tbuckley/cabot-search huggingface dataset:
Effect of tamoxifen on ceramide cytotoxicity in colon cancer cells.
Authors: M. C. Cabot, R. Karimi, M. Kester, S. S. Shanmugavelandy, D. W. Rosenberg, J. P. Madigan
Journal: Journal of Clinical Oncology (2011)

e14112 Background: Poor prognosis in patients with colorectal cancer necessitates the search for new treatment strategies. Ceramide, because of its role in induction of apoptosis in cancer cells, is a promising strategy. Ceramide can be generated in situ by exposure to chemotherapy and ionizing radiation, or it can be administered in the form of short-chain analogs, including nanoliposomal formulations that can be selectively apoptotic for cancer cells. However, conversion of ceramide to inactive metabolites greatly diminishes apoptotic potential. The aim of our investigation was to determine whether cytotoxicity of C6-ceramide could be increased by tamoxifen, which has been shown to be a potent regulator of ceramide metabolism via it’s interaction with Golgi-localized P-glycoprotein (P-gp). Methods: Human colon cancer cell lines HCT-15, HT-29, and LoVo were used. Cell viability (24-72 hr) was assessed spectrophotometrically (n = 6 ± S.D.). Apoptosis was gauged by caspase activation. Metabolic studies utilized [14C]C6-ceramide. Results: C6-ceramide (5.0 µM) and tamoxifen (10 µM) decreased HCT-15 cell viability to 79 ± 6 and 54 ± 3% of control, respectively; the combination decreased viability to 16 ± 4%. This was accompanied by a synergistic 7-fold increase in caspase 3/7 activation. HT-29 cells responded to combination C6-ceramide/tamoxifen in a similar fashion. In LoVo cells, C6-ceramide, tamoxifen, and the combination decreased viability to 84 ± 4, 87 ± 6, and 17 ± 1% of control, respectively, and the combination was synergistic for caspase-3 cleavage. Nanoliposomal formulations of C6-ceramide, tamoxifen, and composites were also effective, yielding viabilities of 76 ± 4, 96 ± 4, and 36 ± 3% of ghost control, respectively. LoVo cells converted C6-ceramide chiefly to C6-glucosylceramide and C6-sphingomyelin; tamoxifen blocked synthesis of the former. Cyclosporin A, another P-gp antagonist, also enhanced C6-ceramide cytotoxicity. Conclusions: Tamoxifen is a favorable partnering agent for enhancing C6-ceramide cytotoxicity in colon cancer cells. The high-frequency expression of P-gp in colorectal cancer presents an adventitious target for augmenting ceramide-based therapies, a strategy that could hold promise for treatment.
Risk of cardiovascular disease among patients with sarcoidosis: a population-based retrospective cohort study, 1976–2013
Authors: Patompong Ungprasert, Cynthia S. Crowson, Eric L. Matteson
Journal: European Respiratory Journal (2016)

A higher incidence of cardiovascular disease (CVD) has been observed in several chronic inflammatory diseases. However, data on sarcoidosis are limited. In this study, 345 patients with incident sarcoidosis in Olmsted County (Minnesota, USA) during 1976–2013 were identified based on comprehensive medical record review. 345 sex- and age-matched comparators were also identified from the same underlying population. Medical records were individually reviewed for CVD, including coronary artery disease, congestive heart failure, atrial fibrillation, cerebrovascular accident, transient ischaemic attack, peripheral arterial disease and abdominal aortic aneurysm. Cox proportional hazards models with adjustment for age, sex, calendar year and cardiovascular risk factors were used to compare the rate of development of CVD between cases and comparators. The prevalence of CVD before the index date was not significantly different between the two groups. Adjusting for age, sex and calendar year, the risk of incident CVD after the index date was significantly elevated among patients with sarcoidosis with an adjusted hazard ratio of 1.57 (95% CI 1.15–2.16). Adjustment for cardiovascular risk factors yielded an adjusted hazard ratio of 1.65 (95% CI 1.08–2.53). Significantly increased risk was also observed for several types of CVD, including coronary artery disease, congestive heart failure, atrial fibrillation and cerebrovascular accident. Increased incidence of CVD among patients with sarcoidosis was demonstrated in this population-based cohort, even after controlling for baseline traditional atherosclerotic risk factors.
301. AAV Capsid Engineering to Improve Transduction in Retina and Brain
Authors: Jennifer Sullivan, Lisa Stanek, Michael Lukason, Elizabeth Barry, Shayla Russell, James Morris, Bryan Mastis, Anna Alves, Jie Bu, Lamya S. Shihabuddin, Seng Cheng, Abraham Scaria
Journal: Molecular Therapy (2016)

Gene therapy vectors based on adeno-associated virus (AAV) are currently in clinical studies for numerous disease indications including Leber's congenital amaurosis, age-related macular degeneration, hemophilia, muscular dystrophy and Parkinson's disease. AAV vectors hold considerable promise as therapeutic agents; however there is potential to further improve the efficiency of AAV gene delivery and efficacy by making modifications to the AAV capsid. The AAV capsid can be engineered to incorporate mutations that alter its transduction activity, tropism, biodistribution and immunogenicity. We have constructed variant AAV vectors harboring a variety of capsid modifications including those that negate receptor binding and have tested these vectors in several tissues including the eye and brain. One variant, AAV2HBKO, is an AAV2 based vector containing mutations of critical amino acids known to be required for binding to its receptor, heparin sulfate proteoglycan. Interestingly, an AAV2HBKO vector delivering a secreted transgene, sFLT02, unexpectedly resulted in a 2-log increase in transduction compared to parental AAV2 when delivered subretinally to the mouse eye. Subretinal delivery of an AAV2HBKO vector expressing EGFP demonstrated that these capsid modifications resulted in an increase in photoreceptor transduction compared to the unmodified AAV2 vector. In contrast, the AAV2HBKO vector demonstrated a lack of transduction activity following intravitreal delivery to the mouse eye. In addition, we evaluated the transduction and tropism of AAV2HBKO in the mouse brain. In a head to head comparison with AAV2, the AAV2HBKO vector facilitated widespread striatal and cortical expression following an intrastriatal injection while AAV2-mediated expression was restricted to the site of injection. Similar to AAV2, the tropism of AAV2HBKO was primarily neuronal with little to no transduction of astrocytes or microglia. Biodistribution data suggests that this vector, when delivered systemically in the mouse, has significantly reduced liver transduction but a higher propensity to be delivered to skeletal muscle and heart compared to the wild-type AAV2 vector. We will present data evaluating the transduction activity, tropism and biodistribution of the AAV2HBKO variant. These studies illustrate the potential for improving the efficiency of AAV gene transfer via targeted capsid engineering.
Impact of Single Nucleotide Polymorphisms in Genes Involved in miRNA Network on Survival and Progression After Autologous Stem Cell Transplantation in Patients with Multiple Myeloma,
Authors: Carlos Fernández de Larrea, Alfons Navarro, Tania Díaz, María Teresa Cibeira, Rut Tejero, Natalia Tovar, Gerardo Ferrer, Laura Rosiñol, Montserrat Rovira, María Rozman, Mariano Monzó, Joan Blade
Journal: Blood (2011)
Diminished Oxidative Stress Responses in Bone Marrow Stromal Cell Lines Derived From Fanconi Anemia (Fanc-D2−/−) Mice
Authors: Hebist Berhane, Michael W. Epperly, Shaonan Cao, Xichen Zhang, Donna Shields, Julie Goff, Melissa Sprachman, Peter Wipf, Song Li, Xiang Gao, Joel S. Greenberger
Journal: Blood (2012)
Clinical characteristics of cancer of unknown primary cancer with poorly differentiated carcinoma and adenocarcinoma
Authors: Makoto Kodaira, Tatsunori Shimoi, Jun Hashimoto, Harukaze Yamamoto, Mayu Yunokawa, Kan Yonemori, Chikako Shimizu, Yasuhiro Fujiwara, Kenji Tamura
Journal: Annals of Oncology (2015)
Abstract 1673: Galunisertib combined with sorafenib affects proliferation, EMT and delays tumor growth in mice and in hepatocellular carcinoma (HCC) patient samples ex vivo
Authors: Annemilai Tijeras-Raballand, Maria Serova, Cindy Neuzillet, Miguel Albuquerque, Nathalie Colnot, Matthias Barral, Anthony Dohan, Matthias Barral, Philippe Bonnin, Marc Pocard, Valérie Paradis, Eric Raymond, Sandrine Faivre, Armand de Gramont
Journal: Cancer Research (2015)

Abstract Introduction: The TGF-β pathway that has been associated with hepatocellular carcinoma (HCC) progression, can be targeted by galunisertib, a selective ATP-mimetic TGF-β receptor (TβR)-I inhibitor currently under clinical investigation in HCC patients after sorafenib failure or ineligible for sorafenib treatment. Our study aimed to investigate the tumor effects of galunisertib with or without sorafenib in different models of HCC and in freshly grown HCC specimens from patients. Material and methods: Transgenic mice developing stage-defined HCC were treated for 12 weeks (W) with either vehicle, sorafenib (30mg/kg), galunisertib (100mg/kg) or sorafenib plus galunisertib. Human hepatocarcinoma HUH7 cells were subcutaneously injected in nude mice and treated daily with either vehicle, sorafenib (60mg/kg) or sorafenib combined with galunisertib (100mg/kg). Ex vivo experiments were realized in surgical specimens from HCC patients that were cut into 300μM and grown in specific media. Slices were randomly exposed to galunisertib (10μM), sorafenib (5μM) and sorafenib plus galunisertib for 48h. At the end of treatments, tumor samples were analyzed by IF or IHC. Results: In transgenic mice, the number of liver tumor macronodules was significantly lower in all treatment arms compared to control placebo (p3 fold decrease in proliferation (Ki67 expression) and 3-5 fold increase in apoptosis induction (caspase-3 expression). Conclusion: In vivo and ex vivo, TGF-β signalling inhibition using galunisertib in combination with sorafenib in HCC models showed promising data on downstream signaling pathway, angiogenesis and tumor growth inhibition and may prevent sorafenib-induced EMT. Citation Format: Annemilai Tijeras-Raballand, Maria Serova, Cindy Neuzillet, Miguel Albuquerque, Nathalie Colnot, Matthias Barral, Anthony Dohan, Matthias Barral, Philippe Bonnin, Marc Pocard, Valérie Paradis, Eric Raymond, Sandrine Faivre, Armand de Gramont. Galunisertib combined with sorafenib affects proliferation, EMT and delays tumor growth in mice and in hepatocellular carcinoma (HCC) patient samples ex vivo. [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 1673. doi:10.1158/1538-7445.AM2015-1673
Psychiatrists urge Obama to request neuropsychiatric review of Trump
Authors: Jeanne Lenzer
Journal: BMJ (2016)

Three psychiatrists have written to President Barrack Obama urging him to request a “full medical and neuropsychiatric evaluation by an impartial team of investigators” of the president elect, Donald Trump.

In their letter to Obama the psychiatrists wrote that they had “grave concerns” over Trump’s “widely reported symptoms of mental instability—including grandiosity, impulsivity, hypersensitivity to slights or criticism, and an apparent inability to distinguish between fantasy and reality,” which they said “lead us to question his fitness for the immense responsibilities of the office.”1

The psychiatrists are …
Rare genetic variants in SMAP1, B3GAT2, and RIMS1 contribute to pediatric venous thromboembolism
Authors: Frank Rühle, Anika Witten, Andrei Barysenka, Andreas Huge, Astrid Arning, Christine Heller, Anne Krümpel, Rolf Mesters, Andre Franke, Wolfgang Lieb, Mona Riemenschneider, Milan Hiersche, Verena Limperger, Ulrike Nowak-Göttl, Monika Stoll
Journal: Blood (2016)
A Significant Better Two Year Survival in the Very Elderly Patients with a Diffuse Large B-Cell Lymphoma (DLBCL) Who Did Complete Standard Therapy: A Population-Based Cohort Study On Treatment, Toxicity and Outcome.
Authors: Karin Boslooper, Peter Joosten, Nic J.G.M. Veeger, Robby Kibbelaar, Eric van Roon, Sjoerd Hovenga, Gerhard Woolthuis, Hanneke C. Kluin-Nelemans, Mels Hoogendoorn
Journal: Blood (2012)
PWE-025 Comparing quality of life in coeliac disease and inflammatory bowel disease: a paradigm shift in our perceptions?: Abstract PWE-025
Authors: S M Barratt, J S Leeds, A J Lobo, M E Mcalindon, K Robinson, H Wilson, S Lin, D S Sanders
Journal: Gut (2010)

<h3>Introduction</h3> The Medical Outcomes Study Short-Form 36-Item Health Survey (SF-36) is a valid and reliable quality of life (QoL) measure in coeliac disease and inflammatory bowel disease (IBD). However, there has never been a study to compare the QoL of individuals with these two diseases. We hypothesised that individuals with IBD report a worse QoL than those individuals with coeliac disease because IBD is considered to be the more severe disease of the two.<sup>1</sup> <h3>Methods</h3> A postal survey (n=1031) of patients with histologically proven Coeliac Disease (n=225), Crohn9s disease (CD) (n=230) and ulcerative colitis (UC) (n=228). We also recruited non-health-seeking age and sex matched controls (n=348). Questionnaire included SF-36, Hospital Anxiety and Depression Scale (HADS), ROME II criteria for Irritable Bowel Syndrome (IBS) and a reflux oesophagitis (RO) screen. Disease-specific assessment included disease duration and either the Harvey-Bradshaw Activity Index (HBI), Simple Colitis Activity Index (SCAI) or assessment of gluten-free diet (GFD) adherence. <h3>Result</h3> Disease duration had a negligible impact on responses in CD, UC and Coeliac Disease (p=ns). At least one RO symptom was reported by 66% of Coeliac Disease respondents, 72% of CD, 62% of UC and 50% of controls. We found stepwise reductions in all respondents9 SF-36 scores and increases in HADS-A and HADS-D scores with increasing RO symptom severity (p=&lt;0.05). 22% of Coeliac Disease respondents, 24% of CD, 16% of UC and 6% of controls met ROME II criteria for IBS, which also reduced respondent wellbeing in all groups (p=&lt;0.0001) (Abstract 025). <h3>Conclusion</h3> This is the first study to report that CD patients experience the worst QoL but surprisingly Coeliac Disease patients had a worse QoL and increased risk of anxiety and depression than UC (p=&lt;0.0001). In addition we observed that both RO and IBS further reduce patient QoL and increase the risk of anxiety and depression.
286. Genome Editing of Inducible Cell Lines for Scalable Production of Improved Lentiviral Vectors for Human Gene Therapy
Authors: Alessio Cantore, Michela Milani, Andrea Annoni, Johannes Lengler, Sara Bartolaccini, Tiziano Di Tomaso, Michael C. Holmes, Friedrich Scheiflinger, Angelo Lombardo, Luigi Naldini
Journal: Molecular Therapy (2016)

Lentiviral vectors (LVs) represent efficient and versatile vehicles for gene therapy. Current manufacturing of clinical-grade LVs mostly relies on transient transfection of plasmids expressing the multiple vector components. This method is labor and cost intensive and becomes challenging when facing the need of scale-up and standardization. The development of stable LV producer cell lines will greatly facilitate overcoming these hurdles. We have generated an inducible LV packaging cell line, carrying the genes encoding for third-generation vector components stably integrated in the genome under the control of tetracycline-regulated promoters. These LV packaging cells are stable in culture even after single-cell cloning and can be scaled up to large volumes. In order to minimize the immunogenicity of LVs for in vivo administration, we set out to remove the highly polymorphic class-I major histocompatibility complexes (MHC-I) expressed on LV packaging cells and incorporated in the LV envelope. We performed genetic disruption of the β-2 microglobulin (B2M) gene, a required component for the assembly and trafficking of all MHC-I to the plasma membrane in LV producer cells, exploiting the RNA-guided Cas9 nuclease. The resulting B2M-negative cells were devoid of surface-exposed MHC-I and produced MHC-free LVs. These LVs retain their infectivity on all tested cells in vitro and efficiently transduced the mouse liver upon intravenous administration. Strikingly, the MHC-free LVs showed significantly reduced immunogenicity in a T-cell activation assay performed on human primary T cells co-cultured with syngeneic monocytes exposed to LV, from several (n=7) healthy donors. To reproducibly generate LV-producer cell lines from these cells, we insert the LV genome of interest in the AAVS1 locus, chosen for robust expression, exploiting engineered nucleases and homology-directed repair. By this strategy, we have obtained several independent producer cell lines for LVs that express marker or therapeutic genes and are devoid of plasmid DNA contamination. LVs produced by these cells reproducibly show titer and infectivity within the lower bound range of standard optimized transient transfection, and effectively transduce relevant target cells, such as hematopoietic stem/progenitor cells and T cells ex vivo and the mouse liver in vivo. Overall, we provide evidence that rationally designed targeted genome engineering can be used to improve the yield, quality, safety and sustainability of LV production for clinical use.
Prospective Validation of a Chronic GvHD-Specific Proteome Pattern (cGvHD-MS14) Post Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Eva M. Weissinger, Daniel Wolff, Jochen Metzger, Christiane E Dobbelstein, Stefanie Buchholz, Elke Dammann, Uwe Borchert, Annika Krons, Helmut Diedrich, Michael Stadler, Anne M Dickinson, Ernst Holler, Hildegard T. Greinix, Juergen Krauter, Arnold Ganser
Journal: Blood (2011)
Abstract 5150: Drosophila models of Ret fusions in papillary thyroid carcinoma
Authors: Sarah Levinson, Ross Cagan
Journal: Cancer Research (2015)

Abstract Ret fusion proteins, including PTC1 (CCDC6-RET) and PTC3 (NcoA4-RET), drive a subset of Papillary Thyroid Carcinomas (PTC). There is currently no treatment for refractory, metastatic PTC, which results in 1500 deaths in the US each year. A challenge in identifying targeted therapies for Ret fusion driven cancers has been the lack of predictive models. We created transgenic, over-expression Drosophila models of PTC1 and PTC3, and found that they cause cancer phenotypes such as delamination, cell migration, and EMT. We conducted a genetic screen of the Drosophila kinome (252 alleles) and a drug screen of FDA approved cancer therapeutics (62 compounds) against flies expressing either PTC1 or PTC3. We found that PTC1 and PTC3, despite containing identical Ret kinase domains, have a different signaling output and are sensitive to different kinase inhibitors. Of the 19 kinases that were identified as hits from the PTC3 kinome screen, only 5 overlap with PTC1 hits. PTC3 is most sensitive to Ponatinib, where as PTC1 is most sensitive to Cabozantinib. These findings suggest that patients may greatly benefit from targeted treatment directed against the specific Ret fusion that they harbor. Citation Format: Sarah Levinson, Ross Cagan. Drosophila models of Ret fusions in papillary thyroid carcinoma. [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 5150. doi:10.1158/1538-7445.AM2015-5150
Acute Myeloblastic Leukemia in Chile. Treatment and Outcomes in Patients Admitted at the Hospital Clinico De La Pontificia Universidad Catolica De Chile Between 2010–2014
Authors: Monica Fuentes, Patricio Rojas, Daniel M Ernst, Francisco Acevedo, Mauricio Sarmiento, Mauricio E Ocqueteau, Pablo A Bertin, Pablo Ramirez
Journal: Blood (2014)
Disability in Surgical Inflammatory Bowel Disease Patients
Authors: Ellie van der List, Andy Chen, Rupert Leong, Ian Whiteley, Matthew Rickard, Grace Chapman, Peter Katelaris, Charles McDonald, Avelyn Kwok, Cheng Hiang Lee, James Cowlishaw, Gordon Jung-Hyuk Park, Crispin Corte, Viraj Kariyawasam
Journal: Clinical Gastroenterology and Hepatology (2016)
RAP-536 Accelerates Recovery From Chemotherapy-Induced Anemia (CIA) without Promoting Tumor Growth In Murine Models of Cancer and CIA
Authors: Samuel M. Cadena, Rajasekhar NVS Suragani, Dianne Mitchell, Jeff Ucran, Katia Liharska, Dianne Sako, Travis Monnell, Kathryn Underwood, Ravindra Kumar, R. Scott Pearsall
Journal: Blood (2010)
Allogeneic Virus-Specific T Cells with HLA Alloreactivity Do Not Produce Graft-Versus-Host Disease In Human Subjects
Authors: J. Joseph Melenhorst, Ann M. Leen, Catherine M. Bollard, Máire F Quigley, David A Price, Cliona M Rooney, Malcolm K. Brenner, A. John Barrett, Helen E. Heslop
Journal: Blood (2010)
Abstract 4085: Depletion of Runx1 promotes epithelial to mesenchymal transition in breast cancer
Authors: Deli Hong, Jane Lian, Janet Stein, Gary Stein
Journal: Cancer Research (2015)

Abstract Runx1 is an essential transcription factor for definitive hematopoiesis and Runx1 translocations are well established as the causative factor of various leukemias. Recent studies have identified Runx1 as one of the most frequently mutated genes in breast cancer patients, and also that Runx1 expression levels are decreased in high-grade primary breast tumors compared to low/mid-grade tumors. The recognition of Runx1 expression in epithelial lining cells of glands suggests that Runx1 functions in maintaining the integrity of that cell layer. Therefore we examined the role of Runx1 during cancer progression. We found that Runx1 is highly expressed in immortalized human mammary epithelial cells (MCF10A) compared with breast cancer epithelial cells (MCF7) and invasive breast cancer cells (MDA-MB-231). To test the hypothesis that Runx1 contributes to the epithelial to mesenchymal transition (EMT) in breast cancer, the EMT was induced in MCF10A cells which resulted in a 50% decrease of Runx1 mRNA, but complete loss of Runx1 protein. This finding suggests a role for Runx1 as an EMT suppressor. To further address the relationship between Runx1 and EMT, Runx1 depleted stable cell lines were generated in both MCF10A and MCF7 cells. We observed that Runx1 knockdown (90%) in MCF10A cells leads to a dramatic change in their morphology towards a mesenchymal state, with a concomitant decrease in expression of the epithelial marker E-cadherin. In addition Runx1 depletion in MCF7 cells directly induced EMT state by repression of E-cadherin, as well as increased expression of mesenchymal genes, including vimentin, N-cadherin and fibronectin. Our results highlight a crucial role for Runx1 in preventing epithelial to mesenchymal transition and tumor progression in breast cancer. This Runx1 mediated mechanism points to novel intervention strategies for early stage breast cancer. Citation Format: Deli Hong, Jane Lian, Janet Stein, Gary Stein. Depletion of Runx1 promotes epithelial to mesenchymal transition 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 4085. doi:10.1158/1538-7445.AM2015-4085
Safety and Efficacy of Subcutaneous-Administered Omacetaxine Mepesuccinate in Imatinib-Resistant Chronic Myeloid Leukemia (CML) Patients Who Harbor the Bcr- Abl T315I Mutation–Results of An Ongoing Multicenter Phase 2/3 Study.
Authors: Jorge Cortes-Franco, H. Jean Khoury, Franck Emmanuel Nicolini, Selim Corm, Jeffrey H. Lipton, Dan Jones, Andreas Hochhaus, Adam R Craig, Annie-Claude Benichou, Eric Humphriss, Hagop Kantarjian
Journal: Blood (2009)
Pegylated Liposomal Doxorubicin (PLD), Vincristine and Reduced-Dose Dexamethasone (DVd) in the Treatment of a Predominantly African American Population with Multiple Myeloma.
Authors: Ahmad Jajeh, Rosalind Catchatourian, David Osafo, Deimante Tamkus, Ghassan Zalzaleh, Anshul Bamrolia
Journal: Blood (2005)