tbuckley/cabot-search huggingface dataset:
Screening for Genital Herpes
Authors: Kenneth A. Katz
Journal: JAMA Dermatology (2016)

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Concurrent chemoradiotherapy plus adjuvant chemotherapy versus chemoradiotherapy alone or radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a meta-analysis
Authors: O. Iocca, E. Ferraro, G. Gadaleta-Caldarola, M. Brandi, G. Filippelli, S. Infusino
Journal: Annals of Oncology (2015)
An evaluation of serum cytokine levels and fatigue and depression in ECOG E4Z02.
Authors: T. A. Rich, J. Manola, D. Cella, R. A. Cruciani, M. Fisch
Journal: Journal of Clinical Oncology (2011)

9046 Background: Carnitine vs. placebo for treatment of fatigue did not improve symptoms in cancer patients (ASCO, 2009). However, in both treatment arms fatigue and depression improved (baseline vs. 4 weeks). IL-6, VEGF, TGF-a, and EGF (plus 6 other cytokines) were analyzed based on the concepts of the sickness behavior, and disruption of circadian signaling models. Methods: A 50% or greater improvement at 4 wks of the Brief Fatigue Index (BFI) and CESD Depression Index was considered a response. Mixed models were used to identify changes in log-transformed cytokine levels (measured in 96 pts) associated with symptom response, carnitine deficiency, age, and concurrent chemotherapy. Results: EGF levels decreased more significantly in older patients (p=0.02), and in carnitine deficient patients with either BFI responses (p=0.002) or CESD responses (p=0.007). IL-6 levels decreased more significantly in patients with BFI responses (p=0.003), in the subset of those patients not currently receiving chemotherapy (p=0.009), and in carnitine deficient patients (p=0.01). Patients with CESD response had smaller declines in VEGF levels than non-responders. (p=0.01) Patients with carnitine deficiency had greater declines in VEGF (p=0.004). Patients currently receiving chemotherapy who had CESD responses had increases in VEGF levels over time (p=0.0007). No associations between changes in TGF-a levels and BFI or CESD response categories were noted. Conclusions: In this prospective, post hoc subset analysis, improved levels of fatigue and depression are significantly associated with two major cytokine families. These data suggest that both pro-inflammatory cytokine and circadian-signaling pathways contribute to symptoms in cancer patients.
Abstract 4167: Snai2(Slug) regulates tumor angiogenesis through the induction of EndoMT
Authors: Nan Wu, Katrina Welch-Reardon, Christopher Hughes
Journal: Cancer Research (2015)

Abstract Anti-angiogenic therapy remains an attractive option in the treatment of cancer since it has the potential to both control growth of the primary tumor and limit metastasis. However, many current anti-angiogenic cancer drugs fail to deliver long-term efficacy, likely due to adaptation of the tumor to utilize alternative angiogenic pathways. The high level of cross talk between pro-angiogenic pathways makes targeting the downstream effectors a potentially more beneficial strategy. We have recently demonstrated that the transcription factor Slug (Snai2), a master regulator of epithelial-to-mesenchymal transition (EMT), is expressed in angiogenic endothelial cells (EC) and can augment sprouting angiogenesis in vitro, likely by inducing a partial endothelial-to-mesenchymal transition (EndoMT). Slug is induced by many pro-angiogenic pathways (e.g. TGFβ, Notch, VEGF) and can directly regulate several key steps in angiogenesis, such as migration and proliferation, making it an attractive anti-angiogenic drug target. In this study we used Slug knockout mice, which are viable but runted, to test the hypothesis that Slug regulates pathological angiogenesis in vivo by inducing an EndoMT. Using a Matrigel plug assay we found that angiogenesis was reduced in Slug knockout mice compared to littermate controls. Initial analysis suggests this is the result of impaired vascular recruitment. In addition, a syngeneic subcutaneous tumor model showed that the growth of wild type tumor cells is reduced by over 50% in Slug knockout mice compared to controls. In an in vitro angiogenesis assay Slug overexpression induces hypersprouting and an increased number of disconnected cells, suggesting the complete loss of cell-cell junctions, consistent with a full EndoMT. RNA-seq comparing Slug overexpressing EC to wild type EC revealed targets that are implicated in both autocrine and paracrine regulation of tumor angiogenesis. In conclusion, these data suggest that EC expression of Slug regulates tumor angiogenesis, and that the level of slug expression may set the threshold between a partial and a full EndoMT. Citation Format: Nan Wu, Katrina Welch-Reardon, Christopher Hughes. Snai2(Slug) regulates tumor angiogenesis through the induction of EndoMT. [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 4167. doi:10.1158/1538-7445.AM2015-4167
Treatment of Minimal Residual Disease (MRD) with Donor Lymphocyte Infusions (DLI) in Acute Leukemia Patients Undergoing an Allogeneic Hemopoietic Stem Cell Transplants (HSCT).
Authors: Alida Dominietto, Giovanna Piaggio, Sarah Pozzi, Francesca Bertolotti, Nicoletta Colombo, Raffaella Grasso, Anna Garuti, Gabriella Cirmena, Maurizio Miglino, Anna Maria Raiola, Maria Teresa van Lint, Francesco Frassoni, Marina Podesta’, Andrea Bacigalupo
Journal: Blood (2005)
Electrospinning: A Bioinspired Ultraporous Nanofiber-Hydrogel Mimic of the Cartilage Extracellular Matrix (Adv. Healthcare Mater. 24/2016)
Authors: Florian A. Formica, Ece Öztürk, Samuel C. Hess, Wendelin J. Stark, Katharina Maniura-Weber, Markus Rottmar, Marcy Zenobi-Wong
Journal: Advanced Healthcare Materials (2016)

M. Zenobi-Wong and co-workers develop cell-seeded, ultraporous composite scaffolds for cartilage regeneration on page 3129. By means of cryoelectrospinning, ice crystals are co-deposited with the polymer. After sublimation, macropores are created which subsequently allow the infiltration of the electrospun membrane with a cell/hydrogel suspension. This procedure provides mechanical stability to the weak but chondrogenic alginate sulfate hydrogel.
333. Intracellular Ankyrin Specific to p24 and zfp Specific to 2-LTR Are Alternatives to CCR5 Knockdown for Stem Cell Gene Therapy
Authors: Chatchai Tayapiwatsna
Journal: Molecular Therapy (2016)

HIV-1 genome integration and capsid assembly are some of the most important steps to viral life cycle. Designed scaffold proteins, zinc finger and ankyrin repeat protein, were characterized as intracellular antiviral agents that can interfere in these steps. Zinc finger protein, 2LTRZFP, plays a vital role in blocking HIV integration. This protein targets the 2-LTR-circle junction of the HIV-1 DNA but it would have no effect on the HIV-infected cells. Another protein, AnkGAG1D4, will then specifically bind to the viral capsid resulting in inhibition of HIV-1 assembly. Since only one particular scaffold protein cannot confer full protection against the virus. Combination of these two proteins became the key to enhance inhibitory function to block HIV-1 replication at early and late infection stage and also help eliminate latent viral reservoirs. The human T cell line modified by using a lentiviral vector bearing 2LTRZFP alone or combination with N-myristoylatedMyr(+)AnkGAG1D4 were protected from viral infection in HIV-1 challenge. Interestingly, the Myr(+)AnkGAG1D4 showed significantly antiviral effect in HIV-1-preinfected SupT1 cells and also possessed a broad antiviral activity against SIV, and SHIV. These results demonstrate that 2LTRZFP and Myr(+)AnkGAG1D4 proteins can be the novel anti-HIV-1 therapeutic agents for human applications.
Validation of the predictive value of modeled hCG decline profiles in low-risk gestational trophoblastic neoplasia (GTN) treated with methotrexate (MTX).
Authors: G. Freyer, B. You, R. Harvey, F. Golfier, H. Mitchell, P. Savage, M. Tod, C. Philip, T. Hajri, M. Seckl
Journal: Journal of Clinical Oncology (2011)

5099 Background: In low-risk GTN, MTX treatment is changed according to serum hCG levels. We previously showed that population modeling of hCG levels using kinetic equations provided parameters that could be used as independent predictors of MTX resistance (You et al; Ann Oncol 2010). In the present study we applied this approach to a large independent patient cohort in which hCG measurements were made using the same immunoassay. Methods: The hCG kinetic profiles of 563 patients with low-risk GTN (281 MTX Resistant: 282 MTX Sensitive) treated at Charing Cross Hospital were retrospectively analyzed in a 3-step validation study. Initially a 189 patient “Model Set” was used to derive kinetic parameters of the model using the NONMEM program. Patient hCG kinetics were described from day0 to day50 using: “[hCG(time)] = hCG0i * exp(–k*time)+ P”, where P is residual hCG tumor production, hCG0i is the initial hCG level, and k is the rate constant. The predictive values of different kinetic parameters (clearance, area under the curve, AUC and P) were assessed using ROC curves and logistic regression. Subsequently, 2 independent datasets comprising 149 and 225 patients with blinded-resistance status (Validation1 and Validation2 sets) were used to assess the validity of the modeling and predictions. Results: Despite large inter-individual variability, individual hCG decline profiles of the Model Set patients were well fitted by the model. The best discriminator of MTX resistant vs. sensitive patients was median P (cut-off = 23: ROC AUC = 77.3). P was the only significant predictor of resistance against WHO score items. The model was then applied to the Validation1 and 2 patient cohorts. Again, the decreasing hCG values were well fitted by the kinetic model. The predictive value of P for MTX resistance was confirmed: Validation1 ROC AUC = 82.1% (Sensitivity = 75%; Specificity = 89%) and Validation2 ROC AUC = 92.0% (Sensitivity = 94%; Specificity = 89%). Conclusions: We have validated population kinetic modeling of hCG decline profiles in a large cohort of low-risk GTN patients treated with MTX and confirmed its clinical utility for early prediction of MTX resistance.
Abstract 596: Differential cellular localization of Ephrin receptor tyrosine kinase B4 (EphB4) in melanoma progression
Authors: Nitin Chakravarti, Jonathan L. Curry, Roland L. Bassett, Victor G. Prieto
Journal: Cancer Research (2015)

Abstract Background: Melanoma is an aggressive cancer with high metastatic potential, and is the most lethal skin malignancies. Ephrin receptor tyrosine kinase B4 (EphB4) modulates diverse physiologic and developmental processes, and may play an important role in melanoma tumorigenesis. In addition, Mertens-Walker et al., reported nuclear translocalization of EphB4 and hypothesized that it may directly regulate gene expression contributing to more aggressive biologic behavior in prostate cancer (Cancer Res 2011; 71 (8 Suppl): Abstract nr 1085). It is unknown whether differential cellular expression of EphB4 contributes to the pathogenesis of melanoma. Methods: To explore the role of EphB4 in melanomagenesis, we have performed semiquantitative immunohistochemical analysis of EphB4 expression as measured by percentage and intensity of cells immunoreactive with anti-EphB4 in melanocytic nevi (n = 59), primary melanomas without metastasis during follow-up (n = 22), primary melanomas with metastasis (n = 17), and metastatic melanoma (n = 32). Results: Melanocytic nevi had significantly higher nuclear EphB4 expression (p = 0.007) and lower cytoplasmic EphB4 expression (p = 0.002) when compared to all categories of melanoma. In fact we observed a dramatic decrease in nuclear EphB4 expression in metastatic melanoma compared to melanocytic nevi (p = 0.0009). In contrast, compared to melanocytic nevi, cytoplasmic expression for EphB4 were higher in primary melanoma (p = 0.005) as well as in melanoma metastases (p = 0.03). Although there was no significant difference in nuclear or cytoplasmic EphB4 expression between primary melanomas with or without metastasis, primary melanomas without metastasis showed significantly higher number of tumor cells having intense nuclear immunoreactivity for EphB4 protein than did metastatic melanomas (p = 0.006). Conclusion: In conclusion, our data indicated that there is a gradual loss of nuclear EphB4 protein as well as increase in the levels of cytoplasmic expression of EphB4 protein associated with melanomagenesis. In addition, our results suggest a potential role for EphB4 as a therapeutic target in melanoma. Citation Format: Nitin Chakravarti, Jonathan L. Curry, Roland L. Bassett, Victor G. Prieto. Differential cellular localization of Ephrin receptor tyrosine kinase B4 (EphB4) in melanoma progression. [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 596. doi:10.1158/1538-7445.AM2015-596
441. Direct Comparison of EF1α and PGK Promoters Reveals Superior Performance of the PGK Promoter for Expression of the Common Gamma Chain in a Canine Model of In Vivo Foamy Virus Gene Therapy for Severe Combined Immunodeficiency
Authors: Christopher R. Burtner, Humbert Olivier, Patricia O'Donnell, Nicholas Hubbard, Daniel Humphrys, Jennifer E. Adair, Grant D. Trobridge, Troy R. Torgerson, Andrew M. Scharenberg, David J. Rawlings, Peter J. Felsburg, Hans-Peter Kiem
Journal: Molecular Therapy (2015)

Foamy viruses (FV) are ideal vectors for in vivo gene therapy because FV infection is non-pathogenic in people, FV are more resistant to serum inactivation than lentiviruses packaged with the vesicular stomatitis virus glycoprotein (VSV-G), and FV exhibit favorable proviral integration patterns compared to gammaretroviruses. In vivo gene therapy with a FV vector expressing the human common gamma chain (γC) under the short EF1α promoter results in a functional immune reconstitution in X-SCID dogs. However, T cell reconstitution occurred through the correction of a limited number of progenitors, possibly due to sub-therapeutic expression of the transgene from the EF1α promoter. To address this, we compared the efficacy of the EF1α and PGK promoters in a direct head-to-head competitive experiment by injecting two X-SCID pups with equal titers of the EF1α and PGK vectors marked with different fluorophores. A significant population of gene-marked lymphocytes appeared in the PGK arm 42 days post in vivo gene therapy, which continued to expand over time (Fig 1A). By 84 days post injection, lymphocyte gene marking in the competitive PGK arm reached 60% in both dogs. In contrast, the EF1α arm peaked at 42 days after in vivo gene therapy and never expanded above 10%. The expansion of gene-marked lymphocytes was followed by the appearance of a therapeutic level of CD3+ T cells in both dogs (Fig 1B). For comparison, this level of lymphocyte gene marking was achieved in only 2 of 5 dogs after 122 and 160 days, respectively, in our previous EF1α-only cohort. The dual-arm dogs exhibit normal peripheral blood cell counts, diverse TCRVB rearrangement, and functional response to T cell activating mitogen. These data highlight the utility of the competitive in vivo gene therapy experiments to explore key parameters of vector design and delivery for primary immunodeficiencies and other blood diseases.
A Phase II Trial of Sequential Treatment with Cytoreductive Therapy and Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation for Relapsed/Refractory Acute Myeloid Leukaemia, High-Risk MDS and Other High Risk Myeoid Malignancies: An Interim Report.
Authors: Dimitris A Tsitsikas, Dana Warcel-Sibony, Heather E. Oakervee, Samir G Agrawal, Matthew Smith, David C Taussig, Johannes de Vos, Elaine Stewart, Hannah Nicholas, John G. Gribben, James D Cavenagh
Journal: Blood (2010)
PO46NANOPARTICLE-ASSOCIATED CELL PENETRATING AND CYTOTOXIC PEPTIDES AS A NOVEL THERAPEUTIC STRATEGY FOR MALIGNANT GLIOMA
Authors: James Kelly, Toby W. Gould, Jennifer H. Ward, Kevin M. Shakesheff, James E. Dixon, Ruman Rahman
Journal: Neuro-Oncology (2015)

INTRODUCTION: Local neurosurgically-applied drug-delivery systems offer an opportunity to target glioblastoma (GBM) residual disease, but consideration must be given to the uptake of delivered agents once diffused from a drug-delivery depot. We assess the glycosaminoglycan-binding enhanced transduction of nanoparticles coated with genetically-engineered peptides, as a direct corollary to biomaterial-based localised drug-delivery systems. METHOD: GBM cells were transduced with biocompatible iron oxide magnetic nanoparticles (dMNP) coated with membrane docking (P21) and cell penetrating (8R) peptides. Protein transduction efficiency was determined by cytochemical staining and metabolic assays. To test the efficacy of the cytotoxic peptide SHEPHERDIN (SHEP), which disrupts the interaction of Survivin with HSP 90, GBM cells were exposed to acute doses of dMNP-P21-8R-SHEP and effects on metabolism measured. RESULTS: Nuclear and cytoplasmic protein transduction of dMNP-8R-P21 was evident in 100% of adult and paediatric GBM cells after 3h exposure, whereas after 16h, only 25% of uncoated nanoparticles traverse the cellular membrane by direct translocation and/or endocytosis. Protein-mediated transduction of dMNP-P21-8R-SHEP results in dose-dependent proliferation impairment of adult and paediatric GBM cells (IC50 25 µM and 20 µM respectively). CONCLUSION: Protein-mediated cellular transduction via membrane docking and cell penetrating peptides has the potential to deliver anti-cancer cargos to brain tumours and diversifies nanoparticle functionality. Early findings characterising SHEP-mediated GBM viability loss and controlled release of dMNP-P21-8R-SHEP from a polymeric microparticle drug-delivery matrix will be discussed.
Abstract 5220: Inflamed and wound recovered tumor microenvironment contributions to lymphatic-mediated metastasis
Authors: Darci Marie Fink, Alicia L. Connor, Philip M. Kelley, Richard M. Tempero, Michael A. Hollingsworth
Journal: Cancer Research (2015)

Abstract Despite the clinical importance of lymph node status in cancer staging, treatment decisions, and patient outcomes, little is known about the earliest events of lymphatic-mediated metastasis of tumor cells. Lymphatic vessels remodel dramatically in response to changes in the inflammatory status of a tissue. Inflammation induces lymphangiogenesis and the resolution of inflammation stimulates lymphatic vessel regression. This study addresses one of the fundamental questions in metastasis biology and places it in the context of a specific microenvironmental state: how does a tumor cell gain entrance to a lymphatic vessel to migrate to a regional lymph node and what is the contribution of inflammation to this process? We sought to better understand lymphatic-mediated metastasis of tumor cells during inflammatory lymphangiogenesis or the resolution of inflammation. We hypothesized that manipulating the inflammatory status of the tumor microenvironment would alter tumor cell and lymphatic endothelium biology to influence lymphatic-mediated metastasis. We have previously established a corneal model of sutured-induced inflammatory lymphangiogenesis and a complimentary experimental arm of inflammation resolution. We transitioned this platform into real-time live imaging studies by using this corneal model in our novel transgenic mouse model background that inducibly expresses fluorescent tdTomato protein in the lymphatic endothelium (LyveCreERT2tdT). CFSE-labeled syngeneic tumor cells were introduced systemically via tail vein injection or locally into a corneal micropocket. Two-color intravital fluorescent stereomicroscopy allowed us to simultaneously track the fate of CFSE+ tumor cells at single-cell resolution and the morphologic changes in the tdTomato+ corneal lymphatic vessels during inflammatory lymphangiogenesis and lymphatic vessel regression. One major finding was the low frequency of lymphatic-mediated metastasis during both inflammation and resolution. Ongoing work continues to explore the contributions of specific cytokines to tumor-lymphatic endothelium interactions and the unique properties of a wound-recovered tumor microenvironment. Citation Format: Darci Marie Fink, Alicia L. Connor, Philip M. Kelley, Richard M. Tempero, Michael A. Hollingsworth. Inflamed and wound recovered tumor microenvironment contributions to lymphatic-mediated metastasis. [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 5220. doi:10.1158/1538-7445.AM2015-5220
Clinical significance and predictive factors of early massive recurrence after radiofrequency ablation in patients with a single small hepatocellular carcinoma
Authors: Ju-Yeon Cho, Moon Seok Choi, Gil Sun Lee, Won Sohn, Jemma Ahn, Dong-Hyun Sinn, Geum-Youn Gwak, Yong-Han Paik, Joon Hyeok Lee, Kwang Cheol Koh, Seung Woon Paik
Journal: Clinical and Molecular Hepatology (2016)

Radiofrequency ablation (RFA) is one of the most frequently applied curative treatments in patients with a single small hepatocellular carcinoma (HCC). However, the clinical significance of and risk factors for early massive recurrence after RFA-a dreadful event limiting further curative treatment-have not been fully evaluated.In total, 438 patients with a single HCC of size ≤3 cm who underwent percutaneous RFA as an initial treatment between 2006 and 2009 were included. Baseline patient characteristics, overall survival, predictive factors, and recurrence after RFA were evaluated. In addition, the incidence, impact on survival, and predictive factors of early massive recurrence, and initial recurrence beyond the Milan criteria within 2 years were also investigated.During the median follow-up of 68.4 months, recurrent HCC was confirmed in 302 (68.9%) patients, with early massive recurrence in 27 patients (6.2%). The 1-, 3-, and 5-year overall survival rates were 95.4%, 84.7%, and 81.8%, respectively, in patients with no recurrence, 99.6%, 86.4%, and 70.1% in patients with recurrence within the Milan criteria or late recurrence, and 92.6%, 46.5%, and 0.05% in patients with early massive recurrence. Multivariable analysis identified older age, Child-Pugh score B or C, and early massive recurrence as predictive of poor overall survival. A tumor size of ≥2 cm and tumor location adjacent to the colon were independent risk factors predictive of early massive recurrence.Early massive recurrence is independently predictive of poor overall survival after RFA in patients with a single small HCC. Tumors sized ≥2 cm and located adjacent to the colon appear to be independent risk factors for early massive recurrence.