tbuckley/cabot-search huggingface dataset:
RUNX1 mutations promote leukemogenesis of myeloid malignancies in ASXL1-mutated leukemia
Authors: Rabindranath Bera, Ming-Chun Chiu, Ying-Jung Huang, Tung-Huei Lin, Ming-Chung Kuo, Lee-Yung Shih
Journal: Journal of Hematology & Oncology (2019)

Abstract Background Additional sex combs-like 1 ( ASXL1 ) mutations have been described in all forms of myeloid neoplasms including chronic myelomonocytic leukemia (CMML) and associated with inferior outcomes, yet the molecular pathogenesis of ASXL1 mutations ( ASXL1 -MT) remains poorly understood. Transformation of CMML to secondary AML (sAML) is one of the leading causes of death in CMML patients. Previously, we observed that transcription factor RUNX1 mutations ( RUNX1 -MT) coexisted with ASXL1 -MT in CMML and at myeloid blast phase of chronic myeloid leukemia. The contribution of RUNX1 mutations in the pathogenesis of myeloid transformation in ASXL1 -mutated leukemia, however, remains unclear. Methods To evaluate the leukemogenic role of RUNX1-MT in ASXL1 -mutated cells, we co-expressed RUNX1 -MT (R135T) and ASXL1 -MT (R693X) in different cell lines and performed immunoblot, co-immunoprecipitation, gene expression microarray, quantitative RT-PCR, cell proliferation, differentiation, and clonogenic assays for in vitro functional analyses. The in vivo effect was investigated using the C57BL/6 mouse bone marrow transplantation (BMT) model. Results Co-expression of two mutant genes increased myeloid stem cells in animal model, suggesting that cooperation of RUNX1 and ASXL1 mutations played a critical role in leukemia transformation. The expression of RUNX1 mutant in ASXL1 -mutated myeloid cells augmented proliferation, blocked differentiation, and increased self-renewal activity. At 9 months post-BMT, mice harboring combined RUNX1 and ASXL1 mutations developed disease characterized by marked splenomegaly, hepatomegaly, and leukocytosis with a shorter latency. Mice transduced with both ASXL1 and RUNX1 mutations enhanced inhibitor of DNA binding 1 (ID1) expression in the spleen, liver, and bone marrow cells. Bone marrow samples from CMML showed that ID1 overexpressed in coexisted mutations of RUNX1 and ASXL1 compared to normal control and either RUNX1 -MT or ASXL1 -MT samples. Moreover, the RUNX1 mutant protein was more stable than WT and increased HIF1-α and its target ID1 gene expression in ASXL1 mutant cells. Conclusion The present study demonstrated the biological and functional evidence for the critical role of RUNX1 -MT in ASXL1 -mutated leukemia in the pathogenesis of myeloid malignancies.
P2.09-17 Real-World Concordance Across Pathologists for PD-L1 Scoring in Non-Small Cell Lung Cancer: Results from a Large Nationwide Initiative
Authors: J. Adam, V. Hofman, A. Mansuet-Lupo, I. Rouquette, J. Vignaud, C. Badoual, H. Bégueret, M. Copin, D. Damotte, C. Danel, F. Forest, S. Garcia, L. Gibault, F. Penault-Llorca, S. Lantuejoul, A. Cazes, N. Le Stang
Journal: Journal of Thoracic Oncology (2019)
Cell type–specific actions of Bcl11b in early T-lineage and group 2 innate lymphoid cells
Authors: Hiroyuki Hosokawa, Maile Romero-Wolf, Qi Yang, Yasutaka Motomura, Ditsa Levanon, Yoram Groner, Kazuyo Moro, Tomoaki Tanaka, Ellen V. Rothenberg
Journal: The Journal of Experimental Medicine (2019)

The zinc finger transcription factor, Bcl11b, is expressed in T cells and group 2 innate lymphoid cells (ILC2s) among hematopoietic cells. In early T-lineage cells, Bcl11b directly binds and represses the gene encoding the E protein antagonist, Id2, preventing pro-T cells from adopting innate-like fates. In contrast, ILC2s co-express both Bcl11b and Id2. To address this contradiction, we have directly compared Bcl11b action mechanisms in pro-T cells and ILC2s. We found that Bcl11b binding to regions across the genome shows distinct cell type–specific motif preferences. Bcl11b occupies functionally different sites in lineage-specific patterns and controls totally different sets of target genes in these cell types. In addition, Bcl11b bears cell type–specific post-translational modifications and organizes different cell type–specific protein complexes. However, both cell types use the same distal enhancer region to control timing of Bcl11b activation. Therefore, although pro-T cells and ILC2s both need Bcl11b for optimal development and function, Bcl11b works substantially differently in these two cell types.
Abstract 15876: Cbl E3 Ubiquitin Ligase Activation Promotes Myocyte Death and Leads to Pathological Cardiac Hypertrophy After Pressure Overload
Authors: Binbin Du, Mikhail A Kolpakov, Jianfen Guo, Tao Wang, Xinji Guo, Khadija Rafiq, Hamid Band, Yanzhou Zhang, Abdelkarim Sabri
Journal: Circulation (2018)

Rationale: The proto-oncogene Casitas b-lineage lymphoma (Cbl) is an adaptor protein with an intrinsic E3 ubiquitin ligase activity that targets receptor tyrosine kinases (RTKs), resulting in their...
OA03.06 ASCL1, NEUROD1, and POU2F3 Drive Distinct Subtypes of Small Cell Lung Cancer with Unique Therapeutic Vulnerabilities
Authors: C. Gay, L. Diao, C. Stewart, Y. Xi, R. Cardnell, S. Swisher, J. Roth, B. Glisson, J. Wang, J. Heymach, L. Byers
Journal: Journal of Thoracic Oncology (2019)
Targeting tauopathy with engineered tau-degrading intrabodies
Authors: Gilbert Gallardo, Connie H. Wong, Sara M. Ricardez, Carolyn N. Mann, Kent H. Lin, Cheryl E. G. Leyns, Hong Jiang, David M. Holtzman
Journal: Molecular Neurodegeneration (2019)

The accumulation of pathological tau is the main component of neurofibrillary tangles and other tau aggregates in several neurodegenerative diseases, referred to as tauopathies. Recently, immunotherapeutic approaches targeting tau have been demonstrated to be beneficial in decreasing tauopathy in animal models. We previously found that passive immunotherapy with anti-tau antibody to human tau or expression of an anti-tau secreted single-chain variable fragment (scFv) in the central nervous system of a mouse model of tauopathy decreased but did not remove all tau-associated pathology. Although these and other studies demonstrate that conventional immunotherapeutic approaches targeting tau can influence tau pathogenesis, the majority of pathological tau remains in the cytosol of cells, not typically accessible to an extracellular antibody. Therefore, we reasoned targeting intracellular tau might be more efficacious in preventing or decreasing tauopathy.By utilizing our anti-tau scFv, we generated anti-tau intrabodies for the expression in the cytosol of neurons. To enhance the degradation capacity of conventional intrabodies, we engineered chimeric anti-tau intrabodies fused to ubiquitin harboring distinct mutations that shuttle intracellular tau for either the proteasome or lysosomal mediated degradation. To evaluate the efficacy in delaying or eliminating tauopathy, we expressed our tau degrading intrabodies or controls in human tau transgenic mice by adeno-associated virus prior to overt tau pathology and after tau deposition.Our results demonstrate, the expression of chimeric anti-tau intrabodies significantly reduce tau protein levels in primary neuronal cultures expression human tau relative to a non-modified anti-tau intrabody. We found the expression of engineered tau-degrading intrabodies destined for proteasomal-mediated degradation are more effective in delaying or eliminating tauopathy than a conventional intrabody in aged human tau transgenic mice.This study, harnesses the strength of intrabodies that are amendable for targeting specific domains or modifications with the cell-intrinsic mechanisms that regulate protein degradation providing a new immunotherapeutic approach with potentially improved efficacy.
Quality improvement is complex and contextual
Authors: Oliver Groene, Rosa Sunol
Journal: BMJ (2019)

Dixon-Woods discusses the current limitations of quality improvement in healthcare and how to deal with them. We would like to add four points.1

First, Dixon-Woods is right that the effectiveness of quality improvement has been subject to evaluation only recently and that many quality improvement studies have methodological flaws.234 A lot of these flaws relate to the complexity of …
Advances in omics-based methods to identify novel targets for malaria and other parasitic protozoan infections
Authors: Annie N. Cowell, Elizabeth A. Winzeler
Journal: Genome Medicine (2019)

A major advance in antimalarial drug discovery has been the shift towards cell-based phenotypic screening, with notable progress in the screening of compounds against the asexual blood stage, liver stage, and gametocytes. A primary method for drug target deconvolution in Plasmodium falciparum is in vitro evolution of compound-resistant parasites followed by whole-genome scans. Several of the most promising antimalarial drug targets, such as translation elongation factor 2 (eEF2) and phenylalanine tRNA synthetase (PheRS), have been identified or confirmed using this method. One drawback of this method is that if a mutated gene is uncharacterized, a substantial effort may be required to determine whether it is a drug target, a drug resistance gene, or if the mutation is merely a background mutation. Thus, the availability of high-throughput, functional genomic datasets can greatly assist with target deconvolution. Studies mapping genome-wide essentiality in P. falciparum or performing transcriptional profiling of the host and parasite during liver-stage infection with P. berghei have identified potentially druggable pathways. Advances in mapping the epigenomic regulation of the malaria parasite genome have also enabled the identification of key processes involved in parasite development. In addition, the examination of the host genome during infection has identified novel gene candidates associated with susceptibility to severe malaria. Here, we review recent studies that have used omics-based methods to identify novel targets for interventions against protozoan parasites, focusing on malaria, and we highlight the advantages and limitations of the approaches used. These approaches have also been extended to other protozoan pathogens, including Toxoplasma, Trypanosoma, and Leishmania spp., and these studies highlight how drug discovery efforts against these pathogens benefit from the utilization of diverse omics-based methods to identify promising drug targets.
P1.04-03 HLA Affinity for Mutant EGFR Derived Peptides Identifies a Group of Patients with EGFR Driven NSCLC and Favorable Prognosis
Authors: A. Dimou, P. Grewe, M. Campbell, T. Brunetti, J. Sidney, A. Sette, A. Van Bokhoven, P. Norman, R. Doebele
Journal: Journal of Thoracic Oncology (2019)
Very Early Molecular Response at 1 Month Is a Predictor of the Outcome of Chronic Phase Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors
Authors: Won-Sik Lee, Hye-Young Song, Hyeoung-Joon Kim, Jee Hyun Kong, Young Rok Do, Jae-Yong Kwak, Sukjoong Oh, Sung-Hyun Kim, Jeong-A Kim, Dae Young Zang, Yeung-Chul Mun, Young-Woong Won, Sung-Eun Lee, Yunsuk Choi, Dong-Wook Kim
Journal: Blood (2017)
MA12.01 Redefining Malignant Pleural Mesothelioma Types as a Continuum Uncovers Immune-Vascular Interactions
Authors: N. Alcala, L. Mangiante, N. Le Stang, C. Gustafson, S. Boyault, F. Damiola, K. Alcala, J. Mazieres, J. Blay, S. Lantuejoul, R. Bueno, C. Caux, N. Girard, J. Mckay, M. Foll, F. Galateau Sallé, L. Fernandez-Cuesta
Journal: Journal of Thoracic Oncology (2019)
P1.04-09 Predictive Clinical and Molecular Features of Long-Term Survivors Receiving Immune Checkpoint Inhibitors for Stage 4 Non-Small Cell Lung Cancer
Authors: A. Franke, S. Antonia, E. Haura, A. Chiappori, T. Tanvetyanon, J.E. Gray, B. Creelan
Journal: Journal of Thoracic Oncology (2019)
PD01.06 CANOPY-2: Phase 3 Study of Canakinumab Plus Docetaxel as Second/Third Line Therapy in Locally Advanced/Metastatic NSCLC
Authors: V.A. Papadimitrakopoulou, Y. Goto, D.W.T. Lim, B. Mookerjee, I. Malet, Z. Zhu, M. Reck, L. Paz-Ares
Journal: Journal of Thoracic Oncology (2019)
Phosphorylation of the Eukaryotic Initiation Factor eIF4E contributes to the translation of specific immediate early genes
Authors: Marisa Montemartini, Giovanna Ficalora, Claudia Perrera, Giuseppe Locatelli, Fabio Gasparri, Paola magnaghi
Journal: Cancer Research (2008)

178  Control of mRNA translation plays a critical role in cell growth, proliferation and differentiation and is highly regulated by important oncogenic pathways (AKT and RAS). A key player in the regulation of translation is the mRNA 5’ cap binding protein eukaryotic translation initiation factor 4E (eIF4E). eIF4E contributes to malignancy by selectively enabling the translation of a limited pool of mRNAs that generally encode key proteins involved in cellular growth, angiogenesis, survival and malignancy (e.g. c-myc, VEGF, ODC, cyclinD1, MMP9, ribonucleotide reductase).  eIF4E can be phosphorylated on Ser209 by MAP kinase signal-integrated kinases (MNKs) in response to mitogenic or stress stimuli, but the effect of this phosphorylation on eIF4E activity is still controversial. Although initial data were in support of an increased binding affinity of phosphoryated eIF4E for CAP, more recent reports indicate that phosphorylation on Ser209 slightly decreases the affinity of eIF4E for capped mRNA in vitro and CAP dependent translation in cellular models.  The apparent paradox of simultaneous activation of pathways leading to an increase in CAP dependent protein translation (through the AKT/mTor pathway) and a decrease in CAP affinity (through MNK activation and eIF4E phosphorylation) is still not completely explained.  We have analyzed the impact of eIF4E phosphorylation on the translation of selected immediate early genes in murine fibroblasts induced with serum.  Using CGP-57380, an MNK specific inhibitor, we have found that MNK activity is critical for the induction of c-fos and junB proteins upon serum stimulation, thus recapitulating the effects of eEIF4E knockdown using siRNA. Significantly, activation of AKT and MAPK pathways, c-fos and junB mRNA induction upon serum stimulation or general protein synthesis were all unaffected by MNK inhibition.  The possibility that junB and c-fos regulation of translation is an example of a more extended mechanism of translational control upon stress relief is discussed.
P2.01-74 Clinical-Pathological Features and Outcome of Patients with Oral Metastases from Lung Cancer: A Multicenter Retrospective Study
Authors: M. Tagliamento, D. Pignataro, P. Bironzo, M. Tiseo, A.M. Militello, G. Banna, D. Galetta, F. Pesola, G. Del Bene, M. Lupatelli, M. Val, E. Olmetto, E. Capelletto, M. Pentenero, S. Novello
Journal: Journal of Thoracic Oncology (2019)
P2.15-07 Bimanual Examination Is Indispensable in the Surgery of Lung Metastatic Tumors!
Authors: Y. Kahya, A. Yücemen, F. Ibrahimov, B. Kazak, B. Yenigün, M. Özkan, C. Yüksel, S. Enön, A. Kayi Cangir
Journal: Journal of Thoracic Oncology (2019)
P2.11-10 Discovery of Potential Biomarkers That Discriminate Early Stage NSCLC from Controls by Non-Targeted Metabolomics Profiling
Authors: J. Kim, R. Balshaw, C. Trevena, S. Banerji, L. Murphy, D. Dawe, L. Tan, S. Srinathan, G. Buduhan, B. Kidane, G. Qing, M. Domaratzki, M. Aliani
Journal: Journal of Thoracic Oncology (2019)
P2.01-16 TACTICAL: A Phase I/II Trial to Assess the Safety and Efficacy of MSCTRAIL in Metastatic Lung Adenocarcinoma
Authors: A. Davies, E. Sage, K. Kolluri, R. Graham, B. Weil, R. Rego, O. Bain, P.S. Patrick, K. Champion, A. Day, B. Popova, G. Wheeler, D. Fullen, T. Kalbur, M. Forster, M. Lowdell, S. Janes
Journal: Journal of Thoracic Oncology (2019)
Outbreak of Escherichia coli O157
Authors: Brant Goode, Ciara O'Reilly, John Dunn, Kathleen Fullerton, Stacey Smith, George Ghneim, James Keen, Lisa Durso, Megan Davies, Sue Montgomery
Journal: JAMA Pediatrics (2009)

Objectives: To identify cases, describe the outbreak, implement control measures, and identify factors associated with infection or protection from infection, including contact with animals and hand hygiene practices. Design: Case finding, a case-control study of 45 cases and 188 controls, environmental investigation, and molecular subtyping of clinical and environmental Escherichia coli O157:H7 isolates. Setting: The 2004 North Carolina State Fair. Participants: ase patients were fair visitors who had laboratory-confirmed E coli O157 infections, hemolytic uremic syndrome (HUS) diagnoses, or bloody diarrheal illnesses. Control subjects were recruited from a randomized list of persons who had purchased fair tickets online. Environmental samples from the fairgrounds were obtained from locations that had held animals during the fair. Main Exposure: Visiting a petting zoo. Main Outcome Measures: Case finding: Summary descriptive statistics of suspected, probable, or confirmed E coli O157:H7 infections, signs, symptoms, and HUS. Environmental investigation: E coli O157:H7 isolates, pulsed-field gel electrophoresis patterns, and spatial distribution of source locations. Case-control study: Odds ratios (ORs) comparing reported fair-related activities, hygiene practices, and zoonotic disease knowledge with outcome. Results: A total of 108 case patients were ascertained, including 41 with laboratory-confirmed illness and 15 who experienced HUS. Forty-five case patients and 188 controls were enrolled in the case-control study. Visits to a petting zoo having substantial environmental E coli O157:H7 contamination were associated with illness (age-adjusted OR, 8.2; 95% confidence interval [CI], 3.3-20.3). Among children 5 years or younger who had visited the implicated petting zoo, contact with animal manure (OR, 6.9; 95% CI, 2.2-21.9) and hand-to-mouth behaviors (OR, 10.6; 95% CI, 2.0-55.0) were associated with illness. Reported hand hygiene practices did not differ significantly (OR, 1.8; 95% CI, 0.3-9.5). Reported awareness of the risk for zoonotic disease was protective (OR, 0.1; 95% CI, 0.03-0.5). Environmental samples from the petting zoo implicated in the case-control study yielded E coli O157:H7, with indistinguishable pulsed-field gel electrophoresis patterns from the predominant strain. Conclusions: We describe one of the largest petting zoo outbreaks of E coli O157:H7 to date. Persons became infected after contact with manure and engaging in hand-to-mouth behaviors in a petting zoo having substantial E coli O157:H7 contamination. Use of alcohol-based hand-sanitizing gels was not protective, although knowledge of the risk for zoonotic infection was protective. Future investigations in similar outbreaks should assess risks for infection and protective measures (eg, physical barriers separating visitors from animal manure, education, and appropriate hand hygiene practices).
The impact of multidisciplinary cancer conferences (MCC) on the treatment of metastatic rectal cancer (MRC) at the Ottawa Hospital Cancer Centre (TOHCC).
Authors: Tanya Di Valentin, Timothy R. Asmis, Rebecca Ann C. Auer
Journal: Journal of Clinical Oncology (2013)

e14686 Background: There is significant controversy surrounding the management of surgically resectable MRC. The use and timing of neoadjuvant chemotherapy, pelvic radiation, and relative risks and benefits of a combined surgical resection are areas of debate among surgeons, medical, and radiation oncologists. The TOHCC multidisciplinary Cancer Conferences (MCC) provide an opportunity to discuss these cases and propose treatment plans for these patients. Methods: We conducted a retrospective chart review of all the cases of MRC which were discussed at MCC at the TOHCC from November 2007 until October 2009. Information collected included patient demographics, site of metastases, the treatment they received prior to their case being discussed at MCC (past surgeries, chemotherapy, radiotherapy), the treatment plan discussed at MCC, treatment actually administered post MCC discussion, and patient outcome at 6 months. Results: Forty-two patients with MRC were reviewed. The most common sites of metastases were liver (45.2%) and lung (31%). Once diagnosed with metastatic disease, prior to the MCC, patients had received the following treatments alone or in combination: chemotherapy (33.3%), radiotherapy (21.4%), surgery (19.0%), no treatment (n=57.1%). After their case was presented, 38 patients (90.5%) received the treatment recommended at the MCC , while 4 (9.5%) did not. Treatment post MCC included: chemotherapy (neoadjuvant: 38.1%; adjuvant: 23.8%; palliative: 28.6%), radiotherapy (neoadjuvant: 14.3%; adjuvant: 7.1%; palliative: 7.1%) and surgery (31.0%). Conclusions: There is no standardized approach to the management of MRC. Given its complexity, many cases are reviewed at MCC, which allow coordination for multidisciplinary care of these patients. The results of this study suggest that in a majority of cases, the recommendations brought forth at MCC are indeed acted upon. Given that these meetings have a significant impact on the treatment plan and outcome of patients with MRC, they should represent the standard of care when treating this disease.
P1.01-113 Phase 1b Trial of Cabozantinib or Cabozantinib Plus Atezolizumab in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC)
Authors: F. Lim, S. Ponce, S. Patel, C. Van Herpen, C. Kurkjian, Y. Lou, Y. Liu, G. Ramsingh, S. Pal, J. Neal
Journal: Journal of Thoracic Oncology (2019)
Avian erythroblastosis virus E26 oncogene homolog-1 (ETS-1) plays a role in renal microvascular pathophysiology in the Dahl salt-sensitive rat
Authors: Wenguang Feng, Zhengrong Guan, Dongqi Xing, Xingsheng Li, Wei-Zhong Ying, Colton E. Remedies, Edward W. Inscho, Paul W. Sanders
Journal: Kidney International (2019)
P1.17-22 Do Statins Improve Outcomes After Radical Radiotherapy for Lung Cancer? An In-Depth Analysis of Over 1100 Patients
Authors: F. Sun, L. Murray, J. Lilley, K. Banfill, B. Wheller, A. Mcwilliam, A. Abravan, M. Van Herk, C. Faivre-Finn, K. Franks
Journal: Journal of Thoracic Oncology (2019)
MA25.04 Blood-Based Tumor Mutation Burden as a Predictive Biomarker for Outcomes After Pembrolizumab Based First Line Therapy in Metastatic NSCLC
Authors: C. Aggarwal, J. Thompson, A. Chien, K. Quinn, M. Lefterova, R. Nagy, S. Yee, M. Lariviere, C. Ciunci, A. Singh, J. Bauml, R. Cohen, C. Langer, E. Carpenter
Journal: Journal of Thoracic Oncology (2019)
Comparison of cytosine base editors and development of the BEable-GPS database for targeting pathogenic SNVs
Authors: Ying Wang, Runze Gao, Jing Wu, Yi-Chun Xiong, Jia Wei, Sipin Zhang, Bei Yang, Jia Chen, Li Yang
Journal: Genome biology (2019)

Abstract A variety of base editors have been developed to achieve C-to-T editing in different genomic contexts. Here, we compare a panel of five base editors on their C-to-T editing efficiencies and product purity at commonly editable sites, including some human pathogenic C-to-T mutations. We further profile the accessibilities of 20 base editors to all possible pathogenic mutations in silico. Finally, we build the BEable-GPS (Base Editable prediction of Global Pathogenic SNVs) database for users to select proper base editors to model or correct disease-related mutations. The in vivo comparison and in silico profiling catalog the availability of base editors and their broad applications in biomedical studies.
P1.09-33 More than 40% of Locally Advanced or Metastatic NSCLC Patients Without EGFR/ALK Alterations Have PD-L1 TPS ≥ 1% in China
Authors: S. Ben, X. Pan, S. Wen, Y. Jiang, J. Guo, X. Fan, Y. Dai, D. Chen, K. Wang, X. Dong, S. Zhang
Journal: Journal of Thoracic Oncology (2019)
Gels for Live Analysis of Compartmentalized Environments (GLAnCE): A tissue model to probe tumour phenotypes at tumour-stroma interfaces
Authors: Elisa D'Arcangelo, Nila C. Wu, Tianhao Chen, Andi Shahaj, Jose L. Cadavid, Linwen Huang, Laurie Ailles, Alison P. McGuigan
Journal: Biomaterials (2019)