tbuckley/cabot-search huggingface dataset:
Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers
Authors: Sarah Naomi Olsen, Ania Wronski, Zafira Castaño, Benjamin Dake, Clare Malone, Thomas De Raedt, Miriam Enos, Yoko S. DeRose, Wenhui Zhou, Stephanie Guerra, Massimo Loda, Alana Welm, Ann H. Partridge, Sandra S. McAllister, Charlotte Kuperwasser, Karen Cichowski
Journal: Cancer Discovery (2016)

Abstract Luminal breast cancers are typically estrogen receptor–positive and generally have the best prognosis. However, a subset of luminal tumors, namely luminal B cancers, frequently metastasize and recur. Unfortunately, the causal events that drive their progression are unknown, and therefore it is difficult to identify individuals who are likely to relapse and should receive escalated treatment. Here, we identify a bifunctional RasGAP tumor suppressor whose expression is lost in almost 50% of luminal B tumors. Moreover, we show that two RasGAP genes are concomitantly suppressed in the most aggressive luminal malignancies. Importantly, these genes cooperatively regulate two major oncogenic pathways, RAS and NF-κB, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo. Finally, although the cooperative effects on RAS drive invasion, NF-κB activation triggers epithelial-to-mesenchymal transition and is required for metastasis. Collectively, these studies reveal important mechanistic insight into the pathogenesis of luminal B tumors and provide functionally relevant prognostic biomarkers that may guide treatment decisions. Significance: The lack of insight into mechanisms that underlie the aggressive behavior of luminal B breast cancers impairs treatment decisions and therapeutic advances. Here, we show that two RasGAP tumor suppressors are concomitantly suppressed in aggressive luminal B tumors and demonstrate that they drive metastasis by activating RAS and NF-κB. Cancer Discov; 7(2); 202–17. ©2016 AACR. See related commentary by Sears and Gray, p. 131. This article is highlighted in the In This Issue feature, p. 115
A New FLVCR Isoform Able to Support Erythropoiesis.
Authors: Deborah Chiabrando, Sonia Mercurio, Samuele Marro, Sharmila Fagoonee, Erika Messana, Emilia Turco, Lorenzo Silengo, Fiorella Altruda, Emanuela Tolosano
Journal: Blood (2009)
Refining Triage to Polycythaemia Vera or Primary Myelofibrosis Based on Targeted Molecular Profiling By Clinical Next Generation Sequencing
Authors: Song Jinming, Mohammad Omar Hussaini, Haipeng Shao, Eric Padron, Jeffrey E Lancet, Rami S. Komrokji, Ling Zhang, Lynn C. Moscinski
Journal: Blood (2015)
PO35DEMOGRAPHICS, TREATMENT AND OUTCOME FOR GLIOBLASTOMA MULTIFORME IN THE EAST MIDLANDS 2009-2013
Authors: Ammar Natalwala, Andrius Anuzis, Tim Hammett, Stuart Smith
Journal: Neuro-Oncology (2015)

INTRODUCTION: A recent study (Brodbelt et al.) has assessed the incidence, treatment and survival of GBM nationally across the UK and by region, basing their case identification on from the National Cancer Registration Service and Hospital Episode Statistics. It is acknowledged that there are omissions from this data, so we sought in this study to evaluate the East Midlands regional incidence, primary treatments and survival of GBM patients, based on confirmed histopathological diagnoses. METHOD: The Neuropathology records for all patients undergoing Neurosurgery in the East Midlands were examined and all cases of GBM identified for the years 2009-13 inclusive. This data was then cross-referenced with hospital records to identify patient demographics, treatment received, overall survival and IDH-1 status. Statistical analysis was conducted using SPSS with all tests two tailed and significance taken at a p value of less than 0.05. RESULTS: 759 cases of histologically confirmed GBM were recorded in the East Midlands over the 5-year period. 60 of these had undergone previous surgery for a GBM or other intrinsic brain tumour, giving a new incidence rate of 3.87 / 100 000 / year. Median age at diagnosis was 63.2 years. 64% of patients underwent craniotomy and median overall survival was 7 months, increasing to 14 months in patients undergoing full radical treatment including temozolomide. 56.5% of patients received craniotomy, radiotherapy and temozolomide. CONCLUSION: Incidence rates, treatment protocols and survival are broadly equivalent between the national study and the East Midlands data. Both datasets demonstrate survival equivalent to the phase III trial data for good performance status patients.
PTH-077 Screening colonoscopy in patients with a family history of colorectal cancer: time to tighten our practice?: Abstract PTH-077
Authors: R J Mead, B Colleypriest
Journal: Gut (2010)

<h3>Introduction</h3> With 18 weeks pathways as the maximum for NHS treatment, pressures on initial diagnostic intervention has increased enormously. Endoscopy is a key part of the gastroenterology service and is the main diagnostic tool for gastrointestinal cancers. At the same time busy units have now embraced the National Bowel cancer Screening programme, providing additional services and high quality through the Global Rating Scale. Increased service levels, and high demand for rapid investigation are focusing minds on efficient effective practice. In our departments we evaluate our practice and screening colonoscopy has been a recent area of analysis. <h3>Methods</h3> We retrospectively interrogated endoscopy databases in two typical district general hospitals. We selected out colonoscopic investigations with a “family history of colorectal cancer” as the only indication. Data on age, polyp detection, cancer detection, and site were recorded. A sampling of approximately 10% of the notes was undertaken to understand the indication, and reason for colonoscopy. These data were scrutinised against the gold standard British Society of Gastroenterology guidelines, and publications leading to this. Our population findings were compared using a χ<sup>2</sup> statistic. <h3>Results</h3> We analysed 298 colonoscopies, 49 patients (16%) had polyps detected, and 1 patient had a rectal cancer. Age ranged from 15 to 83 years old. 55 polyps were detected, 16 rectal, 23 sigmoid, 2 descending, 3 transverse, 6 ascending, and 5 caecal polyps. Modelling population finding from the BSG guidelines, we would expect a polyp detection rate of 24%. Our findings demonstrate a significantly different outcome, and confirms our practice or population is significantly different from the populations informing the guidelines. (χ<sup>2</sup> statistic 7.73, 1 degree of freedom, two tailed p=0.005). Twenty-four referral letters were assessed as an indicative sample of criteria leading to colonoscopy. Only 11 (46%) documented family history consistent with strict adherence to BSG guidelines, suggesting at least our practices contribute to the differing outcomes (Abstract 077). <h3>Conclusion</h3> Screening for a family history of bowel cancer detects significant numbers of adenomatous polyps and cancer at an earlier stage than symptomatic referral. In our population pathology was found in 17%, significantly lower than the populations informing current BSG guidelines. Strict adherence to BSG guidelines may reduce the colonoscopy workload by 33%, and free up 25 colonoscopy lists. These finding across 2 separate hospitals may indicate a wider application in other regions.
The Optimal Body Mass Index Range for Patients With Colorectal Cancer—Reply
Authors: Candyce H. Kroenke, Bette J. Caan, Carla Prado
Journal: JAMA Oncology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Abstract 4163: Targetting VPAC1 for intestinal cancer prevention
Authors: Shaohua Liu, Yunjie Zeng, Nengtai Ouyang
Journal: Cancer Research (2015)

Abstract Vasoactive intestinal peptide (VIP) is a neurotransmitter that primarily functions as a vasodilator. VIP plays its role through binding to its receptors known as VIP/pituitary adenylate cyclase-activating peptide receptors (VPACs). In this study, we examined the expression of VPAC1 in human colon cancer tissues, analyzed the relationship between VPAC1 expression and cancer malignancy, and explored the possible mechanisms using immunohistochemistry and immunofluorescence double staining. The results showed that: 1) poorly-differentiated colon cancers have significantly higher VPAC1 expression than well-differentiated colon cancers do (p&amp;lt;0.01); 2) phospho-EGFR overexpression/activation in the cytoplasm of cancer cells is related to VPAC1 overexpression; 3) blood vessels surrounding colon cancer have significantly more VPAC1-positive than normal colon mucosa does; 4) Tumor-Associated Macrophages (TAMs) of colon cancer have a higher level of VPAC1 expression than macrophages in normal colon mucosa do. These data suggest that VPAC1 overexpression is associated with poorer differentiation of colon cancer, which is likely caused by subsequent EGFR activation in cancer cells. In addition, VPAC1 overexpression in both blood vessels and macrophages in tumors may also play an important role in the development of aggressive cancer. Note: This abstract was not presented at the meeting. Citation Format: Shaohua Liu, Yunjie Zeng, Nengtai Ouyang. Targetting VPAC1 for intestinal cancer prevention. [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 4163. doi:10.1158/1538-7445.AM2015-4163
122. Genetic Modification of Target Cells by Direct Delivery of Active Protein
Authors: Thomas P. Quinn, Montse Morell, Lily Lee, Mei Fong, Michael Haugwitz, Andrew Farmer
Journal: Molecular Therapy (2015)

Precise modification of the human genome has been a goal of researchers for over two decades. Currently, genome modification is performed by either transient or stable delivery of nucleic acids that encode genome modifying components to target cells. This nucleic-acid-based approach has a number of drawbacks, including low efficiency, toxicity, prolonged expression, off target effects, and potential delay in modification due to transcription and translation post-delivery. An alternative approach is direct intracellular delivery of genome-modifying proteins to live cells. This method allows both the timing and dose of target protein to be tightly controlled, thereby improving efficiency. Consistent with this, it has been reported that direct Cas9 protein delivery leads to higher levels of on-target editing and fewer off-target effects (eLife 2014;10.7554/eLife.04766). Direct protein delivery, however, is limited by the need to express and purify protein in E. coli, where issues with protein yield, proper folding, lack of post-translational modification may ultimately reduce activity. The use of recombinant protein is further complicated by a lack of efficient and consistent delivery methods into target cells of interest. Improved methods, combining mammalian based protein production and efficient packaging into particles into one step can address these shortcomings. Here we report cellular delivery of DNA modifying proteins using VSV-G induced microvesicles (Gesicles). Gesicles are produced by co-overexpression of the spike glycoprotein of VSV-G with a protein of interest (POI), within a mammalian packaging cell. This leads to production of Gesicles containing active amounts of the POI expressed in mammalian cells. Based on this principle, we have developed a method for actively packaging genome modifying proteins into the Gesicles via ligand dependent dimerization. This approach allowed us package a POI containing a nuclear localization signal (NLS) efficiently into this particle. Analysis of the physical properties of these Gesicles demonstrated that they are highly stable over multiple freeze-thaw cycles, are consistent in size, and demonstrate minimal aggregation. Functionally, these Gesicles could efficiently deliver genome modifying proteins to a variety of cells, ultimately leading to genomic alterations. This effect could be demonstrated in over a dozen different cell lines; in all cases, cells maintained high viability and the results closely mimicked those obtained with viral transduction. Taken together, this work suggests that Gesicles can be considered a novel and universal tool for genome modification, providing a direct, rapid, and transient method for delivering active genome modifying proteins to target cells.
Clonal Mutational Landscape of Childhood Myelodysplastic Syndromes
Authors: Emilia J Kozyra, Shinsuke Hirabayashi, Victor Bengt Pastor Loyola, Bartlomiej Przychodzen, Axel Karow, Albert Catala, Barbara De Moerloose, Michael Dworzak, Henrik Hasle, Riccardo Masetti, Markus Schmugge, Owen Smith, Jan Starý, Marek Ussowicz, Marry M. van den Heuvel-Eibrink, Vit Campr, Rita Devito, Pascale Paepe, Miguel Hernandez-Marti, Gitte Kerndrup, Roos Leguit, Jadwiga Maldyk, Maureen OxSullivan, Ingrid Simonitsch-Klupp, Irith Baumann, Franco Locatelli, Jaroslaw P. Maciejewski, Brigitte Strahm, Charlotte M Niemeyer, Marcin W Wlodarski
Journal: Blood (2015)
Abstract 474: Regulation of epithelial plasticity of cancer cells by tumor-associated macrophages
Authors: CHIH-CHAN LEE, Muh-Hwa Yang
Journal: Cancer Research (2015)

Abstract Epithelial plasticity of cancer cells is considered to be critical for the metastatic process of cancer cells. Epithelial-mesenchymal transition (EMT) has been proved to associate with cancer metastatic dissemination from primary tumor site to distal metastatic organ. In contrast, accumulated evidence showed that the reversal process of EMT, i.e., mesenchymal-epithelial transition (MET), is critical for metastatic colonization. However, the mechanism for controlling the epithelial plasticity during metastatic process is unclear. Tumor-associated macrophages (TAMs) are the most abundant host immune cells in tumor microenvironments. TAMs have been shown to modulate cancer progression through regulating cancer cell growth and metastasis, and remodeling extracellular matrix. However, it is still unclear about the roles of TAMs in regulating epithelial plasticity during cancer metastasis. Here, we demonstrate the distinct characteristics of that the TAMs in primary and metastatic tumors. The TAMs in metastatic tumors carry a M2-like phenotype; in contrast, the TAMs in primary tumors are composed of heterogeneous population containing both M1-like and M2-like cells. Furthermore, we polarize human monocytes into M1-like and M2-like macrophages and treat cancer cells with M1 and M2 macrophages conditioned medium. We find that different macrophage subtypes have a distinct effect in modulating epithelial plasticity of cancer cells. Interestingly, polarized macrophages regulate cancer cell morphological changes through epigenetic regulation. Therefore, we propose that TAMs in tumor microenvironment may polarize into different subtypes and facilitate cancer metastatic dissemination. These findings have implications for designing alternative strategies aimed at preventing and inhibiting cancer metastasis. Citation Format: CHIH-CHAN LEE, Muh-Hwa Yang. Regulation of epithelial plasticity of cancer cells by tumor-associated macrophages. [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 474. doi:10.1158/1538-7445.AM2015-474
657. Delivery of Genetically Engineered Adipose-Derived Cell Sheets for Treatment of Ischemic Disorders – Development of Application in Animal Models
Authors: Pavel I. Makarevich, Konstantin V. Dergilev, Zoya I. Tsokolaeva, Anastasia Yu Efimenko, Evgeny V. Gluhanuk, Julia O. Gallinger, Polina A. Rodina, Stepan S. Sarkisyan, Ksenia V. Kerova, Yu-Chen Hu, Yelena V. Parfyonova
Journal: Molecular Therapy (2015)

Cell sheet (CS) approach is extensively developed in recent years for a number of applications in regenerative medicine including lesion treatment, tissue-engineered constructs and organoplastics. In this study we have targeted ischemic diseases – myocardial infarction (MI) and peripheral artery disease (PAD) using CS from differetnt sources transplanted as CS to the impaired region. We established a protocol for generation of CS from c-kit+ cardiac primitive cells and cardiosphere cells for delivery to rats with induced MI using clinical-grade fibrin glue for CS adhesion subepicardially. We found CS to be vascularized after transplantation and used ultrasound assessment to detect improvement of left ventricle function and significant positive changes of tissue status in histology studies: capillary density and reduction of fibrosis). Moreover, we conducted a comparative analysis of this approach vs. CS from adipose-derived stomal cells (ADSC) and VEGF-expressing ADSC. The latter were obtained via baculovirus transduction of CS, which enabled significant production of human VEGF165 by murine cells and, thus, enhanced their therapeutic potential. Our previous application of ADSC for therapeutic angiogenesis and established methods for genetic modification of cells allowed us to develop a protocol in limb ischemia model. We have demonstrated, that subcutaneous implantation of CS or VEGF-expressing CS from mouse ADSC resulted in significant improvement of limb perfusion with modified cells to be superior to mock-transduced. Increased blood flow was supported by higher CD31+ capillary density, reduction of necrosis and detection of viable CS subcutaneously with focal proliferation of mADSC and minimal (app. 10%) prevalence of apoptotic cells at 14 days post transplantation. Paracrine mechanism for CS mode of action is suggested due to the fact, that ww found vessel growth within CS mass, which indicates possibility of cells' nutrition and uptake of secreted proteins from the site of transplantation besides diffusion. Thus, our findings indicate, that CS-based delivery for treatment of MI or PAD is a potential method in regenerative medicine in this field and furthermore genetic modification of cells used for CS generation may be a way to "tune up" the cells' paracrine activity and efficacy of their application.
Abstract 3151: T cells engineered to express a chimeric antigen receptor targeting chondroitin sulfate proteoglycan 4 (CSPG4) specifically kill medulloblastoma and produce inflammatory cytokines
Authors: Christopher M. Rota, Nicholas Tschernia, Steven Feldman, Crystal Mackall, Daniel W. Lee
Journal: Cancer Research (2015)

Abstract Human T-cells expressing chimeric antigen receptors (CARs) recognizing common cancer antigens have shown great promise in the clinic with the potential for significant anti-tumor responses. CSPG4 is a chondroitin sulfate proteoglycan previously shown to be overexpressed in melanoma and breast cancer, as well as glioblastoma stem cells. CARs directed against CSPG4 have recently shown promising pre-clinical efficacy against these tumors. We evaluated the feasibility of targeting CSPG4 using CAR T cell therapy in medulloblastoma and neuroblastoma. Response to standard therapies for advanced neuroblastoma and medulloblastoma is poor and carries significant toxicities, which may be ameliorated by immunotherapy. We found that multiple medulloblastoma and neuroblastoma cell lines (DAOY, D283 Med, D425 Med, UW-228, and SKNAS) express CSPG4 at high levels, as does 143b osteosarcoma as a positive control. By contrast, CSPG4 in normal tissue is expressed only on pericytes and in low levels on small bowel as previously assessed by protein array [Beard et al, J Immunother Cancer 2014]. To evaluate therapeutic efficacy, a second generation CAR with a CD3ζ signaling domain and CD28 co-stimulatory domain containing the TP41.2 anti-CSPG4 scFv was transduced using a γ-retrovirus into T cells. CAR T cells were found to specifically kill 20% of DAOY, 50% of D283 Med, and 50% of 143b cancer cells at a 20:1 effector-to-target ratio in a 4-hour chromium release cytotoxicity assay, while not affecting CSPG4 negative control SY5Y (neuroblastoma) and DND41 (T cell leukemia) cells. Both CD4 and CD8 CAR T cells were also shown to produce IFNγ after exposure to 143b cells. Cytokine production in response to other CSPG4+ lines is ongoing as are cytotoxicity studies with neuroblastomas. For our in vivo model, we have begun to evaluate the efficacy of CAR T cells delivered either intravenously or via intratumoral injection against DAOY and D283 Med cells that have been orthotopically implanted in the cerebellum of immunodeficient NOD/SCID/IL2Rγ-/- mice. These results, if successful, will inform the development of a new clinical protocol for the treatment of children and young adults with medulloblastoma and neuroblastoma. Citation Format: Christopher M. Rota, Nicholas Tschernia, Steven Feldman, Crystal Mackall, Daniel W. Lee. T cells engineered to express a chimeric antigen receptor targeting chondroitin sulfate proteoglycan 4 (CSPG4) specifically kill medulloblastoma and produce inflammatory cytokines. [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 3151. doi:10.1158/1538-7445.AM2015-3151
Somatic PTPRT and ANGPT2 Mutations in Large Granulocyte Leukemia
Authors: Emma I Andersson, Samuli Eldfors, Hanna L M Koskela, Pekka Ellonen, Thomas Olson, Andres Jerez, Michael J. Clemente, Olli Kallioniemi, Kimmo Porkka, Thomas P. Loughran, Jaroslaw P. Maciejewski, Caroline Heckman, Satu Mustjoki
Journal: Blood (2012)
Treatment of Patients with Relapsed/Refractory Multiple Myeloma (MM) with Lenalidomide and Dexamethasone with or without Bortezomib: Prospective Evaluation of the Impact of Cytogenetic Abnormalities.
Authors: Meletios A. Dimopoulos, Efstathios Kastritis, Dimitrios Christoulas, Magdalini Migkou, Maria Gavriatopoulou, Maria Gkotzamanidou, Marina Iakovaki, Maria Roussou, Eleni Efstathiou, Evangelos Terpos
Journal: Blood (2009)