tbuckley/cabot-search huggingface dataset:
108. Pseudotyping Baculovirus Based Vectors for Enhanced In Vitro and In Vivo Delivery
Authors: Jondavid de Jong, Laura vanLieshout, Jacob P. vanVloten, Sarah K. Wootton
Journal: Molecular Therapy (2016)

Autographa californica multinucleopolyhedrovirus (AcMNPV) is the best-characterized baculovirus and the platform for well established recombinant protein and vaccine production technologies. In addition to countless examples of recombinant protein production, two commercially available vaccines (Cervarix, and Provenge) are produced via AcMNPV based expression technologies. More recently, Baculovirus based vectors have also garnered attention as gene delivery vectors, including for use in human gene therapy, because of several key characteristics. Baculoviruses can transduce cells of human origin, albeit at MOIs of 100-200, can accommodate large gene insertions (>38 kb), allowing for the inclusion of multiple genes, large promoters, and regulatory elements, are non-replicative in mammalian cells, do not integrate into mammalian chromosomes, and humans lack pre-existing immunity to baculoviruses. In vivo, Baculoviruses have been used to successfully transduce a wide variety of organs from mammalian species, such as mice, rats and rabbit. Despite these reports there is little information on the overall tissue distribution of in vivo delivered baculovirus. Here we test the transduction efficiency of wildtype and pseudotyped baculovirus vectors in various cell lines, and define the biodistribution of these vectors in C57BL/6 mice via intravenous, intrahepatic, and intranasal installation. In vitro, wildtype virus demonstrated good transduction of HEK293 cells and moderate to low transduction of cells originating from the lung and liver. Amongst the pseudotypes tested, the greatest transduction achieved across all cell types (in vitro) was a recombinant displaying a cell-penetrating-peptide-GP64 fusion protein (CPP-GP64), which demonstrated high levels of transduction across all cell lines tested. In vivo, overall transduction by wildtype virus was restricted to the kidneys and liver, and only at moderate to low levels. Similar to the in vitro results, inclusion of a CPP-GP64 greatly enhanced the transduction levels as well as expanded the tissue distribution of in vivo delivered vector.
Prospective Weekly Multiple Viral Monitoring in Blood Using Multiplex PCR Assay Early After Hematopoietic Stem Cell Transplantation
Authors: Taichi Ikebe, Rumiko Tsuchihashi, Yuki Asano-Mori, Hikari Ota, Yuki Taya, Aya Nishida, Sachi Tainosyo, Kazuya Ishiwata, Masanori Tsuji, Hideki Araoka, Naoyuki Uchida, Koji Izutsu, Kazuhiro Masuoka, Atsushi Wake, Akiko Yoneyama, Shigeyoshi Makino, Shuichi Taniguchi
Journal: Blood (2011)
Abstract 2361: TGFβ signaling deficiency enhances tumor associated inflammation in colon cancer
Authors: Daniel R. Principe, Brian DeCant, Riley J. Mangan, Elizabeth A. Wayne, Andrew M. Diaz, Dominic Vitello, Hidayatullah G. Munshi, Paul Grippo, Barbara Jung
Journal: Cancer Research (2015)

Abstract In early colon cancer development, there is considerable evidence suggesting that transforming growth factor-β (TGFβ) serves as a tumor suppressor due to its growth-inhibitory effects in the epithelium. This is in contrast to observations suggesting that in advanced disease, TGFβ promotes tumor progression by contributing to metastasis. Therefore, to better understand the effects of TGFβ signaling on colon cancer, we examined the effect of global or epithelial reduction in TGFβ signaling on tumor progression in the APC murine model of colon cancer. Initially, we examined the relationship between TGFβ signaling and inflammation in human colon cancer specimens. We found that loss of SMAD4 in epithelial cells correlates with increased inflammation in tissue from colon cancer patients. Moreover, APC mice with global TGFBR deficiency (ATG mice) demonstrated increased inflammation that was also associated with loss of SMAD4 in epithelial cells. In contrast, APC mice with epithelial loss of TGFBR signaling (ATC mice) do not demonstrate loss of SMAD4, but have even more pronounced inflammation concomitant with rectal bleeding and prolapse, significant weight loss, the presence of crypt abscesses and lymphoid aggregates, and increased mortality. Similarly, ATC mice, in contrast to the ATG and the APC mice, show markedly increased tumor infiltrating macrophages, splenic macrophages, and serum levels of the cancer-associated cytokines IL8, TGFβ1, and TNFα. Overall, these findings demonstrate that loss of TGFβ signaling, particularly in epithelial cells, dramatically worsens tumor progression. Yet, the attempt to reduce metastasis by treating colon cancer patients with TGFβ inhibitors may result in worse outcome by invoking a robust inflammatory response. Citation Format: Daniel R. Principe, Brian DeCant, Riley J. Mangan, Elizabeth A. Wayne, Andrew M. Diaz, Dominic Vitello, Hidayatullah G. Munshi, Paul Grippo, Barbara Jung. TGFβ signaling deficiency enhances tumor associated inflammation in colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2361. doi:10.1158/1538-7445.AM2015-2361
603. Novel DNA-Shuffled AAV Capsids Show Robust and Unique Gene Delivery and Expression Profiles in the CNS Via Intrathecal Injection
Authors: Bin Xiao, Zhenghua Yuan, Lin Yang, Chunping Qiao, Jianbin Li, Juan Li, Xiao Xiao
Journal: Molecular Therapy (2015)

Aim: Adeno-associated virus (AAV) has great potential for treatment of central nervous system (CNS) diseases. Currently, a few AAV serotypes including AAV9 effectively deliver genes in the CNS. We aimed to screen more AAV serotypes for expression in CNS and compare them to AAV9. Material and methods: Using an existing library containing shuffled capsid genes of AAV serotypes 1 through 9, we characterized a few novel capsids for high expression in the CNS in vivo. Three novel serotypes, AAVH43, AAVH48, and AAVHH67 containing the reporter gene lacZ driven by a CMV promoter were injected in C57BL/6 mice and AAV9 was included as a positive control group (n=4 per group). Prior to vector injection, 25% mannitol solution 200μl was given by tail vein to deduce intracranial pressure. Twenty minutes later, 10μl of virus vectors (1×1011 vg) were slowly injected into the cerebrospinal fluid (CSF) at the intervertenral space between lumbar vertebrae L3 and L4 by a 33-gauge needle connected to a 50μl Hamilton syringe with PE10 tubing. Two weeks later, tissue samples were harvested for lacZ staining and immunostaining. Results: LacZ gene delivered by AAVH43, AAVH48, and AAVHH67 vectors expressed efficiently and similarly to AAV9 in the spinal cord by intrathecal injection. The entire spinal cord from the lumbar up to cervical region showed gene expression. The infected cells were mainly distributed in the posterior funiculus and gray matter. In addition, all 4 vectors infected dorsal root ganglia neurons very efficiently. Immunostaining showed AAVH43, AAVH48 and AAVHH67 vectors with a CMV promoter infected mainly neurons but not glial cells, similar to AAV9. In addition, AAVH43 and AAVH48 had some common characteristics and infected cerebellar cortex much more efficiently than AAV9. Those neurons showed distinctive morphology as Purkinje cells. Further confirmation with cell-type specific antibodies is needed. Conclusion: The AAVH43, AAVH48 and AAVHH67 vectors have similar ability to infect the spinal cord and dorsal root ganglia, equivalent to AAV9, when delivered by intrathecal injection. Moreover, the cerebellar cortex is more susceptible to AAVH43 and AAVH48 infection. With further investigation, the three novel AAV serotypes could be suitable alternative candidates for CNS gene delivery and therapy.
Pre-Transplant Bone Status Evaluation in Patients Undergoing Allogeneic Stem Cell Transplantation.
Authors: Ibrahim Yakoub-Agha, Cecile Wibaux, Leonardo Magro, Audrey Juilliard, Isabelle Legroux-Gerot, Valerie Coiteux, Jean-Pierre Jouet, Bernard Cortet
Journal: Blood (2008)
438. Oncolytic Immunotherapy for Treatment of Breast Cancer, Including Triple-Negative Breast Cancer
Authors: Simona Bramante, Anniina Koski, Ilkka Liikanen, Minna Oksanen, Timo Joensuu, Sari Pesonen, Akseli Hemminki
Journal: Molecular Therapy (2015)

Breast cancer is a heterogeneous disease, characterized by several distinct biological subtypes associated with specifical biological behavior and different clinical outcomes. Triple-negative breast cancer (TNBC) is defined as estrogen receptor (ER)-negative, progesterone receptor (PR)-negative and lacking overexpression of human epidermal growth factor receptor 2 (HER2). Among all the breast cancer subtypes, TNBC (10-15% of breast cancers) is associated with a worse prognosis. Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules. Cyclophosphamide (CP) is a chemotherapy drug that works by slowing or stopping cell growth. At higher doses, CP is associated with increased cytotoxicity and immunosuppression, while at low continuous dosage it shows immunostimulatory and antiangiogenic properties. Therefore, the combination of oncolytic immunovirotherapy with low-dose CP is an appealing approach. We investigated the potency of oncolytic adenovirus Ad5/3-D24-GMCSF on a TNBC cell line and animal models, in combination with low-dose CP or its main active metabolite 4-hydroxycyclophosphamide (4-HP-CP). Furthermore, we summarized the breast cancer-specific human data from the Advanced Therapy Access Program (ATAP). Low-dose CP effectively increased the efficacy of Ad5/3-D24-GMCSF in vitro and in a TNBC xenograft mouse model. In ATAP, treatments appeared safe and well-tolerated. Fourteen out of sixteen breast cancer patients treated were evaluable for possible therapy benefit with modified RECIST criteria: one patient had minor response, four had stable disease, and nine had progressive disease. One patient was alive at 941 days after treatment. Ad5/3-D24-GMCSF in combination with low-dose CP showed promising efficacy in preclinical studies and possible antitumor activity in breast cancer patients refractory to other forms of therapy. This preliminary data supports continuing the clinical development of oncolytic adenoviruses for treatment of breast cancer, including TNBC.
Abstract 1488: Reduced Renal Function is Associated with Increased Aortic Stiffness but not with Left Ventricular Systolic or Diastolic Dysfunction in Patients Undergoing Cardiac Catheterization for Coronary Artery Disease
Authors: Hidekatsu Fukuta, Nobuyuki Ohte, Seiji Mukai, Kaoru Asada, Kazuaki Wakami, Genjiro Kimura
Journal: Circulation (2008)

Although reduced renal function is associated with increased risk for cardiovascular events in various populations, including coronary artery disease (CAD) patients, mechanisms underlying the association remain to be fully elucidated. We hypothesized that increased aortic stiffness and left ventricular (LV) dysfunction may contribute to the increased risk associated with reduced renal function in CAD patients. We studied 348 consecutive patients (age, 67 ± 8 years; males, 77%) undergoing cardiac catheterization for evaluation of CAD. We stratified patients according to estimated glomerular filtration rate (eGFR) of 35 and 60 ml/min/1.73m 2  and examined the relation of eGFR with augmentation index (AI) of ascending aortic pressure and indices of LV systolic and diastolic function (ejection fraction [EF], time constant of decrease in LV pressure [Tau] and LV end-diastolic pressure [EDP]). eGFR correlated with AI (P for trend  0.1; Figure). After adjustment for potential confounders, including age, height, mean aortic pressure, heart rate, traditional cardiovascular risk factors and the severity of CAD, the correlation of eGFR with AI remained significant (AI, adjusted mean ± SE, 0.423 ± 0.013, 0.402 ± 0.008, and 0.385 ± 0.018, for the lower, middle and higher tertiles of eGFR, respectively, P for trend
A polymorphism in the coding sequence of <i>WT1</i> is an independent prognostic marker in 1,101 patients with lobular breast cancer.
Authors: M. Heuser, F. Damm, P. Schuermann, M. Zucknick, M. Shah, P. Harrington, P. Pharoah, M. Schmidt, A. Broeks, R. van Hien, R. A. Tollenaar, H. Nevanlinna, T. Heikkinen, K. Aittomaki, C. Blomqvist, J. Krauter, P. Hillemanns, A. Ganser, T. Park-Simon, T. Dork
Journal: Journal of Clinical Oncology (2011)

10558 Background: We have recently shown that a single nucleotide polymorphism (SNP) in WT1 exon 7 (rs16754) is associated with prognosis in patients with acute myeloid leukemia. To test whether SNP rs16754 is also associated with outcome in other cancers, we investigated the role of this SNP as a candidate polymorphism for breast cancer (BC) survival in a large cohort of BC patients in the context of other prognostic markers. Methods: WT1 SNP rs16754 was genotyped using a TaqMan genotyping assay and genomic DNA from 8,337 BC patients from four European studies of the Breast Cancer Association Consortium (BCAC). The effect of rs16754 genotypes on overall survival was assessed in univariate and multivariate analysis adjusting for known prognostic markers. Results: The minor allele of SNP rs16754 was found heterozygous in 25.2% and homozygous in 2.8% of all studied BC patients. Patient characteristics and pathologic findings were similarly distributed between patients homozygous for the major allele compared to patients heterozygous or homozygous for the minor allele. Overall survival (OS) of patients with lobular BC and at least one minor allele of WT1 SNP rs16754 was significantly shorter compared to patients with lobular BC who were homozygous for the major allele (HR 1.54, 95% CI 1.15 to 2.06, P=.004; 10-year OS 71% vs 81%. Importantly, breast cancer specific survival (BCSS) was significantly shorter in lobular BC patients with at least one minor allele of SNP rs16754 compared to patients who were homozygous for the major allele (HR, 1.55, 95% CI 1.13 to 2.14 , P=.007). In patients with invasive lobular BC (n=1,101), SNP rs16754 status was an independent predictor of OS and BCSS in multivariate analysis (HR 1.44, 95% CI 1.06-1.94, P=.018 and HR 1.49, 95% CI 1.07-2.07, P=.018, respectively) adjusting for nodal status, ER, PR, HER2 status, tumor grade and age. The unfavorable effect of SNP rs16754 became most apparent five years after diagnosis, and was strongest in hormone-receptor positive and in younger patients with lobular BC. Conclusions: WT1 SNP rs16754 may therefore become useful as an independent poor-risk marker in lobular breast cancer patients that might improve risk and treatment stratification.
Protein Tyrosine Phosphatase Receptor Type O (PTPRO) Exhibits Tumor Suppressor Properties in K562 Cells by Dephosphorylating Bcr-Abl.
Authors: Sarmila Majumder, Tasneem Motiwala, Kalpana Ghoshal, Huban Kutay, Jharna Datta, David Lucas, John C. Byrd, Samson T. Jacob
Journal: Blood (2007)
Abstract 4823: Serum level of urokinase plasminogen activator receptor is suggested as diagnostic and prognostic biomarker in prostate cancer
Authors: Sven Wach, Omar Al-Janabi, Katrin Weigelt, Kersten Fischer, Thomas Greither, Marios Marcou, Gerit Theil, Elke Nolte, Hans-Juergen Holzhausen, Robert Stoehr, Verena Huppert, Arndt Hartmann, Paolo Fornara, Bernd Wullich, Helge W. Taubert
Journal: Cancer Research (2015)

Abstract Background: This study aimed to assess the applicability of the soluble urokinase plasminogen activator receptor (suPAR) protein as a diagnostic and/or prognostic biomarker for prostate cancer (PCa) patients. Material and Methods: SuPAR levels were evaluated by ELISA in serum samples from 146 PCa patients, 35 benign prostate hyperplasia (BPH) patients and 18 healthy controls. Results: Antigen levels of suPAR differed between healthy controls and PCa or BPH patients (P&amp;lt;0.001). Additionally, suPAR levels differed between the Gleason sum groups GS = 7 vs. GS&amp;gt;7, with higher levels in the latter group (P = 0.011). For further statistical analysis, patients and proband cohorts were separated according to their serum expression of suPAR in a group with low/intermediate level (≤66% percentile) and a group with high levels (&amp;gt;66% percentile). A significant difference in the disease-specific survival was detected between the low/intermediate and the high suPAR level groups (191.4 vs. 144.5 months; P = 0.039; log rank test). The high level group showed a 3.91-fold increased risk of tumor-related death compared to the low/intermediate suPAR level group but this was not significant (P = 0.055; univariate Cox's regression hazard analysis). Therefore, future studies with larger cohorts of PCa patients as well as prospective surveys are necessary. Conclusion: The differences between the PCa/BPH/healthy control cohorts for suPAR in conjunction with the association of high suPAR antigen levels in the serum with a poor prognosis suggest a diagnostic and prognostic impact of this biomarker for PCa patients. Citation Format: Sven Wach, Omar Al-Janabi, Katrin Weigelt, Kersten Fischer, Thomas Greither, Marios Marcou, Gerit Theil, Elke Nolte, Hans-Juergen Holzhausen, Robert Stoehr, Verena Huppert, Arndt Hartmann, Paolo Fornara, Bernd Wullich, Helge W. Taubert. Serum level of urokinase plasminogen activator receptor is suggested as diagnostic and prognostic biomarker in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4823. doi:10.1158/1538-7445.AM2015-4823
Effect of MOR202, a human CD38 antibody, in combination with lenalidomide and bortezomib, on bone lysis and tumor load in a physiologic model of myeloma.
Authors: J. Endell, C. Samuelsson, R. Boxhammer, S. Strauss, S. Steidl
Journal: Journal of Clinical Oncology (2011)

8078 Background: MOR202, a HuCAL-derived fully human anti-CD38 antibody mediates ADCC of multiple myeloma (MM) patient cells with high potency (EC50 ~200 pM) and represents a promising new therapy for MM patients. Bortezomib (BOR), a proteasome inhibitor, and lenalidomide (LEN), an immunomodulatory agent, two commonly used agents in MM therapy were evaluated for their ability to enhance the cytotoxicity of MOR202 in vitro and in vivo. Methods: Drug effects were assessed in vitro by FACS analysis using a panel of CD38+ MM cell lines. Different incubation schemes were used to separate effects of BOR or LEN on target or effector cells. A novel murine MM model of intra-tibially injected NCI-H929 MM cells was employed to study MOR202 effects in vivo using bone density and M protein plasma levels as endpoints. Synergy was determined according to Chou-Talalay (Pharmacol Rev. 2006 Sep;58(3):621-81). Results: MOR202-mediated cytotoxicity was enhanced in vitro by BOR and LEN. The enhancement by BOR was mediated through a direct cytotoxic effect on MM cells. In contrast, LEN synergistically enhanced MOR202 activity (CI<0.1) by several mechanisms identified to be direct cytotoxicity, activation of effector cells and increased CD38 expression levels on MM cells. In vivo, MOR202 reduced bone lysis dose-dependently by up to 55% at 12 mg/kg compared to vehicle control. Co-administration of a lower dose of 3 mg/kg MOR202 with either 0.6 mg/kg BOR or 50 mg/kg LEN, however, completely abolished bone lysis. Since BOR and LEN at these doses inhibited bone lysis by only 40% and 20%, respectively, these findings support a synergistic effect of combination therapy. The markedly reduced bone lysis in the combination therapy was accompanied by a reduction (>90%) of serum M protein levels, indicating a significant decrease of tumor load. Conclusions: The cytotoxic activity of MOR202 on MM cells was enhanced by BOR and LEN by different mechanisms. Inhibition of MM-mediated bone lysis and tumor load in vivo was enhanced by both compounds in a synergistic manner with MOR202. These results provide a mechanistic rationale for MOR202 drug combinations which warrant further evaluation in future clinical trials.
FMNL1 Is Involved in Immune Response and Hematopoietic Differentiation in MDS
Authors: Matheus Rodrigues Lopes, Fabiola Traina, Paula de Melo Campos, Joao Machado-Neto, Samuel de Souza Medina, Fernando Ferreira Costa, Irene Lorand-Metze, Sara T. Olalla Saad, Patricia Favaro
Journal: Blood (2011)
198. CD4+ IL13Rα2-Specific CAR T Cells Exhibit Potent Effector Function Against Glioblastoma
Authors: Dongrui Wang, Renate Starr, Brenda Aguilar, Alfonso Brito, Brenda Chang, Aniee Sarkissian, Behnam Badie, Michael E. Barish, Stephen J. Forman, Christine E. Brown
Journal: Molecular Therapy (2016)

Adoptive T cell transfer, including chimeric antigen receptor (CAR) T cell therapy, has been successfully applied to the treatment of multiple types of cancer, but the variation in response rates among patients remains an important issue. Recent studies have demonstrated that CAR T cells vary in function and persistence, depending on the specific T cell subpopulation that is engineered and the phenotype of the final T cell product. Specifically, a starting population of central memory T cells (Tcm) has been shown to improve persistence and efficacy of CAR T cell therapy. Tcm consist of both CD4+ and CD8+ pools, but little is known about the contribution of each subset for CAR T cell function. Notably, although CD8+ T cells have long been considered the primary cytotoxic effector population, CD4+ T cells have also been shown to mediate anti-tumor response against some solid tumors which is CD8-independent. It is thus critical to identify the optimal composition of CD4+ and CD8+ CAR T cells for mediating the maximal anti-tumor effect. Here, using both in vitro and in vivo glioblastoma (GBM) models, we examined the anti-tumor activity of IL13Rα2-specific CAR T cells engineered from purified CD4+ or CD8+ Tcm pools. Surprisingly, we discovered a superior antitumor response from CD4+ IL13Rα2-CAR T cells as compared to CD8+ CAR T cells. After co-culture with primary patient-derived GBM cells in vitro, CD4+ CAR T cells displayed more potent tumor killing as compared to CD8+ CAR T cells, especially when effector cell numbers were more limited. Consistently, CD4+ CAR T cells maintained better effector function in vitro when re-challenged with tumor. These CD4+ CAR T cells produced higher levels of cytokine as compared to CD8+ T cells, a difference that was further maintained after tumor re-challenge. We also assessed whether the CD4 versus CD8 composition of the IL13Rα2-CAR T cell product would impact therapeutic efficacy in vivo using primary patient-derived GBM lines orthotopically implanted in NSG mice. When injected intracranial into GBM-bearing mice, the CD4+ CAR T cells resulted in durable antitumor efficacy, mediating tumor-free survival for over 200 days in 7of 7 experimental animals, which was unaffected by mixing with 10% of CD8+ CAR T cells. While CD8+ CAR T cells, as well as 50%-50% or 10%-90% CD4-CD8 mixed populations, also mediated significant antitumor activity, the majority of mice recurred and showed a less durable therapeutic response. These results demonstrate that CD4+ CAR T cells can have potent effector function and suggest that, for at least IL13Rα2-CARs, CD4+ T cells mediated superior anti-tumor immune responses as compared to CD8+ T cells. These studies provide important insight to further elucidate the optimal composition of the CAR T cell product for the treatment of cancer.