tbuckley/cabot-search huggingface dataset:
654. Oncolytic Vesicular Stomatitis Virus Retargeted to the Tumor Stem Cell Marker CD133
Authors: Dina Kleinluetzum, Alexander Muik, Julia Hanauer, Sarah-Katharina Kays, Camilo Ayala-Breton, Kah-Whye Peng, Christian J. Buchholz
Journal: Molecular Therapy (2016)

Therapy resistance and tumor recurrence are often linked to cancer stem cells (CSCs) which represent a minor proportion of highly refractory cancer-propagating cells within a tumor. A putative marker of CSCs is CD133 (prominin-1) which has been suggested to define the tumorigenic population in glioma and hepatocellular cancer (HCC). Moreover, poor prognosis correlates with CD133 expression in cancer biopsies. CD133 is therefore a prime target for novel anti-tumoral strategies. We have previously developed a strategy by which the envelope protein complex of oncolytic measles virus (MV) can be engineered to use CD133 as receptor for cell entry. Notably, MV-CD133 was more effective in killing tumors than non-targeted MV when treating tumors with a high percentage of CD133-positive cells (Bach et al., 2013; Can Res 73, 865). We have meanwhile extended the receptor usage of MV-CD133 to CD46 to effectively infect both CD133-negative and -positive tumor cells. Moreover, to take advantage of the faster replication kinetics and superior cytotoxic activity of the vesicular stomatitis virus (VSV), we used the MV envelope glycoproteins to develop hybrid viruses. The resulting oncolytic virus VSV-CD133 is deleted for its glycoprotein gene G and instead equipped with the mutated MV hemagglutinin (H) and fusion (F) glycoproteins displaying a single-chain antibody (scFv) specific for CD133. The data show that VSV-CD133 infects CD133-positive tumor cells as selectively as MV-CD133, while MV-CD133/CD46 in addition infected CD133−/CD46+ tumor cells. We further studied the cytotoxic activity of VSV-CD133 compared to its MV counterpart. Even though both were effective at killing tumor cells, VSV-CD133 induced cell death more rapidly and at lower MOI than MV-CD133. In a mouse tumor model with subcutaneously transplanted HuH7 cells VSV-CD133 reduced the tumor burden more efficiently than MV-CD133 or MV-CD133/CD46. Most importantly, this increase in efficacy did not come at the expense of safety, as CD133+ human hematopoietic stem cells (HSCs) were neither susceptible to infection nor impaired in growth and differentiation into hematopoietic lineages. Ongoing studies will determine whether the superior oncolytic effects of VSV-CD133 translate into prolonged survival in a mouse model with orthotopically transplanted human primary glioblastoma cells.
Increased ventricle-to-brain ratio in late-onset schizophrenia
Authors: Rabins P, Pearlson G, Jayaram G, Steele C, Tune L
Journal: American Journal of Psychiatry (1987)

For 29 patients with schizophrenia that began after age 44, the mean ventricle-to-brain ratio was significantly higher than for 23 age-matched normal subjects but significantly smaller than for 23 patients with Alzheimer's disease and hallucinations or delusions.
Functional role of CCL5/RANTES for HCC progression during chronic liver disease
Authors: Antje Mohs, Nadine Kuttkat, Johanna Reißing, Henning Wolfgang Zimmermann, Roland Sonntag, Amanda Proudfoot, Sameh A. Youssef, Alain de Bruin, Francisco Javier Cubero, Christian Trautwein
Journal: Journal of Hepatology (2016)
Cardiovascular Effects of Performance-Enhancing Drugs
Authors: André La Gerche, Maria J. Brosnan
Journal: Circulation (2016)

Exercise and competitive sports should be associated with a wide range of health benefits with the potential to inspire a positive community health legacy. However, the reputation of sports is being threatened by an ever-expanding armamentarium of agents with real or perceived benefits in performance enhancement. In addition to the injustice of unfair advantage for dishonest athletes, significant potential health risks are associated with performance-enhancing drugs. Performance-enhancing drugs may have an effect on the cardiovascular system by means of directly altering the myocardium, vasculature, and metabolism. However, less frequently considered is the potential for indirect effects caused through enabling athletes to push beyond normal physiological limits with the potential consequence of exercise-induced arrhythmias. This review will summarize the known health effects of PEDs but will also focus on the potentially greater health threat posed by the covert search for performance-enhancing agents that have yet to be recognized by the World Anti-Doping Agency. History has taught us that athletes are subjected to unmonitored trials with experimental drugs that have little or no established efficacy or safety data. One approach to decrease drug abuse in sports would be to accept that there is a delay from when athletes start experimenting with novel agents to the time when authorities become aware of these drugs. This provides a window of opportunity for athletes to exploit with relative immunity. It could be argued that all off-label use of any agent should be deemed illegal.
Abstract 3361: CD73 expression on tumor-infiltrating breast cancer leukocytes
Authors: Laurence Buisseret, Soizic Garaud, Bertrand Allard, Isabelle Cousineau, Guillaume Chouinard, Christos Sotiriou, Karen Willard-Gallo, John Stagg
Journal: Cancer Research (2015)

Abstract Recent studies have shown that CD73 could be a new promising target in breast cancer (BC). CD73 is a cell surface ecto-nucleotidase, expressed by both tumor cells and immune cells, that catalyses the hydrolysis of AMP into adenosine in the tumor microenvironment. Adenosine has immunosuppressive and tumor-promoting effects and is therefore implicated in the mechanism of tumor immune escape. High CD73 gene expression has recently been associated with a poor prognosis in triple negative BC. While tumor expression of CD73 is well documented, expression of CD73 on tumor-infiltrating immune cells remains poorly characterized. We evaluated the expression of CD73 on immune cells present in fresh tissue homogenates (GentleMACS with no enzymatic digestion) from untreated primary breast tumors and compared to its expression to peripheral blood mononuclear cells (PBMC) from patients with breast cancer. In the peripheral blood, CD73 was found mostly expressed on CD4+ (mean percentage: 13.24±12.88%) and CD8+T cells (mean percentage: 40.78±19.42%) and a major subset of B cells (mean percentage: 51.93±21.83%). Analysis of fresh tumor tissues revealed that less than 25% of CD45+ tumor immune infiltrates express CD73 (mean percentage: 17.63± 5,1%) and was relatively similar to its expression on PBMC (mean percentage: 14.87± 9.5%). In the tumor immune infiltrates, B cells were the immune subset with the higher proportion of CD73+ cells (mean percentage: 53.27±14.63%) while the proportion of CD73+ was lower on tumor-infiltrating CD8+ T cells compared to CD8+ PBMC (p value: 0.022). Notably, we observed that CD73 expression was significantly higher on tumor-infiltrating NK cells and CD14+ myeloid cells compared to peripheral cells (p = 0.005 for NK cells, and p = 0.015 for CD14+ cells). Immunofluorescence analysis confirmed that CD73 is expressed by both tumor cells, CD45+ immune cells and stromal cells in breast cancer. These results suggest that CD73 is differentially expressed on tumor-infiltrating leukocytes compared to PBMCs. Modulation of CD73 activity on tumor-infiltrating leukocytes may therefore contribute to the mechanism-of-action of anti-CD73 therapies. Citation Format: Laurence Buisseret, Soizic Garaud, Bertrand Allard, Isabelle Cousineau, Guillaume Chouinard, Christos Sotiriou, Karen Willard-Gallo, John Stagg. CD73 expression on tumor-infiltrating breast cancer leukocytes. [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 3361. doi:10.1158/1538-7445.AM2015-3361
<i>RECK</i> gene expression in correlation with angiogenesis and angiogenesis-related genes expression in resected non-small cell lung cancer
Authors: K. Takenaka, F. Tanaka, C. Takahashi, M. Noda, H. Wada
Journal: Journal of Clinical Oncology (2004)

9590 Background: RECK is a novel membrane-anchored MMP regulator that can suppress tumor progression through angiogenesis inhibition (Cell 107:789–800, 2001). We had reported preliminary results on RECK expression evaluated with immunohistochemical staining (PASCO 2003), and we conducted a detailed quantitative analyses of RECK gene expression in correlation with angiogenesis and related genes expression. Methods: NSCLC tissues resected from 87 patients were used, and RECK and related genes expression was quantitatively evaluated by a real-time RT-PCR. Results: RECK-gene expression was significantly higher in adenocarcinoma than in squamous cell carcinoma (0.0035 vs 0.0017, p=0.019), and RECK-gene expression was not correlated with any other characteristics including patholocgic stage. The mean intra-tumoral microvessel density (IMVD) was significantly lower in RECK-high tumor (87) than in RECK-low tumor (161, p=0.039); the difference was significant when VEGF-gene expression was high (p=0.040), and not when VEGF-expression was low (p=0.118). RECK expression was positively correlated with VEGF expression (r=0.194, p=0.008), MMP-2 expression (r=0.696, p<0.001), MMP-14 expression (r=0.353, p<0.001), and TGF-beta expression (r=0.468, p<0.001); no significant correlation was observed between RECK expression and MMP-9 expression. The 5-year survival rate of RECK-high patients (72.7%) was significantly higher than that of RECK-low patients (47.9%, p=0.013), and a multivariate analysis revealed that RECK-high was an independent factor to predict a favorable prognosis (p =0.034; hazard ratio and the 95% confidence interval [CI], 0.389 [0.162–0.930]). Conclusions: RECK may inhibit VEGF-induced angiogenesis, and enhanced RECK expression was correlated with a favorable prognosis in NSCLC. No significant financial relationships to disclose.
Abstract 2811: Silver nanoparticles protect human keratinocytes from deleterious effects of ultraviolet radiation: Implications for skin cancer chemoprevention
Authors: Sumit Arora, Nikhil Tyagi, Arun Bhardwaj, Lilia Rusu, Rohan Palanki, Ajay P. Singh, James E. Carter, Seema Singh
Journal: Cancer Research (2015)

Abstract Skin cancer is the most common form of cancer worldwide and its incidence has been increasing at an alarming rate in the United States. A solar ultraviolet (UV) radiation, particularly UVB, is the main etiological cause of skin carcinogenesis due to its DNA damaging ability. Therefore, multidisciplinary scientific research has placed specific emphasis on finding novel ways for skin cancer chemoprevention. Here, we provide first experimental evidence for chemopreventive efficacy of silver-nanoparticles (AgNPs) against UVB-induced DNA damage and apoptosis in immortalized human epidermal keratinocytes (HaCaT). AgNPs synthesized by chemical reduction method were characterized for their physicochemical properties. The nanoparticles were spherical (&amp;gt; 90%) in shape, in the size range of 20-50 nm, and had net negative surface charge with an average zeta potential of - 47.7 mV. AgNPs were largely non-toxic to HaCaT cells and their pretreatment protected them from UVB-induced apoptosis. Significant reduction in cyclobutane pyrimidine dimer (CPD) formation upon UVB exposure was also observed in AgNPs-pretreated HaCaT cells. In addition, AgNPs pre-treatment leads to G1 phase arrest of cell cycle in UVB-exposed HaCaT cells thus allowing sufficient time for CPDs repair. Moreover, enhanced AgNPs internalization and localization into cytoplasmic and nuclear compartments was observed by UVB irradiated HaCaT cells. Furthermore, AgNPs pretreatment altered the expression of various genes involved in cell-cycle, apoptosis and nucleotide-excision repair in UVB-irradiated HaCaT cells. Together, these findings clearly suggest the potential utility of AgNPs as novel chemopreventive agents against UVB-induced skin carcinogenesis. Citation Format: Sumit Arora, Nikhil Tyagi, Arun Bhardwaj, Lilia Rusu, Rohan Palanki, Ajay P. Singh, James E. Carter, Seema Singh. Silver nanoparticles protect human keratinocytes from deleterious effects of ultraviolet radiation: Implications for skin cancer chemoprevention. [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 2811. doi:10.1158/1538-7445.AM2015-2811
Abstract 5446: Continuous real-time measurement of live and dead cells in culture over multiple days
Authors: Terry Riss, Jolanta Vidugiriene, Sarah Duellman, Wenhui Zhou, Gediminas Vidugiris, Mike Valley, Jean Osterman, Ruslan Arbit, Laurent Bernad, Poncho Meisenheimer, James J. Cali
Journal: Cancer Research (2015)

Abstract Recently developed assay technologies have made it possible to use a multi-well plate reader to estimate the number of live or dead cells in culture in real time over a period of days to monitor the effects of long term exposure to test substances. An advantage of the real time assay chemistries is that the cells remain viable and available for other measurements. The purpose of this study was to determine if the real time assay methods could be multiplexed with other assay endpoints and applied to three dimensional (3D) culture models. The measurement of the number of live cells in real time is accomplished by providing a pro-substrate that viable cells (but not dead cells) can convert into a substrate for a luciferase derived from a marine shrimp. The pro-substrate and luciferase can be added with a single reagent addition step and because they are not toxic, they can be incubated with cells in culture for up to three days. Live cell conversion of the pro-substrate into a substrate for luciferase results in a luminescent signal that is proportional to the number of live cells. The signal diminishes immediately upon cell death. Detection of dead cells in real time is accomplished by using a fluorogenic DNA binding dye that is non-permeant and thus non-toxic to live cells. The dye enters dead cells that have a compromised membrane, binds to DNA, and becomes fluorescent. We have demonstrated that the real time assays can be multiplexed to measure both live and dead cells in the same sample. We further demonstrate the use of these assays to measure viability of cells in 3D spheroids formed using the hanging drop culture technique. We also demonstrate multiplexing of real time assays with subsequent measurement of apoptosis or extraction of RNA for expression studies. Utilization of real time assay chemistries that are non-toxic enabled repeated recording of data in a kinetic mode from the same sample of cells which eliminated the need for duplicate cultures and provided flexibility during assay protocol development. The ability to multiplex real time assays improved overall lab efficiency by eliminating the need for duplicate cultures for each experiment. Citation Format: Terry Riss, Jolanta Vidugiriene, Sarah Duellman, Wenhui Zhou, Gediminas Vidugiris, Mike Valley, Jean Osterman, Ruslan Arbit, Laurent Bernad, Poncho Meisenheimer, James J. Cali. Continuous real-time measurement of live and dead cells in culture over multiple days. [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 5446. doi:10.1158/1538-7445.AM2015-5446
Induction of Caspase-Independent Apoptosis by Sickle Cell Disease (SCD) Serum in Non-SCD Leukocytes
Authors: Camila B. Almeida, Fernanda Gonçalves Pereira, Irene Lorand Metze, Sara T.O. Saad, Fernando F. Costa, Nicola Conran
Journal: Blood (2008)
A Phase 1 Study of the BET-Bromodomain Inhibitor OTX015 in Patients with Non-Leukemic Hematologic Malignancies
Authors: Catherine Thieblemont, Anastasios Stathis, Giorgio Inghirami, Lionel Karlin, Franck Morschhauser, Mary Gleeson, Florence Broussais, Sandy Amorim, Gilles Salles, Thierry Facon, David Cunningham, Norbert Vey, Fabrice Bourdel, Patrice Herait, Emanuele Zucca
Journal: Blood (2014)
Firearm Suicide in the United States From a Broader Preventive Perspective
Authors: Nestor D. Kapusta, Robert J. Cramer
Journal: American Journal of Psychiatry (2017)

An often-cited purpose of firearms in the United States beyond sports and hunting is to defend oneself against criminal acts.Indeed, firearms are designed to threaten, injure, or kill.The dilemma is that firearm misuse for other purposes is frequent (Figure 1).As reviewed by Mann and Michel (1) in the October 2016 issue of the Journal, there is considerable evidence for the effectiveness of interventions, such as restrictive laws, to prevent firearm suicide.However, the authors offer a rather pessimistic view concerning the possibility to translate these results into practice, based on two arguments.First, suicides are often committed using firearms that are purchased long before suicidal acts, and recent data show that firearms are available in 43% of U.S. households (2), ready for use and misuse.Such ubiquity of firearms suggests an
133. Use of 2As To Control Protein Subcellular Localization
Authors: Ekaterina Minskaia, Claire Roulston, Garry Luke, Martin D. Ryan
Journal: Molecular Therapy (2015)

A substantial proportion (~39%) of all human proteins are either secreted from the cell, located within the lumen/ membranes of cytoplasmic vesicular structures, or, are plasma membrane proteins. Given that such high proportion of proteins are initially translocated into the endoplasmic reticulum (ER), many therapeutic strategies rely on the ability to co-express multiple proteins – some, or all of which, might be targeted to such sites. This directly applies to in vivo gene therapy strategies, or, when therapeutic proteins may need to be co-expressed with selectable markers (e.g. ex vivo gene therapies). As was shown before, Picornavirus 2A (foot-and-mouth disease virus 2A; F2A) and '2A-like' sequences are powerful tools that allow multiple proteins to be translated and co-expressed from a single transcript mRNA under the control of only one promoter. When 2A is positioned between sequences encoding two, or more, genes, it mediates a co-translational 'cleavage' at its own C-terminus. A major problem with co-expression of certain proteins targeted to, or transiting through, the ER is that the 'cleavage' activity of short F2As can be greatly inhibited by sequences immediately upstream leading to aberrant sub-cellular localisation of some proteins. We have also discovered a number of active cellular 2A-like sequences, associated with non-long terminal repeat (non-LTR) retrotransposons, but also with structural and metabolic proteins: ankyrin repeats, sodium dependent neutral amino acid transporters, and NOD-like receptor (NLR) proteins. Examination of the surrounding protein and gene structure revealed that in the majority of cases these 2A sequences occurred as N-terminal features. Interestingly, using SignalP, many of these novel 2As scored highly as N-terminal signal peptides. Here, we present our latest findings on 2A sequences. A series of test proteins (eGFP and mCherry) were expressed i) followed by 'hybrid' 'self-cleaving' F2A sequences (with different upstream contexts) or ii) downstream of a putative signal 2A. We demonstrate that inhibition of F2A-mediated cleavage in shorter sequences can be overcome by introduction of mutations upstream of 2A changing the context of the sequence between the C-terminus of the upstream protein and 2A sequence. In the case of N-terminal – cellular – (NLR) 2As, 'uncleaved' 2A indeed can act as a signal peptide. If 2A does not 'cleave', it directs a proportion of the newly synthesised reporter protein to the exocytic pathway: if 2A 'cleaves', the protein downstream is localised to the cytoplasm. This type of 2A mediates, therefore, a newly discovered form of dual protein targeting.
Abstract 1560: FGFR4 is expressed in the tumor and stromal compartments of human gliomas of all grades and histologies
Authors: Christiane H. Gjerde, Ercan Mutlu, Lina Leiss, Bjarne Winther Kristensen, Mohummad Aminur Rahman, Per Øyvind Enger
Journal: Cancer Research (2015)

Abstract BACKGROUND: Fibroblast growth factor receptor (FGFR) 4 is reportedly expressed in several cancer types, and is a high-affinity transmembrane receptor for FGF2 which is expressed human astrocytomas. However, the expression of FGFR4 across gliomas of different grades and histologies has not been extensively investigated. METHODS: We performed immunohistochemistry (IHC) of 178 grade II-IV human gliomas from our tumor bank, including 117 GBMs and 61 lower grade gliomas of astrocytic and oligodendroglial lineage. The samples were scored (0-2) separately for staining intensity and fraction of area that was stained and whether staining was predominantly cytoplasmic or nuclear. This scoring was performed separately for tissue from tumor center and periphery, as well as in tumor areas around pseudopalisading (PP) and large necroses. We also performed western blot analysis (n = 22) and real-time qPCR (n = 37). On one tumor sample we performed FISH for EGFR (red)/Centromere chromosome 7 (green), combined with immunofluorescence (IF) for FGFR4. RESULTS: I) FGFR4 is uniformly expressed in human gliomas, although at a varying degree, as confirmed by IHC, western blotting and RT-qPCR. II) FGFR4 expression was detected both in the nuclei and cytoplasm. III) Both a homogenous and a granular staining pattern was observed the cytoplasm, suggesting involvement of different cell types, whereas FISH demonstrated expression in the tumor and stromal cell compartments. IV) Tumors of grade II and III show a statistically significant higher expression than tumors of grade IV as shown by RT-qPCR. V) There is no difference in expression by IHC between tumors of grade II, III and IV. Citation Format: Christiane H. Gjerde, Ercan Mutlu, Lina Leiss, Bjarne Winther Kristensen, Mohummad Aminur Rahman, Per Øyvind Enger. FGFR4 is expressed in the tumor and stromal compartments of human gliomas of all grades and histologies. [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 1560. doi:10.1158/1538-7445.AM2015-1560
Down-regulation of ABCG2, a urate exporter, by parathyroid hormone enhances urate accumulation in secondary hyperparathyroidism
Authors: Ryusei Sugimoto, Hiroshi Watanabe, Komei Ikegami, Yuki Enoki, Tadashi Imafuku, Yoshiaki Sakaguchi, Michiya Murata, Kento Nishida, Shigeyuki Miyamura, Yu Ishima, Motoko Tanaka, Kazutaka Matsushita, Hirotaka Komaba, Masafumi Fukagawa, Masaki Otagiri, Toru Maruyama
Journal: Kidney International (2016)
Bortezomib Targets Multiple Myeloma Endothelial Cells.
Authors: Aldo M. Roccaro, Teru Hideshima, Noopur Raje, Shaji Kumar, Kenji Ishitsuka, Hiroshi Yasui, Norihiko Shiraishi, Makoto Hamasaki, Paul G. Richardson, Kenneth C. Anderson
Journal: Blood (2004)
Individual Pharmacokinetic Targeting of Busulfan in Allogeneic Hematopoietic Stem Cell Transplantation Is Essential for Infants with MLL Gene-Rearranged Acute Lymphoblastic Leukemia: A Report from the JPLSG MLL03 Study
Authors: Takayuki Takachi, Yuki Arakawa, Hiroyoshi Nakamura, Tomoyuki Watanabe, Yuki Aoki, Junjiro Ohshima, Yoshihiro Takahashi, Masahiro Hirayama, Takako Miyamura, Kanji Sugita, Katsuyoshi Koh, Keizo Horibe, Eiichi Ishii, Daisuke Tomizawa
Journal: Blood (2015)