tbuckley/cabot-search huggingface dataset:
Identification of source and sink populations for the emergence and global spread of the East-Asia clone of community-associated MRSA
Authors: Melissa J. Ward, Mariya Goncheva, Emily Richardson, Paul R. McAdam, Emma Raftis, Angela Kearns, Robert S. Daum, Michael Z. David, Tsai Ling Lauderdale, Giles F. Edwards, Graeme R. Nimmo, Geoffrey W. Coombs, Xander Huijsdens, Mark E. J. Woolhouse, J. Ross Fitzgerald
Journal: Genome biology (2016)

Our understanding of the factors influencing the emergence, dissemination and global distribution of epidemic clones of bacteria is limited. ST59 is a major epidemic clone of community-associated MRSA in East Asia, responsible for extensive morbidity and mortality, but has a much lower prevalence in other parts of the world. The geographic origin of ST59 and its international routes of dissemination are unclear and disputed in the literature.To investigate the origin and spread of the ST59 clone, we obtained whole genome sequences of isolates from four continents, sampled over more than a decade, and carried out a time-scaled phylogeographic analysis. We discover that two distinct ST59 clades emerged concurrently, in East Asia and the USA, but underwent clonal expansion at different times. The East Asia clade was strongly enriched for gene determinants associated with antibiotic resistance, consistent with regional differences in antibiotic usage. Both clones spread independently to Australia and Europe, and we found evidence of the persistence of multi-drug resistance following export from East Asia. Direct transfer of strains between Taiwan and the USA was not observed in either direction, consistent with geographic niche exclusion.Our results resolve a longstanding controversy regarding the origin of the ST59 clone, revealing the major global source and sink populations and routes for the spread of multi-drug resistant clones. Additionally, our findings indicate that diversification of the accessory genome of epidemic clones partly reflects region-specific patterns of antibiotic usage, which may influence bacterial fitness after transmission to different geographic locations.
Abstract LB-065: Comparison of the serum proteome in individuals with cancers versus those without cancer, and its application to wellness
Authors: Haiyan Zheng, Caifeng Zhao, Swapan Roy, Amenah Soherwardy, Ravish Amin, Devjit Roy, Matthew Kuruc
Journal: Cancer Research (2016)

Abstract For many diseases, pancreatic cancer for example, long term survival is critically dependent upon early detection. So various strategies for early detectable markers are being investigated. One such strategy is hypothesis driven, first by identifying a singular biomarker, usually derived from genomic analysis of the tumor type, and then determine its derivative protein concentration in blood. This has been challenging as many differentially regulated genes do not generate a differentially regulated protein, or one of sufficient concentration for current means of detection. An alternative biomarker strategy is purely data driven, as panels of proteins may be up and/or down regulated, or altered by post-translational modifications. These can be monitored and quantified to differences in diseased and normal/healthy individuals. In this study we adopt such a data driven strategy using a new product which combines Albumin depletion and on-bead digestion of the enriched serum proteome in a seamless process, called AlbuVoid™ LC-MS On-Bead. From these methods, we were able to compare labeled quantification of proteins from normal and disease state sera - for this case, breast, lung and pancreatic cancer at different clinically defined stages. The methods spectrally quantify over 250 total proteins, in a cost effective and reproducible manner. No offline peptide level fractionation prior to LC-MS was employed, lowering the LC-MS acquisition time 5-10x compared to common serum proteomic workflows. We describe these workflow advantages applied towards a “wellness” proteome algorithm combining knowledge and data surrounding individual normal and healthy proteomes, compared and contrasted to those with a clinically definable disease. From our initial tests, a candidate panel of 20 proteins are determined to be differentially expressed and such data suggests the feasibility for their use in the early detection of cancer. The critical parameters for success to our strategy are considered as well as some of the remaining challenges to clinical utility. Citation Format: Haiyan Zheng, Caifeng Zhao, Swapan Roy, Amenah Soherwardy, Ravish Amin, Devjit Roy, Matthew Kuruc. Comparison of the serum proteome in individuals with cancers versus those without cancer, and its application to wellness. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-065.
Abstract 613: Astrocytes and endothelial colony forming cells (ECFCs) influence the migration and drug response of glioblastoma cells in a 3D culture model
Authors: Marisol Herrera-Perez, Melissa Fishel, Sherry Harbin, Jenna Rickus
Journal: Cancer Research (2016)

Abstract Glioblastoma, a brain cancer with low prognosis, is characterized by rapid infiltration and drug resistance that leads to tumor reappearance. Cell-extrinsic factors, such as the development of a supportive microenvironment and synergistic relationships between normal cells and GBM play an important role in the tumor successful progression. Despite the importance of the microenvironment as a regulator of tumor response, there is a lack of predictive in vitro models that represent the dimensionality and characteristics of the glioma microenvironment. To this end, we developed a 3D in vitro model that recapitulates the composition and physical features of the GBM microenvironment by generating a composite matrix of a hyaluronan supported by collagen. Human astrocytes and endothelial colony forming cells (ECFCs) were incorporated into the matrix and co-cultured with GBM cells to evaluate the effect of normal cells on the GBM 3D cell migration and drug response. Time-lapse microscopy was used to evaluate the 3D migration distance, velocity and persistence of GBM cell lines GBM10, GBM43 and GBAM1 (CD133+) during 18h after drug treatment with temozolomide and a STAT3-inhibitor. Survival of GBM cells was also evaluated 18h and 72 h after drug treatment. All results were compared to standard monolayer culture. Presence of astrocytes and ECFCs increased GBM net migration distance and velocity in the 3D model and in 2D monolayer culture. Additionally, viability of GBM after drug treatment was higher when astrocytes and ECFCs were present in the 3D model compared to only GBM 3D culture and standard monolayer culture. Our results support the importance of the 3D-microenvironment as modulator of tumor response and provide a tunable in vitro platform for primary brain tumor studies aimed to compliment in vivo model observations. Citation Format: Marisol Herrera-Perez, Melissa Fishel, Sherry Harbin, Jenna Rickus. Astrocytes and endothelial colony forming cells (ECFCs) influence the migration and drug response of glioblastoma cells in a 3D culture model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 613.
Abstract 4661: Loss of LKB1 in NSCLC confers sensitivity to MEK inhibition by regulating activation of AKT-FOXO3 pathway
Authors: Tadaaki Yamada, Jacob M. Kaufman, Joseph M. Amann, Seiji Yano, David P. Carbone
Journal: Cancer Research (2016)

Abstract The use of MEK inhibitors for non-small cell lung cancer (NSCLC) has shown little efficacy in clinical trials, even in the case of tumors with mutant KRAS where one might predict good outcomes. From these data, it is clear that the success of MEK inhibitors is going to rely on finding a biomarker that predicts sensitivity to this type of therapy. Our area of interest is finding a way to treat LKB1 mutant tumors and, surprisingly, an in silico screen of drug sensitivity data for NSCLC cell lines determined that four MEK inhibitors were among the top drugs that were significantly associated with LKB1 loss. We confirmed the effects MEK inhibition by evaluating 23 lung cancer cell lines with known LKB1 status. The results of the study showed that MEK inhibition with trametinib led to a significant reduction in cell viability in LKB1 mutant cell lines when compared to cell lines with wild type LKB1. In addition, we investigated MEK sensitivity by restoring wild-type (Wt) LKB1 in lung cancer cell lines with LKB1 loss, or by silencing LKB1 in lung cancer cell LKB1-Wt lines. Transduction of LKB1 resulted in significant MEK resistance in three of the five LKB1 add-back lines, while silencing LKB1 induced MEK sensitivity in all five LKB1-Wt lines tested. The mechanism behind these observed results appears to be through phosphorylation of AKT and its downstream target FOXO3, which are important determinants of the apoptotic response to MEK inhibition. With LKB1 transduction into mutant cell lines we see an increase in the activating phosphorylation of AKT, a protein involved in survival mechanisms, and an increase in the deactivating phosphorylation of FOXO3, a transcription factor implicated in increased levels of apoptosis. Our data suggest that the identification of LKB1 activity may be promising biomarker for the sensitivity to MEK inhibition by regulating activation of AKT-FOXO3 pathway in NSCLC. Citation Format: Tadaaki Yamada, Jacob M. Kaufman, Joseph M. Amann, Seiji Yano, David P. Carbone. Loss of LKB1 in NSCLC confers sensitivity to MEK inhibition by regulating activation of AKT-FOXO3 pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4661.
Abstract 4094: Exosomes secreted from the noncancerous microenvironment promote proliferation, migration, and invasion in breast cancer cells
Authors: Letitia A. Yearby, Terri Cunningham, Jacenta Matthews, KiTani Parker Lemieux.
Journal: Cancer Research (2016)

Abstract Introduction: Triple negative breast cancer (TNBC) is one of the most aggressive forms of five major types of breast cancer. Because TNBC mortality disproportionately affects premenopausal African American women, a health disparity exists within this group. Our research has provided insight on how the noncancerous microenvironment plays a role in TNBC proliferation, migration, and invasion. Exosomes, extracellular vesicles (30-300 nm) produced ubiquitously by mammalian cells, are secreted by noncancerous breast epithelial cells, and have been noted to enhance proliferation, migration and invasion in TNBC. Therefore, the purpose of this study is to determine if exosome-free conditioned media (EFCM), which contains noncancerous MCF10A exosomes, enhances proliferation, migration and invasion in TNBC. Methods: MDA-MB-231 and MCF10A breast epithelial cells were used as cell line models. Proliferation was measured by the alamar blue proliferation assay. The transwell migration assay was used to assess migration, and the Matrigel invasion assay was used to measure migration. ExoELISA assays were also used to detect exosomes in exosome-free conditioned media (EFCM) from MCF10A cells. MCF10A cells were serum-starved for 24 hours, using DMEM/F-12 with 0.5% standard or exosome-depleted FBS (edFBS), to produce exosomal conditioned media (CM) and EFCM. This media was harvested and sterile filtered before use. MDA-MB-231 cells were treated with EFCM in each of the bioassays, and RPMI-1640 was used as a control. Results: MCF10A exosomes introduced via EFCM enhanced proliferation, migration and invasion of MDA-MB-231 cells. Conclusions: Taken together, our findings demonstrate that secreted factors from noncancerous MCF10A cells that have been stressed as a direct result of serum starvation are exosomes. These exosomes recruit TNBC cells to increase proliferation, migration, and invasion. The role of these exosomes in the noncancerous microenvironment is poorly understood, but these data suggest that exosomes from the noncancerous microenvironment have potential to be used in targeted therapies against triple negative breast disease. Citation Format: Letitia A. Yearby, Terri Cunningham, Jacenta Matthews, KiTani Parker Lemieux. Exosomes secreted from the noncancerous microenvironment promote proliferation, migration, and invasion in breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4094.
Apolipoprotein E and Progression of Chronic Kidney Disease—Reply
Authors: Charles C. Hsu, Josef Coresh, W. H. Linda Kao
Journal: JAMA (2006)

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Phase II trial of pegylated interferon alfa-2b in young patients with neurofibromatosis type 1 and unresectable plexiform neurofibromas
Authors: Regina I. Jakacki, Eva Dombi, Seth M. Steinberg, Stewart Goldman, Mark W. Kieran, Nicole J. Ullrich, Ian F. Pollack, Anne Goodwin, Peter E. Manley, Jason Fangusaro, Rudy Allen, Brigitte C. Widemann
Journal: Neuro-Oncology (2016)

There is no proven medical therapy for plexiform neurofibromas (PNs). We undertook a phase II trial of pegylated interferon (PI) to evaluate response and time to progression (TTP). PI was administered as a subcutaneous injection to patients with neurofibromatosis type 1‒related PN, stratified by the presence of symptoms (asymptomatic: stratum 1, symptomatic: stratum 2) or documented imaging progression (stratum 3). Patients in strata 1 and 2 received PI for up to one year if stable, 2 years for those with clinical (stratum 2) or imaging response (≥20% decrease in volume). Patients on stratum 3 continued PI until progression. PI was considered active in stratum 3 if TTP doubled compared with the placebo arm of a previous randomized trial using tipifarnib. Enrolled were 82 evaluable patients (median age 10 y; range 1.6 to 21.4). Fatigue and/or worsening of behavioral issues were the most common toxicities requiring dose modification. Across all strata, imaging responses were seen in 4 patients (5%). Three of 26 symptomatic patients on stratum 2 met the criteria for clinical response without corresponding imaging changes. In stratum 3, median TTP was 29.4 months versus 11.8 for the placebo arm of the previous trial (P=.031). The slope of tumor growth on PI slowed significantly compared with the slope before starting PI (P=.044). In patients with active PN, PI results in more than doubling of the TTP compared with placebo. Imaging changes in symptomatic patients were not associated with changes in clinical status.
Neoadjuvant BRAF (dabrafenib) and MEK (trametinib) inhibition for high-risk resectable stage III and IV melanoma.
Authors: Jennifer Ann Wargo, Rodabe Navroze Amaria, Merrick I. Ross, Robyn P.M. Saw, Jeffrey E. Gershenwald, Patrick Hwu, Sapna Pradyuman Patel, Isabella Claudia Glitza, Adi Diab, Richard Kefford, Richard A Scolyer, Helen Rizos, John F Thompson, Kerwin Shannon, Andrew Spillane, Matteo S. Carlino, Alex Guminski, Lauren Simpson, Michael A. Davies, Georgina V. Long
Journal: Journal of Clinical Oncology (2015)

TPS9091 Background: Significant advances have been made in the treatment of melanoma through the use of mitogen -activated protein kinase pathway (MAPK)-targeted therapies, with several agents now FDA-approved for patients (pts) with BRAF V600 mutations with stage IV or unresectable stage III disease. Based on the efficacy of BRAF inhibitors and combined BRAF/MEK inhibitors in patients with stage IV melanoma, these agents are being investigated as adjuvant therapy in patients with resectable stage III melanoma as part of multi-national phase 3 trials, where the current standard of care is upfront surgery. Mature results from these trials, however, will not be available for some time. A critical question to consider is whether neoadjuvant treatment with MAPK-targeted therapy will improve outcomes in a subset of these patients with significant burden of disease. Methods: Here we report 2 current phase II trials -- at MD Anderson Cancer Center (MD Anderson) and Melanoma Institute Australia (MIA) -- of neoadjuvant combined BRAF inhibition (dabrafenib, at 150 mg by mouth twice a day) and MEK inhibition (trametinib, at 2 mg by mouth once a day) for high risk resectable metastatic melanoma (stage IIIB-C; MIA and MD Anderson) and oligometastatic stage IV (MD Anderson)). Both trials incorporate serial biopsies during the course of treatment for translational research on molecular and immune biomarkers. At MD Anderson, eligible patients are randomized in a 2:1 fashion to neoadjuvant BRAF/MEK x 8 weeks with adjuvant BRAF/MEK x 44 weeks versus upfront surgery and SOC adjuvant therapy (target accrual 84 patients). Endpoints include RECIST response (RR), relapse-free survival (RFS), overall survival (OS), pathologic CR rate, and toxicity. At MIA, all patients receive neoadjuvant BRAF/MEK x 12 weeks, followed by adjuvant BRAF/MEK for 40 weeks (target accrual 35 patients). The primary endpoint is pathologic CR rate, secondary endpoints include RFS, OS, toxicity, and translational endpoints correlated with outcome. This neoadjuvant approach has the potential to establish a new treatment paradigm for patients with high-risk resectable metastatic melanoma harboring a BRAF mutation. Clinical trial information: NCT01972347, NCT02231775.
NEK1 variants confer susceptibility to amyotrophic lateral sclerosis
Authors: Kevin P Kenna, Perry T C van Doormaal, Annelot M Dekker, Nicola Ticozzi, Brendan J Kenna, Frank P Diekstra, Wouter van Rheenen, Kristel R van Eijk, Ashley R Jones, Pamela Keagle, Aleksey Shatunov, William Sproviero, Bradley N Smith, Michael A van Es, Simon D Topp, Aoife Kenna, Jack W Miller, Claudia Fallini, Cinzia Tiloca, Russell L McLaughlin, Caroline Vance, Claire Troakes, Claudia Colombrita, Gabriele Mora, Andrea Calvo, Federico Verde, Safa Al-Sarraj, Andrew King, Daniela Calini, Jacqueline de Belleroche, Frank Baas, Anneke J van der Kooi, Marianne de Visser, Anneloor L M A ten Asbroek, Peter C Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, José Luis Muñoz-Blanco, Tim M Strom, Thomas Meitinger, Karen E Morrison, Giuseppe Lauria, Kelly L Williams, P Nigel Leigh, Garth A Nicholson, Ian P Blair, Claire S Leblond, Patrick A Dion, Guy A Rouleau, Hardev Pall, Pamela J Shaw, Martin R Turner, Kevin Talbot, Franco Taroni, Kevin B Boylan, Marka Van Blitterswijk, Rosa Rademakers, Jesús Esteban-Pérez, Alberto García-Redondo, Phillip Van Damme, Wim Robberecht, Adriano Chio, Cinzia Gellera, Carsten Drepper, Michael Sendtner, Antonia Ratti, Jonathan D Glass, Jesús S Mora, Nazli A Basak, Orla Hardiman, Albert C Ludolph, Peter M Andersen, Jochen H Weishaupt, Robert H Brown, Ammar Al-Chalabi, Vincenzo Silani, Christopher E Shaw, Leonard H van den Berg, Jan H Veldink, John E Landers
Journal: Nature Genetics (2016)
Abstract 1870: Inhibition of Galectin-1 sensitizes oncogenic H-Ras to Rapamycin treatment
Authors: James V. Michael, Jeremy G T Wurtzel, Lawrence E. Goldfinger
Journal: Cancer Research (2016)

Abstract Specific plasma membrane (PM) localization is essential for H-Ras signaling, and relies on post-translational modifications on the C-terminal targeting domain. H-Ras shuttles from the lipid ordered (Lo) domain to the lipid ordered/lipid disordered (Lo/Ld) border upon activation, which is dependent on Galectin-1. We have previously found that H-Ras, which is sequestered in the Lo domain by swapping the C-terminal targeting domain with the Lo-sequestering targeting domain of R-Ras, is deficient in MAPK signal propagation, while having no effect on PI3K activation, nor on H-Ras-driven tumor progression. We have further found that inhibition of PI3K with LY294002 inhibited tumor progression by H-Ras with or without Lo sequestration. Here we show that Lo sequestration of H-Ras attenuated, but did not completely block, H-Ras-induced mTOR signaling (S6kinase phosphorylation) despite similar activation of PI3K as H-Ras. Interestingly, MEK inhibition with U0126 diminished S6kinase phosphorylation by H-Ras, as well as by Lo-sequestered H-Ras. Here we demonstrate that H-Ras-driven allograft tumor growth in mice was substantially blunted upon treatment with mTOR inhibitor Rapamycin, and this effect of Rapamycin was further enhanced in tumors driven by Lo-sequestered H-Ras. Moreover, Rapamycin treatment ablated ERK phosphorylation in H-Ras tumors as well as in tumors with Lo-sequestered H-Ras (in which ERK phosphorylation was already greatly reduced). Together these findings indicate that Lo sequestration of H-Ras inhibits MAPK pathway activation, and that the MAPK pathway engages in crosstalk with mTOR pathways by regulating S6kinase phosphorylation downstream of H-Ras, whereas mTOR activity is required for H-Ras-induced MAPK signaling. These data further indicate that mTOR activation downstream of H-Ras is sufficient to drive tumorigenesis, but this pathway also requires H-Ras-MAPK activation. To recapitulate H-Ras Lo sequestration by the C-terminal targeting domain swap genetic model, we used a Galectin-1 inhibitor, OTX008, to disrupt H-Ras from transitioning between the Lo and Ld domains. OTX008 treatment alone inhibited H-Ras-driven allograft tumor growth to a similar extent as Rapamycin. However, a combination of OTX008 and Rapamycin resulted in nearly complete ablation of H-Ras-dependent tumor growth. These findings indicate that blockade of H-Ras targeting to the lipid ordered/disordered plasma membrane microdomain border, coupled with blockade of mTOR signaling, could provide a novel therapeutic approach to treat H-Ras-associated cancers. Citation Format: James V. Michael, Jeremy G T Wurtzel, Lawrence E. Goldfinger. Inhibition of Galectin-1 sensitizes oncogenic H-Ras to Rapamycin treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1870.