risk of thrombotic events compared to PSC patients post-LT. Optimising management of IBD, including consideration of colectomy, may improve outcomes post LT.
Reactive Oxygen Species Produced By Myeloid Cells Block CD20-Antibody Dependent NK Cell-Mediated Cytotoxicity Against Chronic Lymphocytic Leukemia Cells
Authors: Olle Werlenius, Johan Aurelius, Maria Simpanen, Rebecca E Riise, Ali A Akhiani, Anna Martner, Per-Ola Andersson, Kristoffer Hellstrand, Fredrik B Thorén
Journal: Blood (2014)
Chiral Nanoparticle as a New Efficient Antimicrobial Nanoagent
Authors: Qi Xin, Qian Liu, Lingling Geng, Qiaojun Fang, Jian Ru Gong
Journal: Advanced Healthcare Materials (2016)

d-type functionalized nanoparticles (NPs) can bind to MurD ligase with high affinity and inhibit its peptidoglycan synthetic enzyme activity, and finally cause bacterial killing. In contrast, its L-type counterpart displays a negligible effect, indicating that the chiral structure of the functionalized NPs plays an essential role in their binding interaction with MurD and therefore the antibacterial activity. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Abstract 1144: Antioxidant enzyme-mediated survival of ECM-detached breast cancer cells requires AMPK activation
Authors: Sienna M. Durbin, Calli Versagli, Daniel Pape, Zachary Schafer
Journal: Cancer Research (2015)

Abstract Normal epithelial cells require attachment to the extracellular matrix (ECM) for proper maintenance of metabolic function and survival. However, it has recently become clear that cancer cells must alter their metabolism during times of ECM-detachment in a fashion that promotes their survival. We have discovered that breast cancer cells utilize the activity of antioxidant enzymes to eliminate the detachment-induced elevation in reactive oxygen species (ROS). This decrease in ROS relieves the inhibitory effects that ROS have on fatty acid oxidation (FAO) which in turn facilitates ATP production during times of energy deprivation. Interestingly, this critical role of antioxidant enzymes is not evident in ECM-attached cells suggesting that targeting antioxidant enzymes may be an effective strategy to eliminate ECM-detached cells. Furthermore, our studies have revealed that the molecular mechanisms controlling the regulation of FAO by antioxidant enzymes involve modulation of AMPK protein levels. Thus, our data reveal that antioxidant enzymes and AMPK signaling may be attractive targets for the design of novel therapeutics aimed at eliminating ECM-detached cancer cells. Citation Format: Sienna M. Durbin, Calli Versagli, Daniel Pape, Zachary Schafer. Antioxidant enzyme-mediated survival of ECM-detached breast cancer cells requires AMPK activation. [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 1144. doi:10.1158/1538-7445.AM2015-1144
149. Theranostic Aptamer-Conjugated Liposomal Nanoparticle for Triple Negative Breast Cancer
Authors: Min Woo Kim, Yeon Kyung Lee, Hwa Yeon Jeong, Seong Jae Kang, In Ho Jeong, Moon Jung Choi, Yong Serk Park
Journal: Molecular Therapy (2015)

Triple-negative breast cancers (TNBC) have been focused because of their pathologic features like absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2/neu) expressions and a higher rate of metastasis. Especially, their lack of HER2 expression and aggressive progression make it difficult to utilize HER2-targeted therapeutics and diagnostics to the metastatic TNBC. In this study, first of all quantum dots were incorporated into cationic liposomes consisting of O,O'-dimyristyl-N-lysyl glutamate (DMKE). The quantum dot-incorporating cationic liposomes (QCLs) were then complexed with therapeutic small interfering RNA (siRNA) for sequence-specific RNA interference. The cationic characteristics of the QCLs provided an effective siRNA transfection in vitro, but it had limitations in in vivo applications. To enhance cancer-directed delivery, epidermal growth factor receptor (EGFR) aptamer-polyethylene glycol conjugates were inserted into the prepared QCLs. The advantage of the two-step strategy of QCL preparation includes enhanced diagnostic feature, in vivo long circulation, and TNBC specific gene silencing. This research suggests that aptamer-conjugated QCL can be utilized as a useful theranostic agent for TNBC subtype breast cancers.
Radiation Treatment for Localized Prostate Cancer and the Risk of Developing Myelodysplastic Syndromes (MDS)
Authors: Sudipto Mukherjee, Chandana Reddy, Jay Ciezki, Ramon V. Tiu, Edward A. Copelan, Anjali S. Advani, Yogen Saunthararajah, Katarina Paulic, Jaroslaw P. Maciejewski, Brian J. Bolwell, Eric A. Klein, Mikkael A. Sekeres
Journal: Blood (2011)
Response to: ‘Statin therapy now more common than steroids in clinical practice’ by Pareek and Chankurdar
Authors: Gulsen Ozen, Sofia Pedro, Kaleb Michaud
Journal: Annals of the Rheumatic Diseases (2016)

We appreciate the interest shown by Pareek and Chankurdar1 concerning our recent study on diabetes mellitus (DM) risk associated with disease-modifying antirheumatic drugs and statins in patients with rheumatoid arthritis (RA).2 They pointed out that statin-associated DM risk in patients with RA might be a more important concern than the risk attributed to glucocorticoids (GCs) due to longer treatment durations.1

We agree that statin treatment is potentially continued for a longer duration than GC when initiated in patients with RA, as in the case of our cohort (median (IQR) duration for statins: 13 (6–26) months vs GC: 7 (0–17) months). However, GCs are more frequently used in patients with RA than statins …
Abstract LB-079: Specific epigenetic reader role for cyclin D1
Authors: Gabriele Di Sante, Mathew Craig Casimiro, Chenguang Wang, Zuoren Yu, Marco Crosariol, Ratna K. Vadlamudi, Monica Mann, Peter Tompa, Agnes Tantos, Richard G. Pestell
Journal: Cancer Research (2015)

Abstract Amplification of the CCND1 gene occurs in approximately 30% of human breast cancer and is sufficient when overexpressed for the induction of mammary tumorigenesis. A DNA-associated form of cyclin D1 governs gene expression and chromosomal instability. Herein, the mechanisms governing gene activation by cyclin D1 were defined. Cyclin D1 was recruited to activate gene regulatory regions associated with enrichment of p300, HP1α and reduced HDAC3 and SUV39H1. The recruitment of cyclin D1 into local chromatin was dissociable from its kinase function and required an intrinsically disordered carboxyl-terminus flanked by a glutamine-rich motif. The cyclin D1 epigenetic interaction motif bound acetylated or methylated H3 on specific residues (H3K36me2, H3K9me3). Cyclin D1 bound to the Top2A gene promoter induced Top2A transcription, abundance and sensitivity to Top2A inhibitors. The direct recognition of an epigenetic code by a motif within cyclin D1 and the induction of Top2A may facilitate communication of genome wide expression changes during cell-cycle progression and tumorigenesis. Citation Format: Gabriele Di Sante, Mathew Craig Casimiro, Chenguang Wang, Zuoren Yu, Marco Crosariol, Ratna K. Vadlamudi, Monica Mann, Peter Tompa, Agnes Tantos, Richard G. Pestell. Specific epigenetic reader role for cyclin D1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-079. doi:10.1158/1538-7445.AM2015-LB-079
GMP-Conform Generation and Cultivation of Unrestricted Somatic Stems Cells (USSC) from Cord Blood Using the SEPAX©-Separation Method a Closed Culture System Applying Cell Stacks.
Authors: Teja F. Radke, Anja Buchheiser, Aurélie Lefort, Mahtab Maleki, Peter Wernet, Gesine Kögler
Journal: Blood (2007)
Prohibitin 1 suppresses liver cancer tumorigenesis in mice and human hepatocellular and cholangiocarcinoma cells
Authors: Wei Fan, Heping Yang, Ting Liu, Jiaohong Wang, Tony W.H. Li, Nirmala Mavila, Yuanyuan Tang, JinWon Yang, Hui Peng, Jian Tu, Alagappan Annamalai, Mazen Noureddin, Anuradha Krishnan, Gregory J. Gores, Maria L. Martínez‐Chantar, José M. Mato, Shelly C. Lu
Journal: Hepatology (2016)

Prohibitin 1 (PHB1) is best known as a mitochondrial chaperone, and its role in cancer is conflicting. Mice lacking methionine adenosyltransferase α1 (MATα1) have lower PHB1 expression, and we reported that c‐MYC interacts directly with both proteins. Furthermore, c‐MYC and MATα1 exert opposing effects on liver cancer growth, prompting us to examine the interplay between PHB1, MATα1, and c‐MYC and PHB1's role in liver tumorigenesis. We found that PHB1 is highly expressed in normal hepatocytes and bile duct epithelial cells and down‐regulated in most human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). In HCC and CCA cells, PHB1 expression correlates inversely with growth. PHB1 and MAT1A positively regulate each other's expression, whereas PHB1 negatively regulates the expression of c‐MYC, MAFG, and c‐MAF. Both PHB1 and MATα1 heterodimerize with MAX, bind to the E‐box element, and repress E‐box promoter activity. PHB1 promoter contains a repressive E‐box element and is occupied mainly by MAX, MNT, and MATα1 in nonmalignant cholangiocytes and noncancerous tissues that switched to c‐MYC, c‐MAF, and MAFG in cancer cells and human HCC/CCA. All 8‐month‐old liver‐specific Phb1 knockout mice developed HCC, and one developed CCA. Five‐month‐old Phb1 heterozygotes, but not Phb1 flox mice, developed aberrant bile duct proliferation; and one developed CCA 3.5 months after left and median bile duct ligation. Phb1 heterozygotes had a more profound fall in the expression of glutathione synthetic enzymes and higher hepatic oxidative stress following left and median bile duct ligation. Conclusion : We have identified that PHB1, down‐regulated in most human HCC and CCA, heterodimerizes with MAX to repress the E‐box and positively regulates MAT1A while suppressing c‐MYC , MAFG , and c‐MAF expression; in mice, reduced PHB1 expression predisposes to the development of cholestasis‐induced CCA. (H epatology 2017;65:1249‐1266).
Abstract 4557A: Development of the proteasome deubiquitinase inhibitor VLX1570 for treatment of multiple myeloma
Authors: Xin Wang, Chitralehka Mohanty, Padraig D'Arcy, Maria Hägg Olofsson, Felicitas Bossler, Asher Chanan-Khan, Stig Linder
Journal: Cancer Research (2015)

Abstract Inhibitors of the proteasome-ubiquitin system have been found to be effective in the clinical management of multiple myeloma. We here describe the compound VLX1570, an optimized lead of the 19S deubiquitinase inhibitor b- AP15. VLX1570 was shown to inhibit the enzymatic activities of both USP14 and UCHL5 in vitro, and was shown to induce accumulation of high molecular weight polyubiquitinated proteins in multiple myeloma cells. The compound showed limited inhibitory activity of a panel of kinases. VLX1570 induces apoptosis and cell death of multiple myeloma cell lines at submicromolar concentrations. Importantly, a multiple myeloma cell line selected for bortezomib resistance was found to be sensitive to VLX1570. VLX1570 was found to be able to overcome apoptosis resistance by these cells. Induction of the phosphorylation of stress-activated kinases (JNK and p38) and inhibition of ERK phosphorylation was observed in multiple myeloma cells. We finally showed that VLX1570 confers antineoplastic activity in two different myeloma xenograft models and conclude that VLX1570 is a candidate agent for treatment of multiple myeloma. Citation Format: Xin Wang, Chitralehka Mohanty, Padraig D'Arcy, Maria Hägg Olofsson, Felicitas Bossler, Asher Chanan-Khan, Stig Linder. Development of the proteasome deubiquitinase inhibitor VLX1570 for treatment of multiple myeloma. [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 4557A. doi:10.1158/1538-7445.AM2015-4557A
Abstract 285: MEDI9447: enhancing anti-tumor immunity by targeting CD73 In the tumor microenvironment
Authors: Carl Hay, Erin Sult, Qihui Huang, Scott Hammond, Kathy Mulgrew, Kelly McGlinchey, Stacy Fuhrmann, Raymond Rothstein, Edmund Poon, Ross Stewart, Robert Hollingsworth, Kris Sachsenmeier
Journal: Cancer Research (2015)

Abstract MEDI9447 is a monoclonal antibody specific for the ectoenzyme, CD73. Data is presented in support of the hypothesis that targeting the extracellular production of adenosine by CD73 reduces the immunosuppressive effects of adenosine. We report a range of activities for this antibody, including inhibition of both recombinant and cellular CD73 ectonucleotidase activity, relief from AMP-mediated lymphocyte suppression in vitro, and inhibition of syngeneic tumor growth. In contrast with many other cancer immunotherapy agents such as checkpoint inhibitors or T cell agonists, MEDI9447 drives changes in both myeloid and lymphoid infiltrating leukocyte populations within the tumor microenvironment. Changes include significant increases in CD8 effector cells and activated macrophages, as well as a reduction in the proportions of myeloid-derived suppressor cells (MDSC) and regulatory T lymphocytes. Furthermore, these changes correlate directly with responder and non-responder subpopulations within the arms of animal studies using syngeneic tumors. Data showing additive activity between MEDI9447 and other immune-mediated therapy antibodies demonstrates the importance of relieving adenosine-mediated immunosuppression within tumors. Citation Format: Carl Hay, Erin Sult, Qihui Huang, Scott Hammond, Kathy Mulgrew, Kelly McGlinchey, Stacy Fuhrmann, Raymond Rothstein, Edmund Poon, Ross Stewart, Robert Hollingsworth, Kris Sachsenmeier. MEDI9447: enhancing anti-tumor immunity by targeting CD73 In the tumor microenvironment. [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 285. doi:10.1158/1538-7445.AM2015-285
Pernicious Malaria: a Report of a Case.
Authors: T. Z. Cason, E. G. Birge
Journal: JAMA (1917)

PERNICIOUS MALARIA: A REPORT OF A CASE T. Z. Cason, M.D., and E. G. Birge, M.D., Jacksonville, Fla, This case of pernicious malaria presented several interesting features, particularly the blood picture and the reaction to treatment. Occasionally one obtains a picture of pernicious anemia in these cases, and the absence of parasites in the peripheral circulation throws the diagnosis in doubt unless a complete and careful study of the blood  made during the disease. Treatment with quinin, properly given, promptly relieves the condition, and the improvement which takes place in the blood picture  surprising. History.\p=m-\G.W., man, aged 33, white, farmer, was admitted to St. Luke's Hospital, Jacksonville, Fla., Jan. 16, 1917, in a comatose condition. The abdomen was distended and tympanitic. Physical examination at this time was negative. The family and personal history were unimportant. The Patient had been taken ill in October, and had had occasional headaches since. There was edema around the eyes and affecting the hands and feet with no pain; it was first noticed, November 18. There Was no history of chills. The Patient admitted taking much Quinin during the past few years. There were marked Pyorrhea and marked pallor °J the mucous membranes. ' tie lower margin of the spleen was at the costal border; there was slight tenderness to pressure over this area. Laboratory Examinations. The first slide from this Patient was received at the laboratory, January 17, the clay after bis admission to the hospital. At that time is temperature was subnormal, and there was nothing Particularly pathologic in the Picture of the blood, and the Parasites on examination were absent. We did not receive another slide, January 18, at Which time his temperature Total blood counts, hemoglobin estimation and differential blood