tbuckley/cabot-search huggingface dataset:
Abstract 4316: hMENA11a contributes to HER3-mediated resistance to PI3K inhibitors in HER2 overexpressing breast cancer cells
Authors: Paola Trono, Francesca Di Modugno, Rita Circo, Sheila Spada, Roberta Melchionna, Belinda Palermo, Mariangela Panetta, Silvia Matteoni, Silvia Soddu, Ruggero De Maria, Paola Nisticò
Journal: Cancer Research (2015)

Abstract Human Mena (hMENA), an actin regulatory protein of the ENA/VASP family, cooperates with ErbB receptor family signaling in breast cancer. It is overexpressed in high-risk preneoplastic lesions and in primary breast tumors where it correlates with HER2 overexpression and an activated status of AKT and MAPK. The concomitant overexpression of hMENA and HER2 identifies breast cancer patients with a worse prognosis. hMENA is expressed along with alternatively expressed isoforms, hMENA11a and hMENAΔv6 with opposite functions. By Reverse Phase Protein Assay, we identified a novel role for the epithelial associated hMENA11a isoform in sustaining HER3 activation and pro-survival pathways in HER2 overexpressing breast luminal cancer cells. Since HER3 activation is crucial in mechanisms of cell resistance to PI3K inhibitors, we explored whether hMENA11a is involved in these resistance mechanisms. The specific hMENA11a depletion switched off the HER3-related pathway activated by PI3K inhibitors and impaired the nuclear accumulation of HER3 transcription factor FOXO3a induced by PI3K inhibitors. On the other hand, PI3K inhibitors activated hMENA11a phosphorylation and affected its localization. At the functional level, we found that hMENA11a sustains cell proliferation and survival in response to PI3K inhibitor treatment whereas hMENA11a silencing increases molecules involved in cancer cell apoptosis. As shown in three-dimensional cultured breast cancer cells hMENA11a contributes to cancer cells resistance to PI3K inhibition since the depletion of hMENA11a drastically reduced cell viability upon treatment with PI3K inhibitor BEZ235. Altogether, these results indicate that hMENA11a in HER2 overexpressing breast cancer cells sustains HER3/AKT axis activation and contributes to HER3-mediated resistance mechanisms to PI3K inhibitors. Thus, hMENA11a expression can be proposed as a marker of HER3 activation and of resistance to PI3K inhibition therapies, to select patients who can benefit from these combined targeted treatments. hMENA11a activity may represent a new target for anti-proliferative therapies in breast cancer. Citation Format: Paola Trono, Francesca Di Modugno, Rita Circo, Sheila Spada, Roberta Melchionna, Belinda Palermo, Mariangela Panetta, Silvia Matteoni, Silvia Soddu, Ruggero De Maria, Paola Nisticò. hMENA11a contributes to HER3-mediated resistance to PI3K inhibitors in HER2 overexpressing breast cancer 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 4316. doi:10.1158/1538-7445.AM2015-4316
Engineering hepatitis B virus core particles for targeting HER2 receptors in vitro and in vivo
Authors: Izzat Fahimuddin Bin Mohamed Suffian, Julie Tzu-Wen Wang, Naomi O. Hodgins, Rebecca Klippstein, Mitla Garcia-Maya, Paul Brown, Yuya Nishimura, Hamed Heidari, Sara Bals, Jane K. Sosabowski, Chiaki Ogino, Akihiko Kondo, Khuloud T. Al-Jamal
Journal: Biomaterials (2016)

Hepatitis B Virus core (HBc) particles have been studied for their potential as drug delivery vehicles for cancer therapy. HBc particles are hollow nano-particles of 30-34 nm diameter and 7 nm thick envelopes, consisting of 180-240 units of 21 kDa core monomers. They have the capacity to assemble/dis-assemble in a controlled manner allowing encapsulation of various drugs and other biomolecules. Moreover, other functional motifs, i.e. receptors, receptor binding sequences, peptides and proteins can be expressed. This study focuses on the development of genetically modified HBc particles to specifically recognise and target human epidermal growth factor receptor-2 (HER2)-expressing cancer cells, in vitro and in vivo, for future cancer therapy. The non-specific binding capacity of wild type HBc particles was reduced by genetic deletion of the sequence encoding arginine-rich domains. A specific HER2-targeting was achieved by expressing the ZHER2 affibodies on the HBc particles surface. In vitro studies showed specific uptake of ZHER2-ΔHBc particles in HER2 expressing cancer cells. In vivo studies confirmed positive uptake of ZHER2-ΔHBc particles in HER2-expressing tumours, compared to non-targeted ΔHBc particles in intraperitoneal tumour-bearing mice models. The present results highlight the potential of these nanocarriers in targeting HER2-positive metastatic abdominal cancer following intra-peritoneal administration.
Adverse events after first, single, mesh and non-mesh surgical procedures for stress urinary incontinence and pelvic organ prolapse in Scotland, 1997–2016: a population-based cohort study
Authors: Joanne R Morling, David A McAllister, Wael Agur, Colin M Fischbacher, Cathryn M A Glazener, Karen Guerrero, Leanne Hopkins, Rachael Wood
Journal: The Lancet (2016)
Qualitative and Quantitative Correlation of PML-Rara Fusion Transcript from Peripheral Blood and Bone Marrow Samples By Quantitative Real-Time PCR in Patients with Acute Promyelocytic Leukemia
Authors: Koji Sasaki, Hagop M. Kantarjian, Raja Luthra, Keyur P. Patel, Guillermo Garcia-Manero, Srdan Verstovsek, Elihu H. Estey, Tapan Kadia, Mark Brandt, Sherry Pierce, Zeev Estrov, Alessandra Ferrajoli, Gautam Borthakur, Jorge E. Cortes, Farhad Ravandi
Journal: Blood (2015)
235. Anticancer Effectiveness of Mesenchymal Stem Cells Transfected With Thymidine Phosphorylase for Colorectal Cancer Cells
Authors: Nasrin Salehi, Ching-An Peng
Journal: Molecular Therapy (2015)

Gene-directed enzyme prodrug therapy (GDEPT) consists of targeted delivery to tumor cells with a suicide gene responsible for in situ conversion of a prodrug into cytotoxic metabolites. One of the major bottlenecks of GDEPT is to have the therapeutic gene specifically target on cancer cells prior to the administration of prodrug. Among various gene delivery methods, mesenchymal stem cells (MSCs) have emerged as potential cellular vehicles for gene delivery. They exhibit remarkable tumor-tropic and low immunogenic capacities. In this study, MSCs was engineered to express thymidine phosphorylase (TP) which has the capability of converting prodrug 5'-deoxy-5-fluorouridine into toxic 5-fluorouracil. TP expression in the MSCs post-transfection of TP cDNA was confirmed by immunoblotting analysis and its activity was determined by spectrophotometric assay. Our results showed the anticancer effectiveness of human HT29 colorectal cells co-cultured with TP-expressing MSCs was enhanced with the addition of various dosages of 5'-deoxy-5-fluorouridine.
Abstract 5152: Zebrafish models of myeloid malignancies produced through tet2 and asxl1 genomic editing
Authors: Evisa Gjini, Marc Mansour, Jeffry Sander, Shuning He, Myunggon Ko, Yi Zhou, Scott Rodig, Keith Joung, Leonard Zon, Anjana Rao, Thomas Look
Journal: Cancer Research (2015)

Abstract Myelodysplastic syndromes (MDS) are one of the most common and most difficult to treat of all hematologic malignancies. MDS are diverse clonal disorders of hematopoietic stem cells in the bone marrow that cause dysplastic differentiation in developing progenitors leading to ineffective hematopoiesis, dangerously low circulating blood counts, and evolution to acute myeloid leukemia (AML). We sought to create a faithful zebrafish model of MDS, to study the altered molecular pathways and mechanisms underlying this disease and to provide a means to identify synthetic lethal relationships that can be exploited with small molecule inhibitors to selectively eliminate the mutant cells. Somatic loss-of-function mutations of the Ten-ElevenTranslocation-2 (TET2) and Additional Sex Combs Like 1 (ASXL1) genes are the most frequent clonal somatically acquired genetic abnormalities that have been identified in human MDS and other myeloid malignancies, such as chronic myelomonocytic leukemia (CMML). To generate a zebrafish model of MDS with tet2 and asxl1 loss, we used genome-editing technology to disrupt the zebrafish tet2 and asxl1 genes. The resultant tet2m/m mutant zebrafish are viable and fertile and exhibited normal embryonic and larval hematopoiesis, but developed myelodysplastic syndrome progressing to anemia at 24 months of age. asxl1 m/m mutant zebrafish are embryonic lethal with bone malformations. asxl1 m/m embryos show reduced numbers of hematopoietic and progenitor stem cells (HSPCs), a phenotype which is rescued by Tet2 loss. Combined loss of tet2 and asxl1 in the zebrafish leads to CMML at 5 months of age. These zebrafish lines provide animal models for small molecule and genetic screens in definitive HSPCs to identify synthetic lethal relationships and to dissect the pathways in hematopoietic cells that are altered by loss of function of tet2 and asxl1. Citation Format: Evisa Gjini, Marc Mansour, Jeffry Sander, Shuning He, Myunggon Ko, Yi Zhou, Scott Rodig, Keith Joung, Leonard Zon, Anjana Rao, Thomas Look. Zebrafish models of myeloid malignancies produced through tet2 and asxl1 genomic editing. [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 5152. doi:10.1158/1538-7445.AM2015-5152
A review of six cases of aggressive NK cell leukemia in our institute
Authors: Kazuya Sakai, Yusuke Okamoto, Hiroyuki Sugiura, Kazuya Okada, Aki Sato, Takayuki Sato, Takeshi Maeda, Tatsuhito Onishi, Keizi Notohara, Yasunori Ueda
Journal: Annals of Oncology (2015)
Abstract 3478: A multi-orthogonal strategy for targeting EGFRvIII expressing glioblastomas
Authors: Ying Shen, Jie Li, Frank B Furnari, Arshad Desai, Hong-Zhuan Chen, Clark Chen
Journal: Cancer Research (2015)

Abstract Epidermal Growth Factor Receptor variant III (EGFRvIII) is a recurrent oncogenic EGFR isoform found in 25-64% of glioblastomas, the most common form of primary brain cancer. While EGFRvIII expressing glioblastomas are initially sensitive to EGFR inhibition, emergence of resistance clones is universal. We previously demonstrated that EGFRvIII expressing glioblastoma can be ablated through inhibition of compensatory mechanisms that allow cancer cells to adapt to EGFRvIII induced oncogenic stress. Here we propose that this strategy can be combined with direct inhibition of EGFR signaling. A synthetic lethal RNAi screen revealed synthetic lethality between Polo-Like Kinase 1 (PLK1) inhibition and EGFRvIII expression in glioblastoma cells. PLK1 mediated glioblastoma adaptation to excessive DNA damage associated with EGFRvIII expression through activation of Rad51, a protein essential for homologous recombination (HR). PLK1 inhibition (by BI2536) enhanced the cytotoxic effects of the DNA damaging agent, temozolomide (TMZ), a DNA alkylating agent and the standard-of-care chemotherapy for glioblastoma. This TMZ-sensitizing effect is 3-5 fold more pronounced in a formed Ink4a/Arf(-/-) EGFRvIII GEMM (genetically engineerd murine model)-derived glioblastoma model relative to an Ink4a/Arf(-/-) PDGF-β GEMM-derived glioblastoma model and correlated to the endogenous level of DNA damage accumulation in these models. Importantly, the tumoricidal and TMZ-sensitizing effects of BI2536 were uniformly observed across Ink4a/Arf(-/-) EGFRvIII glioblastoma clones that acquired independent resistance mechanisms to EGFR inhibitors, Gefitinib and Erlotinib, suggesting these resistant clones retain oncogenic stress that required PLK1 compensation. Although BI2536 significantly augmented the anti-neoplastic effect of EGFR inhibitors in the Ink4a/Arf(-/-) EGFRvIII model, complete ablation was not achieved until TMZ was added. Such synergistic effect was not observed in the Ink4a/Arf(-/-) PDGF-β model. Our study revealed a novel synthetic lethal interaction between PLK1 inhibition and EGFRvIII expression. Our results suggest that optimal therapeutic effect against EGFRvIII expressing glioblastomas requires “multi-orthogonal” integration of oncogenic inhibition, oncogenic stress, and conventional chemotherapy, tailored to the molecular physiology associated with the target cancer genome. Citation Format: Ying Shen, Jie Li, Frank B Furnari, Arshad Desai, Hong-Zhuan Chen, Clark Chen. A multi-orthogonal strategy for targeting EGFRvIII expressing glioblastomas. [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 3478. doi:10.1158/1538-7445.AM2015-3478
Myeloma Cells Inhibit the Non-Canonical Wnt Co-Receptor Ror2 in Human Mesenchymal/Osteoprogenitor Cells: Effect of Wnt5a/Ror2 Pathway Activation On MM-Induced Impairment of the Osteogenic Differentiation Process.
Authors: Marina Bolzoni, Simona Colla, Paola Storti, Gaetano Donofrio, Manuela Abeltino, Valentina Sgobba, Sabrina Bonomini, Vittorio Rizzoli, Nicola Giuliani
Journal: Blood (2009)
A Single-Center Retrospective Analysis of a Pediatric Salvage Chemotherapy Regimen for Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia
Authors: Ben A. Blomberg, Hendrik W. Van Deventer, Stuart Gold, Katarzyna Joanna Jamieson, Joshua F. Zeidner, Benyam Muluneh, Dominic Moore, Matthew C. Foster
Journal: Blood (2015)
Abstract 3639: Design and development of a novel series of orally active, selective PI3K-p110β/δ inhibitors for the treatment of solid and hematological cancers
Authors: Stephen J. Shuttleworth
Journal: Cancer Research (2015)

Abstract The phosphatidylinositide 3-kinases (PI3Ks) have emerged as important therapeutic targets for the treatment of solid and hematological malignancies. For solid tumor therapy, the majority of clinical activity has largely centered on pan-class I (p110α, β, δ and γ) inhibitors with limited selectivity, or pan-class I/mTOR dual inhibitors, whereas targeting p110δ and p110γ has been the main focus for hematological cancer treatment in the clinic. Our research at Karus in the PI3K arena has been based upon the emerging role of p110β and p110δ in PTEN-deficient solid and hematological tumorigenesis, and in the emerging role of individual PI3K isoforms in tumor immunotherapy. We have designed and developed a uniquely-selective series of orally-active molecules that inhibit the p110β/δ isoforms, and which display high degrees of specificity over protein kinases and other lipid kinases. Moreover, a spectrum of p110β/δ selectivity has been achieved in this series, which has facilitated interrogation of preferred isoform inhibition profiles required to confer tumor growth inhibition; additionally, by tuning selectivity over the other class I isoforms, elimination of the mechanism-related toxicities associated with the pan-class I inhibitors currently in the clinic can be realized, making such agents potentially more conducive to combination therapy. In vitro and in vivo therapy data for advanced lead compounds will be disclosed. Citation Format: Stephen J. Shuttleworth. Design and development of a novel series of orally active, selective PI3K-p110β/δ inhibitors for the treatment of solid and hematological cancers. [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 3639. doi:10.1158/1538-7445.AM2015-3639
589. Short Hairpin RNAs Based on miR-451 Show Potent Knockdown without Passenger Strand Activity
Authors: Erik Kaadt, Lars Aagaard
Journal: Molecular Therapy (2016)

Based on the recent findings that RNAi designs with shortened shRNA stems bypass Dicer cleavage and rely on Ago2 for processing of the 'effector' guide strand, we have compared designs based on 'classical' shRNA structures with shortened stems and mimics of miR-451. Our results support the complete lack of passenger stands activity which is likely to improve safety in therapeutic applications. We report that miR-451 mimics are more potent than shortened shRNAs and our data further suggests that the U6 promoter is the preferred choice as compared to H1. We suggest that imprecise transcription initiation from H1 promoter makes it hard to predict the actual target site(s) and may thus be a safety concern. Tiling of U6-promoted miR-451 mimics supports this notion and demonstrate that knockdown efficacy vary substantially when shifting the target site one nucleotide.
Right–left ventricular interdependence: a promising predictor of successful extracorporeal membrane oxygenation (ECMO) weaning after assistance for refractory cardiogenic shock
Authors: Nadia Aissaoui, Julia Caudron, Pascal Leprince, Jean-Yves Fagon, Guillaume Lebreton, Alain Combes, Benoit Diebold
Journal: Intensive Care Medicine (2016)
Emergence of Fc-Gamma-Riib-Dominance Contributes to Resistance to Therapeutic Antibodies in Patients with Chronic Lymphocytic Leukaemia
Authors: Melinda Burgess, Sally Mapp, Roberta Mazzieri, Jonathan Ellis, Catherine Cheung, Lynne Chambers, Stephen Mattarollo, Peter Mollee, Devinder Gill, Nicholas Saunders
Journal: Blood (2015)
Abstract 3300: Concerted epigenetic and signaling mechanisms regulate normal stem cell radiosensitivity
Authors: Keith M. Jacobs, Sandeep Misri, Barbara Meyer, Suyash Raj, Cheri L. Zobel, Barry P. Sleckman, Dennis E. Hallahan, Girdhar G. Sharma
Journal: Cancer Research (2015)

Abstract Side effects resulting from ionizing radiation (IR) during cancer radiotherapy often involve normal tissue injury including depletion of tissue regenerative capacity. Utilizing multiple in vivo tissue niches and cell culture models, we demonstrate that normal stem cells are highly radiosensitive while differentiated progeny are radioresistant, and IR-induced apoptosis of stem cells is observed broadly throughout the cell cycle independent of proliferation status. Our study demonstrates that normal stem cells fail to activate the DDR, do not display IR-induced foci in vivo as well as in culture, and exhibit severely attenuated DNA repair. Despite normal sensing of DNA breaks, recruitment/ retention of repair factors at DNA break sites is repressed in stem cells. Stem cells are unable to eliminate constitutive phosphorylation of H2AX-Y142 around break sites, abetting stem cells toward an apoptotic instead of repair pathway. The abrogated DDR in normal stem cells is associated with a constitutively enhanced histone-3 lysine-56 acetylation, which epigenetically contributes to muted retention of repair factors. Reinforced PP2A phosphatase expression was also identified as substantial regulators of stem cell radiosensitivity and transient inhibition of phosphatase activity restores stem cell survival. We thus identify pluralistic interacting molecular and epigenetic mechanisms that collectively control and impart IR hypersensitive phenotype to the normal stem cells. These insights will be crucial in development of prevention and intervention therapeutic strategies to minimize IR-induced stem cell dropout and increase the efficacy of radiotherapy. Citation Format: Keith M. Jacobs, Sandeep Misri, Barbara Meyer, Suyash Raj, Cheri L. Zobel, Barry P. Sleckman, Dennis E. Hallahan, Girdhar G. Sharma. Concerted epigenetic and signaling mechanisms regulate normal stem cell radiosensitivity. [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 3300. doi:10.1158/1538-7445.AM2015-3300
Risk Factors for Infections in Myelofibrosis: Role of Disease Status and Treatment. A Study on 507 Patients
Authors: Nicola Polverelli, Massimo Breccia, Giulia Benevolo, Bruno Martino, Alessia Tieghi, Roberto Latagliata, Lucia Catani, Maura Nicolosi, Margherita Perricone, Marco Romano, Gioia Colafigli, Anna Campana, Francesco Merli, Umberto Vitolo, Giuliana Alimena, Giovanni Martinelli, Michele Cavo, Nicola Vianelli, Francesca Palandri
Journal: Blood (2015)
Longitudinal Trajectories of Metabolic Control From Childhood to Young Adulthood in Type 1 Diabetes From a Large German/Austrian Registry: A Group-Based Modeling Approach
Authors: Anke Schwandt, Julia M. Hermann, Joachim Rosenbauer, Claudia Boettcher, Désirée Dunstheimer, Jürgen Grulich-Henn, Oliver Kuss, Birgit Rami-Merhar, Christian Vogel, Reinhard W. Holl
Journal: Diabetes Care (2016)

OBJECTIVE Worsening of glycemic control in type 1 diabetes during puberty is a common observation. However, HbA1c remains stable or even improves for some youths. The aim is to identify distinct patterns of glycemic control in type 1 diabetes from childhood to young adulthood. RESEARCH DESIGN AND METHODS A total of 6,433 patients with type 1 diabetes were selected from the prospective, multicenter diabetes patient registry Diabetes-Patienten-Verlaufsdokumentation (DPV) (follow-up from age 8 to 19 years, baseline diabetes duration ≥2 years, HbA1c aggregated per year of life). We used latent class growth modeling as the trajectory approach to determine distinct subgroups following a similar trajectory for HbA1c over time. RESULTS Five distinct longitudinal trajectories of HbA1c were determined, comprising group 1 = 40%, group 2 = 27%, group 3 = 15%, group 4 = 13%, and group 5 = 5% of patients. Groups 1–3 indicated stable glycemic control at different HbA1c levels. At baseline, similar HbA1c was observed in group 1 and group 4, but HbA1c deteriorated in group 4 from age 8 to 19 years. Similar patterns were present in group 3 and group 5. We observed differences in self-monitoring of blood glucose, insulin therapy, daily insulin dose, physical activity, BMI SD score, body-height SD score, and migration background across all HbA1c trajectories (all P ≤ 0.001). No sex differences were present. Comparing groups with similar initial HbA1c but different patterns, groups with higher HbA1c increase were characterized by lower frequency of self-monitoring of blood glucose and physical activity and reduced height (all P &amp;lt; 0.01). CONCLUSIONS Using a trajectory approach, we determined five distinct longitudinal patterns of glycemic control from childhood to early adulthood. Diabetes self-care, treatment differences, and demographics were related to different HbA1c courses.
Negative influence of Melanocortin-1 receptor (MC1R) polymorphisms on clinical outcomes of metastatic melanoma (MM) patients (pts) harboring BRAF mutation and treated with BRAF inhibitors (BRAFi)
Authors: M. Guida, S. Strippoli, A. Albano, A. Ferretta, N. Bartolomeo, C. Greco, S. Guida, I. Natalicchio, S. Tommasi, A. Azzariti, G. Guida
Journal: Annals of Oncology (2015)