tbuckley/cabot-search huggingface dataset:
201. Neuron-Specific Systemic Gene Therapy for Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency
Authors: Ni-Chung Lee, Shin-Ichi Muramatsu, Yin-Hsiu Chien, Pin-Wen Chen, Kai-Yuan Tzen, Barry J. Byrne, Wuh-Liang Hwu
Journal: Molecular Therapy (2015)

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disease that causes defective synthesis of dopamine and serotonin, and children with AADC deficiency exhibit severe motor, behavioral and autonomic dysfunctions. We have created an IVS6+4A>T knock-in mouse model of AADC (DdcKI mice) and shown that gene therapy at the neonatal stage can rescue the phenotype. In this study, we extended the treatment to systemic therapy on young mice. After intraperitoneal injection of 7-day-old mice with either AAV9-CMV-hAADC (AAV9-AADC) or yfAAV9/3-Syn-I-mAADC (AAVN-AADC), the treated DdcKI mice showed improvements in weight gain, survival, motor function, autonomic function, and behavior, but the effects of AAVN-AADC were superior. The survival of AAVN-AADC treated DdcKI mice (95%) was slightly better than that of the AAV9-AADC treated mice (78%), but this difference was not significant. Brain AADC activity of both AAV9-AADC and AAVN-AADC treated mice was slightly elevated (2.3% and 2.7% of wild-type, respectively). Untreated DdcKI mice had difficulties maintaining body temperature during cold exposure, and both AAV9-AADC- and AAVN-AADC-treated DdcKI mice exhibited body temperature control similar to that of WT mice in cold environments. Moreover, the AAV9-AADC-treated DdcKI mice exhibited slight hyperactivity. Under low magnification, AADC-positive cells were found in the cortex of AAV9-AADC-treated mice. Therefore, mice with a neurotransmitter deficiency can be rescued at a young age using systemic gene therapy, but a neuron-specific vector may be necessary.
Gene Expression Profiling of B-Lymphocyte and Plasma Cell Populations from Waldenström’s Macroglobulinemia. Comparison with Expression Patterns of the Same Cell-Counterparts from Other B-Cell Neoplasms.
Authors: Norma C. Gutierrez, Enrique M. Ocio, Patricia Maiso, Encarna Ferminan, Manuel Delgado, Ricardo Lopez-Perez, Maria L. Sanchez, Maria J. Arcos, Maria J. Moro, Jose M. Hernandez, Alberto Orfao, Ramon Garcia-Sanz, Jesus M. Hernandez, Jesus F. San Miguel
Journal: Blood (2005)
384. AAV9 -Frataxin Reduces the Symptoms and Prolongs the Life of Friedreich Ataxia Mouse Models
Authors: Jacques P. Tremblay, Catherine Gérard, Xiao Xiao, Mohammed Filali, Zoé Coulombe, Marie Arsenault, Jacques Couet, Juan Li, Marie-Claude Drolet, Pierre Chapdelaine, Amina Chikh
Journal: Molecular Therapy (2015)

Friedreich ataxia (FRDA) is a genetic disease due to increased repeats of the GAA trinucleotide in intron 1 of the frataxin gene. This mutation leads to a reduced expression of frataxin. We have produced an AAV9 coding for human frataxin (AAV9-hFXN). This AAV was delivered by intra-peritoneal injection to young conditionally knockout mice in which the frataxin gene had been knocked-out in some tissues during embryogenesis by breeding them with mice expressing the Cre recombinase gene under the MCK or the NSE promoter. In the first part of the study different doses of virus were tested from 6×1011 v.p. to 6×109 v.p. in NSE-cre mice and all leading to an increase in life spent of the mice. The higher and the lower dose were also tested in MCK-cre mice. A single administration of the AAV9-hFXN at 6×1011 v.p. more than doubled the life of these mice. In fact the MCK-cre mice treated with the AAV9-hFXN were sacrificed for further molecular investigations at the age of 29 weeks without apparent symptoms. Echography analysis of the heart function clearly indicated that the cardiac systolic function was better preserved in the mice that received 6×1011 v.p. of AAV9-hFXN. The human frataxin protein was detected by ELISA in the heart, brain, muscles, kidney and liver with the higher dose of virus in both mouse models. Thus gene therapy with an AAV9-hFXN is a potential treatment of FRDA.
Abstract A37: Targeting RAGE in pancreatic cancer using monoclonal antibodies
Authors: Priyanka Swami, Venkata Indurthi, Stefan W. Vetter, Estelle Leclerc
Journal: Cancer Research (2016)

Abstract Recent studies suggest that the Receptor for Advanced Glycation End Products (RAGE) and its ligands (S100P or HMGB1) are important contributors to the progression of pancreatic cancer. Being a cell surface receptor, RAGE possesses a large extracellular domain that binds its activating ligands. We reasoned that monoclonal antibodies that block the interaction between RAGE and its ligands could impact the progression of pancreatic cancer. We have generated a panel of antibodies recognizing different domains of the receptor and are currently testing their inhibitory effects, in pancreatic cancer cells and in small animal models. Citation Format: Priyanka Swami, Venkata Indurthi, Stefan W. Vetter, Estelle Leclerc.{Authors}. Targeting RAGE in pancreatic cancer using monoclonal antibodies. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A37.
Phase I Study of the [Cu, Zn] Superoxide Dismutase (SOD1) Inhibitor ATN-224 (Bis-Choline Tetrathiomolybdate) in Patients (pts) with Advanced Hematologic Malignancies.
Authors: James R. Berenson, Ralph Vincent Boccia, Asad Bashey, Alexandra M. Levine, Omer N. Koc, Jennifer A. Callahan, Andrew P. Mazar, Steven D. Reich
Journal: Blood (2006)
Abstract 5018: HLA class I expression in a tumor is higher than that out of a tumor: Promising new findings for antigen-specific cancer immunotherapy
Authors: Daisule Nobuoka, Mari Takahashi, Toshiaki Yoshikawa, Takahito Yagi, Toshiyoshi Fujiwara, Tetsuya Nakatsura
Journal: Cancer Research (2015)

Abstract Background: We have demonstrated that intratumoral peptide injection is an attractive strategy that enhances tumor cell antigenicity by means of additional peptide loading onto HLA class I molecules (Nobuoka D, et al. Cancer Immunol Immunother, 62: 639-652, 2013). However, HLA class I expression has been reported to be down-regulated in various malignancies, which may explain why most studies on antigen-specific cancer immunotherapy did not demonstrate a remarkable benefit. Methods: The tissue samples of histologically confirmed hepatocellular carcinoma were obtained from 20 patients who underwent hepatectomy. The paraffin-embedded blocks of tumor area and nontumorous liver were analyzed using monoclonal anti-HLA class I antibody, EMR 8-5. The fresh tissue samples were analyzed using another monoclonal anti-HLA class I antibody, W6/32. Moreover, HLA class I expression in a tumor and that out of a tumor were compared in various types of cancer. Results: Among 20 patients with hepatocellular carcinoma, 14 (70%) were graded as having high expression (++) of HLA class I molecules using EMR 8-5 in cancer cells, whereas 15 patients (75%) were graded as having negative expression (-) in nontumorous hepatocytes. The immunoreactivity level in cancer cells was significantly higher than that in nontumorous hepatocytes (P &amp;lt; 0.05). Moreover, similar observations were obtained using W6/32. In other types of cancer including intrahepatic cholangiocarcinoma, ampullary carcinoma, gallbladder carcinoma, pancreatic carcinoma, esophageal carcinoma, colon carcinoma, and breast carcinoma, most cancer cells has higher expression of HLA class I than surrounding normal cells. Conclusions: HLA class I expression is not so down-regulated as previously reported. Intratumoral peptide injection is applicable in various malignancies. Citation Format: Daisule Nobuoka, Mari Takahashi, Toshiaki Yoshikawa, Takahito Yagi, Toshiyoshi Fujiwara, Tetsuya Nakatsura. HLA class I expression in a tumor is higher than that out of a tumor: Promising new findings for antigen-specific cancer immunotherapy. [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 5018. doi:10.1158/1538-7445.AM2015-5018
RTRB-21SURVIVAL ANALYSIS OF 161 ELDERLY PATIENTS TREATED WITH RADIOTHERAPY WITH CONCOMITANT AND ADJUVANT TEMOZOLOMIDE
Authors: Roy Torcuator, Olutayo Olubiyi, Maher Hulou, Robert Wiemann, Alexandra Golby
Journal: Neuro-Oncology (2015)

INTRODUCTION: Majority of patients with glioblastoma are 65 years and older at the time of diagnosis. There is no standard treatment regimen for this group of elderly patients. The treatment options will include radiation alone, radiation with concomitant and adjuvant temozolomide or temozolomide alone. METHODS: We reviewed the records of 161 GBM patients with age of 70 and above at the time of diagnosis from 2007 until 2014. The demographic information, KPS, type of surgery, MGMT methylation, IDH1 mutation, treatment and overall survival were collected and analyzed. RESULTS: 55% of the patients were males with median age of 76 years (range: 70 - 90) and KPS of 80 (range: 30 - 100). 119 (74%) of patients had surgical resection and 38 (24%) had biopsy only. MGMT methylation status was available in 68% of patients (109/61). MGMT was methylated in 56 (35%) patients and unmethylated in 53 (33%) patients. Majority of patients had no IDH1 mutation. Further treatments included 60 patients (37%) who received radiation 60 Gy with concomitant and adjuvant temozolomide, 29 (18%) were treated with radiation followed by adjuvant temozolomide, 24 (15%) had radiation alone, while 44 (27%) received no further treatment after the surgery. No patient received temozolomide alone. Median overall survival for all patients was 5.45 months. Kaplan-Meier -based analysis showed further treatment after surgery with standard radiation course of 60 Gy with concomitant and adjuvant temozolomide is associated with significantly higher survival (p< 0.001). CONCLUSION: Elderly patients with newly diagnosed glioblastoma may benefit from radiation for 60 Gy with concomitant and adjuvant temozolomide.
Abstract 3214: Genome-wide analysis of stroma-tumor crosstalk pathways in lung cancer: therapeutic implications
Authors: Hyejin Choi, Jianting Shen, Anna Durrans, Tina El Rayes, Kari Fischer, Dingcheng Gao, Steve Wong, Nasser Altorki, Vivek Mittal
Journal: Cancer Research (2015)

Abstract We have systematically dissected the microenvironmental hetereogeneity of lung adenocarcinomas, and provide cellular and molecular landscapes that contribute to carcinogenesis. RNA deep sequencing analysis of individually sorted stromal and tumor epithelial compartments from fresh clinical specimens and a mouse model of KrasG12D; p53-/- tumors identified cell type-specific differentially regulated genes, indicative of tumor “activated/reprogrammed” stroma. We developed a computational crosstalk discovery algorithm to model crosstalk signaling discovery based on ligand-receptor interactions and downstream signaling networks, and identified novel tumor-stroma paracrine and tumor autocrine crosstalk signaling pathways in the lung cancer microenvironment. We have explored the mechanistic basis of selected crosstalk pathways including HGF-MET, IL6-Stat3, Tsp-1-CD36, MMP14-HB-EGF in conferring lung adenocarcinoma progression and in mediating therapeutic resistance, and have used both genetic and pharmacological approaches to block these pathways. This study has the potential for development of therapeutic strategies that target tumor-stroma interactions, and may complement conventional anti-cancer treatments. Citation Format: Hyejin Choi, Jianting Shen, Anna Durrans, Tina El Rayes, Kari Fischer, Dingcheng Gao, Steve Wong, Nasser Altorki, Vivek Mittal. Genome-wide analysis of stroma-tumor crosstalk pathways in lung cancer: therapeutic implications. [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 3214. doi:10.1158/1538-7445.AM2015-3214
Alkaline Phosphatase (ALP) Variation During Carfilzomib Treatment Is Associated to Best Response in Multiple Myeloma.
Authors: Maurizio Zangari, Latha Polavaram, Fenghuang Zhan, Guido J. Tricot, Ravi Vij, Sundar Jagannath, David Siegel, A. Keith Stewart, Luhua Wang, Robert Z Orlowski, Andrew Belch, Andrzej J Jakubowiak, George Somlo, Suzanne Trudel, Nizar J Bahlis, Sagar Lonial, Seema Singhal, Vishal Kukreti
Journal: Blood (2009)
Abstract 1542: Targeting KIF3a and primary cilia differentially affects sonic hedgehog sensitivity and the rate of glioblastoma progression
Authors: Lan Hoang-Minh, Dorit Siebzehnrubl, Loic Deleyrolle, George Ugartemendia, Hunter Futch, Benjamin Griffith, Joshua Breunig, Susan Semple-Rowland, Brent Reynolds, Matthew Sarkisian
Journal: Cancer Research (2015)

Abstract Adults diagnosed with glioblastoma multiforme (GBM) typically have a median survival less than 15 months. GBM patient biopsies and derived cell lines contain subsets of cells extending primary cilia, microtubular antennae that mediate signaling events reported to influence cell proliferation and tumor cell growth. However, it remains unclear how cilia contribute to the phenotypic characteristics of GBM. To determine whether cilia influence GBM tumor progression, we generated several stable patient-derived cell lines devoid of cilia by expressing a dominant-negative form of Kif3a (dnKif3a), a protein normally essential for ciliogenesis. Depending on the line, mice receiving intracranial implants of dnKif3a-expressing cells survived shorter, as long as, or significantly longer than mice implanted with control cells. To determine if ciliated cells derived from different GBM tumors share similar sensitivities to sonic hedgehog (SHH), a mitogen present in adult brain that activates receptor signaling cascades within cilia, we exposed control and dnKif3a-expressing cells in vitro to vehicle or recombinant SHH. Interestingly, only the cell line that prolonged survival in vivo displayed significant increases in proliferation following exposure to SHH, an effect that was blocked by either dnKif3a or pretreatment of the cells with cyclopamine, an inhibitor of the SHH cascade. All cell lines tested appeared to respond to SHH as evidenced by activation of downstream SHH signaling components in their cilia. Collectively, our data suggest that strategies to disrupt primary cilia in GBM patients could lead to inhibition or enhancement of tumor growth potentially by altering cell sensitivity to the extracellular environment. Citation Format: Lan Hoang-Minh, Dorit Siebzehnrubl, Loic Deleyrolle, George Ugartemendia, Hunter Futch, Benjamin Griffith, Joshua Breunig, Susan Semple-Rowland, Brent Reynolds, Matthew Sarkisian. Targeting KIF3a and primary cilia differentially affects sonic hedgehog sensitivity and the rate of glioblastoma 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 1542. doi:10.1158/1538-7445.AM2015-1542
Abstract B64: Using pancreatic organoids to infer therapeutic resistance and sensitivity
Authors: Herve* Tiriac, Mariano* Ponz-Sarvise, Vincenzo* Corbo, Kristopher K.* Frese, Dannielle D.* Engle, Daniel Ohlund, Tobiloba Oni, Chang-il Hwang, Abram Handly-Santana, Brinda Alagesan, Dea Filippini, Kevin Wright, Kenneth H. Yu, Youngkyu Park, David A. Tuveson
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a 5-year survival rate less than 6%. The late diagnosis of the disease and poor efficacy of systemic treatments are major factors for this poor prognosis, and highlight the need for novel PDA models better able to predict resistance/sensitivity to treatment. To fulfill this need, our laboratory developed a three-dimensional culture system that enables the rapid growth of both mouse and human pancreatic ductal organoids. Organoids can be established from healthy or neoplastic tissues using both large (surgical material) and small (fine needle biopsy) samples, thereby providing a novel platform for therapeutic testing for all stages of disease. In this study, we use organoids to evaluate the therapeutic efficacy of the simultaneous inhibition of MEK and AKT kinases, which are activated in PDA by KRAS mutations. Tumor-derived organoids were resistant to both single agents and combination treatment. Genetically engineered mouse models of pancreatic cancer (KPC) also only exhibited a brief response to dual inhibition of MEK and AKT. To assess the potential mechanism of resistance, we evaluated the activation of a number of receptor tyrosine kinases by interrogating both mouse and organoid treated tissues. Members of the ERBB family were activated in KPC animals and tumor-derived organoids treated with both MEK and AKT inhibitors. Accordingly, the addition of an irreversible pan-ERBB inhibitor to the combination of MEK and AKT inhibitors, or MEK inhibitor alone, prevented ERBB-mediated resistance and improved tumor sensitivity to therapeutic intervention. This new therapeutic strategy is efficacious both ex-vivo and in vivo using human tumor-derived organoids and their associated transplant model. Finally, we show that human PDA organoids can be used in high throughput therapeutic screening for the identification of patient-specific therapeutic sensitivities. In summary, pancreatic organoids represent a system that can be used to predict drug sensitivity as well as to identify mechanism of resistance. *Equal contribution Citation Format: Herve Tiriac*, Mariano Ponz-Sarvise*, Vincenzo Corbo*, Kristopher K. Frese*, Dannielle D. Engle*, Daniel Ohlund, Tobiloba Oni, Chang-il Hwang, Abram Handly-Santana, Brinda Alagesan, Dea Filippini, Kevin Wright, Kenneth H. Yu, Youngkyu Park, David A. Tuveson.{Authors}. Using pancreatic organoids to infer therapeutic resistance and sensitivity. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B64.
Comparison of Biodistributions and Therapeutic Efficacies of Pretargeted Radioimmunoconjugates Targeting the CD20, CD22, and DR Molecules on Human B Cell Lymphomas.
Authors: Anastasia Pantelias, John M. Pagel, Nathan Hedin, Yukang Lin, Donald Axworthy, Louis J. Theodore, Oliver W. Press
Journal: Blood (2005)
Abstract 167: Targeting non-coding RNAs with the CRISPR/Cas9 system in human cell lines
Authors: Tsui-Ting Ho, Nanjiang Zhou, Jianguo Huang, Pratirodh Koirala, Min Xu, Roland Fung, Fangting Wu, Yin-Yuan Mo
Journal: Cancer Research (2015)

Abstract The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system (CRISPR/Cas) has been recently shown to be a powerful genome-editing tool in a variety of organisms. However, these studies are mainly focused on protein-coding genes. The present study aims to determine whether this technology can be applied to non-coding genes. One of the challenges for knockout of non-coding genes is that a small deletion or insertion generated by the standard CRISPR/Cas system may not necessarily lead to functional loss of a given non-coding gene because of lacking an open reading frame, especially in polyploidy human cell lines. To overcome this challenge, we adopt a selection system that allows for marker genes to integrate into the genome through homologous recombination (HR). Moreover, we construct a dual guide RNA vector that can make two cuts simultaneously at designated sites such that a large fragment can be deleted. With these approaches, we are able to successfully generate knockouts for miR-21, miR-29a, lncRNA-21A, UCA1 and AK023948 in various human cell lines. Finally, we show that the HR-mediated targeting efficiency can be further improved by suppression of the non-homologous end joining pathway. Together, these results demonstrate the feasibility of knockout for non-coding genes by the CRISPR/Cas system in human cell lines. Citation Format: Tsui-Ting Ho, Nanjiang Zhou, Jianguo Huang, Pratirodh Koirala, Min Xu, Roland Fung, Fangting Wu, Yin-Yuan Mo. Targeting non-coding RNAs with the CRISPR/Cas9 system in human cell lines. [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 167. doi:10.1158/1538-7445.AM2015-167
Abstract 432: Macrophage promotes EMT in gastric cancer through activating CXCR2 signaling
Authors: Chang-Hua Zhang, Guangkai Xia
Journal: Cancer Research (2015)

Abstract Background and aims: Macrophage as a member of the tumor microenvironment and chronic inflammation was considered as an important pro-tumoral factor in cancer. CXCR2 was an inflammation receptor and expressed in gastric cancer. But its’ association with macrophage remains unknown. We aimed to investigate the role of macrophage in the development of gastric cancer from inflammation. Methods: Human GC cell lines AGS, BGC-823 were studied. Western Blot was used to detect the protein expression in gastric cancer cells. Migration of gastric cancer cells were tested by Transwell. Results: Macrophages and gastric cancer cell lines can secret CXCR2′ ligands when coculutred with each other. CXCR2 knock down in gastric cancer cells can decrease migration and inhibit EMT. Macrophage promotes EMT of gastric cancer though CXCR2 signaling. CXCR2's ligands CXCL1 and CXCL5 can activate stat3 and promote the migration of gastric cancer cells. CXCL1 and CXCL5 are responsible for the EMT of gastric cancer. Conclusion: Macrophage can promote gastric cancer EMT through activating CXCR2 signaling. CXCR2 ligands CXCL1 and CXCL5 are the crucial factors for promoting EMT in gastric cancer. Note: This abstract was not presented at the meeting. Citation Format: Chang-Hua Zhang, Guangkai Xia. Macrophage promotes EMT in gastric cancer through activating CXCR2 signaling. [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 432. doi:10.1158/1538-7445.AM2015-432