tbuckley/cabot-search huggingface dataset:
64. Generation of Tumor Cells Resistant to Oncolysis Is Mediated Through Virus Induced APOBEC Expression
Authors: Karishma Rajani, Kevin G. Shim, Nazanin Yeganeh Kazemi, William Gendron, Tim Kottke, Amy Molan, Christopher Driscoll, Reuben Harris, Richard Vile
Journal: Molecular Therapy (2016)

In both pre-clinical, and clinical models, we have observed that treatment of primary tumors with oncolytic viruses can lead to very significant tumor regressions, often with apparent disappearance of the tumor. However, in many cases, tumor subsequently recurs, often extremely aggressively. We have been able to mimic this effect in vitro by growing several different types of tumor cell lines in the presence of different oncolytic viruses at low m.o.i. over several weeks. Under such conditions, we consistently observe the emergence of cells which survive over long periods of time in culture, despite the demonstrable presence of ongoing viral replication. We identified APOBEC3 from a screen of genes which are induced in tumor cells undergoing continual exposure to either reovirus or Vesicular Stomatitis Virus (VSV). In this respect, overexpression of APOBEC3B, a cytidine deaminase, has been identified in human tumors associated with mutations that may drive tumorigenesis. Therefore, we tested the hypothesis that, upon infection with oncolytic viruses, APOBEC3 may help drive tumor cell mutation leading to protection from viral cytotoxicity. Consistent with this, both mRNA and protein levels of APOBEC3 were rapidly induced within 24-72 hours of low M.O.I infection by reovirus, or VSV, of B16 melanoma, GL261 glioma and TC2 prostate tumor murine cell lines. Similar low level infection of human tumor cell lines was associated with rapid induction of the human APOBEC3B mRNA. Interestingly, engineered over-expression of APOBEC3B in tumor lines significantly enhanced the ability of these cells to resist killing by either VSV or reovirus. This effect was inhibited by blockade of PKC signaling upon viral infection but was enhanced by the presence of type I interferons. Correspondingly, inhibition of APOBEC3 using shRNA decreased the frequency of emergence of VSV-resistant tumor populations. These data suggest that infection of tumor cells by oncolytic viruses at low M.O.I (as is likely to be the case during clinical treatments) leads to the induction of cellular proteins, which enhance the ability of resistance to oncolysis to develop. Deep sequencing studies are currently underway to determine the genetic changes in both virus, and target tumor cells, which are associated with APOBEC3 over-expression during chronic exposure to oncolytic virus infection. Finally, data will be presented on how these findings allow the construction of improved viruses for cancer therapy by targeting APOBEC3 induction to improve primary killing and prevent emergence of treatment resistant populations.
The Chemerin/ChemR23 Axis Plays a Pivotal Role in the Pathogenesis of Intestinal Damage in a Murine Model of Graft Versus Host Disease
Authors: Paola Vinci, Camilla Recordati, Donatella Bardelli, Claudia Cappuzzello, Valeria Fumagalli, Erica Dander, Annalisa Del Prete, Silvano Sozzani, Andrea Biondi, Giovanna D'Amico
Journal: Blood (2015)
Pediatric-Type Therapy Including Lineage-Targeted Methotrexate to Improve Early Minimal Residual Disease Response and Survival In Adult Acute Lymphoblastic Leukemia (ALL): Interim Analysis of Northern Italy Leukemia Group Study 10/07
Authors: Renato Bassan, Tamara Intermesoli, Arianna Masciulli, Giuseppe Rossi, Enrico Maria Pogliani, Orietta Spinelli, Giorgio Lambertenghi-Deliliers, Ernesta Audisio, Daniele Mattei, Fabio Ciceri, Vincenzo Cassibba, Claudio Romani, Eros Di Bona, Alessandro Levis, Manuela Tosi, Barbara Peruta, Margherita Parolini, Erika Borlenghi, Monica Fumagalli, Federica Delaini, Rosa Maria Marfisi, Elena Oldani, Roberto Marchioli, Alessandro Rambaldi
Journal: Blood (2010)
602. Stable In Vitro Reprogramming of Lentiviral Vectors for Target Delivery of Genetic Cargo
Authors: Zhilei C. Chen, Nagarjun Kasaraneni, Ana M. Chamoun-Emanuelli
Journal: Molecular Therapy (2016)

Progress in gene therapy has been impeded by the absence of a suitable delivery vector that is both easy to produce and delivers genetic payloads efficiently and specifically to the targeted disease cells. Cell-targeting proteins, primarily monoclonal antibodies, already exist in abundance but there is currently no robust and reproducibly effective way to functionalize viral vectors with these proteins. In the case of antibodies, non-covalent approaches to incorporate antibody onto the lentivirus surface leaves the linkage vulnerable to interference from serum immunoglobulins in immune-competent individuals. In this study, we developed two in vitro chemical biological approaches for facile reprogramming of lentivirus to deliver genetic payloads to specific cell type through covalent functionalization in vitro with cell-binding proteins. Two covalent-bond forming protein-protein pairs were explored to conjugate a HER2-binding protein to lentivirus pseudotyped with a binding-deficient, fusion-competent Sindbis virus envelope protein. Both strategies produced high infectious titers (>106 IU/mL) of HER2-specific lentiviruses. Our new virus reprogramming strategy should be applicable to other viral vectors as well, enabling facile creation of new disease-specific gene delivery vectors.
A Rapid MALDI-TOF Method for Isotyping and Quantitating M-Proteins in a Single Assay: Longitudinal Comparison to Serum Protein Electrophoresis and Hevylite for Monitoring Patients with Monoclonal Gammopathies
Authors: David L Murray, John R. Mills, Maria Alice V Willrich, David Barnidge, Mindy C Kohlhagen, Angela Dispenzieri
Journal: Blood (2015)
Introduction of Clinical Practice Update Committee Articles
Authors: Lawrence S. Friedman, John M. Inadomi, Anthony M. Kalloo, David A. Katzka, Lawrence S. Kim, Johannes Koch, David Lieberman, Gary R. Lichtenstein, Joseph K. Lim, John E. Pandolfino, Andrea S. Shin, Madelin R. Siedler
Journal: Clinical Gastroenterology and Hepatology (2016)
Prasugrel in Children with Sickle Cell Disease: Pharmacokinetic and Pharmacodynamic Characteristics from an Open-Label, Adaptive-Design, Dose-Ranging Study
Authors: Lori Styles, Joseph A. Jakubowski, Darell E. Heiselman, Lori E. Heath, Chunmei Zhou, Charles T. Quinn, Matthew M. Heeney, Rupa Redding-Lallinger, David S. Small, Brian A. Moser, Kenneth J. Winters
Journal: Blood (2012)
Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling
Authors: June H. Myklebust, Joshua Brody, Holbrook E. Kohrt, Arne Kolstad, Debra K. Czerwinski, Sébastien Wälchli, Michael R. Green, Gunhild Trøen, Knut Liestøl, Klaus Beiske, Roch Houot, Jan Delabie, Ash A. Alizadeh, Jonathan M. Irish, Ronald Levy
Journal: Blood (2016)
Experience of Therapy for Pneumonia In Hematopoietic Stem Cell Transplant Recipients Infected by Influenza 2009 H1N1.
Authors: Yi Luo, Huarui Fu, Yamin Tan, Yanlong Zheng, Jimin Shi, Jingsong He, Wenjun Wu, Wanzhou Xie, Haowen Xiao, Zhen Cai, Xiujin Ye, Maofang Lin, He Huang
Journal: Blood (2010)
457. A Characterization of Transgene-Specific “Proteomes” in Lentiviral Vector Clinical Production Lots Identifies Differences between Vectors with High and Low Infectious Titers
Authors: Scott Witting, Lilith Reeves, Frank Witzmann
Journal: Molecular Therapy (2016)

Gene delivery using viral vectors is a powerful tool which can be used to correct genetic diseases and treat acquired illnesses. HIV-based lentiviral vectors (LVs) are advantageous in gene therapy applications for due to their genomic integration and ability to infect non-dividing cells. We have found that scale-up for is successful in retaining physical particle titers; however, the transduction efficiency of certain vectors, particularly in sensitive primary cells (e.g. human CD34+ cells), is significantly less than expected. Our working hypothesis is that current large-scale production methods may concentrate proteins that modulate transduction. To address this possibility, we characterized the "lentiviral vector proteome" of several different clinical vector lots using an Orbitrap Velos Pro Hybrid Mass Spectrophotometer. Since X-VIVO 10 medium was the final product medium in all LV lots, proteins identified in a sample of unused medium were eliminated from the analysis. We first identified a subset of 24 proteins common to ALL vector lots. Not surprisingly, further analysis showed that 6 of these proteins are both "top 25" exosome markers in the ExoCarta database and known gag-pol interacting proteins listed in the HIV-1 Human Interaction Database. Independent of production size and tangential flow filtration brand, we next identified 57 proteins unique to a low titer LV expressing human beta-globin (BG). We similarly identified 47 proteins unique to a high titer LV expressing adenosine deaminase (ADA). BG lots were enriched in proteasome subunit proteins and ADA lots in ribosomal subunit proteins. Interestingly, the ADA lots were also enriched in several 14-3-3 family proteins that are known to modulate intracellular signaling pathways. It is possible that the mere presence or relative levels of specific proteins, such as 14-3-3 proteins, can affect transduction. We can speculate that the mechanism involves indirect effects of the vector transgene on the producer cells which yields a particle that is more stable and/or has an increased capacity to transduce cells.
107. Tracking Target Cell Fate After Oncolytic Herpes Simplex Virus Infection
Authors: Anna Grosskopf, Samuel D. Rabkin, Robert L. Martuza, Hiroaki Wakimoto
Journal: Molecular Therapy (2016)

Oncolytic virus (OV) cancer therapy relies on virus-mediated selective killing of cancer cells and subsequent secondary effects that involve induction of anti-tumor immunity. Although cell death induction is a prerequisite in this therapeutic process, experimental evidence is lacking as to whether OV infection of cancer cells results in their inevitable death. To address this issue, we developed an experimental platform that allows us to track the fate of a cell following OV infection. This system is composed of: 1) Recombinant oncolytic herpes simplex viruses derived from G47delta (ICP6-, gamma34.5-, alpha47-) and MG18L (ICP6-, Us3-) that express a Cre recombinase-EGFP fusion protein (G47delta-CreGFP and MG18L-CreGFP), and 2) tumor cell lines that have been engineered to stably carry a reporter construct, in which Cre-mediated excision of a polyA STOP sequence converts the cell into an expresser of the mCherry fluorescence protein. Using patient-derived and established T98 glioblastoma lines, we show that upon G47delta-CreGFP or MG18L-CreGFP infection, the reporter cells become mCherry positive, indicating virus-induced Cre recombination in the host genome. Monitoring of these cells in culture revealed that although an overwhelming majority of the cells die, a small fraction of mCherry+ cells survive and eventually proliferate. Our results demonstrate the existence of "resistance" after OV infection of cancer cells. Our experimental platform should have versatile utilities for tracking the fate of both neoplastic and non-neoplastic cells during OV therapy in in vitro and in vivo settings.
Abstract 3452: Conversion of abiraterone to D4A drives antitumor activity in castration-resistant prostate cancer
Authors: Zhenfei Li, Nima Sharifi
Journal: Cancer Research (2015)

Abstract Castration resistant prostate cancer (CRPC) still relies on androgens for progression. Abiraterone, an FDA approved CYP17A inhibitor, blocks androgen synthesis and prolongs survival. Abiraterone metabolites are generally thought to be inactive. We have identified a novel abiraterone metabolite, D4A, which inhibits three steroidogenic enzymes and androgen receptor (AR) itself. After abiraterone acetate administration, plasma from mice and patients were analyzed with liquid chromatography-mass spectrometry (LC-MS). The LC-MS results indicate that abiraterone is converted to D4A at detectable concentrations in both mice and patients. To test the function of D4A, the androgen synthesis pathway was analyzed in cell lines and xenografts. After incubation with [3H] labeled androgens, metabolites from cell lines and xenografts were analyzed by HPLC. We found that D4A inhibits activity of the steroidogenic enzymes CYP17A, 3β-hydroxysteroid dehydrogenase (3[[Unsupported Character - Symbol Font ]]HSD) and 5α-reductase. Furthermore D4A competes with the AR agonist R1881 and binds to AR directly. D4A inhibits DHT-induced AR occupancy on the PSA enhancer as detected by chromatin immunoprecipitation and reduces PSA expression. Our findings suggest that D4A is an abiraterone metabolite and a potent inhibitor of the androgen pathway. Citation Format: Zhenfei Li, Nima Sharifi. Conversion of abiraterone to D4A drives antitumor activity in castration-resistant 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 3452. doi:10.1158/1538-7445.AM2015-3452
Abstract 4247: BRCAness by MLPA is clinically useful for tailored treatment in triple-negative breast cancer
Authors: Takashi Ishikawa, Kazutaka Narui, Akimitsu Yamada, Sadatishi Sugae, Yasushi Ichikawa, Mari S. Oba, Saeko Teraoka, Kumiko Kida, Hidetaka Shima, Itaru Endo
Journal: Cancer Research (2015)

Abstract BACKGROUBD: Cytotoxic anticancer drugs are the only clinically available agents for treating triple-negative breast cancer (TNBC). Recent gene expression analysis revealed that TNBC shows considerable overlap with basal-like tumors characterized by a potential loss of BRCA1 function. Further subdivision of TNBC represents an important clinical topic for treatments. We therefore subdivided TNBC into basal-like (BL) and non-BL subtypes defined by EGFR and/or CK5/6 positive in our previous neoadjuvant chemotherapy (NAC) study (KBOG1101 study). We reported that BL subtype were resistant to taxane regimen at AACR2013. AIM: To examine impaired BRCA1 function “BRCAness” is beneficial for tailored chemotherapy in TNBC. METHODS: Sixty-six TNBC cases from a randomized phase II trial comparing Docetaxel and cyclophosphamide x 6 (TC6) with 5-fluorouracil, epirubucin and cyclophosphamide followed by docetaxel (FEC-D) as NAC for hormone receptor-negative breast cancer (Kanagawa Breast Oncology Group 1101 Study). TNBC was subdivided by 1) Immunohistochemistry (IHC) of CK 5/6 and EGFR into BL and non-BL subtypes, and 2) Multiplex Ligation-dependent Probe Amplification (MLPA) of BRCAness into BRCAness and non-BRCAness subtypes. The pCR rates were examined according to each regimen and subtype. 3) The association of grade 3 pCR was examined with Ki-67, p53, aldehyde dehydrogenase (ALDH) 1 and topoisomerase 2A (topoIIα) by IHC and TOP2A by FISH for each regimen. RESULTS: 1) The pCR rates of FEC-D and TC were 37% vs 18.5% in BL(n = 54), while 40.4% and 16.7% in non-BL (n = 11), respectively. FEC-D was superior in both subtypes without statistical significance. 2) In BRCAness (n = 34), FEC-D was significantly superior to TC6 (FEC-D vs TC: 56.3% vs 16.7%, p = 0.030), while not different in non-BRCAness (20.0% vs 16.7%). 3) No factors were associated with pCR. DISCUSSION: TC6 was less effective than FEC-D in TNBC with BRCAness, showing that taxane cannot exert their anticancer role in tumors with BRCA1 dysfunction. Although BL may contain more BRCA1-defective tumors than non-BL, MLPA of BRCAness was better to identify subtype resistant to taxane than BL defined by IHC. BRCAness by MLPA method is practically useful for treatment selection in TNBC. Citation Format: Takashi Ishikawa, Kazutaka Narui, Akimitsu Yamada, Sadatishi Sugae, Yasushi Ichikawa, Mari S. Oba, Saeko Teraoka, Kumiko Kida, Hidetaka Shima, Itaru Endo. BRCAness by MLPA is clinically useful for tailored treatment in triple-negative breast 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 4247. doi:10.1158/1538-7445.AM2015-4247
Renal tubular angiotensin converting enzyme is responsible for nitro-L-arginine methyl ester (L-NAME)-induced salt sensitivity
Authors: Jorge F. Giani, Masahiro Eriguchi, Ellen A. Bernstein, Makoto Katsumata, Xiao Z. Shen, Liang Li, Alicia A. McDonough, Sebastien Fuchs, Kenneth E. Bernstein, Romer A. Gonzalez-Villalobos
Journal: Kidney International (2016)
Copeptin and NT-proBNP as Prognostic Markers for Recurrent Ischemic Cerebrovascular Events in Ischemic Stroke Patients
Authors: Xianwei Zeng, Aijun Deng, Yi Ding, Ying Ni, Tingting Xu, Junling Liu, Bin Yang, Mingqing Gao, Guozhao Ma, Wei Ding, Lei Mu
Journal: Journal of the American College of Cardiology (2016)
Abstract 662: USP8 modulates ubiquitination of LRIG1 for Met degradation
Authors: Ji Min Lee, Bogyou Kim, Kyung-Ah Kim
Journal: Cancer Research (2015)

Abstract The Met receptor tyrosine kinase is an attractive target for cancer therapy as it promotes invasive tumor growth. SAIT301 is a novel anti-Met antibody, which induces LRIG1-mediated Met degradation and inhibits tumor growth. However, detailed downstream mechanism by which LRIG1 mediates target protein down-regulation is unknown. In the present study, we discovered that SAIT301 induces ubiquitination of LRIG1, which in turn promotes recruitment of Met and LRIG1 complex to the lysosome through its interaction with Hrs, resulting in concomitant degradation of both LRIG1 and Met. We also identified USP8 as a LRIG1-specific deubiquitinating enzyme, reporting the interaction between USP8 and LRIG1 for the first time. SAIT301 triggers degradation of LRIG1 by inhibiting the interaction of LRIG1 and USP8, which regulates ubiquitin modification and stability of LRIG1. In summary, SAIT301, a Met targeting antibody, employs ubiquitination of LRIG1 for its highly effective Met degradation. This unique feature of SAIT301 enables it to function as a fully antagonistic antibody without Met activation. We found that USP8 is involved in deubiquitination of LRIG1, influencing the efficiency of Met degradation. The relation of Met, LRIG1 and USP8 strongly supports the potential clinical benefit of a combination treatment of a USP8 inhibitor and a Met inhibitor, such as SAIT301. Citation Format: Ji Min Lee, Bogyou Kim, Kyung-Ah Kim. USP8 modulates ubiquitination of LRIG1 for Met degradation. [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 662. doi:10.1158/1538-7445.AM2015-662
Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho
Authors: Yueh-Lin Wu, Jian Xie, Sung-Wan An, Noelynn Oliver, Nestor X. Barrezueta, Mei-Hsiang Lin, Lutz Birnbaumer, Chou-Long Huang
Journal: Kidney International (2016)
Abstract 1825: Carbonylation and degradation of cardiac myosin binding protein C serves as an indicator of doxorubicin-induced cardiotoxicity
Authors: Baikuntha P. Aryal, Jinsook Jeong, V. Ashutosh Rao
Journal: Cancer Research (2015)

Abstract Dose-dependent oxidative stress by the anthracycline doxorubicin (Dox) and other chemotherapeutic agents causes irreversible cardiac damage, restricting their clinical effectiveness. We hypothesize that irreversible protein oxidation caused by oxidative stress could be correlated with physiological functional impairment. We focused our study on protein carbonylation as an indicator of severe oxidative damage. We identified a specific cardiac protein that showed selective carbonylation under Dox-induced cardiotoxic conditions in a spontaneously hypertensive rat (SHR) model and this protein was confirmed to be a 140 kDa cardiac myosin binding protein C (MyBPC) using mass spectrometry. We further analyzed and confirmed the carbonylation and degradation of this protein using HL-1 cardiomyocytes under Dox-induced oxidative stress, and a purified recombinant rat cardiac MyBPC under metal-catalyzed oxidative stress conditions. Using HL-1 cells we demonstrated that carbonylated MyBPC undergoes proteasome-mediated degradation under Dox-induced oxidative stress. Using immunoprecipitation, co-sedimentation, and actin-binding assays we confirmed the functional impairment of MyBPC as a consequence of carbonylation. Carbonylation of recombinant MyBPC showed significant impairment in its actin binding properties with a dissociation constant of 7.35±1.9 μM compared to 2.7±0.6 μM for native MyBPC. Overall, our findings indicate that MyBPC carbonylation serves as a critical determinant of cardiotoxicity. We are currently investigating the interaction of MyBPC with divalent metal ions and sites of carbonylation under oxidative stress conditions. Citation Format: Baikuntha P. Aryal, Jinsook Jeong, V. Ashutosh Rao. Carbonylation and degradation of cardiac myosin binding protein C serves as an indicator of doxorubicin-induced cardiotoxicity. [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 1825. doi:10.1158/1538-7445.AM2015-1825
Survival, Prognostic Factors, and Rates of Leukemic Transformation in a Multicenter Study of 303 Untreated Patients with MDS and Del(5q).
Authors: Ulrich Germing, Michael Lauseker, Barbara Hildebrandt, Argiris Symeonidis, Jaroslav Cermak, Michael Pfeilstöcker, Thomas Nösslinger, Mikkael A. Sekeres, Jaroslaw P. Maciejewski, Detlef Haase, Julie Schanz, Jf Seymour, Rudolf Weide, Michael Lübbert, Uwe Platzbecker, Peter Valent, Katharina Götze, Reinhard Stauder, Sabine Blum, Karl Anton Kreuzer, Richard F. Schlenk, Carlo Aul, Andrea Kündgen, Joerg Hasford, Aristoteles Giagounidis
Journal: Blood (2009)
Enhancing Nanoparticle Accumulation and Retention in Desmoplastic Tumors via Vascular Disruption for Internal Radiation Therapy
Authors: Andrew B. Satterlee, Juan D. Rojas, Paul A. Dayton, Leaf Huang
Journal: Theranostics (2016)

Aggressive, desmoplastic tumors are notoriously difficult to treat because of their extensive stroma, high interstitial pressure, and resistant tumor microenvironment.We have developed a combination therapy that can significantly slow the growth of large, stroma-rich tumors by causing massive apoptosis in the tumor center while simultaneously increasing nanoparticle uptake through a treatment-induced increase in the accumulation and retention of nanoparticles in the tumor.The vascular disrupting agent Combretastatin A-4 Phosphate (CA4P) is able to increase the accumulation of radiation-containing nanoparticles for internal radiation therapy, and the retention of these delivered radioisotopes is maintained over several days.We use ultrasound to measure the effect of CA4P in live tumor-bearing mice, and we encapsulate the radio-theranostic isotope 177 Lutetium as a therapeutic agent as well as a means to measure nanoparticle accumulation and retention in the tumor.This combination therapy induces prolonged apoptosis in the tumor, decreasing both the fibroblast and total cell density and allowing further tumor growth inhibition using a cisplatin-containing nanoparticle.
ESEN : une comparaison des programmes de vaccination – Deuxième partie : la coqueluche
Authors: D Lévy-Bruhl, R G Pebody, K Osborne, I Veldhuijzen, M Valenciano
Journal: Eurosurveillance (1998)

Cet article est le deuxieme d’une serie de trois articles portant sur la comparaison, dans huit pays, des programmes vaccinaux, des calendriers de vaccination, de la couverture vaccinale et de l’impact epidemiologique de la vaccination contre la diphterie, la coqueluche, la rougeole, les oreillons et la rubeole. Cette etude a ete realisee par le Reseau Europeen de Surveillance serologique (ESEN), reseau finance par l’Union Europeenne (1). Cet article presente les resultats concernant la vaccination contre la coqueluche.