Publications by authors named "Adam Tracy"

22 Publications

  • Page 1 of 1

Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma.

Nat Med 2019 12 2;25(12):1916-1927. Epub 2019 Dec 2.

Dana-Farber Cancer Institute, Boston, MA, USA.

Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.
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http://dx.doi.org/10.1038/s41591-019-0654-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898788PMC
December 2019

Integrative Molecular Characterization of Resistance to Neoadjuvant Chemoradiation in Rectal Cancer.

Clin Cancer Res 2019 09 28;25(18):5561-5571. Epub 2019 Jun 28.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

Purpose: Molecular properties associated with complete response or acquired resistance to concurrent chemotherapy and radiotherapy (CRT) are incompletely characterized. We performed integrated whole-exome/transcriptome sequencing and immune infiltrate analysis on rectal adenocarcinoma tumors prior to neoadjuvant CRT (pre-CRT) and at time of resection (post-CRT) in 17 patients [8 complete/partial responders, 9 nonresponders (NR)].

Results: CRT was not associated with increased tumor mutational burden or neoantigen load and did not alter the distribution of established somatic tumor mutations in rectal cancer. Concurrent / mutations (KP) associated with NR tumors and were enriched for an epithelial-mesenchymal transition transcriptional program. Furthermore, NR was associated with reduced CD4/CD8 T-cell infiltrates and a post-CRT M2 macrophage phenotype. Absence of any local tumor recurrences, KP/NR status predicted worse progression-free survival, suggesting that local immune escape during or after CRT with specific genomic features contributes to distant progression.

Conclusions: Overall, while CRT did not impact genomic profiles, CRT impacted the tumor immune microenvironment, particularly in resistant cases.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744983PMC
September 2019

Genomic Evolutionary Patterns of Leiomyosarcoma and Liposarcoma.

Clin Cancer Res 2019 08 4;25(16):5135-5142. Epub 2019 Jun 4.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Leiomyosarcoma and liposarcoma are common subtypes of soft tissue sarcoma (STS). Patients with metastatic leiomyosarcoma or dedifferentiated liposarcoma (DDLPS) typically have worse outcomes compared with localized leiomyosarcoma or well-differentiated liposarcoma (WDLPS). A better understanding of genetic changes between primary/metastatic leiomyosarcoma and between WDLPS/DDLPS may provide insight into their genetic evolution.

Experimental Design: We interrogated whole-exome sequencing (WES) from "trios" of normal tissue, primary tumor, and metastatic tumor from individual patients with leiomyosarcoma ( = 9), and trios of normal tissue, well-differentiated tumor, and dedifferentiated tumor from individual patients with liposarcoma ( = 19). Specifically, we performed mutational, copy number, and tumor evolution analyses on these cohorts and compared patterns among leiomyosarcoma and liposarcoma trios.

Results: Leiomyosarcoma cases harbored shared drivers through a typical parent/child relationship where the metastatic tumor was derived from the primary tumor. In contrast, while all liposarcoma cases shared the characteristic focal chromosome 12 amplicon, most paired liposarcoma cases did not share additional mutations, suggesting a divergent evolutionary pattern from a common precursor. No highly recurrent genomic alterations from WES were identified that could be implicated as driving the progression of disease in either sarcoma subtype.

Conclusions: From a genomic perspective, leiomyosarcoma metastases contain genetic alterations that are also found in primary tumors. WDLPS and DDLPS, however, appear to divergently evolve from a common precursor harboring 12q amplification, rather than as a transformation to a higher-grade tumor. Further efforts to identify specific drivers of these distinct evolutionary patterns may inform future translational and clinical research in STS.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341441PMC
August 2019

Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma.

Nat Commun 2019 06 3;10(1):2400. Epub 2019 Jun 3.

Department of Pathology, Brigham and Women's Hospital, Boston, USA.

BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi's response and resistance. Cells that acquire drug tolerance exhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they do not terminally differentiate, maintain expression of CCND2, and continue to cycle through S-phase. Moreover, CDK4/CDK6 inhibition delays acquisition of resistance. Therefore, our data provide insights about the mechanisms underlying BETi effects and the appearance of resistance and support the therapeutic use of combined cell-cycle inhibitors with BETi in MYC-amplified medulloblastoma.
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http://dx.doi.org/10.1038/s41467-019-10307-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546744PMC
June 2019

Renal medullary carcinomas depend upon loss and are sensitive to proteasome inhibition.

Elife 2019 03 12;8. Epub 2019 Mar 12.

Broad Institute of Harvard and MIT, Cambridge, United States.

Renal medullary carcinoma (RMC) is a rare and deadly kidney cancer in patients of African descent with sickle cell trait. We have developed faithful patient-derived RMC models and using whole-genome sequencing, we identified loss-of-function intronic fusion events in one allele with concurrent loss of the other allele. Biochemical and functional characterization of these models revealed that RMC requires the loss of for survival. Through integration of RNAi and CRISPR-Cas9 loss-of-function genetic screens and a small-molecule screen, we found that the ubiquitin-proteasome system (UPS) was essential in RMC. Inhibition of the UPS caused a G2/M arrest due to constitutive accumulation of cyclin B1. These observations extend across cancers that harbor loss, which also require expression of the E2 ubiquitin-conjugating enzyme, . Our studies identify a synthetic lethal relationship between -deficient cancers and reliance on the UPS which provides the foundation for a mechanism-informed clinical trial with proteasome inhibitors.
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http://dx.doi.org/10.7554/eLife.44161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436895PMC
March 2019

Randomized trial of 10 days of decitabine ± bortezomib in untreated older patients with AML: CALGB 11002 (Alliance).

Blood Adv 2018 12;2(24):3608-3617

University of Chicago Comprehensive Cancer Center, Chicago, IL.

Novel treatment strategies are needed for older patients with acute myeloid leukemia (AML). This randomized phase 2 trial compared the efficacy and safety of 20 mg/m of IV decitabine on days 1 to 10 alone (arm A) with those of 1.3 mg/m of subcutaneous bortezomib (arm B) on days 1, 4, 8, and 11 for up to 4 10-day cycles followed by monthly 5-day cycles. Previously untreated AML patients age ≥60 years (excluding those with mutations and favorable-risk cytogenetics) without restrictions in performance status (PS) or organ function were eligible. Median age was 72.4 years (range, 60.5-92.3 years); 31 patients (19%) had baseline PS ≥2, 35 (22%) had an antecedent hematological disorder, 58 had (39%) adverse cytogenetics, and 7 (5%) and 23 (14%) had abnormal cardiac or renal function. There were no statistically significant differences in overall survival (OS) or responses between the 2 treatment arms. The overall response rate (complete remission + complete remission with incomplete blood count recovery) was 39% (n = 64), with median OS of 9.3 months. Nineteen responders (31%) underwent allogeneic stem cell transplantation. The most common adverse event was febrile neutropenia, and there were no unexpected toxicities. Adding bortezomib to decitabine did not improve outcomes, but responses were better than those in previous trials using 5-day decitabine cycles. This trial was registered at www.clinicaltrials.gov as #NCT01420926.
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http://dx.doi.org/10.1182/bloodadvances.2018023689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306886PMC
December 2018

Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors.

Nat Genet 2018 09 27;50(9):1271-1281. Epub 2018 Aug 27.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Tumor mutational burden correlates with response to immune checkpoint blockade in multiple solid tumors, although in microsatellite-stable tumors this association is of uncertain clinical utility. Here we uniformly analyzed whole-exome sequencing (WES) of 249 tumors and matched normal tissue from patients with clinically annotated outcomes to immune checkpoint therapy, including radiographic response, across multiple cancer types to examine additional tumor genomic features that contribute to selective response. Our analyses identified genomic correlates of response beyond mutational burden, including somatic events in individual driver genes, certain global mutational signatures, and specific HLA-restricted neoantigens. However, these features were often interrelated, highlighting the complexity of identifying genetic driver events that generate an immunoresponsive tumor environment. This study lays a path forward in analyzing large clinical cohorts in an integrated and multifaceted manner to enhance the ability to discover clinically meaningful predictive features of response to immune checkpoint blockade.
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http://dx.doi.org/10.1038/s41588-018-0200-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119118PMC
September 2018

Author Correction: Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.

Nat Med 2018 Aug;24(8):1290-1291

Mayo Clinic, Rochester, MN, USA.

In the version of this article originally published, an asterisk was omitted from Fig. 1a. The asterisk has been added to the figure. Additionally, a "NOTCH2" label was erroneously included in Fig. 4a. The label has been removed. The errors have been corrected in the PDF and HTML versions of this article.
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http://dx.doi.org/10.1038/s41591-018-0097-4DOI Listing
August 2018

Publisher Correction: Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.

Nat Med 2018 Aug;24(8):1292

Mayo Clinic, Rochester, MN, USA.

In the version of this article originally published, some text above the "Tri-nucleotide sequence motifs" label in Fig. 2a appeared incorrectly. The text was garbled and should have appeared as nucleotide codes.Additionally, the labels on the bars in Fig. 2c were not italicized in the original publication. These are gene symbols, and they should have been italicized.The colored labels above the graphs in Fig. 4b were also erroneously not italicized. These labels represent gene names and loci, and they should have been italicized.
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http://dx.doi.org/10.1038/s41591-018-0098-3DOI Listing
August 2018

Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.

Nat Med 2018 05 30;24(5):679-690. Epub 2018 Apr 30.

Mayo Clinic, Rochester, MN, USA.

Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.
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http://dx.doi.org/10.1038/s41591-018-0016-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613387PMC
May 2018

Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma.

Science 2018 Feb 4;359(6377):801-806. Epub 2018 Jan 4.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the gene ( = 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-1 or PD-L1 (PD-1 ligand) blockade therapy alone or in combination with anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) therapies ( = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and -deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase-signal transducers and activators of transcription), hypoxia, and immune signaling pathways. loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.
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http://dx.doi.org/10.1126/science.aan5951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035749PMC
February 2018

Recurrent and functional regulatory mutations in breast cancer.

Nature 2017 07 28;547(7661):55-60. Epub 2017 Jun 28.

Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts 02129, USA.

Genomic analysis of tumours has led to the identification of hundreds of cancer genes on the basis of the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here we perform deep sequencing in 360 primary breast cancers and develop computational methods to identify significantly mutated promoters. Clear signals are found in the promoters of three genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbours a mutational hotspot in its promoter leading to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that affect protein binding to their promoters and alter expression levels. Our study shows that promoter regions harbour recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions. Power analyses indicate that more such regions remain to be discovered through deep sequencing of adequately sized cohorts of patients.
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http://dx.doi.org/10.1038/nature22992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563978PMC
July 2017

MiR-449a Affects Epithelial Proliferation during the Pseudoglandular and Canalicular Phases of Avian and Mammal Lung Development.

PLoS One 2016 18;11(2):e0149425. Epub 2016 Feb 18.

Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, United States of America.

Congenital diaphragmatic hernia is associated with pulmonary hypoplasia and respiratory distress, which result in high mortality and morbidity. Although several transgenic mouse models of lung hypoplasia exist, the role of miRNAs in this phenotype is incompletely characterized. In this study, we assessed microRNA expression levels during the pseudoglandular to canalicular phase transition of normal human fetal lung development. At this critical time, when the distal respiratory portion of the airways begins to form, microarray analysis showed that the most significantly differentially expressed miRNA was miR-449a. Prediction algorithms determined that N-myc is a target of miR-449a and identified the likely miR-449a:N-myc binding sites, confirmed by luciferase assays and targeted mutagenesis. Functional ex vivo knock-down in organ cultures of murine embryonic lungs, as well as in ovo overexpression in avian embryonic lungs, suggested a role for miR-449a in distal epithelial proliferation. Finally, miR-449a expression was found to be abnormal in rare pulmonary specimens of human fetuses with Congenital Diaphragmatic Hernia in the pseudoglandular or canalicular phase. This study confirms the conserved role of miR-449a for proper pulmonary organogenesis, supporting the delicate balance between expansion of progenitor cells and their terminal differentiation, and proposes the potential involvement of this miRNA in human pulmonary hypoplasia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149425PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758652PMC
August 2016

MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism.

Nat Genet 2016 Mar 1;48(3):273-82. Epub 2016 Feb 1.

Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.
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http://dx.doi.org/10.1038/ng.3500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767685PMC
March 2016

Molecular pathogenesis of congenital diaphragmatic hernia revealed by exome sequencing, developmental data, and bioinformatics.

Proc Natl Acad Sci U S A 2014 Aug 8;111(34):12450-5. Epub 2014 Aug 8.

The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114; Department of Surgery, Harvard Medical School, Boston, MA 02115; Broad Institute, Cambridge, MA 02141;

Congenital diaphragmatic hernia (CDH) is a common and severe birth defect. Despite its clinical significance, the genetic and developmental pathways underlying this disorder are incompletely understood. In this study, we report a catalog of variants detected by a whole exome sequencing study on 275 individuals with CDH. Predicted pathogenic variants in genes previously identified in either humans or mice with diaphragm defects are enriched in our CDH cohort compared with 120 size-matched random gene sets. This enrichment was absent in control populations. Variants in these critical genes can be found in up to 30.9% of individuals with CDH. In addition, we filtered variants by using genes derived from regions of recurrent copy number variations in CDH, expression profiles of the developing diaphragm, protein interaction networks expanded from the known CDH-causing genes, and prioritized genes with ultrarare and highly disruptive variants, in 11.3% of CDH patients. These strategies have identified several high priority genes and developmental pathways that likely contribute to the CDH phenotype. These data are valuable for comparison of candidate genes generated from whole exome sequencing of other CDH cohorts or multiplex kindreds and provide ideal candidates for further functional studies. Furthermore, we propose that these genes and pathways will enhance our understanding of the heterogeneous molecular etiology of CDH.
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http://dx.doi.org/10.1073/pnas.1412509111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151769PMC
August 2014

SUPERACID-PROMOTED HYDROXYALKYLATION OF 1,2-INDANDIONES.

Synth Commun 2013 ;43(16):2171-2177

Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115.

1,2-Indandione reacts efficiently with arenes to give 2,2-diaryl-1-indanones by the hydroxyalkylation reaction. The Brønsted superacid CFSOH (triflic acid) is an effective catalyst for these condensation reactions. The requisite 1,2-indandiones were prepared from the 1-indanones.
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http://dx.doi.org/10.1080/00397911.2012.693239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797623PMC
January 2013

Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks.

Am J Med Genet A 2012 Dec 19;158A(12):3148-58. Epub 2012 Nov 19.

Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

Chromosome 8p23.1 is a common hotspot associated with major congenital malformations, including congenital diaphragmatic hernia (CDH) and cardiac defects. We present findings from high-resolution arrays in patients who carry a loss (n = 18) or a gain (n = 1) of sub-band 8p23.1. We confirm a region involved in both diaphragmatic and heart malformations. Results from a novel CNVConnect algorithm, prioritizing protein-protein interactions between products of genes in the 8p23.1 hotspot and products of previously known CDH causing genes, implicated GATA4, NEIL2, and SOX7 in diaphragmatic defects. Sequence analysis of these genes in 226 chromosomally normal CDH patients, as well as in a small number of deletion 8p23.1 patients, showed rare unreported variants in the coding region; these may be contributing to the diaphragmatic phenotype. We also demonstrated that two of these three genes were expressed in the E11.5-12.5 primordial mouse diaphragm, the developmental stage at which CDH is thought to occur. This combination of bioinformatics and expression studies can be applied to other chromosomal hotspots, as well as private microdeletions or microduplications, to identify causative genes and their interaction networks.
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http://dx.doi.org/10.1002/ajmg.a.35665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761361PMC
December 2012

Utilization of the hydroxyalkylation reaction to prepare bis(benzocrown ethers).

Tetrahedron Lett 2012 Apr 2;53(14):1701-1704. Epub 2012 Feb 2.

Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115.

The hydroxyalkylation reaction has been used to condense benzocrown ethers with various aldehydes and ketones. The condensation reactions are catalyzed by triflic or sulfuric acid. The products from the reactions are bis(benzocrown ethers) and they are formed in good yields (42-98%, 13 examples).
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http://dx.doi.org/10.1016/j.tetlet.2012.01.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383084PMC
April 2012

Congenital diaphragmatic hernia candidate genes derived from embryonic transcriptomes.

Proc Natl Acad Sci U S A 2012 Feb 6;109(8):2978-83. Epub 2012 Feb 6.

Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114, USA.

Congenital diaphragmatic hernia (CDH) is a common (1 in 3,000 live births) major congenital malformation that results in significant morbidity and mortality. The discovery of CDH loci using standard genetic approaches has been hindered by its genetic heterogeneity. We hypothesized that gene expression profiling of developing embryonic diaphragms would help identify genes likely to be associated with diaphragm defects. We generated a time series of whole-transcriptome expression profiles from laser captured embryonic mouse diaphragms at embryonic day (E)11.5 and E12.5 when experimental perturbations lead to CDH phenotypes, and E16.5 when the diaphragm is fully formed. Gene sets defining biologically relevant pathways and temporal expression trends were identified by using a series of bioinformatic algorithms. These developmental sets were then compared with a manually curated list of genes previously shown to cause diaphragm defects in humans and in mouse models. Our integrative filtering strategy identified 27 candidates for CDH. We examined the diaphragms of knockout mice for one of the candidate genes, pre-B-cell leukemia transcription factor 1 (Pbx1), and identified a range of previously undetected diaphragmatic defects. Our study demonstrates the utility of genetic characterization of normal development as an integral part of a disease gene identification and prioritization strategy for CDH, an approach that can be extended to other diseases and developmental anomalies.
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http://dx.doi.org/10.1073/pnas.1121621109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286948PMC
February 2012

Protolytic defluorination of trifluoromethyl-substituted arenes.

Org Biomol Chem 2011 Jun 6;9(12):4545-9. Epub 2011 May 6.

Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, Illinois 60115, USA.

A series of trifluoromethyl-substituted arenes were studied in their reactions with Brønsted superacids. The products from these reactions suggest the formation of reactive electrophiles, such as carbocations, acylium cations or equivalent electrophilic species. As such, Friedel-Crafts-type reactions occur between these species and arene nucleophiles. NMR studies were done, and the results suggest the formation of an acyl group from the trifluoromethyl groups in the superacid.
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http://dx.doi.org/10.1039/c0ob01276aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168975PMC
June 2011

NetAffx Gene Ontology Mining Tool: a visual approach for microarray data analysis.

Bioinformatics 2004 Jun 12;20(9):1462-3. Epub 2004 Feb 12.

Affymetrix Corporation, Bioinformatics, 6550 Vallejo Street, Suite 100, Emeryville, CA 94608, USA.

Summary: The NetAffx Gene Ontology (GO) Mining Tool is a web-based, interactive tool that permits traversal of the GO graph in the context of microarray data. It accepts a list of Affymetrix probe sets and renders a GO graph as a heat map colored according to significance measurements. The rendered graph is interactive, with nodes linked to public web sites and to lists of the relevant probe sets. The GO Mining Tool provides visualization combining biological annotation with expression data, encompassing thousands of genes in one interactive view.

Availability: GO Mining Tool is freely available at http://www.affymetrix.com/analysis/query/go_analysis.affx
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http://dx.doi.org/10.1093/bioinformatics/bth087DOI Listing
June 2004
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