tbuckley/cabot-search huggingface dataset:
Fusion of the dendritic cell-targeting chemokine MIP3α to melanoma antigen Gp100 in a therapeutic DNA vaccine significantly enhances immunogenicity and survival in a mouse melanoma model
Authors: James T. Gordy, Kun Luo, Hong Zhang, Arya Biragyn, Richard B. Markham
Journal: Journal for ImmunoTherapy of Cancer (2016)

Although therapeutic cancer vaccines have been mostly disappointing in the clinic, the advent of novel immunotherapies and the future promise of neoantigen-based therapies have created the need for new vaccine modalities that can easily adapt to current and future developments in cancer immunotherapy. One such novel platform is a DNA vaccine fusing the chemokine Macrophage Inflammatory Protein-3α (MIP-3α) to an antigen, here melanoma antigen gp100. Previous published work has indicated that MIP-3α targets nascent peptides to immature dendritic cells, leading to processing by class I and II MHC pathways. This platform has shown enhanced efficacy in prophylactic melanoma and therapeutic lymphoma model systems.The B16F10 melanoma syngeneic mouse model system was utilized, with a standard therapeutic protocol: challenge with lethal dose of B16F10 cells (5 × 104) on day 0 and then vaccinate by intramuscular electroporation with 50 μg plasmid on days three, 10, and 17. Efficacy was assessed by analysis of tumor burden, tumor growth, and mouse survival, using the statistical tests ANOVA, mixed effects regression, and log-rank, respectively. Immunogenicity was assessed by ELISA and flow cytometric methods, including intracellular cytokine staining to assess vaccine-specific T-cell responses, all tested by ANOVA.We demonstrate that the addition of MIP3α to gp100 significantly enhances systemic anti-gp100 immunological parameters. Further, chemokine-fusion vaccine therapy significantly reduces tumor burden, slows tumor growth, and enhances mouse overall survival compared to antigen-only, irrelevant-antigen, and mock vaccines, with efficacy mediated by both CD4+ and CD8+ effector T cells. Antigen-only, irrelevant-antigen, and chemokine-fusion vaccines elicit significantly higher and similar CD4+ and CD8+ tumor-infiltrating lymphocyte (TIL) levels compared to mock vaccine. However, vaccine-specific CD8+ TILs are significantly higher in the chemokine-fusion vaccine group, indicating that the critical step induced by the fusion vaccine construct is the enhancement of vaccine-specific T-cell effectors.The current study shows that fusion of MIP3α to melanoma antigen gp100 enhances the immunogenicity and efficacy of a DNA vaccine in a therapeutic B16F10 mouse melanoma model. This study analyzes an adaptable and easily produced MIP3α-antigen modular vaccine platform that could lend itself to a variety of functionalities, including combination treatments and neoantigen vaccination in the pursuit of personalized cancer therapy.
miR-138-5p contributes to cell proliferation and invasion by targeting Survivin in bladder cancer cells
Authors: Rong Yang, Minghui Liu, Hongwei Liang, Suhan Guo, Xu Guo, Min Yuan, Huibo Lian, Xiang Yan, Shiwei Zhang, Xi Chen, Feng Fang, Hongqian Guo, Chenyu Zhang
Journal: Molecular Cancer (2016)

Survivin (encoded by the gene BIRC5) plays an important role in the carcinogenesis of bladder cancer. Identifying miRNAs that target Survivin in the setting of bladder cancer will help to develop Survivin-based therapies for bladder cancer.The expression levels of miR-138-5p and Survivin protein were measured in 12 resected bladder cancer specimens. The correlation between miR-138-5p and Survivin was further examined by evaluating Survivin expression in human bladder cancer cell lines that either overexpressed or knocked down miR-138-5p. A luciferase reporter assay was performed to test the direct binding of miR-138-5p to the target gene BIRC5. We also investigated the biological role of miR-138-5p targeting to Survivin in bladder cancer cell lines both in vivo and in vitro.In this study, we found that the Survivin protein was either absent or weakly expressed in normal adjacent tissues and consistently up-regulated in bladder cancer tissues; however, the mRNA levels did not vary as much, suggesting that a post-transcriptional mechanism was involved. Because microRNAs are powerful post-transcriptional regulators of gene expression, we used bioinformatic analyses to search for microRNAs that could potentially target BIRC5 in the setting of bladder cancer. We identified 2 specific targeting sites for miR-138-5p in the 3' untranslated region (3'-UTR) of BIRC5. We further identified an inverse correlation between miR-138-5p and Survivin protein levels in bladder cancer tissue samples. By overexpressing or knocking down miR-138-5p in bladder cancer cells, we experimentally confirmed that miR-138-5p directly recognizes the 3'-UTR of the BIRC5 transcript and regulates Survivin expression. Furthermore, the biological consequences of the targeting of BIRC5 by miR-138-5p were examined in vitro via cell proliferation and invasion assays and in vivo using a mouse xenograft tumor model. We demonstrated that BIRC5 repression by miR-138-5p suppressed the proliferative and invasive characteristics of bladder cancer cells and that miR-138-5p exerted an anti-tumor effect by negatively regulating BIRC5 in a xenograft mouse model.Taken together, our findings provide the first clues regarding the role of miR-138-5p as a tumor suppressor in bladder cancer by inhibiting BIRC5 translation.
Abstract 3189: Tunneling nanotube formation is significantly upregulated in invasive cancer cells
Authors: Snider Desir, Subbaya Subramanian, Clifford Steer, Emil Lou
Journal: Cancer Research (2015)

Abstract Introduction: Intercellular communication is critical for cancer growth and progression. Research to date has focused on gap junctions, micro-vesicles/exosomes, and diffusible factors. There is limited understanding of how efficient cell-to-cell communication occurs between distant cells in the complex tumor microenvironment. Tunneling nanotubes (TNTs) are thin, non-adherent actin filament-based, open conduits that facilitate direct sharing of various cellular cargos between cells. TNTs can be 50-800 nanometers in diameter and up to several hundred micrometers in length in vitro. Our lab was the first to provide in vivo evidence of TNTs in human solid tumors. We hypothesized that TNT formation is significantly upregulated in human cancers compared to their non-malignant counterparts. In this study, we examined the rate of TNT formation in cell lines from multiple human cancers. Methods: Cell lines from four cancers (colon, mesothelioma, pancreatic, and ovarian cancer) were plated at similar density in 6-well tissue culture plates. The number of TNTs and cells in 10 randomly chosen fields of each well were quantified every 24 hrs for up to 96 hrs and representative images were taken. Experiments were performed in duplicate for each cell line. Results: The number of TNTs per cell (TNTs/cell), which we have titled “TNT index,” was calculated in order to control for cell proliferation. The ratio of TNTs formed between malignant colorectal cells compared benign adenoma ranged from 20:1 to 100:1 by 96 hrs. For mesothelioma, malignant:mesothelial TNTs/cell ratio ranged from 8:1 to 78:1 over 72 hrs. The mesothelioma cells were too confluent at 96 hrs to quantify TNTs. The pancreatic malignant:stellate human pancreatic ductal epithelial TNTs/cell ratio ranged between 2:1 to 63:1. Interestingly, we found that non-malignant ovarian epithelial (IOSE) cells had a significantly higher rate of TNT formation than malignant ovarian cells. Conclusions: We have demonstrated that malignant cells have significantly higher rates of TNT formation compared to stromal or premalignant cells of their corresponding tumor. TNTs potentially provide malignant cells a direct route for transmitting influential messages across long distances in the complex tumor microenvironment. We believe that upregulation of TNTs in cancer may amplify cellular cross-talk and thus increase rates of tumor recurrence and invasion. Citation Format: Snider Desir, Subbaya Subramanian, Clifford Steer, Emil Lou. Tunneling nanotube formation is significantly upregulated in invasive cancer 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 3189. doi:10.1158/1538-7445.AM2015-3189
Group 5 drugs for multidrug-resistant tuberculosis: individual patient data meta-analysis
Authors: Greg J. Fox, Andrea Benedetti, Helen Cox, Won-Jung Koh, Piret Viiklepp, Shama Ahuja, Geoffrey Pasvol, Dick Menzies
Journal: European Respiratory Journal (2016)

The role of so-called “group 5” second-line drugs as a part of antibiotic therapy for multidrug-resistant tuberculosis (MDR-TB) is widely debated. We performed an individual patient data meta-analysis to evaluate the effectiveness of several group 5 drugs including amoxicillin/clavulanic acid, thioacetazone, the macrolide antibiotics, linezolid, clofazimine and terizidone for treatment of patients with MDR-TB. Detailed individual patient data were obtained from 31 published cohort studies of MDR-TB therapy. Pooled treatment outcomes for each group 5 drug were calculated using a random effects meta-analysis. Primary analyses compared treatment success to a combined outcome of failure, relapse or death. Among 9282 included patients, 2191 received at least one group 5 drug. We found no improvement in treatment success among patients taking clofazimine, amoxicillin/clavulanic acid or macrolide antibiotics, despite applying a number of statistical approaches to control confounding. Thioacetazone was associated with increased treatment success (OR 2.6, 95% CI 1.1–6.1) when matched controls were selected from studies in which the group 5 drugs were not used at all, although this result was heavily influenced by a single study. The development of more effective antibiotics to treat drug-resistant TB remains an urgent priority.
Patterns of Relapse and Progression in Multiple Myeloma Patients Treated with Conventional and Novel Agent-Based Therapy: A Single Centre Experience
Authors: Bethany E Monteith, Esther Masih-Khan, Eshetu G Atenafu, Christine Chen, Anca Prica, Donna Reece, Rodger Tiedemann, Suzanne Trudel, Vishal Kukreti
Journal: Blood (2015)
NCCTG N0572 phase I/II trial of sorafenib and temsirolimus in patients with recurrent glioblastoma: A North Central Cancer Treatment Group study.
Authors: K. A. Jaeckle, D. Schiff, S. K. Anderson, E. Galanis, P. J. Stella, P. J. Flynn, J. N. Sarkaria, B. W. Scheithauer, B. J. Erickson, J. C. Buckner
Journal: Journal of Clinical Oncology (2011)

2033 Background: Hyperactivation of Ras/Raf/MEK/ERK (MAPK) and PI3K/Akt/mTOR signaling contributes to proliferation and inhibition of apoptosis in GBM. In NCCTG N997B, modest activity of temsirolimus (mTOR inhibitor) was observed in recurrent GBM, and others have demonstrated limited activity of sorafenib (Raf, PDGFR, VEGFR inhibitor) in GBM. Methods: We initiated a Phase I/II study of sorafenib plus temsirolimus for VEGF-inhibitor naïve recurrent GBM patients (pts) following prior surgery, RT, and < 2 prior chemo regimens. A Phase I dose-escalation design was employed, utilizing sorafenib (PO bid /D) and temsirolimus (IV /wk) until progression. The study used a 2-stage Fleming version of Simon’s Optimal design, powered to detect an increase in PFS6 from 8% to 23%, which required 41 evaluable pts. The primary endpoint was PFS6; secondary endpoints were OS, TTP, and ORR. Data will be mature for the primary endpoint analysis in April 2011. Toxicity (TOX) was assessed using CTC ver 3.0. Results: The Phase I MTD was sorafenib 200 mg bid/D and temsirolimus 20mg/M2/wk. At interim efficacy analysis the study met the decision rule, and full accrual ensued. To date, median TTP in 37 progressing patients was 2.6 mos. (range, 0.1-15.2). For 29 pts who have expired to date, median OS was 4.2 mos (range, 0.6-25.2). Sixteen pts are alive and 8 have not yet progressed (median F/U 4.9 mos; max, 20.7 mos). Overall RR was 10.2% (4/39; PR=1; REGR=3). Grade 3+ non-heme TOX was observed in 55% (23/42 evaluable pts; fatigue=8, hypophosphatemia =7, triglycerides= 4, cholesterol =5, weakness=3. Grade 4 heme TOX occurred in 7% (3/42 evaluable pts; neutropenia=2, lymphopenia=2, leukopenia=1, thrombocytopenia=1). 17.5% (7/40) of pts went off treatment due to toxicity. Conclusions: Limited activity of the combination of sorafenib and temsirolimus was observed, and with moderate toxicity. A separate study arm is ongoing for pts failing prior VEGF inhibitors, exploring for activity in this resistant cohort. Supported by NCI CA-25224
Clonal Profile Analysis of Leukemic Progenitors and Diagnosis Blast Cells in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia
Authors: Marinella Veltroni, Maddalena Paganin, Chiara Frasson, Giulia Fabbri, Antonio Marzollo, Elena Seganfreddo, Emanuela Giarin, Elena Fortunato, Maurizio Aricó, Giuseppe Basso
Journal: Blood (2008)
Azacitidine Is Effective in Patients with Low / Intermediate-1 Risk Myelodysplastic Syndrome Managed in Community Based Practice: Preliminary Data From the Spanish Compassionate Use Registry.
Authors: Regina Garcia, Dunia de Miguel, Maria-Teresa Bernal, Mar Tormo, Guillermo Sanz, Raquel de Paz, Antonio Figueredo, Maria E Amutio, José L. Guzmán
Journal: Blood (2009)
280. Lentiviral-Mediated Gene Therapy Restores B Cell Homeostasis and Tolerance in Wiskott-Aldrich Syndrome Patients
Authors: Maria Carmina Castiello, Francesca Pala, Henner Morbach, Jean-Nicolas Schickel, Samantha Scaramuzza, Nicolas Chamberlain, Neil Romberg, Francesca Ferrua, Fabio Candotti, Mirjam van der Burg, Luigi Naldini, Alessandro Aiuti, Eric Meffre, Marita Bosticardo, Anna Villa
Journal: Molecular Therapy (2016)

Wiskott-Aldrich Syndrome (WAS) is a severe X-linked primary immunodeficiency characterized by micro-thrombocytopenia, eczema and increased risk of infections, autoimmunity and tumors. Allogeneic hematopoietic stem cell (HSC) transplantation is a recognized curative treatment for WAS, but when a matched donor is not available, administration of WAS gene-corrected autologous HSCs represents a valid alternative therapeutic approach. Since alterations of WAS protein (WASp)-deficient B lymphocytes contribute to immunodeficiency and autoimmunity in WAS, we followed the B cell reconstitution in 4 WAS patients treated by lentiviral vector-gene therapy (GT) after a reduced-intensity conditioning regimen combined with anti-CD20 administration. We analyzed the B cell subset distribution in the bone marrow and peripheral blood by flow cytometry and the autoantibody profile by a high-throughput autoantigen microarray platform before and after GT. Lentiviral vector-transduced progenitor cells were able to repopulate the B cell compartment with a normal distribution of transitional, naïve and memory B cells. The reduction in the proportion of autoimmune-associated CD21low B cells and in the plasma levels of B cell-activating factor was associated with the decreased autoantibody production in WAS patients after GT. Then, we evaluated the functionality of B cell tolerance checkpoints by testing the reactivity of recombinant antibodies isolated from single B cells. Before GT, we found a decreased frequency of autoreactive new emigrant/transitional B cells in WAS patients, suggesting a hyperfunctional central B cell checkpoint in the absence of WASp. In contrast, high frequency of polyreactive and Hep2 reactive clones were found in mature naïve B cells of WAS patients, indicating a defective peripheral B cell checkpoint. Both central and peripheral B cell tolerance checkpoints were restored after GT, further supporting the qualitative efficacy of this treatment. In conclusion, WASp plays an important role in the regulation of B cell homeostasis and in the establishment of B cell tolerance in humans and lentiviral-mediated GT is able to ameliorate the functionality of B cell compartment contributing to the clinical and immunological improvement in WAS patients.
18F-FDG PET/CT Features of Chronic Sclerosing Sialadenitis Presenting as Localized IgG4-Related Disease
Authors: Nobuo Kashiwagi, Eisuke Enoki, Chisa Hosokawa, Kenta Sakaguchi, Takamichi Murakami
Journal: Clinical Nuclear Medicine (2016)

Chronic sclerosing sialadenitis is a benign inflammatory condition that most commonly affects the submandibular gland in elderly individuals. It is currently known to belong to the spectrum of IgG4-related systemic diseases, which is reflected by systemic involvement on 18F-FDG PET/CT images. We presented a case of a 73-year-old man with histologically proven IgG4-related chronic sclerosing sialadenitis, unilateral localized form, on whole-body 18F-FDG PET/CT images that mimicked submandibular carcinoma with lymph node metastasis.
246. Intra-Articular Gene Transfer of miR-15b Attenuates Molecular Mediators of Hemophilic Arthropathy in a Murine Model of Hemophilia
Authors: Dwaipayan Sen, Praveen K. Vemula, Giridhara R. Jayandharan
Journal: Molecular Therapy (2015)

Hemophilic arthropathy is a major co-morbidity in patients with hemophilia and caused by recurrent bleeds (hemarthrosis) in the joints. Despite the availability of protein replacement therapy, newer and targeted strategies are required to prevent the onset of blood-induced arthropathy, particularly in patients who develop inhibitors. Thus, a thorough understanding of the molecular mediators contributing to joint damage becomes pivotal to not only pinpoint mechanisms but also reveal biomarkers of the disease and targets for further intervention. Recently, in a murine model of hemophilia A, we identified that nuclear factor (NF)-kB and its associated factors-hypoxia inducing factor (HIF)-1/2α, vascular epithelial growth factor (VEGF)-α and matrix metallo proteinases(MMP) 3, contribute to the development of arthropathy [J Thromb Haemost 2013; 11:293-306]. In addition, several microRNA (miR) were also differentially expressed following an episodic bleeding. One of these, miR-15b is known to modulate expression of hypoxic and pro-angiogeneic genes. To document the expression pattern of miR-15b during development of arthropathy, the acute hemarthrosis model of hemophhilia A was studied on 1,3,7 and 24h after a single-injury and the chronic hemarthrosis model was studied at 60, 75 and 90 days after multiple injury. We then measured miR-15b levels by qPCR at each one of these time points. miR-15b was downregulated (~1 to 4 fold) from 3hrs after a single bleeding episode to the 90-day time point where the animals have 2 to 6 bleedings into the joint cavity. The maximal down regulation (-4 fold) of miR-15b was observed at 60 days. These data suggest that miR-15b is consistently and progressively repressed from the onset of synovitis to the development of arthropathy in the murine model of hemophilia A. To test if intra-articular overexpression of this miR modulates the molecular biomarkers of joint disease, we administered an adeno-associated virus (AAV)5 vector encoding miR15b into the joints of a chronic model of hemarthrosis. Our results demonstrate that miR15b over-expression downregulates markers such as VEGF-α, HIF 2α (~70% and ~34% respectively) in affected joints. In addition, co-administration of AAV5-miR15b intra-articularly and AAV2-factor VIII intravenously, attenuated the expression of MMPs 1, 3, 9 and 14 (~14% to 60%). Sixty days after intra-articular gene therapy, there was a considerable decrease in the joint scores of animals treated intra-articularly with AAV5-miR-15b when compared to the control AAV5-luc vector (1.6 Vs 2.6). These data provide the first evidence that targeted and local AAV mediated gene delivery of miRs can be potentially used as therapeutic agent to ameliorate hemophilic arthropathy.
516. Chimeric Antigen Receptors With Distinct Signaling Domains Can Reprogram T Cells
Authors: Omkar U. Kawalekar, Roddy S. O'Connor, Joseph Fraietta, Sonia Guedan, John Scholler, Michael C. Milone, Carl H. June
Journal: Molecular Therapy (2015)

CARs have shown great promise in the field of targeted immunotherapy against cancer. These serve as a powerful tool that help redirect T cells to recognize and target tumor cells. Despite extensive clinical testing, the underlying attributes that ensure optimal T cell survival and effector functions are yet to be delineated. Here we analyze the effects of different signaling domains on the proliferation and function of CAR T cells. We report how different CAR costimulatory domains can affect cell longevity.
565. CCR5-Uco-TALEN – A Novel Transcription Activator-Like Effector Nuclease That Mediates High-Efficiency Knockout of HIV Co-Receptor CCR5 in Primary T Cells After mRNA Transfection
Authors: Ulrike Mock, Rafal Machowicz, Ilona Hauber, Stefan Horn, Pierre Abramowski, Belinda Berdien, Joachim Hauber, Boris Fehse
Journal: Molecular Therapy (2015)

Besides its physiological role, the chemokine receptor CCR5 plays an essential part during HIV infection, acting as the co-receptor for so-called R5-tropic strains that usually mediate initial infection. Notably, homozygosity for CCR5D32, a natural deletion variant of CCR5, largely confers resistance towards HIV infection. Consequently, CCR5 has been proposed as a promising target for HIV therapy. The interest in using CCR5 as a therapeutic target has increased even further after the first report on the cure from HIV in an individual ("Berlin patient") who received an allogeneic stem cell graft from a CCR5D32-homozygous donor to treat his acute leukemia. Since allogeneic transplantation is not a realistic treatment scenario for HIV, genetic disruption of CCR5 by the means of designer nucleases was proposed as an auspicious gene-therapy approach. We developed a novel transcription activator-like effector nuclease (TALEN), CCR5-Uco-TALEN for highly specific CCR5 knockout. We established efficient TALEN delivery into primary T lymphocytes using mRNA electroporation, a gentle and truly transient gene-transfer technique. After mRNA transfection, CCR5-Uco-TALEN routinely mediated high-rate CCR5 knockout (>90% in PM1 and >50 % in primary T cells) combined with low off-target activity, as demonstrated by flow cytometry, next-generation sequencing and a newly devised, very handy digital-PCR technique. Importantly, CCR5-edited cells were not only resistant towards HIV-derived lentiviral vectors, but also protected from infection with the wild-type CCR5-tropic HIV-1BaL strain. Indeed, 12-day exposure to HIV-1BaL resulted in almost complete suppression of viral replication as well as selection of CCR5-gene edited T cells. In summary, we have introduced a novel TALEN for high-efficiency targeted CCR5 knockout. The proposed mRNA-based gene-editing protocol does not rely on gene-modified organisms and is thus highly compatible with large-scale production and GMP requirements. Together, CCR5-Uco-TALEN and the proposed mRNA-based transfection strategy should therefore be excellently suited for clinical translation.
Clinical outcomes in 21 patients with gastrointestinal stromal tumor(GIST)treated in phase I trials: the NCCHE Experience
Authors: Yoshiaki Nagatani, Kohei Shitara, Hideaki Bando, Wataru Okamoto, Takashi Kojima, Takayuki Yoshino, Toshirou Nishida, Toshihiko Doi
Journal: Annals of Oncology (2015)
Risk Factors of Outcomes after Haploidentical Hematopoietic Stem Cell Transplants for Children with High Risk Acute Leukaemia. A Survey on Behalf of the EBMT.
Authors: Jaqueline Cornish, Thomas Klingebiel, Myriam Labopin, Phillip J. Darbyshire, Rachel Hough, Franco Locatelli, Dietrich Niethammer, Giorgio Dini, Vanderson Rocha
Journal: Blood (2005)
Identification of BDCA-2 and High Levels of CD123 Expression as Useful Markers for the Diagnosis of Plasmacytoid Dendritic Cell Leukemia.
Authors: Francine Garnache-Ottou, Marie-Christine Jacob, Sabeha Biichle, Laurence Chaperot, Franck Trimoreau, Joel Plumas, Pierre Tiberghien, Philippe Saas, Jean Feuillard
Journal: Blood (2005)