tbuckley/cabot-search huggingface dataset:
201. Modulation of the Antitumor Immune Response Using Semireplication-Competent VSV Armed with Immunostimulatory Transgenes
Authors: Johanna Reul, Christian J. Buchholz, Alexander Muik
Journal: Molecular Therapy (2016)

Immunotherapy has been shown to be an effective treatment modality for various cancer types. A branch of immunotherapy is oncolytic immunovirotherapy, which relies on arming oncolytic viruses with immunomodulatory cargo. A potent oncolytic virus candidate is the vesicular stomatitis virus (VSV), showing impressive antitumor activity in a variety of animal models. However, to overcome the neurotoxicity of VSV a semireplication-competent VSV vector system (srVSV) has been generated, which is based on two trans-complementing, propagation deficient VSV vectors. As a consequence, infectious progeny can only be produced in double infected cells. We aim at establishing a system that couples the oncolytic function of srVSV with its ability to accommodate multiple transgenes. Immunostimulatory transgene expression in combination with the oncolysis-induced inflammatory milieu at the tumor site might suffice to interfere with tumoral immunotolerance mechanisms and to induce a long-term antitumor immune response eliminating residual and metastatic cancer. The immunostimulatory transgenes GM-CSF, Flt3L, B7-1-Ig and the tumor-associated antigens ErbB2, CTLA4-ErbB2 were cloned into the genome of the srVSV vector system. All VSV vectors were successfully generated de novo and functional analyses revealed that the vectors were able to transcomplement, induce oncolysis and express the respective transgene in vitro. To investigate antitumor efficacy in vivo, a suitable VSV-permissive syngeneic tumor mouse model was identified. As VSV is exquisitely sensitive to type I interferon induced antiviral responses, a total of five different murine tumor cell lines were analyzed concerning their interferon sensitivity. In vitro and in vivo analyses revealed that the murine colon cancer cell line MC38 is an appropriate tumor model, as MC38 cells were productively infectable even when pretreated with high doses of IFN-α and established s.c. MC38 tumors allowed for sustained transgene-expression over an extended period of time. Initial in vivo data confirm the potential of transgene-armed as well as control srVSV to induce an antitumor immune response eventually leading to cure in some animals. The immune response was analyzed by evaluating tumor-specific T cells using ELISpot and MHC class I tetramer staining. Furthermore, immunological tumor rejection was shown after tumor rechallenge of cured mice. Taken together, the data indicate that srVSV in combination with different transgenes can induce a long-term antitumor immune response. Further research is warranted to identify the most promising transgene combinations.
Risk of New-Onset Diabetes and Cardiovascular Risk Reduction From High-Dose Statin Therapy in Pre-Diabetics and Non–Pre-Diabetics
Authors: Payal Kohli, David D. Waters, Rita Nemr, Benoit J. Arsenault, Michael Messig, David A. DeMicco, Rachel Laskey, John J.P. Kastelein
Journal: Journal of the American College of Cardiology (2015)
Making patient relevant clinical research a reality
Authors: Sally Crowe, Ceinwen Giles
Journal: BMJ (2016)

Researchers, funders, and publishers all have work to do

Clinical research aims to improve the knowledge base in the prevention, treatment, care, and cure of disease while delivering good value for money and avoiding research waste.1 However, a wide gap exists between what generally receives funding and what patients, carers, and the public would like to see examined.2 3 4

There is, of course, a moral imperative to understand the priorities of those who may benefit from research. But incorporating patient perspectives more thoroughly into clinical research would also broaden its scope and help answer the research questions likely to bring about the biggest improvements in our understanding of disease.

Several problems underlie our current inability to make research relevant to patients and the wider public. Most importantly, research is a power rich and hierarchical environment in which successful clinical researchers are at the top and patients, carers, and the public are viewed as passive beneficiaries at the bottom. These power dynamics and the status quo …
Environmental Nanoparticles Are Significantly over-Expressed in Acute Myeloid Leukemia: a Novel Pathogenetic Cofactor?
Authors: Giuseppe Visani, Anita Manti, Laura Valentini, Barbara Canonico, Federica Loscocco, Alessandro Isidori, Elisa Gabucci, Pietro Gobbi, Stefano Montanari, Marco Rocchi, Stefano Papa, Maria Antonietta Gatti
Journal: Blood (2015)
Abstract 3007: Intracellular detection of hypoxia in live cells
Authors: Bhaskar S. Mandavilli, Michael O'Grady
Journal: Cancer Research (2015)

Abstract Hypoxia is an important phenomenon in many physiological processes and involved in many human diseases including cancer. Inflammation can lead to significant hypoxia in tissues. The study of hypoxia has been complicated with the lack of proper instrumentation to induce hypoxia in cells and image cells under hypoxic conditions. Here, we describe a live cell-based method to conveniently measure hypoxia using a new Image-iT® Hypoxia Probe and a specialized microscope incubator which can control oxygen concentrations down to 1%, The Image-iT® Hypoxia Probe is an oxygen sensing fluorescent probe, is quenched with increasing oxygen concentrations, and has excitation and emission peaks of 483 and 616 nm respectively. The probe is sensitive to varying concentrations of oxygen and can detect as low as 1% O2 concentrations in cells. Imaging of cells with the Image-iT® Hypoxia Probe in the incubator prevents re-oxygenation of cells and gives more precise measurement of hypoxia in cells, allowing for reversible and dynamic measurements of hypoxia in cells. Using this system, we measured hypoxia in several cell lines including A549, HeLa and U-2 OS. The Image-iT® Hypoxia Probe is also very good at detecting hypoxia in 3D tumor spheroids generated using different methods. The new hypoxia probe gives good signal to noise with more than 3-fold changes at 5% O2 levels with robust statistics. The Image-iT® Hypoxia Probe provides a good system for precise, robust and reproducible measurements of hypoxia in cells. Citation Format: Bhaskar S. Mandavilli, Michael O'Grady. Intracellular detection of hypoxia in live cells. [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 3007. doi:10.1158/1538-7445.AM2015-3007
Sleep disturbance in patients with operable breast cancer receiving adjuvant hormone therapy.
Authors: S. Aksoy, D. S. Dede, S. Yaman, C. Ozkan, I. H. Gullu, K. Altundag
Journal: Journal of Clinical Oncology (2011)

e11125 Background: Data suggest that individuals with breast cancer experience significant sleep disturbance pre-, during, and post-chemotherapy and/or radiation therapy. But there is no enough data about the sleep disturbances in operable breast cancer patients receiving adjuvant hormone therapy. The objectives of this study were to examine the of sleep quality in breast cancer patients receiving adjuvant hormone therapy and compare with healthy controls. Methods: In this cross-sectional study we analyzed the sleep disturbances in patients with stage I-III breast cancer and healthy controls. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). Demographic and tumor characteristics were also collected along with size, grade, lymph node, estrogen, progesterone, HER2 status, grade and history of chemotherapy. Results: Seventy-eight patients receiving tamoxifen (Tmx), 109 receiving aromatase inhibitors (AIs), and 39 healthy controls were included the study. Median age of the patients and health controls was 49 years old. Patients receiving Tmx and AIs had 48.7% and 62.4% severe sleep disturbances according to global PSQI scores, respectively. Whereas healthy controls had 47.4% severe sleep disturbances. There was no statistically significant difference in sleep quality, sleep latency, sleep duration, sleep disturbance, sleep medication, daytime dysfunction sleep efficiency between patients receiving Tmx and health controls. Patients receiving AIs had statistically significant poorer sleep latency and sleep quality than patients receiving Tmx. The most frequent other problems that may affect the sleep were pain (14%) and nocturia (9%). Conclusions: Patients receiving AIs had more frequently experienced sleep disturbances compared to patients receiving Tmx and healthy controls. This finding may be related to low estrogen levels that caused by AIs and postmenopausal status. Determinant of sleep disturbances in patients receiving AIs should be determined in prospective studies. Detection and treatment of sleep disturbances and daytime impairment may minimize disruption to health-related quality of life in these patients.
Decitabine-Induced Differentiation Syndrome in a Patient with Acute Myeloid Leukemia: A Case Report.
Authors: William Blum, Kristie A. Blum, Cheryl Kefauver, Mollie Moran, Kenneth Chan, John C. Byrd, Spero Cataland, Michael R. Grever, Guido Marcucci
Journal: Blood (2004)
Natural History of the Central Structural Abnormalities in Choroideremia
Authors: Tomas S Aleman, Grace Han, Leona W Serrano, Nicole M Fuerst, Emily S Charlson, Denise J Pearson, Daniel C Chung, Anastasia Traband, Wei Pan, Gui-Shuang Ying, Jean Bennett, Albert M Maguire, Jessica I W Morgan
Journal: Ophthalmology (2016)
Gene polymorphisms in antioxidant enzymes correlate with the efficacy of androgen-deprivation therapy for prostate cancer with implications of oxidative stress
Authors: M. Shiota, N. Fujimoto, M. Itsumi, A. Takeuchi, J. Inokuchi, K. Tatsugami, A. Yokomizo, S. Kajioka, T. Uchiumi, M. Eto
Journal: Annals of Oncology (2016)
Abstract 4187: Expression of ion channels in a cervical cancer mouse model
Authors: ANA RAMIREZ, EUNICE VERA, PAUL LAMBERT, PATRICIO GARIGLIO, JAVIER CAMACHO
Journal: Cancer Research (2015)

Abstract Introduction. Because some ion channels have been suggested as early tumor markers and therapeutic targets, in the present study we examined the expression of ion channels in the cervical cancer transgenic mouse model K14E7 expressing the HPV16 E7 oncogene under the control of the human keratin 14 promoter. Methods. We used the K14E7 transgenic mouse; some groups were treated with 17β-estradiol. Continuous release pellets delivering 0.05 mg of 17β-estradiol were implanted into 4-6 weeks old female mice during 90 days to obtain low grade cervical dysplasia or during 180 days to produce cervical cancer. The cervix was removed at the end of the treatment. Protein and mRNA expression of 4 ion channels (Cav3.1, Cav3.2, Kv10.1, KCa1.1) were analyzed by qRT-PCR and immunohistochemistry, respectively. Results. We found increased expression of Cav3.1, Kv10.1 and KCa1.1 in mice with cervical dysplasia in comparison to control animals. This increase was even higher in animals with cervical cancer. In contrast, Cav3.2 expression decreased in animals with cervical dysplasia and increased in mice with cervical cancer. We also found overexpression of the KCa1.1 protein in the transformed zone of the cervical cancer group, but not in the control group. Conclusions. The channel expression profile here studied might serve as a cervical cancer marker. This work was partially supported by Conacyt grant 141126 to JC. Citation Format: ANA RAMIREZ, EUNICE VERA, PAUL LAMBERT, PATRICIO GARIGLIO, JAVIER CAMACHO. Expression of ion channels in a cervical cancer mouse model. [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 4187. doi:10.1158/1538-7445.AM2015-4187
Functional Differences in GATA-1 Affinity for Double Versus Single GATA-1 Binding Sites Dictate Synergistic Versus Antagonistic Interactions of PU.1 and GATA-1 in Myeloid Gene Transcription.
Authors: Jian Du, Dharmesh Vyas, Qing Xi, Steven J. Ackerman
Journal: Blood (2004)
Abstract 4471: The antitumor activity of hyaluronic acid nimuselide-NH2 bioconjugate (CA102N) in human colorectal cancer (CRC)
Authors: Eskouhie Tchaparian
Journal: Cancer Research (2015)

Abstract Carrier mediated drug delivery systems are promising next generation therapeutics for targeted delivery and improved efficacy and safety of cytotoxic drugs. Hyaluronic Acid conjugated drugs (HACD) are novel carrier-mediated drug delivery systems (Targeting Carrier™) characterized by CD44-mediated endocytosis of Hyaluronic Acid (HA) and intracellular drug release. The present study investigates the in vitro and in vivo antitumor activity of CA102N, an HA- Cyclooxygenase-2 inhibitor conjugate, HA-Nimesulide, currently in preclinical development. Cyclooxygenase-2 (COX-2) inhibitors are a class of compounds that are associated with anticancer properties. CA102N was able to selectively inhibit HCT116 and HT29, CRC cancer cell growth in vitro with an IC50 of 57.7 and 77.14 μM respectively. In in vivo studies, strong anti-tumor effects and rapid tumor shrinkage was observed within 3 days posttherapy in mice bearing HT-29 xenografts treated with either 1.5 or 4.5 mg/kg of relative amount of the conjugate. Further, full and sustained regression of tumors was also attained during the entire observational period (14 days) after the last dose. No treatment related toxicity was noticed in mice. HACD drug delivery systems may offer great advantages in the development of a new class of bioconjugated drugs for intracellular delivery and enhanced safety of potent cytotoxic drugs. Citation Format: Eskouhie Tchaparian. The antitumor activity of hyaluronic acid nimuselide-NH2 bioconjugate (CA102N) in human colorectal cancer (CRC). [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 4471. doi:10.1158/1538-7445.AM2015-4471
A Polyclonal Population of Piga Mutant CD52 and GPI Anchor Negative T Cells Can Give Early Immune Protection after Alemtuzumab-Based T Cell Depleted Allogeneic Stem Cell Transplantation
Authors: Floris C. Loeff, J.H. Frederik Falkenburg, Lois Hageman, Sabrina A.J. Veld, Marian van de Meent, Constantijn J.M. Halkes, Inge Jedema
Journal: Blood (2015)
MDS with Isolated Trisomy 8. a Type of MDS Frequently Associated with Myeloproliferative Features? A Report from the GFM
Authors: Louis Drevon, Alice Marceau, Virginie Eclache, S. Dominique Raynaud, Valentine Richez, Inès Berkaoui, Odile Maarek, Wendy Cuccuini, Daniel Lusina, Celine Berthon, Sophie Dimicoli-Salazar, Audrey Bidet, Jean-Philippe Vial, Sophie Park, Aspasia Stamatoullas, Christina Vieira Dos Santos, Thorsten Braun, Rosa Sapena, Aline Renneville, Lionel Ades, Pierre Fenaux
Journal: Blood (2015)
Abstract 2428: Translational study of F14512, a novel vectorised epipodophyllotoxin, which demonstrates a marked activity on ovarian cancer models from patients
Authors: Benoît Thibault, Gregoire Zorza, Samuel Meignan, Nicolas Guilbaud, Christian Bailly, Jean-Pierre Delord, Bettina Couderc, Anna Kruczynski, Pierre Ferre, Jean-Philippe Annereau
Journal: Cancer Research (2015)

Abstract Epithelial ovarian cancer is the fourth cause of death among cancer-bearing women, frequently associated with carboplatin resistance, underlining the need of more efficient and targeted therapies. F14512 is a novel concept of drug vectorization that we propose here to investigate in ovarian cancer models. F14512 is an epipodophyllotoxin-core linked to a spermine chain, which enters selectively tumor cells via the polyamine transport system (PTS), currently in clinical phase II evaluation in AML. We compared the effects of F14512 versus etoposide against OVCAR-3, IGROV-1, SKOV-3, A2780S and A2780R cancer cell lines. Using the F17073 PTS fluorescent probe, we determined the PTS activity of these cells and of 18 clinical samples. As results, F14512 displayed strong anti-proliferative and pro-apoptotic activities in carboplatin-resistant models, being increased in cell lines with high levels of PTS. Consistently, at a dose of 1.25 mg/kg, F14512 significantly inhibited tumor growth in cisplatin-resistant SKOV-3 xenograft model. Interestingly, ex vivo analysis indicated that 15 patients sample out of 18 presented a higher F17073 fluorescent probe incorporation into CD326-positive tumor cells as compared to normal cells, even in the case of 2 platinum-refractory patients. Therefore, F14512 is a targeted drug with a potent anti-tumor efficacy regardless the status of cisplatin resistance. The high PTS activity detected in fresh clinical samples highlights the potential of F14512 as a new therapy for PTS-positive and platinum resistant ovarian cancer patients. Citation Format: Benoît Thibault, Gregoire Zorza, Samuel Meignan, Nicolas Guilbaud, Christian Bailly, Jean-Pierre Delord, Bettina Couderc, Anna Kruczynski, Pierre Ferre, Jean-Philippe Annereau. Translational study of F14512, a novel vectorised epipodophyllotoxin, which demonstrates a marked activity on ovarian cancer models from patients. [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 2428. doi:10.1158/1538-7445.AM2015-2428
412. Development of GD2-Specific Immunoliposomes for Immunotherapy of Neuroblastoma
Authors: Wei Huang, Daofeng Liu, Linjie Guo, Gianpietro Dotti, Leonid S. Metelitsa
Journal: Molecular Therapy (2015)

Tumor growth creates a highly immunosuppressive tumor microenvironment (TME) that impairs T-cell localization, persistence, or the execution of their effector function. This represents a major and as yet unsolved critical challenge to the development of effective adoptive immunotherapy of solid tumors. To selectively target TME in neuroblastoma and make it permissible for survival and function of tumor-specific T cells, we have developed a novel nanoparticle (NP) delivery platform which consists of 150 nm immunoliposomes rendered specific for neuroblastoma cells using the Fab fragment obtained from the anti-GD2 mAb clone 14g2a. To ensure high density surface coverage and correct orientation of anti-GD2 Fab on the NPs, we synthesized a fusion protein consisting of 14g2a Fab and folate receptor (Fab14g2a-FR) and attached it on the outer layer of the immunoliposomes enriched with folic acid. Rhodamine-labeled GD2-specific but not control NPs could specifically bind GD2-positive CHLA-255 neuroblastoma cells but not GD2-negative LA-N-6 neuroblastoma cells in vitro as determined by FACS. To examine the in vivo biodistribution of NPs, DiR-labeled GD2-specific or non-specific NPs were injected to NOD/SCID mice implanted with CHLA-255 cells. Tumor tissues and normal organs were imaged after 72 hours using ex vivo fluorescence imaging. Up to 58% of GD2-specific NPs accumulated at the tumor sites. The only other organ with significant accumulation of NPs was the liver. Minor traceable portions were detected in the spleen and lung. To utilize the observed targeting capabilities of GD2-specific NPs to achieve antitumor effects, we are now loading NPs with recombinant human (rhIL-7) and will test whether the preferential delivery of rhIL-7 to the tumor site and liver, a major site of NB metastasis, will increase the survival and anti-tumor activity of T and NKT cells engineered to express a GD2-specific chimeric antigen receptor with IL-7Rα. The results of this study will inform design of immunotherapy of neuroblastoma and other tumors in combination with TME-modifying NPs.
Vitamin D contributes to mast cell stabilization
Authors: Z.‐Q. Liu, X.‐X. Li, S.‐Q. Qiu, Y. Yu, M.‐G. Li, L.‐T. Yang, L.‐J. Li, S. Wang, P.‐Y. Zheng, Z.‐G. Liu, P.‐C. Yang
Journal: Allergy (2016)

Mast cells are the major effector cells in allergic disorders and many other informatory disorders. The mechanism of mast cell stabilization is not fully understood. Cumulative reports indicate that vitamin D (VitD) contributes to the homeostasis in the body. This study tests a hypothesis that VitD is required in the maintenance of the stability of mast cells.The stability of mast cell lines, HMC1 cells, RBL-2H3 cells, p815 cells, and mouse bone marrow-derived mast cells (BMMC) was tested in the presence or absence of VitD3.Mast cells activated automatically in a VitD-deficient environment. Exposure to calcitriol in the culture increased the expression of VitD receptor (VDR) in mast cells. VDR formed complexes with Lyn in mast cells to inhibit the binding of Lyn to the β chain of FcεRI and MyD88, which decreased the phosphorylation of Syk, decreased the levels of MAPK and NF-κB. VDR bound to the promoter of TNF-α to decrease the acetylation of histone H3/H4, RNA polymerase II and OCT1 (a transcription factor of TNF-α) at the promoter locus and repressed the expression of TNF-α in mast cells.The data demonstrate that VitD is required to maintain the stability of mast cells. The deficiency of VitD results in mast cell activation.