tbuckley/cabot-search huggingface dataset:
361. IV Gene Therapy Corrects Feline GM1 Gangliosidosis Long Term
Authors: Heather Edwards, Ashley Randle, Miguel Sena-Esteves, Douglas Martin
Journal: Molecular Therapy (2016)

GM1 gangliosidosis is a fatal neurodegenerative disease that affects all ages. Intracranial injection of adeno-associated viral (AAV) gene therapy has resulted in a >6 fold increase in lifespan. While untreated GM1 cats live to 8.0±0.6 months, many treated cats are still alive at 5-6 years of age (Sci Transl Med 2014. 6, 231). To bypass the invasiveness of brain injection, AAV9 at 1.5e13 vg/kg was injected into the cephalic vein in two GM1 cats at one month of age. Currently over 2 years of age (Fig. 1A), IV treated cats have been followed with biomarkers derived from blood, urine, cerebrospinal fluid (CSF), electrodiagnostics, abdominal ultrasound, 7T magnetic resonance imaging (MRI), and MR spectroscopy. Neurologic abnormalities are limited to mild hindlimb muscle atrophy and fine ear tremors, with remarkable preservation of brain architecture (Fig. 1B). Evaluation of CSF showed complete normalization (p<0.05) of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) compared to untreated GM1 cats (Fig 1. C). The defective lysosomal enzyme, β-galactosidase, was increased to ~15 fold normal levels in CSF (Fig. 1D). MR spectroscopy revealed correction of brain metabolites associated with microgliosis (myoinositol; Ins), neuroaxonal loss (N-acetylaspartate; NAA) and demyelination (glycerophosphocholine and phosphocholine; GPC+PCh) (Fig. 1E), and metabolite levels correlated with clinical signs (R2 = 0.66, 0.50 and 0.63, respectively). No evidence of tumorigenesis or peripheral toxicity has been noted. Intravenous administration of AAV gene therapy shows promise as an alternative for intracranial administration, although further experiments are required to determine maximum survival.
Population Pharmacokinetics of Cyclophosphamide in Patients with Thalassaemia Major Undergoing HSCT Shows Body Weight, CYP450, GST and ALDH Polymorphisms as Covariates Explaining Inter-Individual Variation.
Authors: Poonkuzhali Balasubramanian, John Carl Panetta, Salamun Desire, Shaji R Velayudhan, Vikram Mathews, Biju George, Auro Viswabandya, Mammen Chandy, Alok Srivastava
Journal: Blood (2009)
Potential Predictive Value of <i>TP53</i> and <i>KRAS</i> Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma
Authors: Zhong-Yi Dong, Wen-Zhao Zhong, Xu-Chao Zhang, Jian Su, Zhi Xie, Si-Yang Liu, Hai-Yan Tu, Hua-Jun Chen, Yue-Li Sun, Qing Zhou, Jin-Ji Yang, Xue-Ning Yang, Jia-Xin Lin, Hong-Hong Yan, Hao-Ran Zhai, Li-Xu Yan, Ri-Qiang Liao, Si-Pei Wu, Yi-Long Wu
Journal: Clinical Cancer Research (2016)

Purpose: Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood.Experimental Design: We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.Results: We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+ Meanwhile, TP53- or KRAS-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that TP53 or KRAS mutation patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 inhibitors.Conclusions: This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti-PD-1/PD-L1 immunotherapy. Clin Cancer Res; 23(12); 3012-24. ©2016 AACR.
Impact of AKT inhibitor MK-2206 on erlotinib resistance in non-small cell lung cancer (NSCLC).
Authors: P. C. Mack, N. Farneth, C. Mahaffey, P. Lara, D. R. Gandara
Journal: Journal of Clinical Oncology (2011)

7573 Background: Mechanisms of acquired resistance to erlotinib (E) in NSCLC include aberrant activation of alternative receptor tyrosine kinases and/or their downstream signal transduction cascades (e.g, c-Met and AKT), indicating a need for strategies to detect such resistance mechanisms and agents to overcome them. The effects of MK2206, a selective AKT inhibitor, on E activity in NSCLC cell lines with diverse oncogenic mutation profiles and a range of E sensitivity were investigated. We hypothesized that inhibition of AKT signaling would augment E activity and reverse resistance. Methods: Four cell lines were evaluated: HCC827 (EGFR-mutant, E-hypersensitive), H1666 (EGFR-wild type, E-sensitive), H358 (EGFR-wild type, E-sensitive) and A549 (EGFR-wild type, E-resistant). Treatment effects were assessed by MTT assay, colony formation, flow cytometry and immunoblotting for signaling and apoptosis. Results: The combination of MK2206 and E showed significantly enhanced growth inhibition compared to single-agent treatment in all lines tested, including E-resistant cells. Addition of the c-Met ligand, HGF, blocked anti-proliferative and cytotoxic effects of E. Treatment with MK-2206 restored E sensitivity in cells rendered resistant by HGF. In comparison, c-Met inhibition (using PHA665752) effectively overcame HGF-mediated resistance, but was ineffective as a single agent or in combination with E. In E-resistant A549 cells, the addition of MK2206 significantly reduced colony formation compared to the single agents. Conclusions: MK2206 enhanced E activity in both E-sensitive and E-resistant NSCLC cell lines, and re-sensitized cells rendered resistant through c-Met activation by HGF. This paradigm is currently being tested in an ongoing NCI-sponsored phase II trial of MK-2206 in combination with E in patients with advanced NSCLC (stratified by EGFR mutational status) who have previously benefited from E-based therapy.
Unrelated Hematopoietic Stem Cell Transplantation with Reduced Intensity Regimens in High Risk Patients for Age or Disease: Results from Two Independent Prospective GITMO Studies.
Authors: Alberto Bosi, Andrea Bacigalupo, Davide Soligo, Renato Fanin, Teresa Lamparelli, Fabio Benedetti, Letizia Lombardini, Nicoletta Sacchi, Simona Pollicheni, Alessandro Rambaldi
Journal: Blood (2005)
Maternal Clonal Marrow Stromal Cells Expanded by “Subfractionation Culturing Method” Used for the Treatment of Refractory Chronic Graft Versus Host Disease of an Allogeneic Blood Stem Cell Recipient from an Unrelated Donor.
Authors: Chul Soo Kim, Sun Uck Song, Moon Hee Lee, Joo Han Lim, Hyeon Gyu Yi, Hyunmin Park, Jin Soo Kim, Hyung Kil Kim
Journal: Blood (2007)
Abstract 5586: Breast cancer risk prediction: An update to the Rosner-Colditz breast cancer incidence model
Authors: Megan Rice, Shelley Tworoger, Susan Hankinson, Rulla Tamimi, A Heather Eliassen, Graham Colditz, Bernard Rosner
Journal: Cancer Research (2015)

Abstract Purpose: To update and build on the Rosner-Colditz breast cancer incidence model by evaluating the contributions to breast cancer risk of childhood and adolescent somatotype, fruit and vegetable intake, breastfeeding, and physical activity. Secondarily, we evaluated the contributions of these variables to breast cancer incidence models defined by ER and PR status of the tumor. Methods: Using data from the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHSII), we added childhood somatotype (average of somatotype at ages 5 and 10; 9 unit scale), adolescent somatotype (average of somatotype at ages 10 and 20; 9 unit scale), fruit and vegetable intake (servings/day), breastfeeding (months), and physical activity (METs/week) to the Rosner-Colditz breast cancer incidence model to determine whether these variables improved the discriminatory power of the model. We evaluated the contribution of these variables to a model for all invasive breast cancer as well as to models for ER+/PR+, ER+/PR-, and ER-/PR- breast cancer. Results: In the NHS/NHSII, we accrued over 3000 cases of invasive breast cancer with complete data on the selected breast cancer risk factors. Compared to the original Rosner-Colditz model, the models that included childhood or adolescent somatotype were significantly improved (p&amp;lt;0.001). The relative risk (RR) of invasive breast cancer for a 4 unit change in somatotype was 0.69 for childhood somatotype and 0.59 for adolescent somatotype. Including childhood somatotype increased the age-adjusted concordance statistic from 0.613 to 0.616 whereas including adolescent somatotype increased the age-adjusted concordance statistic from 0.613 to 0.618. Childhood and adolescent somatotypes also significantly improved ER+/PR+ and ER-/PR- breast cancer incidence models (p&amp;lt;0.02). Breastfeeding and vegetable intake suggestively improved the ER-/PR- model. The RR for five servings of vegetables per day was 0.82, while the RR for 12 months of breastfeeding was 0.87. While these variables were significantly associated with ER-/PR- breast cancer risk in the updated models, the differences in concordance statistics comparing models with to models without these variables were not statistically significant. Conclusion: Childhood and adolescent somatotype significantly improved breast cancer risk classification in the NHS/NHSII. Citation Format: Megan Rice, Shelley Tworoger, Susan Hankinson, Rulla Tamimi, A Heather Eliassen, Graham Colditz, Bernard Rosner. Breast cancer risk prediction: An update to the Rosner-Colditz breast cancer incidence model. [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 5586. doi:10.1158/1538-7445.AM2015-5586
267. Image-Guided, Liver-Targeted Hydrodynamic Gene Delivery in Dogs – Preclinical Assessment of Effectiveness and Safety of the Procedure
Authors: Kenya Kamimura, Hiroyuki Abe, Takeshi Yokoo, Tsutomu Kanefuji, Takeshi Suda, Yuji Kobayashi, Guisheng Zhang, Masafumi Oda, Yutaka Aoyagi, Shuji Terai, Dexi Liu
Journal: Molecular Therapy (2015)

Image-guided, liver-targeted hydrodynamic gene delivery was evaluated in dogs to assess the safety and effectiveness of the procedure for human clinical trial. The procedure involves image-guided catheter insertion to hepatic veins in the dogs followed by computer-controlled hydrodynamic gene delivery using newly developed injector for clinical use. Optimum parameters for the procedure, including the location of the balloon catheter in the hepatic vein, intravascular pressure upon injection, injection volume, and sequential injections to multiple lobes of the injected liver, were employed as previously we reported. Hydrodynamic injection of human factor IX expressing plasmid (pBS-hFIX) was performed in 7 dogs (female, 20 kg) and short- and long-term effects of the procedure were assessed. We demonstrate that plasma level of human factor IX and coagulation activity in dogs increased from the background level at ~20 ng/ml and ~8% to 21768.1 ng/ml and 36.8%, respectively in 1 week after hydrodynamic gene delivery and sustained for 4 weeks. Transgene expression in the hepatocytes was also confirmed by immunohistochemical stainings. For safety assessment, we demonstrated that the impacts of image-guided liver-targeted hydrodynamic gene delivery are localized in the site of injection in the liver. Histological analysis showed significant expansion of sinusoids at the injected site to 190% of their original size. Hepatic microcirculation analysis of liver-targeted hydrodynamic injection using reflectance spectrophotometry showed significant decrease of the oxygen saturation of the Hb in the blood of the injected lobe from 30 to 0 unit upon the injection and recovered smoothly after the injection. Serum analysis showed a transient, 10- to 20-fold increase in hepatobiliary enzymes, including aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase after hydrodynamic injections, which recovered within 4 days. We also explored for the first time, the levels of the cytokines following the hydrodynamic injections to the large animals. There was no increase in the systemic inflammatory cytokines of IFN-γ, IL-8, IL-18, and IL-4, although an increase in serum levels of TNF-α, IL-10, MCP-1, canine KC, and IL-6, which were related to vascular stretching representing the sinusoidal expansion was observed. No impacts on their respiratory, cardiovascular conditions, or long-term body weight changes were observed throughout the study. These results of preclinical assessments support the clinical applications of image-guided, liver-targeted hydrodynamic gene delivery. This work was supported in part by NIH grants RO1EB002946 and RO1HL075542, and by Japanese Society for the Promotion of Science Grants 22890064, 23790595, and 26860354.
Seventy-four lung cancer patients under 50 years old
Authors: Yuko Abe, Yoshiro Tanio, Junpei Takashima, Koichi Ogawa, Yuki Akazawa, Kiyonobu Ueno, Yasunobu Funakoshi, Kenichi Oomori, Shigetoshi Shimamoto, Hiroaki Fushimi
Journal: Annals of Oncology (2015)
95. Incorporation of AAV Serotype 2 Viral Protein 2 into Other AAV Serotype Capsids
Authors: Daniel Zhang, Jun Li, Yinglu Feng, Adam Snowden, Georgy Aslanidi, Nicholas Muzyczka, Arun Srivastava, Changquan Ling, Chen Ling
Journal: Molecular Therapy (2016)

It was previously documented that large ligands inserted after residue 138 in the adeno-associated virus serotype 2 (AAV2) viral protein 2 (VP2) is tolerant to produce nearly wild-type levels of recombinant AAV2 (rAAV2) vectors (J Virol. 78(12):6595-609, 2004). Furthermore, insertion of enhanced green fluorescent protein (EGFP) into VP2 resulted in a rAAV2 particle, whose trafficking could be temporally monitored using confocal microscopy. Here, we examined whether AAV2 VP2 (2VP2) could be incorporated into other AAV serotype capsids during viral production. A pcDNA3.1-based plasmid was generated to over-express only the 5'-EGFP-tagged 2VP2 (EGFP-2VP2), but not other viral proteins, such as AAV2 Reps, VP1, or VP3. Then, rAAV1~10 vectors were produced in HEK293 cells using PEI-mediated, quadruple-plasmid transfection. The four plasmids for each rAAV vector included a packaging plasmid that contains AAV2 rep genes and a corresponding cap gene, a helper plasmid that provides essential genes from adenovirus, an ITR-containing plasmid that carries a reporter gene encoding firefly luciferase (Fluc), and the pcDNA3.1-EGFP-2VP2 plasmid. The expression of corresponding VP2 in each serotype capsid was not blocked. Purified viral stocks were separated by SDS-12% acrylamide gel electrophoresis and analyzed by Western blot assays with the B1 antibody or EGFP antibody. The results indicated that the EGFP-2VP2 protein was successfully inserted into all tested rAAV vectors, except for rAAV5. Approximately one-tenth to one-half of the total VP2 was substituted by EGFP-2VP2, depending on the serotype. Next, we characterized the novel rAAV2 and rAAV3 particles that had EGFP-2VP2 insertions. Four vectors (WT-rAAV2, rAAV2-EGFP-2VP2, WT-rAAV3, rAAV3-EGFP-2VP2) carrying the fluc gene were used to transduce a human hepatocellular carcinoma cell line, Huh7, under identical conditions in vitro. There was no difference in the transgene expression between the WT and EGFP-2VP2-inserted vectors. Furthermore, when heparin was added in the cell culture, the transduction efficiency of both rAAV2 vectors was inhibited in a dose-dependent manner. On the other hand, the transduction efficiency of rAAV3-2VP2-EGFP vectors showed a similar pattern to that was previously reported for WT-rAAV3 vectors, in which low doses of heparin significantly enhanced rAAV3 transduction, but high doses inhibited it. The tropism of rAAV2-EGFP-2VP2 vectors was further characterized in vivo following tail-vein injection of Balb/c mice and showed no difference compared with the WT-rAAV2 vectors. Finally, the trafficking of both rAAV2-EGFP-2VP2 and rAAV3-EGFp-2VP2 was temporally monitored using confocal microscopy. In summary, we have demonstrated an easy method that can be used to insert large peptides into most AAV serotype particles. This system may provide significant information to study rAAV transduction.
Abstract 975: Monoclonal antibody targeting of ADAM17 is an effective treatment for metastatic colorectal cancer resulting in tumor growth control and reductions of cancer stem cells
Authors: Joseph Dosch, Elizabeth Ziemke, Theodore Welling, Karin Hardiman, Juidth Sebolt-Leopold, Emil Michelotti, Robert Hollingsworth, Elaine Hurt
Journal: Cancer Research (2015)

Abstract ADAM17/TACE (TNFα converting enzyme) has been implicated to play a role in the drug resistance of colorectal cancers. The present study addresses the hypothesis that MEDI3622, a specific ADAM17 monoclonal antibody known to possess both human and mouse cross reactivity, represents a viable therapeutic strategy to improve outcome in the treatment of metastatic colorectal cancer (mCRC). We have generated both in vitro and in vivo data in patient-derived CRC models to provide compelling support for further exploration of this treatment strategy. A heterogeneous panel of low passage colorectal patient-derived xenografts (PDX) has been established from biospecimens procured during patient surgeries conducted at University of Michigan. All xenograft models have been genomically profiled and their histologies mimicked those observed in the original samples. As anticipated, approximately half of these models harbor an oncogenic KRAS mutation and exhibit widely differing histologies, consistent with the heterogeneity encountered in the clinic. Efficacy testing of MEDI3622 has shown that this agent significantly impaired tumor growth in 3 of the 5 PDX models examined, including one model that is KRASMT. Furthermore, cancer stem cell function in these CRC models is negatively impacted by MEDI3622, reducing tumor initiation frequencies in tumor re-implantation studies at the conclusion of treatment. Therefore our results suggest that a monoclonal antibody approach that targets ADAM17 may provide an attractive therapeutic strategy for the treatment of metastatic colorectal cancer both by reducing tumor growth and inhibiting cancer stem cells. Citation Format: Joseph Dosch, Elizabeth Ziemke, Theodore Welling, Karin Hardiman, Juidth Sebolt-Leopold, Emil Michelotti, Robert Hollingsworth, Elaine Hurt. Monoclonal antibody targeting of ADAM17 is an effective treatment for metastatic colorectal cancer resulting in tumor growth control and reductions of cancer stem 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 975. doi:10.1158/1538-7445.AM2015-975
Abstract 3169: Influence of systemic and local immune response on overall survival after hepatic resection of colorectal liver metastasis
Authors: Takeomi Hamada, Ishizaki Hidenobu, Yukihiro Haruyama, Rouko Hamada, Koichi Yano, Kazuhiro Otani, Yoshiro Fujii, Kazuhiro Kondo, Hiroaki Kataoka
Journal: Cancer Research (2015)

Abstract Background: Colorectal cancer progression is dependent on complex interactions between the tumor and the host. Tumor infiltrating lymphocytes (TIL) have been reported as a prognostic factor in colorectal cancer. The aim of this study was to assess the prognostic value of pre-operative systemic immune biomarkers and TIL in patients with resectable colorectal liver metastases (CLM). Methods: Clinicopathological data were reviewed for patients (n = 31) underwent hepatic resections for CLM between 2000 and 2008. Prognostic variables are factors of the primary lesion, factors of the metastatic lesion, and factors of host inflammatory biomarkers measured from routine pre-operative blood tests (modified Glasgow Prognostic Score and neutrophil to lymphocyte ratio (NLR)). Univariate and multivariate analyses for prognostic factors were performed. To evaluate the local immune responses for resected metastatic lesion, immunohistochemical analysis was performed. The immune subsets were CD8+ T cells, CD45RO+ T cells, Fork head box p3+ (FOXP3+) T cells, and CD66b+ neutrophils. Results: The number of metastases ≥ 4, extrahepatic metastasis, adjuvant chemotherapy, and raised NLR &amp;gt; 4.1 were correlated with cancer-specific survival in univariate analysis. On multivariate analysis, the number of metastases ≥ 4, adjuvant chemotherapy, and elevated NLR remained independent prognostic indicators (metastases ≥ 4: HR = 0.09, CI = 0.01-0.56, p = 0.0102, adjuvant chemotherapy: HR = 0.08, CI = 0.01-0.39, p = 0.0025, NLR: HR = 0.11, CI = 0.01-0.99, p = 0.0494). Accumulation of CD45RO+ T cells and FOXP3+ T cells in the metasatic tumors were significantly associated with favorable survival in patients with resectable CLM (P = 0.02 and 0.04, respectively). Conclusions: The results of the present study show that the NLR has prognostic value in patients who conduct a hepatic resection for CLM. Moreover, accumulation of CD45RO+ T cells and FOXP3+ T cells in metastatic lesions are independent favorable prognostic factor. Based on the present results and previously literature, systemic immune response including NLR and local immune response may be promising as prognostic factor of patients with resectable CLM. Citation Format: Takeomi Hamada, Ishizaki Hidenobu, Yukihiro Haruyama, Rouko Hamada, Koichi Yano, Kazuhiro Otani, Yoshiro Fujii, Kazuhiro Kondo, Hiroaki Kataoka. Influence of systemic and local immune response on overall survival after hepatic resection of colorectal liver metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3169. doi:10.1158/1538-7445.AM2015-3169
“An Intention-to-Treat Analysis of Rome Transplant Network Policy for Alternative Donor Search in Patients Lacking a HLA Matched Related donor”.
Authors: Alessandra Picardi, Paolo de Fabritiis, Teresa Dentamaro, Giulio De Rossi, Maurizio Caniglia, Rita Pinto, Maria Concetta Petti, Andrea Mengarelli, Luciana Annino, Anna Chierichini, Bruno Monarca, Enrico Montefusco, Giuseppe Avvisati, Maria Cristina Tirindelli, Ilaria Mangione, Laura Cudillo, Raffaella Cerretti, Gottardo De Angelis, Ambra Di Veroli, William Arcese
Journal: Blood (2009)