tbuckley/cabot-search huggingface dataset:
289. Safe and Effective Gene Therapy for Wiskott – Aldrich Syndrome Using an Insulated Lentiviral Vector
Authors: Swati Singh, Blythe Sather, Iram Khan, Socheath Kim, Brenda Seymour, Matthew Wielgosz, Hans-Peter Kiem, Jennifer Adair, Denny Liggett, Arthur Nienhuis, David J. Rawlings
Journal: Molecular Therapy (2015)

Wiskott–Aldrich Syndrome (WAS) is a severe X-linked immunodeficiency disorder characterized by recurrent infection, thrombocytopenia, and autoimmunity resulting from mutations within the WAS gene. The encoded gene product, WAS protein (WASp), is a scaffold protein important for activation of the actin cytoskeleton downstream of multiple hematopoietic receptors. Development of safe and effective hematopoietic stem cell (HSC) gene therapy for WAS would provide a valuable treatment alternative to allogeneic bone marrow transplantation. Of critical importance for such an approach is the capacity to achieve sufficient WASp expression in relevant lineages to correct the multiple deficits, while avoiding development of autoimmune disease. We previously tested a panel of self-inactivating (SIN) lentiviral (LV) vectors expressing human WAS via alternative internal promoters and observed optimal expression and rescue using the modified γ-retroviral derived LTR, MND. To improve the potential safety and stability of expression, we incorporated a 650bp chimeric insulator from the chicken β-globin locus into this LV. Using in vitro assays the insulated LV exhibited minimal LMO2 transactivation and no evidence for immortalization of cultured HSC. Next, we generated a stable high-titer producer clone expressing this candidate clinical LV, CL20-i650–MND-WAS. Here, we evaluate the efficacy and safety of the insulted vs uninsulated LV (CL20-MND-WAS) in a large cohort of primary and secondary transplanted Was/- mice. Both vectors enabled stable engraftment of WASp expressing cells in all hematopoietic lineages, positive selection of WASp+ cells, and rescued functional and developmental T and B cell defects without evidence for toxicity. Inclusion of the insulator allowed for higher expression levels at lower numbers of viral integration per cell; a feature that was further exaggerated in secondary recipients. Finally, in parallel, we evaluated CL20-i650–MND LV expressing a fluorescent marker using CD34+ autologous HSC transplants in a non-human primate model (Macaca nemestrina) and observed long term stable polyclonal engraftment of LV expressing hematopoietic cells for up to 2 yr. Based on these extensive pre-clinical and toxicity studies we anticipate that CL20-i650–MND-WAS LV will provide sustained rescue of platelet and lymphocyte development and function in vivo (facilitated, in part, via the insulator) without evidence of toxicity. We plan to directly test this hypothesis in an upcoming WAS LV clinical trial.
Placenta Derived Stem Cells (PDAC) Suppress the Allo-MLR and the EBV Regression Assay.
Authors: Casper Paludan, Ryhor Harbacheuski, Rose Ann Murray, Megan Mendillo, Jorge Soler, Jia-Lun Wang, Qian Ye, James Edinger, Wolfgang Hofgartner, Gilla Kaplan, Robert Hariri
Journal: Blood (2006)
Abstract 2359: Adrenergic regulation of MCP-1 leads to enhanced macrophage recruitment and ovarian carcinoma growth
Authors: Guillermo N. Armaiz-Pena, Vianey Gonzalez-Villasana, Archana S. Nagaraja, Cristian Rodriguez-Aguayo, Piotr Dorniak, Rebecca Previs, Nouara Sadaoui, Rebecca Stone, Koji Matsuo, Heather J. Dalton, Susan K. Lutgendorf, Anil K. Sood, Gabriel Lopez-Berestein
Journal: Cancer Research (2015)

Abstract Increased adrenergic signaling is known to promote tumor progression, but the underlying mechanisms remain poorly understood. Tumor associated macrophages (TAMs) are key components of the tumor microenvironment that contribute to pro-inflammatory processes and tumor growth. Recently, it has been reported that patients with higher levels of adrenergic signaling have higher counts of MMP-9-producing TAMs. Here, we examined factors responsible for stress-mediated effects on monocyte/macrophage recruitment into the tumor microenvironment and the resultant effects on tumor growth. Conditioned media from norepinephrine- or epinephrine-treated ADRB positive SKOV3ip1 ovarian cancer cells had significantly increased levels of pro-inflammatory cytokines, such as MCP1, fractalkine, IL6, IL8 and VEGF. MCP1, a key modulator of monocyte/macrophage recruitment, gene and protein levels were significantly increased in vitro after catecholamine exposure, which was mediated by cAMP and PKA, while this effect was abrogated by a beta-blocker. SKOV3ip1 tumor samples from mice, subjected to daily restraint stress, had elevated MCP1 gene and protein expression levels, increased CD14+ cells, and increased infiltration of CD68+ cells. Both, propranolol, a non-specific beta-blocker, and hMCP1 siRNA packaged in DOPC nanoparticles significantly abrogated daily restraint stress-induced tumor growth and inhibited infiltration of CD68+ and F4/80+ cells. Of patient samples evaluated (n = 462), 28% had elevated absolute peripheral blood monocyte (&amp;gt;0.7 × 106/μL) and 43% had high peripheral blood monocytes when measured as the percent of white blood cell content (&amp;gt;8%). Elevated peripheral blood monocytes and increased CD68+ cells (&amp;gt;15/hpf) in samples from ovarian cancer patients were significantly associated with advanced disease and worse overall survival. In summary, increased adrenergic signaling is associated with enhanced macrophage infiltration mediated by tumor cell-derived MCP1 production. Citation Format: Guillermo N. Armaiz-Pena, Vianey Gonzalez-Villasana, Archana S. Nagaraja, Cristian Rodriguez-Aguayo, Piotr Dorniak, Rebecca Previs, Nouara Sadaoui, Rebecca Stone, Koji Matsuo, Heather J. Dalton, Susan K. Lutgendorf, Anil K. Sood, Gabriel Lopez-Berestein. Adrenergic regulation of MCP-1 leads to enhanced macrophage recruitment and ovarian carcinoma growth. [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 2359. doi:10.1158/1538-7445.AM2015-2359
Abstract 3170: IL17 favours carcinogenesis and limits the anti-tumor responses in pancreatic cancer
Authors: Paola Cappello, Roberta Curto, Gianluca Mucciolo, Simona Rolla, Elisabetta Tonoli, Francesco Novelli
Journal: Cancer Research (2015)

Abstract Pancreatic ductal adenocarcinoma (PDA) is a fatal medical condition with few advances in therapy and patient survival. The role of IL17 and Th17 in cancer progression and anti-tumor immunity is still controversial. In this study we have investigated the role of IL17 and Th17 in PDA carcinogenesis and anti-tumor responses. IL-17 production and Th17 percentage in blood from PDA patients and control subjects as well from genetically engineered mice (GEM) that spontaneously develop PDA, were analysed by ELISA and FACS respectively. Survival of GEM mice crossed with IL-17 KO mice (GEM/IL17KO) was analysed by Kaplan-Meier analysis. WT or IL17KO mice that were prophylactically vaccinated with a plasmid coding for the PDA-associated antigen α-enolase (ENO1) (1-3), were subsequently injected with PDA cell line derived from GEM. Tumor growth and the induction of an antigen-specific immune response were monitored. We have found a statistically significant increase of peripheral Th17 cells and a decrease of Th1 in PDA patients compared to healthy subjects. GEM mice showed 3-fold more RORγT+ cells at the onset of duct transformation, which dropped to the level of control mice at 20 weeks and lasted until 35 weeks. Notably, GEM/IL17 KO mice survived significantly more than GEM mice, even if there were no changes in the tumor onset. In addition, in GEM/IL17 KO mice, we observed an increased fibrotic reaction compared to GEM mice starting from early stage of disease. Lastly, ENO-1 DNA vaccination in IL17KO mice significantly decreased PDA cells growth and enhanced the CD8 T cell response compared to that observed in WT mice. Our data suggest that the absence of IL17 does not affect the tumor onset but the progression, likely affecting the immune response, which seems to be able to better counteract tumor growth in the absence of this cytokine. Tomaino et al., J Proteome Res. 2007;6:4025-31; Cappello et al, Int. J. Cancer. 2009;125:639-48; Cappello P et al, Gastroenterology. 2013;144:1098-106. Citation Format: Paola Cappello, Roberta Curto, Gianluca Mucciolo, Simona Rolla, Elisabetta Tonoli, Francesco Novelli. IL17 favours carcinogenesis and limits the anti-tumor responses in pancreatic 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 3170. doi:10.1158/1538-7445.AM2015-3170
Abstract 149: Overexpression of the long non-coding RNA PVT1 and its role in cervical carcinogenesis
Authors: Marissa Iden, Samantha Fye, Ramani Ramchandran, Janet S. Rader
Journal: Cancer Research (2015)

Abstract Although it is becoming increasingly clear that long non-coding RNAs (lncRNAs) are intricately involved in numerous cancer types, the mechanisms by which they influence carcinogenesis remain poorly understood. The plasmacytoma variant translocation 1 gene (PVT1) is a lncRNA that has been designated as an oncogene due to its contribution to the phenotype of multiple cancers. Further, our lab has recently demonstrated that human papillomavirus (HPV) integration, a hallmark of invasive cervical cancer (ICC), into the PVT1 locus occurs in multiple cervical tumors. The present study was designed to investigate the role of PVT1 in cervical carcinogenesis. PVT1 expression was measured by quantitative PCR (qPCR) in 41 ICC samples, 20 normal cervix samples, and four cervical cell lines (SiHa, HeLa, DoTc2, and E6/E7-transformed ectocervical epithelial cells). Further, we used siRNA-targeted knockdown in conjunction with functional assays to examine PVT1's effects on cervical cancer cell proliferation, migration and invasion, apoptosis, and cisplatin-resistance. Our results demonstrate that PVT1 expression is significantly increased in ICC tissue versus normal cervix. PVT1 knockdown in cervical cancer cell lines resulted in significantly decreased cell proliferation, migration and invasion. Further, apoptosis and cisplatin cytotoxicity were significantly increased in PVT1 siRNA-transfected cells. Collectively, our data suggest that PVT1 may play a crucial role in cervical carcinogenesis. Future work will focus on determining the mechanism(s) by which this lncRNA exerts its multiple effects on cancer-related processes. Citation Format: Marissa Iden, Samantha Fye, Ramani Ramchandran, Janet S. Rader. Overexpression of the long non-coding RNA PVT1 and its role in cervical carcinogenesis. [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 149. doi:10.1158/1538-7445.AM2015-149
Neutrophil Gelatinase-Associated Lipocalin Levels in Patients with Thalassemia and Sickle Cell Disease: Correlation with Renal Injury
Authors: Ioannis Papassotiriou, Voskaridou Ersi, Alexandra Margeli, Theresa Nwagha, Athanassia Kotrotsou, Dimitra Kyriakopoulou, Christos Poziopoulos, Antonios Kattamis
Journal: Blood (2014)
Abstract LB-074: The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc
Authors: Xiao-Xin Sun, Xia He, Li Yin, Rosalie Sears, Mushui Dai
Journal: Cancer Research (2015)

Abstract c-Myc protein stability and activity are tightly regulated by the ubiquitin-proteasome system. Aberrant stabilization of c-Myc contributes to many human cancers. c-Myc is ubiquitinated by SCFFbw7 and several other ubiquitin ligases, whereas it is deubiquitinated and stabilized by ubiquitin-specific protease (USP) USP28. The bulk of c-Myc degradation appears to occur in the nucleolus. However, whether c-Myc is regulated by deubiquitination in the nucleolus is not known. Here, we report that the nucleolar deubiquitinating enzyme USP36 is a novel c-Myc deubiquitinase. USP36 interacts with and deubiquitinates c-Myc in cells and in vitro, leading to the stabilization of c-Myc. This USP36 regulation of c-Myc occurs in the nucleolus. Interestingly, USP36 interacts with the nucleolar Fbw7γ, but not the nucleoplasmic Fbw7α. Yet, it abolished c-Myc degradation mediated both by Fbw7γ and by Fbw7α. Consistently, knockdown of USP36 reduces the levels of c-Myc and suppresses cell proliferation. We further show that USP36 itself is a c-Myc target gene, suggesting that USP36 and c-Myc form a positive feedback regulatory loop. High expression levels of USP36 are found in a subset of human breast and lung cancers. Altogether, these results identified USP36 as a crucial and bono fide deubiquitinating enzyme controlling c-Myc's nucleolar degradation pathway. Citation Format: Xiao-Xin Sun, Xia He, Li Yin, Rosalie Sears, Mushui Dai. The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc. [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 LB-074. doi:10.1158/1538-7445.AM2015-LB-074
Abstract 1444: Docosahexaenoic acid reduces cancer cell migration may link with actin binding proteins and miRNA 17-92 cluster expressions changes
Authors: Mehboob Ali, Kathryn M. Heyob, Lynette K. Rogers
Journal: Cancer Research (2015)

Abstract Metastasis and progression, reflected by higher migration and longer cell survival, are major contributing factors in making cancers the leading cause of death worldwide. Cancer cells exhibit higher migration rates and greater cell viability facilitated by actin binding protein-mediated cytoskeletal remodeling and secondary messengers (cAMP and/or cGMP) signaling. Studies have shown that docosahexaenoic acid (DHA), a poly unsaturated fatty acid, inhibits cancer cell metastatic phenotype. Moreover, miRNA-17∼92 cluster has been reported to be highly expressed in metastasis. Therefore, we put forward a hypothesis that DHA will induce changes in actin binding protein dynamics and miRNA-17∼92 cluster expression to inhibit cancer cell migration and viability. Non-cance (MLE12) and cancer (A549) cells were treated with 8-Br-cAMP and/or DHA for 30 min, 3h, 6h and 24h. Actin binding proteins (profilin, cofilin, vimentin and gelsolin) and miRNA-17∼92 cluster expression were analyzed by western blot and qRT PCR respectively. Cell migration was estimated by wound assay and transwell apparatus. F-actin content and actin binding proteins were measured using confocal microscopy at the leading edges of wound. Proliferation and cell viability were estimated by flow cytometer, IF using ki-67, and cleaved-caspase-3 antibodies. F-actin content, cell migration and proliferation were increased while cell viability was decreased by cAMP. DHA treatment reverses the increase in actin content and cell migration in cancer cells but not in non-cancer cells. These findings correlate with changes in actin binding protein content and miRNA 17∼92 cluster expression. Thus, DHA specifically inhibits cancer cell migration, proliferation, and viability and this effect correlates with decreases in actin binding protein levels and miRNA-17∼92 cluster expression. In conclusion, DHA supplementation suppresses cellular changes related to metastatic potential in cancer cells and could provide therapeutic potential against cancer cell metastasis. Moreover, actin binding proteins and miRNA-17∼92 cluster expression could serve as innovative therapeutic targets and biomarkers for cancer progression. Citation Format: Mehboob Ali, Kathryn M. Heyob, Lynette K. Rogers. Docosahexaenoic acid reduces cancer cell migration may link with actin binding proteins and miRNA 17-92 cluster expressions changes. [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 1444. doi:10.1158/1538-7445.AM2015-1444
Joan Campbell Griffin
Authors: Michael Griffin
Journal: BMJ (2015)

Joan Campbell Griffin (nee Dickinson) trained as a doctor in the early 1940s, at a time when it was still unusual for women to go into medicine. She studied at Durham University Medical School based in Newcastle where she was one of only 15 women in a class of 80. She started medical school with her twin brother, Peter, and like other female medical students, she was hardworking and diligent and keen to demonstrate that she was as able as any of her male counterparts. She qualified in 1944 …
733. Somatically Repairing Compound Heterozygous Recessive Mutations by Chromosomal Cut-and-Paste for In Vivo Gene Therapy
Authors: Dan Wang, Haiwei Mou, Karen Tran, Jia Li, Blake Y. Wang, Dominic J. Gessler, Phillip WL Tai, Qin Su, Wen Xue, Guangping Gao
Journal: Molecular Therapy (2016)

Patients affected by monogenic recessive genetic disorders often carry two different mutated alleles of the same gene, which is known as compound heterozygous. Theoretically, exchanging the genetic material between the two mutated alleles will reconstitute a mutation-free allele that can be therapeutic (Figure). We hypothesized that generating DNA double-stranded breaks at the same location on both mutant alleles can induce allele exchange, reconstitute a mutation-free allele, and therefore yield therapeutic benefit. We first tested this hypothesis in a targeted knock-in mouse model that carries GFPN-term-intron-tdTomatoC-term and tdTomatoN-term-intron-GFPC-term expression cassettes, respectively, at the same genomic location on each copy of Chr 11. Therefore, allele exchange at the intronic region will reconstitute the full-length GFP and tdTomato, serving as a reporter system. We injected recombinant AAV (rAAV) vectors expressing SpCas9 and sgRNA targeting the intron into adult mice by tail vein injection. Five weeks later, we observed GFP and tdTomato fluorescence in cryosections of peripheral tissues including liver and heart, whereas there was no such fluorescence observed in the tissue samples from untreated mice, demonstrating that allele exchange occurred, and that the reconstituted alleles yielded protein expression. Furthermore, we generated mice that carry two different mutations of the Aspa gene as a compound heterozygous mouse model of Canavan disease. We treated these mice with rAAV vectors expressing SpCas9 and sgRNA targeting an intron between the two mutation sites. Three weeks after treatment, we detected reconstituted, mutation-free Aspa DNA sequence by allele-specific PCR and single-molecule, high-throughput DNA sequencing in the liver. The reconstituted Aspa allele carried insertion at the predicted SpCas9 cleavage site, indicating that the DNA allele exchange was mediated by the non-homologous end joining DNA repair pathway. We also observed allele exchange in mouse liver using the SaCas9 system. Evaluation of the therapeutic benefit following Cas9/sgRNA-mediated allele exchange in various compound heterozygous mouse models and patient cell lines is underway. The gene repairing strategy described here is a novel approach to tackling a broad range of autosomal recessive genetic disorders.
In Patients with Aggressive Non-Hodgkin Lymphoma Treated with CHOP Therapy the Rapidity of Early Response, as Determined by Residual FDG Uptake, Does Not Impact on the Overall Prognosis.
Authors: Eldad J. Dann, Eyal Fuchs, Ada Tamir, Irit Avivi, Diana Gaitini, Ora Israel, Jacob M. Rowe, Rachel Bar-Shalom
Journal: Blood (2007)
A Quantitative Trait Locus for Cholesterol/Low Density Lipoprotein within the Promoter of the Factor IX Gene.
Authors: Kevin R. Viel, Manana Khachidze, Alfonso Buil, José Manuel Soria, Juan Carlos Souto, Jordi Fontcuberta, Francisco Blanco-Vaca, Jordi Ordoñez-Llanos, Laura Almasy, Howard Tom
Journal: Blood (2004)
Abstract 5482: CYP2D6 genotype and response to neoadjuvant tamoxifen therapy: a prospective study in Japan
Authors: Hitoshi Zembutsu, Seigo Nakamura, Sadako Akashi, Takashi Kuwayama, Chie Watanabe, Hiroyuki Takei, Takashi Ishikawa, Yoshie Hasegawa, Soo Chin Lee, Tan Ern Yu, Ayami Matsukata, Hiroshi Matsumoto, Goro Kutomi, Yusuke Nakamura
Journal: Cancer Research (2015)

Abstract Although lots of CYP2D6-Tamoxifen studies have been reported, the results of the association are still controversial. Because prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy, we have initiated the prospective study to clarify the relationship between CYP2D6 genotype and response to preoperative Tamoxifen therapy using a surrogate marker of Ki-67 labeling index in cancer tissue (C-GENT study) since July, 2012. Of the 342 patients who have been recruited in this study, we analyzed 173 cases whose genotyping and measurement of Ki-67 Labeling Index were completed. We observed significant Ki-67 decrease after 2-4 weeks preoperative Tamoxifen therapy (P = 0.000052). Moreover, the patients with CYP2D6 *V/*V is unlikely to show Ki-67 decrease compared with those with CYP2D6 Wt/Wt or Wt/*V (P = 0.00046). Although further analysis should be continuing using a larger number of samples registered in this study, our results suggested that polymorphisms in CYP2D6 could be a key predictor for the prognosis of patients with breast cancer treated with tamoxifen. Citation Format: Hitoshi Zembutsu, Seigo Nakamura, Sadako Akashi, Takashi Kuwayama, Chie Watanabe, Hiroyuki Takei, Takashi Ishikawa, Yoshie Hasegawa, Soo Chin Lee, Tan Ern Yu, Ayami Matsukata, Hiroshi Matsumoto, Goro Kutomi, Yusuke Nakamura. CYP2D6 genotype and response to neoadjuvant tamoxifen therapy: a prospective study in Japan. [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 5482. doi:10.1158/1538-7445.AM2015-5482