tbuckley/cabot-search huggingface dataset:
Targeted Disruption of Smad4 in Cardiomyocytes Results in Cardiac Hypertrophy and Heart Failure
Authors: JianWang, NingXu, XinhengFeng, NingHou, JiShuaiZhang, XuanCheng, YeguangChen, YouyiZhang, XiaoYang
Journal: Circulation Research (2005)

Transforming growth factor-βs (TGF-βs) are pleiotropic cytokines involved in many physiological and pathological processes, including heart development and heart disease. Smad4 is the central intracellular mediator of TGF-β signaling. To investigate the function of Smad4 in heart development further, we generated a strain of cardiomyocyte-specific Smad4 knockout mice using the Cre–loxP system. Unexpectedly, the deletion of Smad4 in cardiomyocytes resulted in cardiac hypertrophy characterized by an increase in the size of cardiac myocytes, age-associated fibrosis, and reexpression of certain fetal genes. Approximately 70% of the Smad4 mutant mice died spontaneously between 5 and 12 months of age. Echocardiography and an invasive hemodynamic study of the left ventricle revealed markedly decreased cardiac contractility in Smad4 mutant mice compared with littermate controls. Moreover, phosphorylated extracellular signal–regulated kinase (ERK) 1/2 and mitogen-activated protein kinase–ERK (MEK) 1 were increased...
Abstract 1336: Autophagy inhibition reverses EMT and reduces 3D growth of pancreatic adenocarcinoma cells <i>in vitro</i> and <i>in vivo</i>
Authors: Jane B. Pearce, Ciara H. O'Flanagan, Stephen D. Hursting
Journal: Cancer Research (2018)

Abstract Pancreatic cancer is the 4th most fatal cancer in US men and women, with 5-year survival rates under 5%. Obesity is one risk factor known to increase pancreatic cancer risk by facilitating tumorigenesis and metabolic processes associated with pancreatic tumor growth and progression. Autophagy is the catabolic process of recycling cellular organelles to provide energy to the cell and is often induced when cells become stressed. Autophagy plays a critical role in cancer growth and metastasis, and in many cancers autophagy inhibition decreases the size of tumors in in vivo models. Our current studies investigate the link between the autophagy inhibition and the invasiveness of pancreatic cancer. To understand the role of autophagy on invasion, EMT and 3D growth in pancreatic cancer, Kras-driven Panc02 mouse pancreatic cancer cells were transduced using CRISPR/Cas9 to cleave the gene encoding autophagy related protein 5 (Atg5). Atg5 deletion resulted in striking morphological alterations, including a more epithelial-like appearance. In addition, Atg5 deletion resulted in increased expression of the epithelial marker E-Cadherin, concurrent with decreased expression of mesenchymal markers N-Cadherin and Snail. Furthermore, Atg5 deletion resulted in significant decreased invasiveness and ability to form colonies under anchorage-independent conditions, with no significant difference in 2D cell growth. Orthotopic, intrapancreatic injection of these cells into C57BL/6 mice resulted in reduced tumor take and growth. Taken together, these results for the first time show that autophagy inhibition results in reduced EMT and 3D growth in pancreatic adenocarcinoma and highlight autophagy's role in pancreatic adenocarcinoma progression. Citation Format: Jane B. Pearce, Ciara H. O'Flanagan, Stephen D. Hursting. Autophagy inhibition reverses EMT and reduces 3D growth of pancreatic adenocarcinoma cells in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1336.
Role of Myocardial Inducible Nitric Oxide Synthase in Contractile Dysfunction and β-Adrenergic Hyporesponsiveness in Rats With Experimental Volume-Overload Heart Failure
Authors: OlgaGealekman, ZaidAbassi, IritRubinstein, JosephWinaver, OferBinah
Journal: Circulation (2002)

Background— Whereas nitric oxide (NO) has been implicated in the pathophysiology of heart failure (HF), the significance and functional role of different NO synthase (NOS) isoforms in this pathology are controversial. Our aim was to study in the myocardium of rats with volume-overload–induced HF the expression, activity, and localization of endothelial (eNOS) and inducible (iNOS) isoforms and the involvement of iNOS in depressed cardiac contractile properties, intracellular Ca2+ ([Ca2+]i) transients, and β-adrenergic hyporesponsiveness. Methods and Results— HF was induced by aortocaval fistula (ACF). Compensated and decompensated subgroups of HF were selected on the basis of daily sodium excretion. ACF induced cardiac hypertrophy in rats with compensated (36%) and decompensated (76%) HF. Whereas in HF rats, cardiac eNOS expression and activity were unchanged, iNOS expression and activity increased ≈2-fold. iNOS immunostaining was observed in ventricular myocytes of compensated and decompensated HF rats bu...
Abstract 756: Development of next-generation antibody-drug conjugates for resistant HER2-positive tumors
Authors: Vincent Lacasse, Jeffrey V. Leyton, Simon Beaudoin, Mark Barok, Heikki Joensuu
Journal: Cancer Research (2018)

Abstract Antibody-Drug Conjugates (ADC) represent a promising therapeutic modality for improving the clinical management of cancer. However, there now exists resistant mechanisms by cancer cells that are effective at ultimately reducing the cellular accumulation of the delivered drug and hence, reducing cytotoxic effectiveness. Kadcyla® (trastuzumab-emtansine [T-DM1]) is a benchmark as it is the first solid-tumor approved ADC. Despite this new therapeutic option, approximately 43% of patients achieve complete or partial response and most who initially respond develop resistance soon after. In order to transform current ADCs to more effective products improved intracellular delivery strategies could provide solutions. Our group developed is a natural composite compound (termed Accum) that conjugates to surface lysines and enables antibodies to escape endosomal entrapment followed by active routing to the nucleus. Modified antibodies retain high tumor cell selectivity, enhanced cellular accumulation, and improved tumor delivery of molecular payloads in vivo. We asked whether the modification of Accum-modified T-DM1 maintained its intracellular delivery mechanism and cytotoxic effectiveness in T-DM1-resistant cells. The cancer cell lines N87, OE19 (gastric), JIMT1, SK-BR-3 (breast), SKOV3 and SKOV3.IP1 (ovarian) were treated with increasing concentrations of T-DM1 in a 3 day on, 10 days off fashion for a period of 1 to 2 months. Resistant clones were identified. Parental and resistant cells were placed and passaged in SILAC (Stably Labeled Amino acid for Cell culture) media for proteomic analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS). Cells were also treated with Accum-T-DM1 and mechanistic underpinnings determined. The IC50 of Accum-T-DM1 was increased 50- and 10-fold relative to T-DM1 in parental OE19, and JIMT1 cells, respectively. T-DM1 resistant cell lines were successfully generated for each tumor type. Typically, the T-DM1 IC50 values were increased ≥100-fold in resistant cells compared to parental cells. Preliminary proteomic studies revealed HER2 expression is marginally reduced in resistant cells. IP of Accum-T-DM1 co-precipitated showed the interaction with α-importin. This study is a work in progress of modifying T-DM1 with Accum and demonstrating enhanced cytotoxicity in T-DM1 resistant HER2-positive tumor cells. Ongoing studies will determine DM1 accumulation levels, potential resistance mechanisms, and ultimately cytotoxic effectiveness. Citation Format: Vincent Lacasse, Jeffrey V. Leyton, Simon Beaudoin, Mark Barok, Heikki Joensuu. Development of next-generation antibody-drug conjugates for resistant HER2-positive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 756.
Abstract 3015: Precise investigation of cancer stem cells in mouse glioblastoma
Authors: Xuanhua P. Xie, Dan R. Laks, Daochun Sun, Asaf Poran, Ashley M. Laughney, German Belenguer, Joan Massague, Xiuping Zhou, Isabel Farinas, Olivier Elemento, Luis F. Parada
Journal: Cancer Research (2018)

Abstract In this study, we employ mouse models to investigate features and roles of cancer stem cells (CSCs) in glioblastoma (GBM). A nestin-TK-GFP transgene is firstly used to label CSCs in a fully penetrant mouse model of GBM (M7: hGFAP-Cre; Nf1fl/+; p53fl/fl; Ptenfl/+). Food-mediated ganciclovir (GCV) delivery kills proliferative transgene positive cells and significantly prolongs the lives of the transgene bearing mice. Isolation and transplantation of the tumor cells indicates the GFP+ cells are more tumorigenic than the GFP- cells. We then generate and characterize a novel transgene (CGD: nestin-CreERT2-H2BeGFP-hDTR) that labels all the neural stem/progenitor cells in the subventricular zone (SVZ). This transgene efficiently promotes brain tumors by eliminating tumor suppressor genes (CGD-M4: CGD; Nf1fl/+; p53fl/+; Ptenfl/+) in the corresponding cells. The CGD-GFP+ tumor cells are quiescent in vivo, yet form more spheres in vitro than the GFP- cells. The GFP+ cells are competent to develop tumors in a serial transplantation assay and constantly maintain a quiescent subpopulation pool in the newly formed tumors. Diphtheria toxin treatment ablates the CGD-GFP+ tumor cells and greatly reduces the tumor bulk. Temozolomide, the conventional chemotherapy for human GBM patients, benefits only mice transplanted with GFP- but not CGD-GFP+ tumor cells. Our study demonstrates the essential role of CSCs in GBM initiation, recurrence, and drug resistance. Further analysis of the CGD-GFP+ cells might delineate novel treatments for this deadly disease. Citation Format: Xuanhua P. Xie, Dan R. Laks, Daochun Sun, Asaf Poran, Ashley M. Laughney, German Belenguer, Joan Massague, Xiuping Zhou, Isabel Farinas, Olivier Elemento, Luis F. Parada. Precise investigation of cancer stem cells in mouse glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3015.
Abstract 489: Up-regulation of miR-130b is involved in prostate cancer racial disparity through FHIT pathway inactivation
Authors: Yutaka Hashimoto, Masrisa Shiina, Taku Kato, Soichiro Yamamura, Yuichiro Tanaka, Shahana Majid, Sharanjot Saini, Varahram Shahryari, Priyanka Kulkarni, Pritha Dasgupta, Divya Bhagiratha, Nadeem Bhat, Guoren Deng, Laura Tabatabai, Deepak Kumar, Rajvir Dahiya
Journal: Cancer Research (2018)

Abstract Purpose: Prostate cancer (PCa) is a common cancer in men. African-American (AfA) men have higher incidence and significantly higher prostate cancer mortality rates than Caucasian-American (CaA) men. In this study, we investigated the biochemical role of miR-130b in this disparity. Methods: We used meta-analyses and data from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). PCa cell lines from CaA (DU145, LNCaP, PC3), AfA (MDA-PCa-2b, E006AA-hT) and a normal epithelial cell line (PWR1E) were used for examining miR-130b expression levels and/or establishing stable miR-130b knock-down clones. Total RNA was extracted from clinical samples and cell lines. miR-130b and mRNA levels of its target genes were determined by quantitative real-time PCR (qPCR). qPCR based gene expression arrays were used to identify miR-130b target genes. Cell proliferation, apoptosis and cell cycle were monitored after stable miR-130b knock down. Western blotting was performed to detect miR-130b target protein expression levels. Results: TCGA data showed up-regulation of miR-130b in AfA PCa tissue samples compared with CaA samples. miR-130b was significantly up-regulated in AfA prostate cancer tissues and cell lines compared to CaA cells and tissues. Utilizing SFVAMC and NDRI patient cohorts, we confirmed that miR-130b expression was linked to a racial difference between AfA/CaA PCa patients. Knock down of miR-130b showed decreased growth and cell cycle arrest, though the effect was less in CaA compared to AfA cells. We found unique changes in biological pathways associated with miR-130b knock down in AfA cells by qPCR array. Evaluation of the altered pathways showed that Fragile Histidine Triad (FHIT) was markedly changed in the AfA compared with CaA cells. Conclusion: These results demonstrate that miR-130b may be a central regulator of key events that contribute racial differences in prostate cancer. FHIT may also be a new AfA specific tumor-suppressive pathway that may be of therapeutic importance in AfA prostate cancer patients. Citation Format: Yutaka Hashimoto, Masrisa Shiina, Taku Kato, Soichiro Yamamura, Yuichiro Tanaka, Shahana Majid, Sharanjot Saini, Varahram Shahryari, Priyanka Kulkarni, Pritha Dasgupta, Divya Bhagiratha, Nadeem Bhat, Guoren Deng, Laura Tabatabai, Deepak Kumar, Rajvir Dahiya. Up-regulation of miR-130b is involved in prostate cancer racial disparity through FHIT pathway inactivation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 489.
Abstract 1143: Prox1 and Notch mark distinct colorectal cancer stem cell populations
Authors: Jenny Högström, Sarika Heino, Pauliina Kallio, Marianne Lähde, Veli-Matti Leppänen, Seppo Kaijalainen, Diego Balboa, Timo Otonkoski, Sylvie Robine, Zoltan Wiener, Kari Alitalo
Journal: Cancer Research (2018)

Abstract Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality. Signaling pathways, such as the Wnt and Notch pathways, are essential for the maintenance and differentiation of wild-type intestinal stem cells. We have shown that the Prox1 transcription promotes expansion of the colorectal cancer stem cell pool and that a subpopulation of the Prox1+ CRC cells display stem cell activity. Because of these results we have further analyzed the role of Prox1 in the regulation of CRC stem cell. Here, we report that Prox1 regulates CRC stem-like cells via bidirectional interaction with Notch1 during CRC initiation and progression. Using genetic in vivo models and ex vivo 3D organoid cultures, we show that Notch inhibition decreases the number of Lgr5+ stem cells whereas it increases expression of the Prox1. Although Notch inhibition led to increased proliferation of the Prox1 positive cells, it did not affect their ability to give rise to differentiated Prox1 negative progeny. Ectopic overexpression of the active fragment of Notch1 suppressed Prox1 expression and inhibited stem cell activity in the CRC cells. On the other hand, the PROX1-NuRD complex suppressed the Notch signaling pathway and Prox1 deletion increased Notch target gene expression and promoter activity, indicating reciprocal regulation between Prox1 and Notch1. Thus, although Prox1 and Notch suppress each other in colorectal cancer cells, Prox1+ cells can function as a stem cell population without the need for Notch pathway activity. Citation Format: Jenny Högström, Sarika Heino, Pauliina Kallio, Marianne Lähde, Veli-Matti Leppänen, Seppo Kaijalainen, Diego Balboa, Timo Otonkoski, Sylvie Robine, Zoltan Wiener, Kari Alitalo. Prox1 and Notch mark distinct colorectal cancer stem cell populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1143.
Abstract 3283: NDEx, the Network Data Exchange: Collaboration, publication and data sharing for cancer pathways
Authors: Dexter R. Pratt
Journal: Cancer Research (2018)

Abstract Computable network models of pathway mechanisms, molecular interactions, and cellular function are widely developed and used in cancer genome analysis. Dissemination and reuse of networks, however, needs common data standards, facile access by visualization and analysis applications, mechanisms for pre-publication collaboration, and integration with the publishing process. We present NDEx, the Network Data Exchange, an online resource (www.ndexbio.org) that addresses these needs by providing a framework in which users can store, share, access, and disseminate networks. These networks can range from small pathways to large interaction data or to hierarchical cell models. NDEx is user-driven, where every researcher can be an author, easily creating publicly available network resources with full control of the data content and organization. Networks can range from standard resources disseminated by organizations to novel, up-to-date content from individual scientists. Collaborators can privately share their networks for review and reference or for integration in analysis workflows across multiple scripts and applications. Access to NDEx by an extensive API and client libraries supports network-enabled application development. Published networks can go beyond diagrams and static supplemental data, becoming immediately accessible and interactive. Integration with academic publishing is underway, facilitated by features such as anonymous access by reviewers and minting of DOIs for networks. NDEx breaks down barriers to scientific discourse involving networks, fostering collaboration within and between communities. Citation Format: Dexter R. Pratt. NDEx, the Network Data Exchange: Collaboration, publication and data sharing for cancer pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3283.
Abstract 4299: Mutual influence of ROS, pH and CLIC1 membrane protein in the regulation of G1/S phase progression in human glioblastoma stem cells
Authors: Ivan Verduci, Marta Peretti, Federica Maddalena Raciti, Valentina Carlini, Alessandra Patarozzi, Sara Barozzi, Massimiliano Garrè, Sarah Sertic, Alex Costa, Antonio Daga, Federica Barbieri, Tullio Florio, Michele Mazzanti
Journal: Cancer Research (2018)

Abstract Glioblastoma (GB) is the most lethal, aggressive and diffuse brain tumor. The main challenge of successful treatment is targeting the cancer stem cell (CSC) sub-population responsible for tumor origin, progression and recurrence. Chloride Intracellular Channel 1 (CLIC1), highly expressed in CSCs, is constitutively present in the plasma membrane where it is associated with chloride ion permeability. In vitro, CLIC1 inhibition leads to a significant arrest of GB CSCs in G1 phase of the cell cycle. Furthermore, CLIC1 knockdown impairs tumor growth in vivo. Here we demonstrate that CLIC1 membrane localization and function is specific for GB CSCs. Mesenchymal stem cells (MSCs) do not show CLIC1-associated chloride permeability and inhibition of CLIC1 protein function has no influence on MSC cell cycle progression. Investigation of the basic functions of GB CSCs reveals a constitutive state of oxidative stress and cytoplasmic alkalinization compared with MSCs. We now report that these three elements are temporally linked during CSC G1/S transition. Impeding CLIC1-mediated chloride current prevents both intracellular ROS accumulation and pH changes. CLIC1 membrane functional impairment results in GB CSCs resetting from an allostatic tumorigenic condition to a homeostatic steady state. In contrast, inhibiting NADPH oxidase and the NHE1 proton pump results in cell death of both GB CSCs and MSCs. Our results show that CLIC1 membrane protein is crucial and specific for GB CSC proliferation, and is a promising pharmacological target for successful brain tumor therapies. This work was supported by grant n.16713, IG 2015 to MM Italian Association for Cancer Research (AIRC). Citation Format: Ivan Verduci, Marta Peretti, Federica Maddalena Raciti, Valentina Carlini, Alessandra Patarozzi, Sara Barozzi, Massimiliano Garrè, Sarah Sertic, Alex Costa, Antonio Daga, Federica Barbieri, Tullio Florio, Michele Mazzanti. Mutual influence of ROS, pH and CLIC1 membrane protein in the regulation of G1/S phase progression in human glioblastoma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4299.
It’s All in the Delivery: Designing Hydrogels for Cell and Non-viral Gene Therapies
Authors: Richard L. Youngblood, Norman F. Truong, Tatiana Segura, Lonnie D. Shea
Journal: Molecular Therapy (2018)

Hydrogels provide a regenerative medicine platform with their ability to create an environment that supports transplanted or endogenous infiltrating cells and enables these cells to restore or replace the function of tissues lost to disease or trauma. Furthermore, these systems have been employed as delivery vehicles for therapeutic genes, which can direct and/or enhance the function of the transplanted or endogenous cells. Herein, we review recent advances in the development of hydrogels for cell and non-viral gene delivery through understanding the design parameters, including both physical and biological components, on promoting transgene expression, cell engraftment, and ultimately cell function. Furthermore, this review identifies emerging opportunities for combining cell and gene delivery approaches to overcome challenges to the field.Graphical abstract
Enhancing Oligodendrocyte Myelination Rescues Synaptic Loss and Improves Functional Recovery after Chronic Hypoxia
Authors: Fei Wang, Yu-Jian Yang, Nian Yang, Xian-Jun Chen, Nan-Xin Huang, Jun Zhang, Yi Wu, Zhi Liu, Xing Gao, Tao Li, Guang-Qiang Pan, Shu-Bao Liu, Hong-Li Li, Stephen P.J. Fancy, Lan Xiao, Jonah R. Chan, Feng Mei
Journal: Neuron (2018)

Highlights•Chronic hypoxia causes hypomyelination, synaptic loss, and functional deficits•Hypomyelination results in synaptic and functional deficits•Enhancing myelination rescues hypoxia-induced synaptic and functional deficits•Myelination-enhancing drugs improve functional recovery against hypoxiaSummaryTo address the significance of enhancing myelination for functional recovery after white matter injury (WMI) in preterm infants, we characterized hypomyelination associated with chronic hypoxia and identified structural and functional deficits of excitatory cortical synapses with a prolonged motor deficit. We demonstrate that genetically delaying myelination phenocopies the synaptic and functional deficits observed in mice after hypoxia, suggesting that myelination may possibly facilitate excitatory presynaptic innervation. As a gain-of-function experiment, we specifically ablated the muscarinic receptor 1 (M1R), a negative regulator of oligodendrocyte differentiation in oligodendrocyte precursor cells. Genetically enhancing oligodendrocyte differentiation and myelination rescued the synaptic loss after chronic hypoxia and promoted functional recovery. As a proof of concept, drug-based myelination therapies also resulted in accelerated differentiation and myelination with functional recovery after chronic hypoxia. Together, our data indicate that myelination-enhancing strategies in preterm infants may represent a promising therapeutic approach for structural/functional recovery after hypoxic WMI.Graphical abstract
National Coverage Analysis of CAR-T Therapies — Policy, Evidence, and Payment
Authors: Peter B. Bach
Journal: New England Journal of Medicine (2018)

Interview with Dr. Peter Bach on payment approaches Medicare could consider for costly new CAR-T treatments. (07:38)Download Even if CMS concludes that CAR-T therapy provides a net benefit for Medicare patients, it could limit who can provide the therapy, require collection of further outcome data, limit coverage to clinical trials, and design a payment approach promoting price competition.