tbuckley/cabot-search huggingface dataset:
Abstract A09: PDXovo: Ultra-fast in vivo drug sensitivity matrices for renal cell carcinoma patients prior to administration of targeted therapy
Authors: Matt Lowerison, Hon S. Leong, Yaroslav Fedyshyn, Ann F. Chambers, James Lacefield, Nicholas E. Power
Journal: Clinical Cancer Research (2016)

Abstract Our next generation PDX model of renal cell carcinoma (RCC) offers the ability to pre-determine de novo drug resistance in fresh patient tumor samples prior to targeted therapy. Implantation of tumor specimens into the chorioallantoic membrane (CAM) of the chicken embryo results in high engraftment efficiencies within two days permitting large-scale “tumor avatar” studies due to its angiogenic microenvironment. Functional tumor heterogeneity studies can be performed in context of drug resistance within two weeks, an approach that could guide the selection of drugs and anticipate outcomes for RCC patients. This ultrafast PDX model is mirrored by high-frequency ultrasound imaging that permits quantitation of tumor volume and tumor vascularity in a high-throughput manner. Using this “tumor avatar” model paired with a prospective RCC patient cohort, we observe intratumoral functional heterogeneity in the context of Sunitinib treatment as determined by high-frequency ultrasound imaging, highlighting its interventional potential in the clinic. Citation Format: Matt Lowerison, Hon S. Leong, Yaroslav Fedyshyn, Ann F. Chambers, James Lacefield, Nicholas E. Power. PDXovo: Ultra-fast in vivo drug sensitivity matrices for renal cell carcinoma patients prior to administration of targeted therapy. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A09.
PP17. RHO GTPASE SIGNALLING IN CANCER CELL INVASION AND ANGIOGENESIS IN BRAIN TUMOURS
Authors: Mr Teklu Egnuni, Prof Valerie Speirs, Dr Aruna Chakrabarty, Dr Heiko Wurdak, Dr Mihaela Lorger, Prof Susan Short, Dr Georgia Mavria
Journal: Neuro-Oncology (2017)

INTRODUCTION: Rho GTPases are molecular switches that cycle between GDP-bound inactive and GTP-bound active states. They transduce signals from the extracellular environment and downstream of oncogenes to control the actin cytoskeleton, and cellular functions including cell motility, cell cycle progression, polarity, malignant transformation, invasion and metastasis. Activation of Rho proteins is controlled by guanine nucleotide exchange factors (GEFs), and GTPase activating proteins (GAPs). Rho GEFs and GAPs are frequently overexpressed in tumours and they are tractable targets for cancer therapy. Rho proteins Rac1 and Cdc42 are deregulated in GBM. Our study is focused on understanding the role of Rac GEF DOCK4 and Cdc42 GEF DOCK9 [Abraham S, Scarcia M, ..Mavria G (2015) Nat Commun. 6: 7286] in the tumour cell and stroma cell compartments of glioblastomas. METHOD: i) The role of DOCK4 and DOCK9 in GBM invasion was analysed using organotypic spheroid assays, the U251 model and patient-derived models of GBM ii) DOCK4 expression was analysed in GBM patient samples and related to expression of stem cell marker nestin. iii) Blood vessel types were characterised in GBM patient samples and related to histological parameters and patient outcome following treatments. iii) The role of DOCK4 was investigated in the vasculature of heterozygous Dock4 null mice and syngeneic GBM tumour models implanted orthotopically. RESULTS: i) There was reduced outgrowth of GBM cells in spheroid assays with DOCK4 or DOCK9 knockdown. A complex of DOCK4 with DOCK9 was identified by immunoprecipitation in U251 cells. ii) Paired DOCK4 and nestin scores of immunostaining from 19 GBM patient samples showed DOCK4 scores correlated with nestin scores using two-tailed Spearmans Rho. Oncomine microarray data shows significant increase of DOCK4 levels in cultured GBM cells isolated from tumours (n=25) compared to neural stem cells (p=8.16 x 104). iii) Hyperproliferative blood vessels in GBM show larger diameter compared to normal blood vessels and increased number of glomeruloid structures was observed in recurrences iv) Heterozygous Dock4 genetic deletion results in reduction of blood vessel diameter. CONCLUSIONS: Tumour cell invasion into adjacent normal brain and vascular proliferation are pathologic hallmarks of GBM. Our results show that DOCK4 may be implicated in both vascular growth and glioblastoma invasion. Delineating further the signalling network in which DOCK4 participates may shed considerable light in these processes and identify new targets for treatments.
A member of the gut mycobiota modulates host purine metabolism exacerbating colitis in mice
Authors: Tyson R. Chiaro, Ray Soto, W. Zac Stephens, Jason L. Kubinak, Charisse Petersen, Lasha Gogokhia, Rickesha Bell, Julio C. Delgado, James Cox, Warren Voth, Jessica Brown, David J. Stillman, Ryan M. O’Connell, Anne E. Tebo, June L. Round
Journal: Science Translational Medicine (2017)

Saccharomyces cerevisiae induces purine metabolism in mouse intestinal epithelia, resulting in an exacerbation of colitis.
MIR150 Is Involved in the Monocyte Subset Differentiation and Its Down-Regulation Leads to Classical Monocyte Accumulation in Chronic Myelomonocytic Leukemia
Authors: Dorothee Selimoglu-Buet, Julie Riviere, Margot Morabito, Catherine Lacout, Aurelie Chauveau, Camille Debord, Raphaël Itzykson, Pierre Fenaux, Nathalie M. Droin, Éric Solary
Journal: Blood (2016)
Modulation of CD38 Expression Levels on Multiple Myeloma Tumor Cells By All-Trans Retinoic Acid Improves the Efficacy of the Anti-CD38 Monoclonal Antibody Daratumumab
Authors: Inger S. Nijhof, Henk M. Lokhorst, Berris van Kessel, Richard W.J. Groen, Anton C. Martens, Parul Doshi, Saskia K. Klein, Tuna Mutis, Kate Sasser, Niels W.C.J. van de Donk
Journal: Blood (2014)
TET2 and ASXL1 Mutations in Leukemic Transformation of Chronic Myeloproliferative Neoplasms.
Authors: Omar Abdel-Wahab, Taghi Manshouri, Jay Patel, Kelly Harris, Jin Juan Yao, Cyrus V. Hedvat, Adriana Heguy, Carlos Bueso-Ramos, Hagop M. Kantarjian, Ross L. Levine, Srdan Verstovsek
Journal: Blood (2009)
In-Vitro Cytotoxicity of Tipifarnib (Zarnestra TM) in Pediatric AML and ALL Samples Is Independent of RAS Mutations.
Authors: Bianca F. Goemans, Christian M. Zwaan, Gertjan J.L. Kaspers, Karel Hählen, Dirk Reinhardt, Ursula Creutzig, Michael C. Heinrich
Journal: Blood (2004)
Regulation of stem-like cancer cells by glutamine through β-catenin pathway mediated by redox signaling
Authors: Jianwei Liao, Pan-Pan Liu, Guoxin Hou, Jiajia Shao, Jing Yang, Kaiyan Liu, Wenhua Lu, Shijun Wen, Yumin Hu, Peng Huang
Journal: Molecular Cancer (2017)

Cancer stem cells (CSCs) are thought to play an important role in tumor recurrence and drug resistance, and present a major challenge in cancer therapy. The tumor microenvironment such as growth factors, nutrients and oxygen affect CSC generation and proliferation by providing the necessary energy sources and growth signals. The side population (SP) analysis has been used to detect the stem-like cancer cell populations based on their high expression of ABCG2 that exports Hoechst-33342 and certain cytotoxic drugs from the cells. The purpose of this research is to investigate the effect of a main nutrient molecule, glutamine, on SP cells and the possible underlying mechanism(s).Biochemical assays and flow cytometric analysis were used to evaluate the effect of glutamine on stem-like side population cells in vitro. Molecular analyses including RNAi interfering, qRT-PCR, and immunoblotting were employed to investigate the molecular signaling in response to glutamine deprivation and its influence on tumor formation capacity in vivo.We show that glutamine supports the maintenance of the stem cell phenotype by promoting glutathione synthesis and thus maintaining redox balance for SP cells. A deprivation of glutamine in the culture medium significantly reduced the proportion of SP cells. L-asparaginase, an enzyme that catalyzes the hydrolysis of asparagine and glutamine to aspartic acid and glutamate, respectively, mimics the effect of glutamine withdrawal and also diminished the proportion of SP cells. Mechanistically, glutamine deprivation increases intracellular ROS levels, leading to down-regulation of the β-catenin pathway.Glutamine plays a significant role in maintaining the stemness of cancer cells by a redox-mediated mechanism mediated by β-catenin. Inhibition of glutamine metabolism or deprivation of glutamine by L-asparaginase may be a new strategy to eliminate CSCs and overcome drug resistance.
A systematic review of clinical decision support systems for antimicrobial management: are we failing to investigate these interventions appropriately?
Authors: T.M. Rawson, L.S.P. Moore, B. Hernandez, E. Charani, E. Castro-Sanchez, P. Herrero, B. Hayhoe, W. Hope, P. Georgiou, A.H. Holmes
Journal: Clinical Microbiology and Infection (2017)

Clinical decision support systems (CDSS) for antimicrobial management can support clinicians to optimize antimicrobial therapy. We reviewed all original literature (qualitative and quantitative) to understand the current scope of CDSS for antimicrobial management and analyse existing methods used to evaluate and report such systems.PRISMA guidelines were followed. Medline, EMBASE, HMIC Health and Management and Global Health databases were searched from 1 January 1980 to 31 October 2015. All primary research studies describing CDSS for antimicrobial management in adults in primary or secondary care were included. For qualitative studies, thematic synthesis was performed. Quality was assessed using Integrated quality Criteria for the Review Of Multiple Study designs (ICROMS) criteria. CDSS reporting was assessed against a reporting framework for behaviour change intervention implementation.Fifty-eight original articles were included describing 38 independent CDSS. The majority of systems target antimicrobial prescribing (29/38;76%), are platforms integrated with electronic medical records (28/38;74%), and have a rules-based infrastructure providing decision support (29/38;76%). On evaluation against the intervention reporting framework, CDSS studies fail to report consideration of the non-expert, end-user workflow. They have narrow focus, such as antimicrobial selection, and use proxy outcome measures. Engagement with CDSS by clinicians was poor.Greater consideration of the factors that drive non-expert decision making must be considered when designing CDSS interventions. Future work must aim to expand CDSS beyond simply selecting appropriate antimicrobials with clear and systematic reporting frameworks for CDSS interventions developed to address current gaps identified in the reporting of evidence.
Cost-effectiveness of robot-assisted lobectomy compared with VATS lobectomy for early-stage lung cancer in the National Health Insurance Program of Korea.
Authors: Hyun-Sung Lee, Hee-Jin Jang, Seong Yong Park, Jungnam Joo, Jae Ill Zo
Journal: Journal of Clinical Oncology (2012)

e16534 Background: Robotic surgery has proven to be one of the most effective cutting-edge technologies for successful minimally invasive surgery. This study aimed to evaluate the cost-effectiveness of robot-assisted lobectomy (RAL) for the treatment of early stage lung cancer with video-assisted thoracic surgery (VATS) lobectomy. Methods: From February 2009 to April 2011, one hundred twenty patients underwent RAL for clinical stage I or II non-small cell lung cancer. The consecutive 100 patients who underwent RAL were compared with 100 patients who underwent VATS lobectomy during the similar period under intent-to-treat analysis. Clinicopathologic characteristics and surgical outcomes were analyzed. Adverse events were defined as operative morbidities, mortality and conversion to open thoracotomy. The adverse events were adjusted by NCI-CTCAE 3.0 grade. Incremental cost-effective ratio (ICER) was defined as difference of total cost divided by difference of adjusted adverse events. Results: Tumor size was slightly larger in RAL group with 3.2cm in mean size of tumor. RAL needed longer operation time than VATS group. However, the console time during operation was similar with operation time in VATS lobectomy. The median length of postoperative stay was significantly shorter after robotic surgery than VATS. Operative morbidities developed in 9 patients in RAL and 21 in VATS (p=0.028). Conversions to thoracotomy were happened in 2 cases in RAL and 7 cases in VATS (p=0.170). The total hospital costs were higher in RAL than those in VATS ($14,186 vs. $11,509, p&lt;0.001). ICER between RAL and VATS was $16,111 (80% CI; $9,190~$33,860) and NNT (numbers needed to treat) was 6.01. If six patients are treated by RAL, one case of adverse operative events could be diminished and its additional cost is $16,111. Conclusions: Robot-assisted lobectomy for early stage lung cancer is safe as well as feasible, and it results in a satisfying postoperative outcome compared with those after VATS lobectomy. Despite higher total costs, RAL is highly cost-effective to treat early stage lung cancer in National Health Insurance Program of Korea.
The role of the complement system in cancer
Authors: Vahid Afshar-Kharghan
Journal: Journal of Clinical Investigation (2017)

In addition to being a component of innate immunity and an ancient defense mechanism against invading pathogens, complement activation also participates in the adaptive immune response, inflammation, hemostasis, embryogenesis, and organ repair and development. Activation of the complement system via classical, lectin, or alternative pathways generates anaphylatoxins (C3a and C5a) and membrane attack complex (C5b-9) and opsonizes targeted cells. Complement activation end products and their receptors mediate cell-cell interactions that regulate several biological functions in the extravascular tissue. Signaling of anaphylatoxin receptors or assembly of membrane attack complex promotes cell dedifferentiation, proliferation, and migration in addition to reducing apoptosis. As a result, complement activation in the tumor microenvironment enhances tumor growth and increases metastasis. In this Review, I discuss immune and nonimmune functions of complement proteins and the tumor-promoting effect of complement activation.
Preoperative chemotherapy plus bevacizumab with early salvage therapy based on FDG-PET response in locally advanced gastroesophageal junction and gastric adenocarcinoma.
Authors: Geoffrey Yuyat Ku, David Paul Kelsen, Vivian E. Strong, Heiko Schöder, Yelena Yuriy Janjigian, Manish A. Shah, Daniel G. Coit, Murray F. Brennan, Marinela Capanu, David H. Ilson
Journal: Journal of Clinical Oncology (2013)

4101 Background: Response on FDG-PET scan during preoperative chemotherapy has prognostic significance. We performed a phase II trial to examine the effectiveness of FDG-PET directed early switching to salvage chemotherapy measured by 2-year disease free survival (DFS). Methods: Pts with PET avid, endoscopic ultrasound and laparoscopically staged T3 or N+ resectable gastric or GEJ adenocarcinoma received induction epirubicin 50mg/m 2 , cisplatin 60mg/m 2 Day 1, capecitabine 625mg/m 2 BID Days 1-21 (ECX) and bevacizumab 15mg/kg Day 1. PET scan was repeated at Week 3. PET responders (≥35% decline in SUV) continued with ECX for 2 more cycles. PET non-responders were switched to 2 cycles of salvage therapy: docetaxel 30mg/m 2 and irinotecan 50mg/m 2 Days 1 and 8 q21 days and bevacizumab 15mg/kg Day 1. All pts went to surgery 4 weeks after Cycle 3. Results: Twenty of planned 60 pts were enrolled before the study closed for poor accrual. Eleven (55%) had a PET response after induction. Ten of 11 underwent R0 resection: 1/10 path complete response, 3/10 path partial response. Nine PET non-responders were switched to the salvage regimen. Seven of 9 non-responders had R0 resection, none achieved a pathological response. The median DFS for PET responders was 27.8 mos (95% CI 10.3-27.8) and DFS in salvage group has not been reached. There was no significant difference in DFS between the two groups (p= 0.4). Follow up for overall survival is ongoing. Conclusions: Response on PET scan during induction chemotherapy can identify early treatment failures. The results for therapy cross-over indicate a potentially improved DFS with salvage chemotherapy. Results from this trial are hypothesis generating and merit evaluation in a larger clinical trial. Updated survival data will be presented. Clinical trial information: NCT00737438.
A phase I/II study to assess the safety and efficacy of pazopanib and MK-3475 in subjects with advanced renal cell carcinoma.
Authors: David F. McDermott, Jeffrey R. Infante, Martin Henner Voss, Robert J. Motzer, John B. A. G. Haanen, Simon Chowdhury, Rodolfo F. Perini, Robert Iannone, Rachel Hodge, David Figueroa, Benjamin B. Suttle, Alicia Allred, Stephen D. Rubin, Brian I. Rini
Journal: Journal of Clinical Oncology (2014)

TPS4604^ Background: Pazopanib is an angiogenesis inhibitor targeting VEGFR-1, -2, and -3; PDGFR-α and -β; and the receptor c-Kit, and is indicated for the treatment of subjects with advanced RCC and advanced soft tissue sarcoma. MK-3475 (Merck) is a potent and highly-selective humanized mAb of the IgG4/kappa isotype designed to block directly the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Proangiogenic factors suppress various immune functions whereas antiangiogenic agents have potential to modulate the tumor microenvironment and improve immunotherapy. High expression of PD-L1 on tumor cells, and to a lesser extent of PD-L2, has been found to correlate with poor prognosis and survival in various cancer types including RCC [Thompson 2007]. An analysis of patients with RCC treated with paz demonstrated that elevated expression of PD-L1 correlates with shorter PFS [Figueroa 2013]. Additionally an objective response rate of 27% in RCC patients was reported in an early phase study with another antibody to PD-1 forall doses tested[Topalian 2012]. These findings suggest that MK-3475 may potentiate the activity of paz in patients with RCC. This Phase I/II trial has been undertaken to test the safety and tolerability of paz in combination with MK-3475 in advanced RCC, and assess the efficacy of the combination as compared with paz or MK-3475 alone. Methods: This is an open-label, 2-part multi-center study of paz and/or MK-3475 in treatment-naïve subjects with advanced predominantly clear cell RCC. Part 1 is Phase I dose escalation using a modified 3+ 3 design, with combination dosing starting at 800mg/day paz + 2mg/kgQ2W MK-3475, followed by an expansion cohort to confirm the maximum tolerated regimen and the recommended Phase 2 dose. Part 2 is a randomized 3-arm (1:1:1) Phase II study to evaluate the clinical efficacy and safety of paz + MK-3475 as compared to paz or MK-3475 alone. The primary endpoint in Part 2 is PFS by RECIST v1.1. Secondary endpoints are PFS rate at 18 months, PFS by modified RECIST criteria, overall response, stable disease ≥6 months, time to response, duration of response, overall survival, safety and tolerability. Part 1 has opened to enrollment. Clinical trial information: NCT02014636.
Clinical application of targeted deep sequencing for predicting responsiveness to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in never-smoking lung adenocarcinomas (NSLA).
Authors: Ji-Youn Han, Yeon-Su Lee, Geon Kook Lee, Jung-Ah Hwang, Seung-Hyun Hong, Sung Jin Yoon, Jin Soo Lee
Journal: Journal of Clinical Oncology (2013)

e19019 Background: Most patients with EGFR-mutant lung adenocarcinoma response well to EGFR-TKIs. However, a subset of patients showed primary resistance to EGFR-TKIs. The routine conventional methods have limitation in predicting primary resistance among EGFR mutant lung cancers. We performed targeted deep sequencing to explore the accuracy and additional values in predicting responsiveness to EGFR-TKIs in NSLA. Methods: We performed direct sequencing to identify EGFR mutations in 48 NSLA received gefitinib or erlotinib for their recurrent advanced disease after surgery. The peptide nucleic acid (PNA) clamp polymerase chain reaction (PCR) was used to confirm the EGFR mutation status. To exclude well known causes of resistance, we analyzed KRAS, BRAF and PIK3CA mutations by PNA clamp PCR, ALK rearrangement by FISH, and RET and ROS-1 rearrangements by reverse transcriptase (RT)-PCR and quantitative real-time PCR. After screening, Ion Torrent Personal Genome Machine (PGM) was performed in 31 patients harboring EGFR exon 19 deletions (19DEL) or L858R mutations or none of above molecular changes. Results: The conventional screening found 25 EGFR mutations (10 19DEL; 9 L858R, 1 G719X, 4 double EGFR mutations, 1 concomitant L858R and PIK3CA mutations), 4 KRAS mutations, 3 ALK, 2 RET and 2 ROS-1 rearrangements. No mutation was found in 12 patients. After screening, samples were divided into 4 groups; 1) good responders to EGFR-TKIs with only 19DEL or L858R (n=15); 2) non-responder to EGFR-TKI with only 19DEL or L858R (n=4); 3) non-responders to EGFR-TKI without any mutation (n=8); 4) stable disease to EGFR-TKI without any mutations (n=4). With PMG, all conventionally detected mutations were confirmed, and some additional mutations were detected in a subset of samples; two KRAS and one PIK3CA mutations in group 3, one concomitant PIK3CA and L858R mutations in group 3, one PIK3CA mutation in group 2, and one 19DEL mutation in group 4. Conclusions: Targeted deep sequencing may improve the detection of clinically actionable genomic alterations and enable mutation-driven personalized approach in lung cancer patients.
KIT Mutations Are Rare Among Elderly AML Patients: A SWOG Report
Authors: Fabiana Ostronoff, Megan Othus, Phoenix A. Ho, Stephen H. Petersdorf, Jeanne E. Anderson, John E. Godwin, Cheryl L Willman, Jerald P. Radich, Frederick R. Appelbaum, Derek L. Stirewalt, Soheil Meshinchi
Journal: Blood (2011)
The birth of a human-specific neural gene by incomplete duplication and gene fusion
Authors: Max L. Dougherty, Xander Nuttle, Osnat Penn, Bradley J. Nelson, John Huddleston, Carl Baker, Lana Harshman, Michael H. Duyzend, Mario Ventura, Francesca Antonacci, Richard Sandstrom, Megan Y. Dennis, Evan E. Eichler
Journal: Genome biology (2017)

Gene innovation by duplication is a fundamental evolutionary process but is difficult to study in humans due to the large size, high sequence identity, and mosaic nature of segmental duplication blocks. The human-specific gene hydrocephalus-inducing 2, HYDIN2, was generated by a 364 kbp duplication of 79 internal exons of the large ciliary gene HYDIN from chromosome 16q22.2 to chromosome 1q21.1. Because the HYDIN2 locus lacks the ancestral promoter and seven terminal exons of the progenitor gene, we sought to characterize transcription at this locus by coupling reverse transcription polymerase chain reaction and long-read sequencing. 5' RACE indicates a transcription start site for HYDIN2 outside of the duplication and we observe fusion transcripts spanning both the 5' and 3' breakpoints. We observe extensive splicing diversity leading to the formation of altered open reading frames (ORFs) that appear to be under relaxed selection. We show that HYDIN2 adopted a new promoter that drives an altered pattern of expression, with highest levels in neural tissues. We estimate that the HYDIN duplication occurred ~3.2 million years ago and find that it is nearly fixed (99.9%) for diploid copy number in contemporary humans. Examination of 73 chromosome 1q21 rearrangement patients reveals that HYDIN2 is deleted or duplicated in most cases. Together, these data support a model of rapid gene innovation by fusion of incomplete segmental duplications, altered tissue expression, and potential subfunctionalization or neofunctionalization of HYDIN2 early in the evolution of the Homo lineage.
Monocytic CCR2+ Myeloid Derived Suppressor Cells Promote Immune Escape by Limiting Activated CD8 T Cell Infiltration Into the Tumor Microenvironment
Authors: Alexander Lesokhin, Tobias Hohl, Taha Merghoub, Daniel Hirschhorn-cymerman, Eric G. Pamer, Alan N Houghton, Jedd D Wolchok
Journal: Blood (2011)