215 results on '"A. B. Olshen"'
Search Results
2. Perturbations in common and distinct inflammatory pathways associated with morning and evening fatigue in outpatients receiving chemotherapy
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Kord M. Kober, Carolyn Harris, Yvette P. Conley, Anand Dhruva, Vasuda Dokiparthi, Marilyn J. Hammer, Jon D. Levine, Kate Oppegaard, Steven Paul, Joosun Shin, Anatol Sucher, Fay Wright, Brian Yuen, Adam B. Olshen, and Christine Miaskowski
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cancer ,chemotherapy ,cytokines ,fatigue ,gene expression ,inflammation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Moderate to severe fatigue occurs in up to 94% of patients with cancer. Recent evidence suggests that morning and evening fatigue are distinct dimensions of physical fatigue. The purposes of this study were to evaluate the transcriptome for common and distinct perturbed inflammatory pathways in patients receiving chemotherapy who reported low versus high levels of morning or low versus high levels of evening cancer‐related fatigue. Methods Patients completed questionnaires during the week prior to their chemotherapy treatment. Severity of morning and evening fatigue was evaluated using the Lee Fatigue Scale. Gene expression and pathway impact analyses (PIA) were performed in two independent samples using RNA‐sequencing (n = 357) and microarray (n = 360). Patterns of interactions between and among these perturbed pathways were evaluated using a knowledge network (KN). Results Across the PIA, nine perturbed pathways (FDR
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- 2023
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3. Does multi-way, long-range chromatin contact data advance 3D genome reconstruction?
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Adam B. Olshen and Mark R. Segal
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Multi-dimensional scaling ,SPRITE ,Conformation capture ,Pairwise distance ,Procrustes alignment ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Methods for inferring the three-dimensional (3D) configuration of chromatin from conformation capture assays that provide strictly pairwise interactions, notably Hi-C, utilize the attendant contact matrix as input. More recent assays, in particular split-pool recognition of interactions by tag extension (SPRITE), capture multi-way interactions instead of solely pairwise contacts. These assays yield contacts that straddle appreciably greater genomic distances than Hi-C, in addition to instances of exceptionally high-order chromatin interaction. Such attributes are anticipated to be consequential with respect to 3D genome reconstruction, a task yet to be undertaken with multi-way contact data. However, performing such 3D reconstruction using distance-based reconstruction techniques requires framing multi-way contacts as (pairwise) distances. Comparing approaches for so doing, and assessing the resultant impact of long-range and multi-way contacts, are the objectives of this study. Results We obtained 3D reconstructions via multi-dimensional scaling under a variety of weighting schemes for mapping SPRITE multi-way contacts to pairwise distances. Resultant configurations were compared following Procrustes alignment and relationships were assessed between associated Procrustes root mean square errors and key features such as the extent of multi-way and/or long-range contacts. We found that these features had surprisingly limited influence on 3D reconstruction, a finding we attribute to their influence being diminished by the preponderance of pairwise contacts. Conclusion Distance-based 3D genome reconstruction using SPRITE multi-way contact data is not appreciably affected by the weighting scheme used to convert multi-way interactions to pairwise distances.
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- 2023
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4. Venetoclax and dinaciclib elicit synergistic preclinical efficacy against hypodiploid acute lymphoblastic leukemia
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Holly Pariury, Joshua Fandel, Stefanie Bachl, Kenny K. Ang, Sarine Markossian, Chris G. Wilson, Benjamin S. Braun, Bogdan Popescu, Margo Wohlfeil, Kyle Beckman, Simayijiang Xirenayi, Ritu P. Roy, Adam B. Olshen, Catherine Smith, Michelle R. Arkin, Mignon L. Loh, and Ernesto Diaz-Flores
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive blood cancer with a poor prognosis despite intensive chemotherapy or stem cell transplant. Children and adolescents with positive end-of-induction minimal residual disease have an overall survival lower than 30%. However, data regarding therapeutic alternatives for this disease is nearly nonexistent, emphasizing the critical need for new or adjunctive therapies that can improve outcomes. We previously reported on the therapeutic efficacy of venetoclax (ABT-199) in hypodiploid B-lineage ALL but with limitations as monotherapy. In this study, we set out to identify drugs enhancing the anti-leukemic effect of venetoclax in hypodiploid ALL. Using a highthroughput drug screen, we identified dinaciclib, a cyclin-dependent kinase inhibitor that worked synergistically with venetoclax to induce cell death in hypodiploid cell lines. This combination eradicated leukemic blasts within hypodiploid ALL patient-derived xenografts mice with low off-target toxicity. Our findings suggest that dual inhibition of BCL-2 (venetoclax) and CDK9/MCL-1 (dinaciclib) is a promising therapeutic approach in hypodiploid ALL, warranting further investigation to inform clinical trials in this high-risk patient population.
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- 2023
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5. Therapeutic implications of transcriptomics in head and neck cancer patient-derived xenografts
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Rex H. Lee, Ritu Roy, Hua Li, Aaron Hechmer, Tian Ran Zhu, Adila Izgutdina, Adam B. Olshen, Daniel E. Johnson, and Jennifer R. Grandis
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Medicine ,Science - Abstract
There are currently no clinical strategies utilizing tumor gene expression to inform therapeutic selection for patients with head and neck squamous cell carcinoma (HNSCC). One of the challenges in developing predictive biomarkers is the limited characterization of preclinical HNSCC models. Patient-derived xenografts (PDXs) are increasingly recognized as translationally relevant preclinical avatars for human tumors; however, the overall transcriptomic concordance of HNSCC PDXs with primary human HNSCC is understudied, especially in human papillomavirus-associated (HPV+) disease. Here, we characterized 64 HNSCC PDXs (16 HPV+ and 48 HPV-) at the transcriptomic level using RNA-sequencing. The range of human-specific reads per PDX varied from 64.6%-96.5%, with a comparison of the most differentially expressed genes before and after removal of mouse transcripts revealing no significant benefit to filtering out mouse mRNA reads in this cohort. We demonstrate that four previously established HNSCC molecular subtypes found in The Cancer Genome Atlas (TCGA) are also clearly recapitulated in HNSCC PDXs. Unsupervised hierarchical clustering yielded a striking natural division of HNSCC PDXs by HPV status, with C19orf57 (BRME1), a gene previously correlated with positive response to cisplatin in cervical cancer, among the most significantly differentially expressed genes between HPV+ and HPV- PDXs. In vivo experiments demonstrated a possible relationship between increased C19orf57 expression and superior anti-tumor responses of PDXs to cisplatin, which should be investigated further. These findings highlight the value of PDXs as models for HPV+ and HPV- HNSCC, providing a resource for future discovery of predictive biomarkers to guide treatment selection in HNSCC.
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- 2023
6. Pan-cancer identification of clinically relevant genomic subtypes using outcome-weighted integrative clustering
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Arshi Arora, Adam B. Olshen, Venkatraman E. Seshan, and Ronglai Shen
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Integrative clustering ,Supervised learning ,Patient survival ,Prognostic molecular stratification ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Comprehensive molecular profiling has revealed somatic variations in cancer at genomic, epigenomic, transcriptomic, and proteomic levels. The accumulating data has shown clearly that molecular phenotypes of cancer are complex and influenced by a multitude of factors. Conventional unsupervised clustering applied to a large patient population is inevitably driven by the dominant variation from major factors such as cell-of-origin or histology. Translation of these data into clinical relevance requires more effective extraction of information directly associated with patient outcome. Methods Drawing from ideas in supervised text classification, we developed survClust, an outcome-weighted clustering algorithm for integrative molecular stratification focusing on patient survival. survClust was performed on 18 cancer types across multiple data modalities including somatic mutation, DNA copy number, DNA methylation, and mRNA, miRNA, and protein expression from the Cancer Genome Atlas study to identify novel prognostic subtypes. Results Our analysis identified the prognostic role of high tumor mutation burden with concurrently high CD8 T cell immune marker expression and the aggressive clinical behavior associated with CDKN2A deletion across cancer types. Visualization of somatic alterations, at a genome-wide scale (total mutation burden, mutational signature, fraction genome altered) and at the individual gene level, using circomap further revealed indolent versus aggressive subgroups in a pan-cancer setting. Conclusions Our analysis has revealed prognostic molecular subtypes not previously identified by unsupervised clustering. The algorithm and tools we developed have direct utility toward patient stratification based on tumor genomics to inform clinical decision-making. The survClust software tool is available at https://github.com/arorarshi/survClust .
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- 2020
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7. COVIDNearTerm: A simple method to forecast COVID-19 hospitalizations
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Adam B. Olshen, Ariadna Garcia, Kristopher I. Kapphahn, Yingjie Weng, Jason Vargo, John A. Pugliese, David Crow, Paul D. Wesson, George W. Rutherford, Mithat Gonen, and Manisha Desai
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COVID-19 ,forecasting ,hospitalization ,prediction ,SARS-CoV-2 ,Medicine - Abstract
Abstract Introduction: COVID-19 has caused tremendous death and suffering since it first emerged in 2019. Soon after its emergence, models were developed to help predict the course of various disease metrics, and these models have been relied upon to help guide public health policy. Methods: Here we present a method called COVIDNearTerm to “forecast” hospitalizations in the short term, two to four weeks from the time of prediction. COVIDNearTerm is based on an autoregressive model and utilizes a parametric bootstrap approach to make predictions. It is easy to use as it requires only previous hospitalization data, and there is an open-source R package that implements the algorithm. We evaluated COVIDNearTerm on San Francisco Bay Area hospitalizations and compared it to models from the California COVID Assessment Tool (CalCAT). Results: We found that COVIDNearTerm predictions were more accurate than the CalCAT ensemble predictions for all comparisons and any CalCAT component for a majority of comparisons. For instance, at the county level our 14-day hospitalization median absolute percentage errors ranged from 16 to 36%. For those same comparisons, the CalCAT ensemble errors were between 30 and 59%. Conclusion: COVIDNearTerm is a simple and useful tool for predicting near-term COVID-19 hospitalizations.
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- 2022
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8. Caveolin-1 and Sox-2 are predictive biomarkers of cetuximab response in head and neck cancer
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Mehdi Bouhaddou, Rex H. Lee, Hua Li, Neil E. Bhola, Rachel A. O’Keefe, Mohammad Naser, Tian Ran Zhu, Kelechi Nwachuku, Umamaheswar Duvvuri, Adam B. Olshen, Ritu Roy, Aaron Hechmer, Jennifer Bolen, Stephen B. Keysar, Antonio Jimeno, Gordon B. Mills, Scott Vandenberg, Danielle L. Swaney, Daniel E. Johnson, Nevan J. Krogan, and Jennifer R. Grandis
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Therapeutics ,Medicine - Abstract
The epidermal growth factor receptor (EGFR) inhibitor cetuximab is the only FDA-approved oncogene-targeting therapy for head and neck squamous cell carcinoma (HNSCC). Despite variable treatment response, no biomarkers exist to stratify patients for cetuximab therapy in HNSCC. Here, we applied unbiased hierarchical clustering to reverse-phase protein array molecular profiles from patient-derived xenograft (PDX) tumors and revealed 2 PDX clusters defined by protein networks associated with EGFR inhibitor resistance. In vivo validation revealed unbiased clustering to classify PDX tumors according to cetuximab response with 88% accuracy. Next, a support vector machine classifier algorithm identified a minimalist biomarker signature consisting of 8 proteins — caveolin-1, Sox-2, AXL, STING, Brd4, claudin-7, connexin-43, and fibronectin — with expression that strongly predicted cetuximab response in PDXs using either protein or mRNA. A combination of caveolin-1 and Sox-2 protein levels was sufficient to maintain high predictive accuracy, which we validated in tumor samples from patients with HNSCC with known clinical response to cetuximab. These results support further investigation into the combined use of caveolin-1 and Sox-2 as predictive biomarkers for cetuximab response in the clinic.
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- 2021
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9. Epigenetic Regulation of Inflammatory Mechanisms and a Psychological Symptom Cluster in Patients Receiving Chemotherapy
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Carolyn S. Harris, Christine A. Miaskowski, Yvette P. Conley, Marilyn J. Hammer, Laura B. Dunn, Anand A. Dhruva, Jon D. Levine, Adam B. Olshen, and Kord M. Kober
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General Nursing - Published
- 2023
10. Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia
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Elliot Stieglitz, Tali Mazor, Adam B. Olshen, Huimin Geng, Laura C. Gelston, Jon Akutagawa, Daniel B. Lipka, Christoph Plass, Christian Flotho, Farid F. Chehab, Benjamin S. Braun, Joseph F. Costello, and Mignon L. Loh
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Science - Abstract
Juvenile myelomonocytic leukemia (JMML) is an aggressive disease with limited options for treatment. Here, the authors utilize DNA methylation based subgroups in JMML to predict clinical outcome.
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- 2017
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11. Gastrointestinal Symptom Cluster is Associated With Epigenetic Regulation of Lymphotoxin Beta in Oncology Patients Receiving Chemotherapy
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Carolyn S. Harris, Christine A. Miaskowski, Yvette P. Conley, Marilyn J. Hammer, Anand A. Dhruva, Jon D. Levine, Adam B. Olshen, and Kord M. Kober
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Research and Theory - Abstract
Objectives While the gastrointestinal symptom cluster (GISC) is common in patients receiving chemotherapy, limited information is available on its underlying mechanism(s). Emerging evidence suggests a role for inflammatory processes through the actions of the nuclear factor kappa B (NF-κB) signaling pathway. This study evaluated for associations between a GISC and levels of DNA methylation for genes within this pathway. Methods Prior to their second or third cycle of chemotherapy, 1071 outpatients reported symptom occurrence using the Memorial Symptom Assessment Scale. A GISC was identified using exploratory factor analysis. Differential methylation analyses were performed in two independent samples using EPIC ( n = 925) and 450K ( n = 146) microarrays. Trans expression-associated CpG (eCpG) loci for 56 NF-κB signaling pathway genes were evaluated. Loci significance were assessed using an exploratory false discovery rate (FDR) of 25% for the EPIC sample. For the validation assessment using the 450K sample, significance was assessed at an unadjusted p-value of 0.05. Results For the EPIC sample, the GISC was associated with increased expression of lymphotoxin beta ( LTB) at one differentially methylated trans eCpG locus (cg03171795; FDR = 0.168). This association was not validated in the 450K sample. Conclusions This study is the first to identify an association between a GISC and epigenetic regulation of a gene that is involved in the initiation of gastrointestinal immune responses. Findings suggest that increased LTB expression by hypermethylation of a trans eCpG locus is involved in the occurrence of this cluster in patients receiving chemotherapy. LTB may be a potential therapeutic target for this common cluster.
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- 2022
12. Association between Ancestry-Specific 6q25 Variants and Breast Cancer Subtypes in Peruvian Women
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Valentina A. Zavala, Sandro Casavilca-Zambrano, Jeannie Navarro-Vásquez, Carlos A. Castañeda, Guillermo Valencia, Zaida Morante, Monica Calderón, Julio E. Abugattas, Henry Gómez, Hugo A. Fuentes, Ruddy Liendo-Picoaga, Jose M. Cotrina, Claudia Monge, Silvia P. Neciosup, Scott Huntsman, Donglei Hu, Sixto E. Sánchez, Michelle A. Williams, Angel Núñez-Marrero, Lenin Godoy, Aaron Hechmer, Adam B. Olshen, Julie Dutil, Elad Ziv, Jovanny Zabaleta, Bizu Gelaye, Jule Vásquez, Marco Gálvez-Nino, Daniel Enriquez-Vera, Tatiana Vidaurre, and Laura Fejerman
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Receptor, ErbB-2 ,Epidemiology ,Breast Neoplasms ,Medical and Health Sciences ,Chromosomes ,ErbB-2 ,Receptors ,Breast Cancer ,Peru ,Genetics ,2.1 Biological and endogenous factors ,Humans ,Aetiology ,Progesterone ,Cancer ,Hispanic or Latino ,Estrogen ,Good Health and Well Being ,Logistic Models ,Receptors, Estrogen ,Oncology ,Chromosomes, Human, Pair 6 ,Female ,Pair 6 ,Receptors, Progesterone ,Human ,Receptor - Abstract
Background: Breast cancer incidence in the United States is lower in Hispanic/Latina (H/L) compared with African American/Black or Non-Hispanic White women. An Indigenous American breast cancer–protective germline variant (rs140068132) has been reported near the estrogen receptor 1 gene. This study tests the association of rs140068132 and other polymorphisms in the 6q25 region with subtype-specific breast cancer risk in H/Ls of high Indigenous American ancestry. Methods: Genotypes were obtained for 5,094 Peruvian women with (1,755) and without (3,337) breast cancer. Associations between genotype and overall and subtype-specific risk for the protective variant were tested using logistic regression models and conditional analyses, including other risk-associated polymorphisms in the region. Results: We replicated the reported association between rs140068132 and breast cancer risk overall [odds ratio (OR), 0.53; 95% confidence interval (CI), 0.47–0.59], as well as the lower odds of developing hormone receptor negative (HR−) versus HR+ disease (OR, 0.77; 95% CI, 0.61–0.97). Models, including HER2, showed further heterogeneity with reduced odds for HR+HER2+ (OR, 0.68; 95% CI, 0.51–0.92), HR−HER2+ (OR, 0.63; 95% CI, 0.44–0.90) and HR−HER2− (OR, 0.77; 95% CI, 0.56–1.05) compared with HR+HER2−. Inclusion of other risk-associated variants did not change these observations. Conclusions: The rs140068132 polymorphism is associated with decreased risk of breast cancer in Peruvians and is more protective against HR− and HER2+ diseases independently of other breast cancer-associated variants in the 6q25 region. Impact: These results could inform functional analyses to understand the mechanism by which rs140068132-G reduces risk of breast cancer development in a subtype-specific manner. They also illustrate the importance of including diverse individuals in genetic studies.
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- 2022
13. Supplementary Methods from Two Distinct Routes to Oral Cancer Differing in Genome Instability and Risk for Cervical Node Metastasis
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Donna G. Albertson, Brian L. Schmidt, Daniel Pinkel, Adam B. Olshen, Richard C. K. Jordan, Henrik Bengtsson, Taku Tokuyasu, Jesse Paquette, Gregory Hamilton, Antoine M. Snijders, Ritu Roy, and Aditi Bhattacharya
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PDF file - 84K
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- 2023
14. Supplementary Figure 6 from Two Distinct Routes to Oral Cancer Differing in Genome Instability and Risk for Cervical Node Metastasis
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Donna G. Albertson, Brian L. Schmidt, Daniel Pinkel, Adam B. Olshen, Richard C. K. Jordan, Henrik Bengtsson, Taku Tokuyasu, Jesse Paquette, Gregory Hamilton, Antoine M. Snijders, Ritu Roy, and Aditi Bhattacharya
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PDF file - 1MB
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- 2023
15. Supplementary Tables 1-14 from Two Distinct Routes to Oral Cancer Differing in Genome Instability and Risk for Cervical Node Metastasis
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Donna G. Albertson, Brian L. Schmidt, Daniel Pinkel, Adam B. Olshen, Richard C. K. Jordan, Henrik Bengtsson, Taku Tokuyasu, Jesse Paquette, Gregory Hamilton, Antoine M. Snijders, Ritu Roy, and Aditi Bhattacharya
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PDF file - 1MB
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- 2023
16. Supplementary Data from Antitumor Activity of SNX-2112, a Synthetic Heat Shock Protein-90 Inhibitor, in MET-Amplified Tumor Cells with or without Resistance to Selective MET Inhibition
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Martin R. Weiser, David B. Solit, Neal Rosen, James G. Christensen, Martina Mittlboeck, Adam B. Olshen, Agnes Viale, Zhaoshi Zeng, David Liska, Chin-Tung Chen, Mark Y. Sun, and Thomas Bachleitner-Hofmann
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Supplementary Figures S1-S2; Supplementary Table S1.
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- 2023
17. Data from Two Distinct Routes to Oral Cancer Differing in Genome Instability and Risk for Cervical Node Metastasis
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Donna G. Albertson, Brian L. Schmidt, Daniel Pinkel, Adam B. Olshen, Richard C. K. Jordan, Henrik Bengtsson, Taku Tokuyasu, Jesse Paquette, Gregory Hamilton, Antoine M. Snijders, Ritu Roy, and Aditi Bhattacharya
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Purpose: Problems in management of oral cancers or precancers include identification of patients at risk for metastasis, tumor recurrence, and second primary tumors or risk for progression of precancers (dysplasia) to cancer. Thus, the objective of this study was to clarify the role of genomic aberrations in oral cancer progression and metastasis.Experimental Design: The spectrum of copy number alterations in oral dysplasia and squamous cell carcinomas (SCC) was determined by array comparative genomic hybridization. Associations with clinical characteristics were studied and results confirmed in an independent cohort.Results: The presence of one or more of the chromosomal aberrations +3q24-qter, -8pter-p23.1, +8q12-q24.2, and +20 distinguishes a major subgroup (70%–80% of lesions, termed 3q8pq20 subtype) from the remainder (20%–30% of lesions, non-3q8pq20). The 3q8pq20 subtype is associated with chromosomal instability and differential methylation in the most chromosomally unstable tumors. The two subtypes differ significantly in clinical outcome with risk for cervical (neck) lymph node metastasis almost exclusively associated with the 3q8pq20 subtype in two independent oral SCC cohorts.Conclusions: Two subtypes of oral lesions indicative of at least two pathways for oral cancer development were distinguished that differ in chromosomal instability and risk for metastasis, suggesting that +3q,–8p, +8q, and +20 constitute a biomarker with clinical utility for identifying patients at risk for metastasis. Moreover, although increased numbers of genomic alterations can be harbingers of progression to cancer, dysplastic lesions lacking copy number changes cannot be considered benign as they are potential precursors to non-3q8pq20 locally invasive, yet not metastatic oral SCC. Clin Cancer Res; 17(22); 7024–34. ©2011 AACR.
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- 2023
18. Supplementary Figures 1-5 and 7-10 from Two Distinct Routes to Oral Cancer Differing in Genome Instability and Risk for Cervical Node Metastasis
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Donna G. Albertson, Brian L. Schmidt, Daniel Pinkel, Adam B. Olshen, Richard C. K. Jordan, Henrik Bengtsson, Taku Tokuyasu, Jesse Paquette, Gregory Hamilton, Antoine M. Snijders, Ritu Roy, and Aditi Bhattacharya
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PDF file - 3.7MB
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- 2023
19. Data from Antitumor Activity of SNX-2112, a Synthetic Heat Shock Protein-90 Inhibitor, in MET-Amplified Tumor Cells with or without Resistance to Selective MET Inhibition
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Martin R. Weiser, David B. Solit, Neal Rosen, James G. Christensen, Martina Mittlboeck, Adam B. Olshen, Agnes Viale, Zhaoshi Zeng, David Liska, Chin-Tung Chen, Mark Y. Sun, and Thomas Bachleitner-Hofmann
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Purpose: Heat shock protein-90 (HSP-90), a molecular chaperone required by numerous oncogenic kinases [e.g., HER-2, epidermal growth factor receptor (EGFR), Raf-1, v-Src, and AKT] for conformational stability, has attracted wide interest as a novel target for cancer therapy. HSP-90 inhibition induces degradation of HSP-90 client proteins, leading to a combinatorial inhibition of multiple oncogenic signaling pathways with consecutive growth arrest and apoptosis. MET, a tyrosine kinase that is constitutively active in tumor cells with MET oncogene amplification, has recently been identified as another HSP-90 client.Experimental Design: The aim of our study was to assess the efficacy of SNX-2112, a synthetic HSP-90 inhibitor, in 3 different MET-amplified tumor cell lines (GTL-16, MKN-45, and EBC-1) as well as PR-GTL-16 cells, a GTL-16 subline selected for resistance to the highly selective MET kinase inhibitor PHA-665752.Results: In all cell lines, SNX-2112 led to degradation of MET, HER-2, EGFR, and AKT, as well as abrogation of Ras/Raf/MEK/MAPK and PI3K/AKT signaling, followed by complete cell cycle arrest. SNX-5542, an orally bioavailable prodrug of SNX-2112, displayed significant antitumor efficacy in vivo in nude mice bearing MET-amplified tumor xenografts. Importantly, HSP-90 inhibition maintained its antitumor efficacy in PR-GTL-16 cells both in vitro and in vivo, suggesting that HSP-90 inhibition could be a particularly valuable strategy in MET-amplified tumors that have acquired resistance to MET kinase inhibition.Conclusions: Our study provides evidence for the efficacy of HSP-90 inhibition in MET-amplified cancer cells, particularly when MET kinase inhibitor resistance has emerged. Clin Cancer Res; 17(1); 122–33. ©2011 AACR.
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- 2023
20. Supplementary Figures 1-3 from Global Gene Expression Profiling of Pleural Mesotheliomas: Overexpression of Aurora Kinases and P16/CDKN2A Deletion as Prognostic Factors and Critical Evaluation of Microarray-Based Prognostic Prediction
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Marc Ladanyi, Adam B. Olshen, Valerie Rusch, Maureen F. Zakowski, Lee Krug, Sanaa Hussain, Peter B. Illei, Kazuhiko Wakahara, Takatoshi Ohno, Shigeki Shimizu, Raja Flores, Shannon Chuai, and Fernando López-Ríos
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Supplementary Figures 1-3 from Global Gene Expression Profiling of Pleural Mesotheliomas: Overexpression of Aurora Kinases and P16/CDKN2A Deletion as Prognostic Factors and Critical Evaluation of Microarray-Based Prognostic Prediction
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- 2023
21. Data from Down-Regulation of Stem Cell Genes, Including Those in a 200-kb Gene Cluster at 12p13.31, Is Associated with In vivo Differentiation of Human Male Germ Cell Tumors
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R.S.K. Chaganti, George J. Bosl, Victor E. Reuter, Debbie Dobrzynski, Adam B. Olshen, Rajendrakumar S.V. Chadalavada, Jane Houldsworth, and James E. Korkola
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Adult male germ cell tumors (GCTs) comprise distinct groups: seminomas and nonseminomas, which include pluripotent embryonal carcinomas as well as other histologic subtypes exhibiting various stages of differentiation. Almost all GCTs show 12p gain, but the target genes have not been clearly defined. To identify 12p target genes, we examined Affymetrix (Santa Clara, CA) U133A+B microarray (∼83% coverage of 12p genes) expression profiles of 17 seminomas, 84 nonseminoma GCTs, and 5 normal testis samples. Seventy-three genes on 12p were significantly overexpressed, including GLUT3 and REA (overexpressed in all GCTs) and CCND2 and FLJ22028 (overexpressed in all GCTs, except choriocarcinomas). We characterized a 200-kb gene cluster at 12p13.31 that exhibited coordinated overexpression in embryonal carcinomas and seminomas, which included the known stem cell genes NANOG, STELLA, and GDF3 and two previously uncharacterized genes. A search for other coordinately regulated genomic clusters of stem cell genes did not reveal any genomic regions similar to that at 12p13.31. Comparison of embryonal carcinoma with seminomas revealed relative overexpression of several stem cell–associated genes in embryonal carcinoma, including several core “stemness” genes (EBAF, TDGF1, and SOX2) and several downstream targets of WNT, NODAL, and FGF signaling (FGF4, NODAL, and ZFP42). Our results indicate that 12p gain is a functionally relevant change leading to activation of proliferation and reestablishment/maintenance of stem cell function through activation of key stem cell genes. Furthermore, the differential expression of core stem cell genes may explain the differences in pluripotency between embryonal carcinomas and seminomas. (Cancer Res 2006; 66(2): 820-7)
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- 2023
22. Supplementary Tables 3A-6A from Global Gene Expression Profiling of Pleural Mesotheliomas: Overexpression of Aurora Kinases and P16/CDKN2A Deletion as Prognostic Factors and Critical Evaluation of Microarray-Based Prognostic Prediction
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Marc Ladanyi, Adam B. Olshen, Valerie Rusch, Maureen F. Zakowski, Lee Krug, Sanaa Hussain, Peter B. Illei, Kazuhiko Wakahara, Takatoshi Ohno, Shigeki Shimizu, Raja Flores, Shannon Chuai, and Fernando López-Ríos
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Supplementary Tables 3A-6A from Global Gene Expression Profiling of Pleural Mesotheliomas: Overexpression of Aurora Kinases and P16/CDKN2A Deletion as Prognostic Factors and Critical Evaluation of Microarray-Based Prognostic Prediction
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- 2023
23. Data from Global Gene Expression Profiling of Pleural Mesotheliomas: Overexpression of Aurora Kinases and P16/CDKN2A Deletion as Prognostic Factors and Critical Evaluation of Microarray-Based Prognostic Prediction
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Marc Ladanyi, Adam B. Olshen, Valerie Rusch, Maureen F. Zakowski, Lee Krug, Sanaa Hussain, Peter B. Illei, Kazuhiko Wakahara, Takatoshi Ohno, Shigeki Shimizu, Raja Flores, Shannon Chuai, and Fernando López-Ríos
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Most gene expression profiling studies of mesothelioma have been based on relatively small sample numbers, limiting their statistical power. We did Affymetrix U133A microarray analysis on 99 pleural mesotheliomas, in which multivariate analysis showed advanced-stage, sarcomatous histology and P16/CDKN2A homozygous deletion to be significant independent adverse prognostic factors. Comparison of the expression profiles of epithelioid versus sarcomatous mesotheliomas identified many genes significantly overexpressed among the former, including previously unrecognized ones, such as uroplakins and kallikrein 11, both confirmed by immunohistochemistry. Examination of the gene expression correlates of survival showed that more aggressive mesotheliomas expressed higher levels of Aurora kinases A and B and functionally related genes involved in mitosis and cell cycle control. Independent confirmation of the negative effect of Aurora kinase B was obtained by immunohistochemistry in a separate patient cohort. A role for Aurora kinases in the aggressive behavior of mesotheliomas is of potential clinical interest because of the recent development of small-molecule inhibitors. We then used our data to develop microarray-based predictors of 1 year survival; these achieved a maximal accuracy of 68% in cross-validation. However, this was inferior to prognostic prediction based on standard clinicopathologic variables and P16/CDNK2A status (accuracy, 73%), and adding the microarray model to the latter did not improve overall accuracy. Finally, we evaluated three recently published microarray-based outcome prediction models, but their accuracies ranged from 63% to 67%, consistently lower than reported. Gene expression profiling of mesotheliomas is an important discovery tool, but its power in clinical prognostication has been overestimated. (Cancer Res 2006; 66(6): 2970-9)
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- 2023
24. Supplementary Figures 1-4 from Down-Regulation of Stem Cell Genes, Including Those in a 200-kb Gene Cluster at 12p13.31, Is Associated with In vivo Differentiation of Human Male Germ Cell Tumors
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R.S.K. Chaganti, George J. Bosl, Victor E. Reuter, Debbie Dobrzynski, Adam B. Olshen, Rajendrakumar S.V. Chadalavada, Jane Houldsworth, and James E. Korkola
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Supplementary Figures 1-4 from Down-Regulation of Stem Cell Genes, Including Those in a 200-kb Gene Cluster at 12p13.31, Is Associated with In vivo Differentiation of Human Male Germ Cell Tumors
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- 2023
25. Supplementary Table 1 from Microfluidic-Based Multiplex qRT-PCR Identifies Diagnostic and Prognostic microRNA Signatures in the Sera of Prostate Cancer Patients
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Robert Blelloch, Peter Carroll, Joan F. Hilton, Jeffry Simko, Hubert Stöppler, Lawrence Fong, Andrew Peek, Lauren Baehner, Adam B. Olshen, and Felix Moltzahn
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Supplementary Table 1 from Microfluidic-Based Multiplex qRT-PCR Identifies Diagnostic and Prognostic microRNA Signatures in the Sera of Prostate Cancer Patients
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- 2023
26. Supplementary Figures 1-7 from Microfluidic-Based Multiplex qRT-PCR Identifies Diagnostic and Prognostic microRNA Signatures in the Sera of Prostate Cancer Patients
- Author
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Robert Blelloch, Peter Carroll, Joan F. Hilton, Jeffry Simko, Hubert Stöppler, Lawrence Fong, Andrew Peek, Lauren Baehner, Adam B. Olshen, and Felix Moltzahn
- Abstract
Supplementary Figures 1-7 from Microfluidic-Based Multiplex qRT-PCR Identifies Diagnostic and Prognostic microRNA Signatures in the Sera of Prostate Cancer Patients
- Published
- 2023
27. Supplementary Table 1-5 from Down-Regulation of Stem Cell Genes, Including Those in a 200-kb Gene Cluster at 12p13.31, Is Associated with In vivo Differentiation of Human Male Germ Cell Tumors
- Author
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R.S.K. Chaganti, George J. Bosl, Victor E. Reuter, Debbie Dobrzynski, Adam B. Olshen, Rajendrakumar S.V. Chadalavada, Jane Houldsworth, and James E. Korkola
- Abstract
Supplementary Table 1-5 from Down-Regulation of Stem Cell Genes, Including Those in a 200-kb Gene Cluster at 12p13.31, Is Associated with In vivo Differentiation of Human Male Germ Cell Tumors
- Published
- 2023
28. Supplementary Array Data from Global Gene Expression Profiling of Pleural Mesotheliomas: Overexpression of Aurora Kinases and P16/CDKN2A Deletion as Prognostic Factors and Critical Evaluation of Microarray-Based Prognostic Prediction
- Author
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Marc Ladanyi, Adam B. Olshen, Valerie Rusch, Maureen F. Zakowski, Lee Krug, Sanaa Hussain, Peter B. Illei, Kazuhiko Wakahara, Takatoshi Ohno, Shigeki Shimizu, Raja Flores, Shannon Chuai, and Fernando López-Ríos
- Abstract
Please paste this website into your browser to access data
- Published
- 2023
29. Exploring the genetic and epigenetic origins of juvenile myelomonocytic leukemia using newborn screening samples
- Author
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Elliot Stieglitz, Adam B. Olshen, Julia Meyer, Jahan-Yar Parsa, Adam J. de Smith, Astrid Behnert, Mignon L. Loh, and Aaron Hechmer
- Subjects
Male ,Cancer Research ,Newborn screening ,Juvenile myelomonocytic leukemia ,Gene Expression Regulation, Leukemic ,Infant, Newborn ,Hematology ,DNA Methylation ,Biology ,Prognosis ,medicine.disease ,Article ,Epigenesis, Genetic ,Neonatal Screening ,Leukemia, Myelomonocytic, Juvenile ,Oncology ,Case-Control Studies ,Mutation ,Immunology ,Biomarkers, Tumor ,medicine ,Humans ,Female ,Epigenetics ,Follow-Up Studies - Published
- 2021
30. A Transcriptional Classifier Identifies Pediatric T-Cell Acute Lymphoblastic Leukemias at High Risk for End of Induction Minimal Residual Disease
- Author
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Lauren K. Meyer, Ritu P. Roy, Petri Pölönen, Abdelrahman Elsayed, Benjamin J. Huang, Shunsuke Kimura, Cristina Delgado-Martin, Tiffaney L. Vincent, Theresa Ryan, Brent L. Wood, Zhiguo Chen, Yu Liu, Jinghui Zhang, Terzah M. Horton, Mignon L. Loh, Meenakshi Devidas, Elizabeth A. Raetz, Robert J. Hayashi, Stuart S. Winter, Kimberly P. Dunsmore, Stephen P. Hunger, Stanley B. Pounds, Michelle L. Hermiston, Jun J. Yang, Charles G. Mullighan, David T. Teachey, and Adam B. Olshen
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
31. A TARGETED GENE EXPRESSION CLASSIFIER IDENTIFIES PEDIATRIC T-ALL PATIENTS AT HIGH RISK FOR END INDUCTION MINIMAL RESIDUAL DISEASE POSITIVITY
- Author
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L. Meyer, Ritu P. Roy, B. Huang, S. Kimura, Petri Polonen, C. Delgado-Martin, T. Vincent, T. Ryan, B. Wood, Y. Liu, J. Zhang, C. Mullighan, T. Horton, M. Loh, M. Devidas, E. Raetz, R. Hayashi, S. Winter, K. Dunsmore, S. Hunger, D. Teachey, M. Hermiston, and Adam B. Olshen
- Subjects
Cancer Research ,Oncology ,Hematology - Published
- 2022
32. Prediction of evening fatigue severity in outpatients receiving chemotherapy: less may be more
- Author
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Anand Dhruva, Adam B. Olshen, Christine Miaskowski, Yvette P. Conley, Bruce A. Cooper, Kord M. Kober, Ritu Roy, and Raymond Javan Chan
- Subjects
medicine.medical_specialty ,Chemotherapy ,Evening ,business.industry ,medicine.medical_treatment ,Public Health, Environmental and Occupational Health ,Medicine (miscellaneous) ,Patient characteristics ,medicine.disease ,Article ,Behavioral Neuroscience ,medicine ,Physical therapy ,Oncology patients ,Lung cancer ,business ,Psychosocial - Abstract
Background: Fatigue is the most common and debilitating symptom experienced by oncology patients undergoing chemotherapy. Little is known about patient characteristics that predict changes in fatigue severity over time. Purpose: To predict the severity of evening fatigue in the week following the administration of chemotherapy using machine learning approaches. Methods: Outpatients with breast, gastrointestinal, gynecological, or lung cancer (N = 1217) completed questionnaires one week prior to and one week following administration of chemotherapy. Evening fatigue was measured with the Lee Fatigue Scale (LFS). Separate prediction models for evening fatigue severity were created using clinical, symptom, and psychosocial adjustment characteristics and either evening fatigue scores or individual fatigue item scores. Prediction models were created using two regression and three machine learning approaches. Results: Random forest (RF) models provided the best fit across all models. For the RF model using individual LFS item scores, two of the 13 individual LFS items (i.e. ‘worn out’, ‘exhausted’) were the strongest predictors. Conclusion: This study is the first to use machine learning techniques to predict evening fatigue severity in the week following chemotherapy from fatigue scores obtained in the week prior to chemotherapy. Our findings suggest that the language used to assess clinical fatigue in oncology patients is important and that two simple questions may be used to predict evening fatigue severity.
- Published
- 2021
33. International Consensus Definition of DNA Methylation Subgroups in Juvenile Myelomonocytic Leukemia
- Author
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Mark Hartmann, Julia Meyer, Mignon L. Loh, Peter Nöllke, Elliot Stieglitz, Manabu Wakamatsu, Daniel B. Lipka, Maximilian Schönung, Norihiro Murakami, Adam B. Olshen, Christoph Plass, Christian Flotho, Hideki Muramatsu, Yusuke Okuno, and Charlotte M. Niemeyer
- Subjects
Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Consensus ,Adolescent ,Datasets as Topic ,Kaplan-Meier Estimate ,Risk Assessment ,Article ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Child ,Juvenile myelomonocytic leukemia ,Gene Expression Regulation, Leukemic ,business.industry ,Infant, Newborn ,Infant ,Methylation ,DNA Methylation ,Prognosis ,medicine.disease ,PTPN11 ,Clinical trial ,030104 developmental biology ,Leukemia, Myelomonocytic, Juvenile ,Genetic marker ,Child, Preschool ,030220 oncology & carcinogenesis ,Cohort ,DNA methylation ,Classification methods ,CpG Islands ,Female ,business - Abstract
Purpose: Known clinical and genetic markers have limitations in predicting disease course and outcome in juvenile myelomonocytic leukemia (JMML). DNA methylation patterns in JMML have correlated with outcome across multiple studies, suggesting it as a biomarker to improve patient stratification. However, standardized approaches to classify JMML on the basis of DNA methylation patterns are lacking. We, therefore, sought to define an international consensus for DNA methylation subgroups in JMML and develop classification methods for clinical implementation. Experimental Design: Published DNA methylation data from 255 patients with JMML were used to develop and internally validate a classifier model. Accuracy across platforms (EPIC-arrays and MethylSeq) was tested using a technical validation cohort (32 patients). The suitability of both methods for single-patient classification was demonstrated using an independent cohort (47 patients). Results: Analysis of pooled, published data established three DNA methylation subgroups as a de facto standard. Unfavorable prognostic parameters (PTPN11 mutation, elevated fetal hemoglobin, and older age) were significantly enriched in the high methylation (HM) subgroup. A classifier was then developed that predicted subgroups with 98% accuracy across different technological platforms. Applying the classifier to an independent validation cohort confirmed an association of HM with secondary mutations, high relapse incidence, and inferior overall survival (OS), while the low methylation subgroup was associated with a favorable disease course. Multivariable analysis established DNA methylation subgroups as the only significant factor predicting OS. Conclusions: This study provides an international consensus definition for DNA methylation subgroups in JMML. We developed and validated methods which will facilitate the design of risk-stratified clinical trials in JMML.
- Published
- 2021
34. Assessing gene-level translational control from ribosome profiling.
- Author
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Adam B. Olshen, Andrew C. Hsieh, Craig R. Stumpf, Richard A. Olshen, Davide Ruggero, and Barry S. Taylor
- Published
- 2013
- Full Text
- View/download PDF
35. Molecular and phenotypic diversity of CBL-mutated juvenile myelomonocytic leukemia
- Author
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Mark Fluchel, Margaret L. MacMillan, Sarah K. Tasian, Elliot Stieglitz, Rukhmi Bhat, Satheesh Chonat, Jason E. Farrar, Anna Hecht, Benjamin Oshrine, Dennis John Kuo, Eric Wong, Catherine Aftandilian, Aaron Hechmer, Maria Luisa Sulis, Kelly W. Maloney, Wolf-Karsten Hofmann, Julia Meyer, Haydar Frangoul, Adam B. Olshen, Aru Narendran, Astrid Behnert, Jennifer H. Han, Mignon L. Loh, David Van Mater, Farid F. Chehab, Sung Won Choi, Kirk R. Schultz, Edward A. Kolb, and Luke Maese
- Subjects
0303 health sciences ,Myeloid ,Juvenile myelomonocytic leukemia ,business.industry ,Somatic cell ,Hematology ,Disease ,medicine.disease ,Phenotype ,Uniparental disomy ,Germline ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,business ,Gene ,030304 developmental biology - Abstract
Mutations in the CBL gene were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to patients with other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found that this disease is highly diverse in presentation and overall outcome. Moreover, we discovered somatically acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish patients with somatic CBL mutations from those with germline CBL mutations, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among patients with germline CBL mutations. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.
- Published
- 2020
36. Parent-specific copy number in paired tumor-normal studies using circular binary segmentation.
- Author
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Adam B. Olshen, Henrik Bengtsson, Pierre Neuvial, Paul T. Spellman, Richard A. Olshen, and Venkatraman E. Seshan
- Published
- 2011
- Full Text
- View/download PDF
37. Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis.
- Author
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Ronglai Shen, Adam B. Olshen, and Marc Ladanyi
- Published
- 2009
- Full Text
- View/download PDF
38. Discovering Dominant Tumor Immune Archetypes in A Pan-Cancer Census
- Author
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Alexis J. Combes, Bushra Samad, Jessica Tsui, Nayvin W. Chew, Peter Yan, Gabriella C. Reeder, Divyashree Kushnoor, Alan Shen, Brittany Davidson, Andrea J. Barczak, Michael Adkisson, Austin Edwards, Mohammad Naser, Kevin C. Barry, Tristan Courau, Taymour Hammoudi, Rafael J. Argüello, Arjun Arkal Rao, Adam B. Olshen, Cathy Cai, Jenny Zhan, Katelyn C. Davis, Robin K. Kelley, Jocelyn S. Chapman, Chloe E. Atreya, Amar Patel, Adil I. Daud, Patrick Ha, Aaron A. Diaz, Johannes R. Kratz, Eric A. Collisson, Gabriela K. Fragiadakis, David J. Erle, Alexandre Boissonnas, Saurabh Asthana, Vincent Chan, Matthew F. Krummel, Matthew Spitzer, Lawrence Fong, Amanda Nelson, Raj Kumar, Justin Lee, Arun Burra, Joy Hsu, Caroline Hackett, Karen Tolentino, Jasmine Sjarif, Peter Johnson, Evans Shao, Darrell Abrau, Leonard Lupin, Cole Shaw, Zachary Collins, Tasha Lea, Carlos Corvera, Eric Nakakura, Julia Carnevale, Michael Alvarado, Kimberley Loo, Lawrence Chen, Melissa Chow, Jennifer Grandis, Will Ryan, Ivan El-Sayed, David Jablons, Gavitt Woodard, Maxwell W. Meng, Sima P. Porten, Hideho Okada, Margaret Tempero, Andrew Ko, Kim Kirkwood, Scott Vandenberg, Denise Guevarra, Erica Oropeza, Chris Cyr, Pat Glenn, Jennifer Bolen, Amanda Morton, Walter Eckalbar, University of California [San Francisco] (UC San Francisco), University of California (UC), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Department of Epidemiology and Biostatistics, University of California, San Francisco, and University of California (UC)-University of California (UC)
- Subjects
Universities ,Computational Biology ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Censuses ,[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy ,Flow Cytometry ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cohort Studies ,Gene Expression Regulation, Neoplastic ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,Neoplasms ,Biomarkers, Tumor ,Tumor Microenvironment ,Cluster Analysis ,Humans ,San Francisco ,RNA-Seq ,Transcriptome ,ComputingMilieux_MISCELLANEOUS - Abstract
Cancers display significant heterogeneity with respect to tissue of origin, driver mutations, and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system-here "archetypes"-creating prototypical non-destructive tumor immune microenvironments (TMEs) and modulating tumor-targeting. To discover the dominant immune system archetypes, the University of California, San Francisco (UCSF) Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.
- Published
- 2021
39. COVIDNearTerm: A Simple Method to Forecast COVID-19 Hospitalizations
- Author
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Paul Wesson, Ariadna Garcia, Manisha Desai, Yingjie Weng, Kristopher Kapphahn, Adam B. Olshen, George W. Rutherford, and Mithat Gonen
- Subjects
R package ,Open source ,Autoregressive model ,Coronavirus disease 2019 (COVID-19) ,Computer science ,Statistics ,County level ,Public health policy ,Parametric statistics ,Term (time) - Abstract
1AbstractCOVID-19 has caused tremendous death and suffering since it first emerged in 2019. In response, models were developed to help predict the course of various disease metrics, and these models have been relied upon to help guide public health policy. Here we present a method called COVIDNearTerm to “forecast” hospitalizations in the short term, two to four weeks from the time of prediction. COVIDNearTerm is based on an autoregressive model and utilizes a parametric bootstrap approach to make predictions. We evaluated COVIDNearTerm on San Francisco Bay Area hospitalizations and compared it to models from the California COVID Assessment Tool (CalCAT). We found that that COVIDNearTerm pre-dictions were more accurate than the CalCAT ensemble predictions for all comparisons and any CalCAT component for a majority of comparisons. For instance, at the county level our 14-day hospitalization median absolute percentage errors ranged from 16% to 36%. For those same comparisons the CalCAT ensemble errors were between 30% and 59%. COVIDNearT-erm is also easier to use than some other methods. It requires only previous hospitalization data and there is an open source R package that implements the algorithm.
- Published
- 2021
40. A faster circular binary segmentation algorithm for the analysis of array CGH data.
- Author
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E. S. Venkatraman and Adam B. Olshen
- Published
- 2007
- Full Text
- View/download PDF
41. Development and Validation of a Gene-Based Model for Outcome Prediction in Germ Cell Tumors Using a Combined Genomic and Expression Profiling Approach.
- Author
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James E Korkola, Sandy Heck, Adam B Olshen, Darren R Feldman, Victor E Reuter, Jane Houldsworth, George J Bosl, and R S K Chaganti
- Subjects
Medicine ,Science - Abstract
Germ Cell Tumors (GCT) have a high cure rate, but we currently lack the ability to accurately identify the small subset of patients who will die from their disease. We used a combined genomic and expression profiling approach to identify genomic regions and underlying genes that are predictive of outcome in GCT patients. We performed array-based comparative genomic hybridization (CGH) on 53 non-seminomatous GCTs (NSGCTs) treated with cisplatin based chemotherapy and defined altered genomic regions using Circular Binary Segmentation. We identified 14 regions associated with two year disease-free survival (2yDFS) and 16 regions associated with five year disease-specific survival (5yDSS). From corresponding expression data, we identified 101 probe sets that showed significant changes in expression. We built several models based on these differentially expressed genes, then tested them in an independent validation set of 54 NSGCTs. These predictive models correctly classified outcome in 64-79.6% of patients in the validation set, depending on the endpoint utilized. Survival analysis demonstrated a significant separation of patients with good versus poor predicted outcome when using a combined gene set model. Multivariate analysis using clinical risk classification with the combined gene model indicated that they were independent prognostic markers. This novel set of predictive genes from altered genomic regions is almost entirely independent of our previously identified set of predictive genes for patients with NSGCTs. These genes may aid in the identification of the small subset of patients who are at high risk of poor outcome.
- Published
- 2015
- Full Text
- View/download PDF
42. Deriving quantitative conclusions from microarray expression data.
- Author
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Adam B. Olshen and Ajay N. Jain
- Published
- 2002
- Full Text
- View/download PDF
43. Caveolin-1 and Sox-2 are predictive biomarkers of cetuximab response in head and neck cancer
- Author
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Jennifer Bolen, Neil E. Bhola, Stephen B. Keysar, Umamaheswar Duvvuri, Aaron Hechmer, Danielle L. Swaney, Antonio Jimeno, Mohammad Naser, Daniel Johnson, Kelechi Nwachuku, Tian Ran Zhu, Jennifer R. Grandis, Ritu Roy, Nevan J. Krogan, Rex H. Lee, Scott R. VandenBerg, Rachel A. O'Keefe, Adam B. Olshen, Mehdi Bouhaddou, Hua Li, and Gordon B. Mills
- Subjects
Caveolin 1 ,Cetuximab ,Antineoplastic Agents ,Therapeutics ,Mice ,Rare Diseases ,Antineoplastic Agents, Immunological ,Genetics ,Biomarkers, Tumor ,Medicine ,Animals ,Humans ,Epidermal growth factor receptor ,Dental/Oral and Craniofacial Disease ,neoplasms ,EGFR inhibitors ,Cancer ,screening and diagnosis ,Tumor ,biology ,business.industry ,SOXB1 Transcription Factors ,Head and neck cancer ,Human Genome ,General Medicine ,medicine.disease ,Head and neck squamous-cell carcinoma ,digestive system diseases ,Detection ,Immunological ,Orphan Drug ,Good Health and Well Being ,Head and Neck Neoplasms ,Cancer research ,biology.protein ,Biomarker (medicine) ,business ,Biomarkers ,medicine.drug ,4.2 Evaluation of markers and technologies ,Research Article - Abstract
The epidermal growth factor receptor (EGFR) inhibitor cetuximab is the only FDA-approved oncogene-targeting therapy for head and neck squamous cell carcinoma (HNSCC). Despite variable treatment response, no biomarkers exist to stratify patients for cetuximab therapy in HNSCC. Here, we applied unbiased hierarchical clustering to reverse-phase protein array molecular profiles from patient-derived xenograft (PDX) tumors and revealed 2 PDX clusters defined by protein networks associated with EGFR inhibitor resistance. In vivo validation revealed unbiased clustering to classify PDX tumors according to cetuximab response with 88% accuracy. Next, a support vector machine classifier algorithm identified a minimalist biomarker signature consisting of 8 proteins - caveolin-1, Sox-2, AXL, STING, Brd4, claudin-7, connexin-43, and fibronectin - with expression that strongly predicted cetuximab response in PDXs using either protein or mRNA. A combination of caveolin-1 and Sox-2 protein levels was sufficient to maintain high predictive accuracy, which we validated in tumor samples from patients with HNSCC with known clinical response to cetuximab. These results support further investigation into the combined use of caveolin-1 and Sox-2 as predictive biomarkers for cetuximab response in the clinic.
- Published
- 2021
44. The role of HER2 and HER3 in HER2-amplified cancers beyond breast cancers
- Author
-
Avisek Majumder, Veronica Steri, Mark M. Moasser, Manbir Sandhu, Debarko Banerji, and Adam B. Olshen
- Subjects
Receptor, ErbB-3 ,Receptor, ErbB-2 ,Science ,Breast Neoplasms ,Biology ,Endometrium ,Article ,Cell Line ,Mice ,ErbB-2 ,Downregulation and upregulation ,Mice, Inbred NOD ,In vivo ,Cell Line, Tumor ,Neoplasms ,ErbB-3 ,Breast Cancer ,medicine ,Animals ,Humans ,Phosphorylation ,skin and connective tissue diseases ,neoplasms ,Cancer ,Neoplastic ,Tumor ,Multidisciplinary ,Stomach ,Lapatinib ,Oncogenes ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,body regions ,medicine.anatomical_structure ,Gene Expression Regulation ,Cancer cell ,Cancer research ,Medicine ,Inbred NOD ,Female ,Function (biology) ,Receptor - Abstract
HER2 and HER3 play key driving functions in the pathophysiology of HER2-amplified breast cancers, but this function is less well characterized in other cancers driven by HER2 amplification. This study aimed to explore the role of HER2 and HER3 signaling in other types of HER2-amplified cancer. The expression and signaling activity of HER2, HER3, and downstream pathway proteins were studied in cell panels representing HER2-amplified cancers of the breast, bladder, colon and rectal, stomach, esophagus, lung, tongue, and endometrium along with controls lacking HER2 amplification. We report that HER2-amplified cancers are addicted to HER2 across different cancer types and the depth of addiction is best linked with the expression level of HER2, but not with HER3 expression. We report that the expression and constitutive phosphorylation of HER3 are ubiquitous in HER2-amplified breast cancer cell lines, but much more variable in HER2-amplified cancer cells from other tissues. We observed the lapatinib-induced compensatory upregulation of HER3 signaling in many types of HER2-amplified cancers, although with much variability. We find that HER3 expression is essential for in vivo tumorigenic growth in some HER2-amplified tumors but not others. Importantly HER3 expression level does not correlate well with its functional importance. More biomarkers will be needed to guide the optimal use of HER3 inhibitors in HER2-amplified cancers from non-breast origin. Unlike oncogenes activated through mutational events, the activation of HER2 through overexpression represents a gradient of activities and depth of addiction and the response to inhibitors follows a similar gradient.
- Published
- 2021
45. Ferrous iron-activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors
- Author
-
Honglin Jiang, Ryan K. Muir, Ryan L. Gonciarz, Adam B. Olshen, Iwei Yeh, Byron C. Hann, Ning Zhao, Yung-hua Wang, Spencer C. Behr, James E. Korkola, Michael J. Evans, Eric A. Collisson, and Adam R. Renslo
- Subjects
Proto-Oncogene Proteins p21(ras) ,Cell Line, Tumor ,Iron ,Neoplasms ,Immunology ,Mutation ,Immunology and Allergy ,Animals ,Protein Kinase Inhibitors ,Signal Transduction - Abstract
KRAS mutations drive a quarter of cancer mortality, and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at the doses needed to adequately extinguish RAS/RAF/MAPK signaling in the tumor cell. We found that oncogenic KRAS signaling induced ferrous iron (Fe2+) accumulation early in and throughout mutant KRAS-mediated transformation. We converted an FDA-approved MEK inhibitor into a ferrous iron–activatable drug conjugate (FeADC) and achieved potent MAPK blockade in tumor cells while sparing normal tissues. This innovation allowed sustainable, effective treatment of tumor-bearing animals, with tumor-selective drug activation, producing superior systemic tolerability. Ferrous iron accumulation is an exploitable feature of KRAS transformation, and FeADCs hold promise for improving the treatment of KRAS-driven solid tumors.
- Published
- 2021
46. In utero and early-life exposure to thirdhand smoke causes profound changes to the immune system
- Author
-
Todd P. Whitehead, Aaron Hechmer, Priyatama Pandey, Adam J. de Smith, Mi Zhou, Antoine M. Snijders, Catherine Metayer, Briana Fitch, Jian-Hua Mao, Scott C. Kogan, Abel Po-Hao Huang, Suzaynn F. Schick, Joseph L. Wiemels, and Adam B. Olshen
- Subjects
0301 basic medicine ,thirdhand smoke ,Immunology & Inflammation ,Lymphoma ,Medical and Health Sciences ,Transgenic ,immunology ,Mice ,0302 clinical medicine ,Smoke ,2.1 Biological and endogenous factors ,Aetiology ,Research Articles ,Cancer ,Pediatric ,Leukemia ,leukemia ,General Medicine ,Hematology ,medicine.anatomical_structure ,In utero ,030220 oncology & carcinogenesis ,Toxicity ,Knockout mouse ,Pediatric Research Initiative ,Offspring ,Pediatric Cancer ,Childhood Leukemia ,Mice, Transgenic ,03 medical and health sciences ,Immune system ,Rare Diseases ,Tobacco ,medicine ,Animals ,Tobacco Smoke and Health ,business.industry ,Prevention ,Perinatal Period - Conditions Originating in Perinatal Period ,medicine.disease ,Therapeutics & Molecular Medicine ,Transplantation ,030104 developmental biology ,Cardiovascular System & Hematology ,Immune System ,Immunology ,Tobacco Smoke Pollution ,Bone marrow ,business - Abstract
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Thirdhand smoke (THS) is the residual tobacco contamination that remains after the smoke clears. We investigated the effects of THS exposure in utero and during early life in a transgenic Cdkn2a knockout mouse model that is vulnerable to the development of leukemia/lymphoma. Female mice, and their offspring, were exposed from the first day of pregnancy to weaning. Plasma cytokines, body weight and hematologic parameters were measured in the offspring. To investigate THS exposure effects on the development of leukemia/lymphoma, bone marrow (BM) was collected from control and THS-exposed mice and transplanted into BM-ablated recipient mice, which were followed for tumor development for 1 year. We found that in utero and early-life THS exposure caused significant changes in plasma cytokine concentrations and in immune cell populations; changes appeared more pronounced in male mice. Spleen (SP) and BM B-cell populations were significantly lower in THS-exposed mice. We furthermore observed that THS exposure increased the leukemia/lymphoma-free survival in BM transplantation recipient mice, potentially caused by THS-induced B-cell toxicity. A trend towards increased solid tumors in irradiated mice reconstituted with THS-exposed BM stimulates the hypothesis that the immunosuppressive effects of in utero and early-life THS exposure might contribute to carcinogenesis by lowering the host defense to other toxic exposures. Our study adds to expanding evidence that THS exposure alters the immune system and that in utero and early-life developmental periods represent vulnerable windows of susceptibility for these effects.
- Published
- 2021
47. A Pilot Study Using a Multistaged Integrated Analysis of Gene Expression and Methylation to Evaluate Mechanisms for Evening Fatigue in Women Who Received Chemotherapy for Breast Cancer
- Author
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Christine Miaskowski, Annesa Flentje, Kord M. Kober, Steven M. Paul, Adam B. Olshen, Marilyn J. Hammer, Elena Flowers, Yvette P. Conley, and Jon D. Levine
- Subjects
Adult ,Oncology ,medicine.medical_specialty ,Evening ,medicine.medical_treatment ,Gene Expression ,Antineoplastic Agents ,Breast Neoplasms ,Pilot Projects ,Context (language use) ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Gene expression ,medicine ,Humans ,Fatigue ,Aged ,030304 developmental biology ,0303 health sciences ,Chemotherapy ,Research and Theory ,business.industry ,Cancer ,Articles ,Methylation ,DNA Methylation ,Middle Aged ,medicine.disease ,Circadian Rhythm ,Phenotype ,030220 oncology & carcinogenesis ,Female ,business - Abstract
Context: Fatigue is the most common symptom associated with cancer and its treatment. Investigation of molecular mechanisms associated with fatigue may identify new therapeutic targets. Objective: The objective of this pilot study was to evaluate the relationships between gene expression and methylation status and evening fatigue severity in women with breast cancer who received chemotherapy. Methods: Latent class analysis (LCA) was used to identify evening fatigue phenotypes. In this analysis, the lowest (i.e., moderate, n = 7) and highest (i.e., very high, n = 29) fatigue-severity classes identified using LCA were analyzed via two stages. First, a total of 32,609 transcripts from whole blood were evaluated for differences in expression levels between the classes. Next, 637 methylation sites located within the putative transcription factor binding sites for those genes demonstrating differential expression were evaluated for differential methylation state between the classes. Results: A total of 89 transcripts in 75 unique genes were differentially expressed between the moderate (the lowest fatigue-severity class identified) and very high evening fatigue classes. In addition, 23 differentially methylated probes and three differentially methylated regions were found between the moderate and very high evening fatigue classes. Conclusions: Using a multistaged integrated analysis of gene expression and methylation, differential methylation was identified in the regulatory regions of genes associated with previously hypothesized mechanisms for fatigue, including inflammation, immune function, neurotransmission, circadian rhythm, skeletal muscle energy, carbohydrate metabolism, and renal function as well as core biological processes including gene transcription and the cell-cycle regulation.
- Published
- 2019
48. Targeted Genomic Profiling of Acral Melanoma
- Author
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Eric Jorgenson, Maryam M. Asgari, Boris C. Bastian, Mengshu Xu, A. Hunter Shain, Andreas von Deimling, Iwei Yeh, Jeffrey P. North, David E. Reuss, William A. Robinson, Pui-Yan Kwok, Hong Wu, Adam B. Olshen, and Ling Shen
- Subjects
Neuroblastoma RAS viral oncogene homolog ,Cancer Research ,Skin Neoplasms ,Databases, Factual ,Mutant ,0302 clinical medicine ,Models ,2.1 Biological and endogenous factors ,Medicine ,Molecular Targeted Therapy ,Aetiology ,skin and connective tissue diseases ,Melanoma ,Data Curation ,Cancer ,YAP1 ,0303 health sciences ,Tumor ,biology ,Articles ,Genomics ,Immunohistochemistry ,Oncology ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Mdm2 ,Development of treatments and therapeutic interventions ,Signal Transduction ,Oncology and Carcinogenesis ,Models, Biological ,Databases ,03 medical and health sciences ,Cyclin D1 ,Genetics ,Biomarkers, Tumor ,Humans ,Genetic Predisposition to Disease ,Oncology & Carcinogenesis ,EP300 ,neoplasms ,Factual ,Genetic Association Studies ,Neoplasm Staging ,030304 developmental biology ,business.industry ,Human Genome ,Computational Biology ,Biological ,medicine.disease ,Good Health and Well Being ,Mutation ,biology.protein ,Cancer research ,business ,Biomarkers - Abstract
Background Acral melanoma is a rare type of melanoma that affects world populations irrespective of skin color and has worse survival than other cutaneous melanomas. It has relatively few single nucleotide mutations without the UV signature of cutaneous melanomas, but instead has a genetic landscape characterized by structural rearrangements and amplifications. BRAF mutations are less common than in other cutaneous melanomas, and knowledge about alternative therapeutic targets is incomplete. Methods To identify alternative therapeutic targets, we performed targeted deep-sequencing on 122 acral melanomas. We confirmed the loss of the tumor suppressors p16 and NF1 by immunohistochemistry in select cases. Results In addition to BRAF (21.3%), NRAS (27.9%), and KIT (11.5%) mutations, we identified a broad array of MAPK pathway activating alterations, including fusions of BRAF (2.5%), NTRK3 (2.5%), ALK (0.8%), and PRKCA (0.8%), which can be targeted by available inhibitors. Inactivation of NF1 occurred in 18 cases (14.8%). Inactivation of the NF1 cooperating factor SPRED1 occurred in eight cases (6.6%) as an alternative mechanism of disrupting the negative regulation of RAS. Amplifications recurrently affected narrow loci containing PAK1 and GAB2 (n = 27, 22.1%), CDK4 (n = 27, 22.1%), CCND1 (n = 24, 19.7%), EP300 (n = 20, 16.4%), YAP1 (n = 15, 12.3%), MDM2 (n = 13, 10.7%), and TERT (n = 13, 10.7%) providing additional and possibly complementary therapeutic targets. Acral melanomas with BRAFV600E mutations harbored fewer genomic amplifications and were more common in patients with European ancestry. Conclusion Our findings support a new, molecularly based subclassification of acral melanoma with potential therapeutic implications: BRAFV600E mutant acral melanomas with characteristics similar to nonacral melanomas that could benefit from BRAF inhibitor therapy, and non-BRAFV600E mutant acral melanomas. Acral melanomas without BRAFV600E mutations harbor a broad array of therapeutically relevant alterations. Expanded molecular profiling would increase the detection of potentially targetable alterations for this subtype of acral melanoma.
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- 2019
49. Magnetic resonance spectroscopy (MRS) can identify painful lumbar discs and may facilitate improved clinical outcomes of lumbar surgeries for discogenic pain
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Matthew G. Gornet, Adam B. Olshen, Anne G. Copay, Robert K. Eastlack, Ryan Benz, Jeffrey C. Lotz, John P. Claude, James C. Peacock, and Francine W. Schranck
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Adult ,Male ,Provocative discography ,medicine.medical_specialty ,Discogenic pain ,Magnetic Resonance Spectroscopy ,Intervertebral Disc Degeneration ,Sensitivity and Specificity ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Lumbar ,Lumbar surgery ,medicine ,Humans ,Orthopedics and Sports Medicine ,Intervertebral Disc ,Myelography ,Adjacent level ,Aged ,030222 orthopedics ,Lumbar Vertebrae ,business.industry ,Middle Aged ,Magnetic Resonance Imaging ,Low back pain ,Chronic low back pain ,Treatment Outcome ,nervous system ,Female ,Proteoglycans ,Surgery ,Neurosurgery ,Radiology ,medicine.symptom ,business ,Low Back Pain ,Biomarkers ,030217 neurology & neurosurgery - Abstract
The goal of this study was to refine clinical MRS to optimize performance and then determine whether MRS-derived biomarkers reliably identify painful discs, quantify degeneration severity, and forecast surgical outcomes for chronic low back pain (CLBP) patients. We performed an observational diagnostic development and accuracy study. Six hundred and twenty-three (623) discs in 139 patients were scanned using MRS, with 275 discs also receiving provocative discography (PD). MRS data were used to quantify spectral features related to disc structure (collagen and proteoglycan) and acidity (lactate, alanine, propionate). Ratios of acidity to structure were used to calculate pain potential. MRS-SCOREs were compared to PD and Pfirrmann grade. Clinical utility was judged by evaluating surgical success for 75 of the subjects who underwent lumbar surgery. Two hundred and six (206) discs had both a successful MRS and independent pain diagnosis. When comparing to PD, MRS had a total accuracy of 85%, sensitivity of 82%, and specificity of 88%. These increased to 93%, 91%, and 93% respectively, in non-herniated discs. The MRS structure measures differed significantly between Pfirrmann grades, except grade I versus grade II. When all MRS positive discs were treated, surgical success was 97% versus 57% when the treated level was MRS negative, or 54% when the non-treated adjacent level was MRS positive. MRS correlates with PD and may support improved surgical outcomes for CLBP patients. Noninvasive MRS is a potentially valuable approach to clarifying pain mechanisms and designing CLBP therapies that are customized to the patient. These slides can be retrieved under Electronic Supplementary Material.
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- 2019
50. Changes in abundance of oral microbiota associated with oral cancer.
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Brian L Schmidt, Justin Kuczynski, Aditi Bhattacharya, Bing Huey, Patricia M Corby, Erica L S Queiroz, Kira Nightingale, A Ross Kerr, Mark D DeLacure, Ratna Veeramachaneni, Adam B Olshen, Donna G Albertson, and Muy-Teck Teh
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Medicine ,Science - Abstract
Individual bacteria and shifts in the composition of the microbiome have been associated with human diseases including cancer. To investigate changes in the microbiome associated with oral cancers, we profiled cancers and anatomically matched contralateral normal tissue from the same patient by sequencing 16S rDNA hypervariable region amplicons. In cancer samples from both a discovery and a subsequent confirmation cohort, abundance of Firmicutes (especially Streptococcus) and Actinobacteria (especially Rothia) was significantly decreased relative to contralateral normal samples from the same patient. Significant decreases in abundance of these phyla were observed for pre-cancers, but not when comparing samples from contralateral sites (tongue and floor of mouth) from healthy individuals. Weighted UniFrac principal coordinates analysis based on 12 taxa separated most cancers from other samples with greatest separation of node positive cases. These studies begin to develop a framework for exploiting the oral microbiome for monitoring oral cancer development, progression and recurrence.
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- 2014
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