tbuckley/cabot-search huggingface dataset:
640. A Tissue Engineered Nipple and Areola Complex
Authors: Nicholas C. Pashos, Michelle E. Scarritt, Jeffery M. Gimble, Abigail E. Chaffin, Bruce A. Bunnell
Journal: Molecular Therapy (2015)

There are more than 2.8 million breast cancer survivors in the United States, many of who have undergone reconstructive surgery. Approximately 36% of patients with early stage diagnoses and 60% of patients with late stage diagnoses undergo mastectomies. Moreover, immediate breast reconstruction following mastectomies has become more common, significantly increasing at an average rate of 5% per year, from 20.8% in 1998 to 37.8% in 2008. This increasing trend is not surprising as breast reconstruction likely provides psychological benefits for women who undergo mastectomies. There is evidence to suggest that nipple and areola complex (NAC) reconstruction affects psychological wellbeing by enhancing body image and selfesteem, or decreasing the feeling of distress felt by female patients with mastectomies. Due to this, there exists a need for a reproducible and more naturally aesthetic architecture for NAC reconstruction. Current strategies for NAC reconstruction are limited to surgical techniques that create a NAC-like structure from existing local tissue, secondary site grafting, 3D tattooing, or using commercially available acellular dermal matrix sheets, such as Alloderm. Generating a tissue engineered, biocompatible NAC implant, made of decellularized whole NAC, for use in place of surgically created NAC structures is a promising approach to NAC reconstruction following mastectomies. To date, no tissue engineering and cellular therapy strategies have been developed focused on NAC reconstruction. The application of decellularization to the whole, semi-glandular NAC can create a non-immunogenic NAC that retains the microarchitecture and gross structures of a native NAC. This tissue engineering approach to whole NAC structure regeneration allows for the effective removal of cellular material, the retention of the extracellular matrix components and structure, as well as cell adhesion molecules. Once decellularized, NAC scaffolds would be seeded with autologous cells to create a graft that is patient-specific. Preliminary studies have shown, using tissues from a Rhesus Macaque Non- Human Primate animal model, that biologically derived scaffolds were able to be reproducibly isolated with effective removal of nuclear material—less than ≈50ng of 200bp DNA per mg of sample remaining. Through histological analysis of the NAC scaffolds it was shown that the presence of extracellular matrix and adhesion proteins were maintained after the decellularization process. Additionally, bioactivity of the scaffolds were assessed using rhesus bone marrow-derived stem cells for one week, under dynamic cell culture conditions. Herein, a tissue engineered, regenerative medicine approach to reconstruct the nipple and areola complex using a biologically derived scaffold and autologous cell sources is described.
Abstract A1-55: Combination of a three-microRNA signature and TP53 genotype predicts responses to platinum-based doublet chemotherapy in patients with lung adenocarcinoma
Authors: Kouya Shiraishi, Motonobu Saito, Takashi Kohno
Journal: Cancer Research (2015)

Abstract Platinum-based doublet, i.e., a combination of a platinum agent and another agent, is a standard regimen to treat non-small cell lung cancer, since molecular target therapy using tyrosine kinase inhibitors is effective only in a subset of patients with tumors with druggable oncogene mutations. Therefore, to identify biomarkers that can discriminate responders who received platinum-based chemotherapy before treatment is important to improve the efficacy of chemotherapy for non-small cell lung cancer. We found that a SNP in TP53 tumor suppressor gene, TP53-Arg72Pro is associated with response to the platinum-based doublet therapy (Shiraishi et al, JCO, 2010). We recently assessed intra-tumor micro (mi)RNA expression as a biomarker for predicting responses to platinum-based chemotherapy in patients with recurrent lung adenocarcinoma. Microarray-based screening of 904 miRNAs followed by quantitative reverse transcription-PCR-based verification in 40 test cohort samples, including 16 (40.0%) responders, was performed to identify miRNAs that are differentially expressed in chemotherapy responders and non-responders. Differential expression was confirmed in a validation cohort (n = 63 samples), including 18 (28.6%) responders. A signature comprising three miRNAs (miR1290, miR196b, and miR135a*) enabled the prediction of a chemotherapeutic response (rather than progression-free and overall survival) with high accuracy in both the test and validation cohorts (82.5% and 77.8%). Examination of the latter was performed using miRNAs extracted from archived formalin-fixed paraffin-embedded tissues. Genotype data for the TP53-Arg72Pro polymorphism, which is associated with responses to platinum-based doublet chemotherapy, were subsequently incorporated into the prediction analysis. Finally, combining this miRNA signature with the TP53-Arg72Pro polymorphism genotype marginally improved the predictive power (Saito et al., Clin. Cancer Res. 2014). Citation Format: Kouya Shiraishi, Motonobu Saito, Takashi Kohno. Combination of a three-microRNA signature and TP53 genotype predicts responses to platinum-based doublet chemotherapy in patients with lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-55.
Abstract 4903: Microarray gene expression analysis of human prostate cancer PC-3 cells targeted by Salmonella typhimurium A1-R
Authors: Ming Zhao, Wen Wu, Chongyi Lu, Yong Zhang, Robert M. Hoffman, Hui Qi, Meng Yang, Yanqin Gu, Yiyu Lu, Shibing Su, Hui Zhang, Qianmei Zhou, Qilong Chen
Journal: Cancer Research (2015)

Abstract The transcriptional profile of PC-3 human prostate cancer cells infected with tumor-targeting Salmonella typhimurium A1-R (A1-R) was analyzed with by microarray. PC-3 is highly sensitive to A1-R. Numerous genes involved in diverse cellular processes, including apoptosis, necrotic cell death, neutrophil chemotaxis and innate immunity were significantly up-regulated by A1-R bacterial infection. Such up-regulated genes include TNF-a, Fos and JUN which are involved in cell death and IL-1A and CXCL which are involved in neutrophil chemotaxes. Knowledge of the up-regulated gene profile will be exploited for enhancing prostate tumor targeting by A1-R. Keywords: Salmonella typhimurium A1-R, human prostate cancer, microarray, apoptosis, necrotic cell death, neutrophil chemotaxis, tumor-targeting. Citation Format: Ming Zhao, Wen Wu, Chongyi Lu, Yong Zhang, Robert M. Hoffman, Hui Qi, Meng Yang, Yanqin Gu, Yiyu Lu, Shibing Su, Hui Zhang, Qianmei Zhou, Qilong Chen. Microarray gene expression analysis of human prostate cancer PC-3 cells targeted by Salmonella typhimurium A1-R. [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 4903. doi:10.1158/1538-7445.AM2015-4903
Abstract 4084: Transient SNAIL1 expression is necessary for metastatic competence in breast cancer
Authors: Hung D. Tran, Michael Kim, Krishna Luitel, Kun Zhang, Gregory Longmore, David D. Tran
Journal: Cancer Research (2015)

Abstract SNAIL1 has been suggested to regulate breast cancer metastasis based on analyses of human breast tumor transcriptomes and experiments using cancer cell lines and xenografts. However, in vivo genetic experimental support for a role for SNAIL1 in breast cancer metastasis that develops in an immunocompetent tumor microenvironment has not been determined. To address this question, we created a genetic SNAIL1 model by coupling an endogenous SNAIL1 reporter with an inducible SNAIL1 transgene. Using multiple genetic models of breast cancer, we demonstrated that endogenous SNAIL1 expression was restricted to primary tumors that ultimately disseminate. SNAIL1 gene deletion either during the premalignant phase or after primary tumors have reached a palpable size blunted metastasis, indicating that late metastasis was the main driver of metastasis and that this was dependent on SNAIL1. Importantly, SNAIL1 expression during breast cancer metastasis was transient and forced transient, but not continuous, SNAIL1 expression in breast tumors was sufficient to increase metastasis. Citation Format: Hung D. Tran, Michael Kim, Krishna Luitel, Kun Zhang, Gregory Longmore, David D. Tran. Transient SNAIL1 expression is necessary for metastatic competence in breast 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 4084. doi:10.1158/1538-7445.AM2015-4084
Broad Activity of Apto-253 in AML and Other Hematologic Malignancies Correlates with KLF4 Expression Level
Authors: Stephen E. Kurtz, Daniel Bottomly, Beth Wilmot, Shannon K. McWeeney, William Rice, Stephen B Howell, Avanish Vellanki, Brian J. Druker, Jeffrey W. Tyner
Journal: Blood (2015)
APTO-253 Induces KLF4 to Promote Potent in Vitro Pro-Apoptotic Activity in Hematologic Cancer Cell Lines and Antitumor Efficacy As a Single Agent and in Combination with Azacitidine in Animal Models of Acute Myelogenous Leukemia (AML)
Authors: William G Rice, Avanish Vellanki, Yoon Lee, Jeff Lightfoot, Robert Peralta, Mona Jamerlan, Hongnan Jin, Ronnie Lum, Tiffany Cheng
Journal: Blood (2014)
Etoposide Containing Preparative Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia.
Authors: Takeshi Saito, Osamu Asai, Nobuaki Dobashi, Shingo Yano, Tamotsu Ichiba, Hiroshi Osawa, Yutaka Takei, Katuki Sugiyama, Yutaka Okawa, Sinobu Takahara, Yuko Yamaguchi, Jiro Minami, Noriko Usui, Masayuki Kobayashi
Journal: Blood (2004)
Elucidating genetic events in human hepatocellular carcinoma
Authors: C. Rosario, R. Gladdy, M. Ko, A. Pollett, J. Dennis, C. Swallow
Journal: Journal of Clinical Oncology (2009)

e15590 Background: Hepatocellular carcinoma (HCC) is prevalent world wide with increasing incidence in North America. 4q is a commonly deleted region in HCC and is lost in 32% of premalignant cirrhotic nodules but the precise molecular lesion involved in tumor initiation remains unknown. Human Plk4, a member of the polo family of cell cycle regulating serine /threonine kinases is located on 4q28. Plk4 is a haploinsufficient tumor suppressor in mice, with 50% of animals developing spontaneous tumors, most commonly multifocal primary HCC. We hypothesize that Plk4 plays a role in the initiation of human HCC. Our purpose was to determine the levels of Plk4 in human HCC and investigate possible genetic interactions with the tumor suppressor p53. Methods: Formalin-fixed paraffin-embedded sections of human HCCs, adjacent non-neoplastic liver tissue and gallbladder tissue were microdissected. DNA was extracted and manual LOH analysis was performed. To asses Plk4 expression, RNA from the hepatoma cases was used for real time RT-PCR. To elucidate a genetic interaction, Plk4 p53 compound mutant mice were generated and murine embryonic fibroblasts (MEFs) were derived and cultured. Results: In HCC Plk4 LOH rates varied from 57% for the marker closest to Plk4 to 8% for the marker furthest away (n=32). Using an intragenic marker the rate of LOH was 45% (n=24). Studies in CRC (n=46) and pancreas cancer specimens (n=40) showed only background levels of LOH. Expression of Plk4 in HCC tumor samples that displayed LOH at the Plk4 locus was reduced compared to non-neoplastic liver. Plk4 ± p53 −/− mice showed acceleration of tumor formation compared to Plk4 +/+ p53 −/− mice. Plk4 ± p53 −/− MEFs had increased levels multinucleation, centrosome amplification and aneuploidy compared to Plk4 +/+ p53 −/− cells. In addition these cells were tumorigenic in vivo whereas Plk4 +/+ p53 −/− cells were not. Conclusions: Our results demonstrate significant rates of LOH at the Plk4 locus specifically in human HCC and indicate that this is associated with decreased Plk4 expression. In addition, our studies of compound mutant mice suggest a possible genetic interaction of Plk4 and p53 in tumor development. No significant financial relationships to disclose.
Diagnostic PD-L1 immunohistochemistry in NSCLC: Results of the first German harmonization study.
Authors: Andreas H. Scheel, Manfred Dietel, Lukas C. Heukamp, Korinna Jöhrens, Thomas Kirchner, Simone Reu, Josef Ruschoff, Hans-Ulrich Schildhaus, Peter Schirmacher, Markus Tiemann, Arne Warth, Wilko Weichert, Rieke Nila Fischer, Juergen Wolf, Reinhard Buettner
Journal: Journal of Clinical Oncology (2016)

3028 Background: Immunohistochemistry for PD-L1 (PD-L1 IHC) may be predictive for anti-PD-1 and anti-PD-L1 immunotherapy in non-small cell lung cancer (NSCLC). Several PD-L1 IHC assays with individual reagents and scoring-criteria are developed in parallel. Biomarker testing and clinical decision making would profit from one harmonized 'PD-L1 status'. Methods: Fifteen NSCLC resection specimens were centrally stained with the PD-L1 IHC assays 28-8, 22C3, SP142 and SP263. The slides were scored by nine German pathologists. Proportions of PD-L1 positive tumor cells (TC) and immune cells (IC) were scored according to a 6-step scoring system that integrates all cut-off criteria employed by the four assays. Interobserver and interassay concordance were analyzed with 'R' Version 3.2.3. Results: Proportion-scoring of PD-L1 positive TC showed moderate interobserver concordance coefficients for the 6-step scoring system as well as a simplified 6-step score (Light's kappa = 0.4 - 0.5). The integrated dichotomous proportion cut-offs ( ≥ 1%, ≥ 5%, ≥ 10%, ≥ 50%) showed good concordance coefficients (κ = 0.6 - 0.8). The proportion-scoring of PD-L1 positive IC yielded low interobserver concordance coefficients both for the 6-step-score (κ < 0.2) and the dichotomous cut-offs (κ = 0.12 - 0.25). The staining-intensity yielded low-to-moderate concordance for TC and IC. The assays 28-8 and 22C3 stained comparable TC-proportions. In some cases, SP142 stained fewer TC but more IC, SP263 stained more TC and IC. The differences in TC-proportions would translate into different classifications by any of the dichotomous cut-offs. Conclusions: The data indicate that unified PD-L1 IHC scoring-criteria for tumor cells are feasible while scoring of immune cells requires detailed training. The four tested PD-L1 assays do not show comparable staining-patterns in all cases of NSCLC. The results obtained by each assay are not interchangeable. Thus, more studies are required to archive a harmonized 'PD-L1 status' in NSCLC. In particular, more data on the predictive value of one assay for multiple substances are needed.
Abstract 2609: Disruption of CAS scaffolds: A novel mechanism for microtubule targeting agents
Authors: Nicholas F. Dybdal-Hargreaves, Cristina C. Rohena, April L. Risinger, Susan L. Mooberry
Journal: Cancer Research (2015)

Abstract Microtubule targeting agents (MTAs) are an important class of anticancer drugs. While their anticancer mechanisms were considered exclusively as antimitotic for decades, evidence now suggests that the ability of MTAs to inhibit functions of interphase microtubules likely plays an essential role in their clinical anticancer actions. Interphase microtubules are responsible for intracellular trafficking of many constituents including proteins involved in signal transduction. Efficient signal transduction requires precise coordination of signaling partners through their appropriate localization. Scaffold proteins regulate signal transduction pathways by assembling signaling components into complexes both temporally and spatially. Assembly of scaffold complexes can be dependent on a functional microtubule network. Several scaffold proteins have been identified with importance in breast cancer, including BCAR1, a member of the crk associated substrate (CAS) family of scaffolds. BCAR1 expression in breast cancer is associated with resistance to anti-estrogens. We hypothesized that the ability of diverse MTAs to interrupt the function of these signaling scaffolds could contribute to their activities in breast cancer cells. The effects of eribulin, vinorelbine, paclitaxel, docetaxel, and ixabepilone on the localization and associated signaling of BCAR1 was evaluated. The MTAs disrupted the localization of BCAR1 and differential effects were noted among the MTAs. There were also distinct effects of the agents on BCAR1 associated signaling. To determine whether BCAR1 expression was related to sensitivity of breast cancer cell lines to specific MTAs we separated the breast cancer cell lines based on their ability to initiate cytotoxic or only antiproliferative effects and evaluated them for BCAR1 expression. Two cell lines with the highest BCAR1 expression were resistant to the cytotoxic effects of each MTA of this panel. Thus, high levels of BCAR1 in breast cancer cells can overcome the ability of diverse MTAs to disrupt scaffold function and lead to resistance. Our results suggest that the ability of MTAs to interrupt BCAR1 scaffolds represents a new mechanism of action for these drugs. However, MTA disruption of the BCAR1 CAS scaffold complexes can be overcome by high BCAR1 expression. Funding for the work was provided by Eisai Inc. Citation Format: Nicholas F. Dybdal-Hargreaves, Cristina C. Rohena, April L. Risinger, Susan L. Mooberry. Disruption of CAS scaffolds: A novel mechanism for microtubule targeting agents. [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 2609. doi:10.1158/1538-7445.AM2015-2609
Abstract 5488: Utilizing a pathway based analysis of genome wide association data to identify biomarkers of toxicity in breast cancer patients
Authors: Behzad Bidadi, Krishna R. Kalari, Matthias Rubner, Alexander Hein, Matthias W. Beckmann, Peter A. Fasching, Brigitte Rack, Wolfgang Janni, Richard Weinshilboum, Liewei Wang
Journal: Cancer Research (2015)

Abstract Breast cancer is the most common invasive cancer in women worldwide and treatment related toxicity has high inter-patient variability. Our goal was to identify additional genetic predictors of toxicity by completing a pathway based analysis taking advantage of the genotyping results obtained through a GWAS of the same patients. For our analysis, we have utilized GWA data from the SUCCESS-A trial in which 3,754 breast cancer patients were treated with adjuvant chemotherapy. We have included SNPs associated with 112 genes involved in drug disposition and 375 genes in selected cancer pathways. We identified 35 SNPs associated with neutropenia (P-value &amp;lt;1×10−4). These patients initially received three cycles consisting of 5-fluorouracil (5-FU), cyclophosphamide, and epirubicin. Currently we are characterizing the function of three SNPs located within an intron of the hyaluronan mediated motility receptor (HMMR) gene that are associated with the neutropenia phenotype (P-value &amp;lt;1×10−4). These SNPs are highly associated with the expression of a gene encoding a B-cell survival factor, TNFSF13B, (P-value &amp;lt;1×10−5). Our in vitro studies using lymphoblastoid cell lines (LCLs) selected based on the genotypes of HMMR gene showed that heterozygous and homozygous variant cells (n = 6) have an increased sensitivity to 5-fluorouracil, but not cyclophosphamide or epirubicin when compared with homozygous wild-type cells (n = 6). LCLs exposed to the previously mentioned chemotherapeutic agents resulted in an upregulation of TNFSF13B gene expression and downregulation of HMMR gene expression. We have utilized a pathway based approach to analyzing GWA data to identify several SNPs in the HMMR gene highly associated with the expression of one of the top signals in the cytopenia GWAS. Our goal is to further characterize the role of HMMR gene variants in chemotherapy response by assessing whether combinations of these agents in vitro (including 5-FU) also have a genotype dependent response to cytotoxicity. Citation Format: Behzad Bidadi, Krishna R. Kalari, Matthias Rubner, Alexander Hein, Matthias W. Beckmann, Peter A. Fasching, Brigitte Rack, Wolfgang Janni, Richard Weinshilboum, Liewei Wang. Utilizing a pathway based analysis of genome wide association data to identify biomarkers of toxicity in breast cancer patients. [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 5488. doi:10.1158/1538-7445.AM2015-5488
Abstract 1696: Blocking activity of a novel anti-MET humanized monoclonal antibody, KTN0216, is enhanced by IgG2 isotype in HGF-dependent and Met-amplified tumors
Authors: Sreekala Mandiyan, Brett S. Robinson, Lida Kimmel, Gerald McMahon, Yaron Hadari, Yan Yang
Journal: Cancer Research (2015)

Abstract Aberrant activation of MET kinase can be mediated by ligand-dependent mechanisms through paracrine or autocrine stimulation by its ligand, HGF, or by ligand-independent mechanisms through gene amplification, over-expression or mutation. Both mechanisms of activating MET have been associated with promoting tumor growth and progression. The discovery of antagonistic MET antibodies has been challenging as many anti-MET antibodies promote kinase activation that leads to cell proliferation and migration. We have systematically screened MET antibodies using cell based functional assays and identified a number of antibodies that potently block MET-dependent cell proliferation, cell scattering as well as tumor growth in vivo. One such antibody, KTN-MET-IgG1, binds to the Sema/PSI domain and prevents HGF-MET interaction; additionally it induces receptor ubiqutination and degradation. To evaluate if the IgG isotype influences activity on MET activation and tumor growth we grafted the binding domains of this antibody onto 2 other IgG backbones: KTN-MET-IgG2 and KTN-MET-IgG4. Surprisingly, grafting the antibody variable regions onto the IgG2 framework dramatically enhanced the anti-MET activity in vitro and in vivo. Comparing to KTN-MET-IgG1 and KTN-MET-IgG4 antibodies with KTN-MET-IgG2 antibody, it demonstrated significantly better inhibition of receptor phosphorylation and cell proliferation in MET amplified tumor cell lines (EBC1, SNU5) and comparable activity in HGF-dependent tumor cell lines (A549, U87MG). KTN-MET-IgG2 treatment of tumor bearing mice achieved potent and prolonged suppression of tumor growth using the U87MG glioblastoma xenograft model and tumor growth regression with tumors remaining below detection for over 90 days post last dosing using the SNU5 gastric cancer xenograft model. In summary, we have found a novel IgG2 anti-MET antibody that inhibits tumor growth driven by HGF-dependent MET activation and MET amplification. A model to help explain the contribution of IgG2 isotype to enhanced blocking activity will be presented. The humanized version of KTN-MET-IgG2, KTN0216, is currently in preclinical development to evaluate tumor types best suited for KTN0216 treatment. Citation Format: Sreekala Mandiyan, Brett S. Robinson, Lida Kimmel, Gerald McMahon, Yaron Hadari, Yan Yang. Blocking activity of a novel anti-MET humanized monoclonal antibody, KTN0216, is enhanced by IgG2 isotype in HGF-dependent and Met-amplified tumors. [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 1696. doi:10.1158/1538-7445.AM2015-1696