Publications by authors named "David Tuck"

56 Publications

Real-World Outcomes for Patients Treated With Immune Checkpoint Inhibitors in the Veterans Affairs System.

JCO Clin Cancer Inform 2020 10;4:918-928

VA Boston Healthcare System, Boston, MA.

Purpose: Increasingly broad patient groups are being treated with immune checkpoint inhibitors (ICIs) in clinical practice, but few studies have assessed their usage and outcomes in large, comprehensive real-world cohorts. We identified patients who received ICIs in the Veterans Affairs (VA) health care system and described patient characteristics and survival outcomes across multiple indications.

Methods: We conducted a retrospective analysis using electronic health record data from VA facilities nationwide. Overall survival (OS) from time of ICI initiation for key indications was estimated by Kaplan-Meier. We also stratified OS by frailty status, as defined by a surrogate index developed in VA data. For select indications, we further compared outcomes to historic and concurrent control patients treated with standard-of-care regimens at the VA.

Results: We identified 11,888 patients who were treated with ICIs and determined the cancer type and indication for which they were treated. The cohort is enriched for patient groups that are under-represented in pivotal clinical trials (PCTs), including older, non-White, and/or higher disease burdened patients. Generally, OS observed in the VA cohort is lower than that reported in PCTs. After stratifying VA patients by frailty status, OS among nonfrail patients is more similar to OS reported in PCTs for some indications. Compared with internal VA control cohorts, patients treated with ICIs generally exhibited longer OS for all indications considered.

Conclusion: This study describes ICI outcomes across multiple tumor types in a real-world population at the VA. For most indications, real-world survival outcomes are observed to be lower than those reported in PCTs, but patients receiving ICIs still achieve longer survival relative to patients receiving standard of care.
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http://dx.doi.org/10.1200/CCI.20.00084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608595PMC
October 2020

Prevalence and outcome of COVID-19 infection in cancer patients: a national Veterans Affairs study.

J Natl Cancer Inst 2020 Oct 8. Epub 2020 Oct 8.

VA Boston Healthcare System, Boston, MA.

Background: Emerging data suggest variability in susceptibility and outcome to COVID-19 infection. Identifying risk-factors associated with infection and outcomes in cancer patients is necessary to develop healthcare recommendations.

Methods: We analyzed electronic health records of the US Veterans Affairs healthcare system and assessed the prevalence of COVID-19 infection in cancer patients. We evaluated the proportion of cancer patients tested for COVID-19 who were positive, as well as outcome attributable to COVID-19, and stratified by clinical characteristics including demographics, comorbidities, cancer treatment and cancer type. All statistical tests are two-sided.

Results: Of 22914 cancer patients tested for COVID-19, 1794 (7.8%) were positive. The prevalence of COVID-19 was similar across age. Higher prevalence was observed in African-American (AA) (15.0%) compared to White (5.5%; P<.001) and in patients with hematologic malignancy compared to those with solid tumors (10.9% vs 7.8%; P<.001). Conversely, prevalence was lower in current smokers and patients who recently received cancer therapy (<6 months). The COVID-19 attributable mortality was 10.9%. Higher attributable mortality rates were observed in older patients, those with higher Charlson comorbidity score, and in certain cancer types. Recent (<6 months) or past treatment did not influence attributable mortality. Importantly, AA patients had 3.5-fold higher COVID-19 attributable hospitalization, however had similar attributable mortality as White patients.

Conclusion: Pre-existence of cancer affects both susceptibility to COVID-19 infection and eventual outcome. The overall COVID-19 attributable mortality in cancer patients is affected by age, comorbidity and specific cancer types, however, race or recent treatment including immunotherapy does not impact outcome.
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http://dx.doi.org/10.1093/jnci/djaa159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665587PMC
October 2020

External validation of a prognostic model for mortality among patients with non-small-cell lung cancer using the Veterans Precision Oncology Data Commons.

Semin Oncol 2019 Aug - Oct;46(4-5):327-333. Epub 2019 Oct 30.

VA Boston Healthcare System, Boston, MA; Harvard Medical School, Boston, MA; Dana-Farber Cancer Institute, Boston, MA. Electronic address:

Background: There is wide interest in developing prognostic models in non-small-cell lung cancer (NSCLC) due to the heterogeneity of the disease. Models developed at other healthcare institutions may not be directly applicable for patients treated at the Department of Veterans Affairs (VA). External validation of a candidate prognostic model among VA patients would be crucial before it can be implemented to aid clinical decision-making.

Methods: A prognostic model for mortality developed in the Military Health System (MHS) was applied to data from the VA Precision Oncology Data Repository (VA-PODR), which is available to researchers inside and outside the VA at the Veterans Precision Oncology Data Commons (VPODC). Measures of discrimination and calibration were calculated for the MHS model. The MHS model was also refitted in VA-PODR data using the same risk factors to compare the effect of specific factors and predictive performance when the model is developed using VA data.

Results: Time-dependent AUC of the MHS prognostic model was 0.788, 0.806, 0.780, and 0.779 for predicting survival at 1, 2, 3, and 5 years following diagnosis, respectively. Significant discrepancies were found between predicted and observed rates of survival, particularly for later years. When the model is refit in VA-PODR data, it achieved cross-validated AUCs of 0.739, 0.773, 0.769, and 0.807 at the same time points, and discrepancies between predicted and observed survival were reduced.

Conclusions: Validation of the MHS prognostic model in VA-PODR demonstrates that its discrimination remains strong when applied to VA patients. Nevertheless, further calibration to VA data may be needed to improve its risk estimation performance. This study highlights the utility of VA-PODR and the VPODC as a national resource for developing analytic tools that are well adapted to the Veteran population.
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http://dx.doi.org/10.1053/j.seminoncol.2019.09.006DOI Listing
January 2020

The Veterans Precision Oncology Data Commons: Transforming VA data into a national resource for research in precision oncology.

Semin Oncol 2019 Aug - Oct;46(4-5):314-320. Epub 2019 Oct 2.

VA Boston Healthcare System, Boston University School of Medicine, Boston, Massachusetts.

The Department of Veterans Affairs (VA) has a strong track record providing high-quality, evidence-based care to cancer patients. In order to accelerate discoveries that will further improve care for Veterans with cancer, the VA has partnered with the Center for Translational Data Science at the University of Chicago and the Open Commons Consortium to establish a data sharing platform, the Veterans Precision Oncology Data Commons (VPODC). The VPODC makes clinical, genomic, and imaging data from the VA available to the research community at large. In this paper, we detail our motivation for data sharing, describe the VPODC, and outline our collaboration model. By transforming VA data into a national resource for research in precision oncology, the VPODC seeks to foster innovation through collaboration and resource sharing that will ultimately lead to improved care for Veterans with cancer.
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http://dx.doi.org/10.1053/j.seminoncol.2019.09.002DOI Listing
January 2020

CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase I trial.

Haematologica 2017 11 31;102(11):1923-1930. Epub 2017 Aug 31.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

CUDC-907 is a first-in-class, oral small molecule inhibitor of both HDAC (class I and II) and PI3K (class Iα, β, and δ) enzymes, with demonstrated anti-tumor activity in multiple pre-clinical models, including MYC-driven ones. In this report, we present the safety and preliminary activity results of CUDC-907, with and without rituximab, in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), with a particular focus on those with MYC-altered disease. Thirty-seven DLBCL patients were enrolled, 14 with confirmed MYC-altered disease. Twenty-five patients received monotherapy treatment, and 12 received the combination of CUDC-907 with rituximab. CUDC-907 monotherapy and combination demonstrated similar safety profiles consisting primarily of Grade 1/2 hematologic and gastrointestinal events. The most frequently reported Grade ≥3 treatment-related events were thrombocytopenia, neutropenia, diarrhea, fatigue, and anemia. Eleven responses (5 complete responses and 6 partial responses) were reported, for a response rate of 37% (11 out of 30) in evaluable patients [30% (11 out of 37) including all patients]. The objective response rate in evaluable MYC-altered DLBCL patients was 64% (7 out of 11; 4 complete responses and 3 partial responses), while it was 29% (2 out of 7) in MYC unaltered, and 17% (2 out of 12) in those with unknown MYC status. Median duration of response was 11.2 months overall; 13.6 months in MYC-altered patients, 6.0 months in MYC unaltered, and 7.8 months in those with MYC status unknown. The tolerable safety profile and encouraging evidence of durable anti-tumor activity, particularly in MYC-altered patients, support the continued development of CUDC-907 in these populations of high unmet need. ().
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http://dx.doi.org/10.3324/haematol.2017.172882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664396PMC
November 2017

New Cancer Immunotherapy Agents in Development: a report from an associated program of the 31Annual Meeting of the Society for Immunotherapy of Cancer, 2016.

J Immunother Cancer 2017 20;5:50. Epub 2017 Jun 20.

Genentech/Roche, 1 DNA Way, South San Francisco, CA 94080 USA.

This report is a summary of 'New Cancer Immunotherapy Agents in Development' program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre-clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy.
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http://dx.doi.org/10.1186/s40425-017-0253-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477277PMC
April 2018

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers.

Mol Cancer Ther 2017 02 15;16(2):285-299. Epub 2016 Dec 15.

Curis, Inc., Lexington, Massachusetts.

Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDAC) and phosphoinositide 3-kinases (PI3K), can reduce MYC protein levels and suppress the growth of MYC-driven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear. In this study, we demonstrated that HDAC and PI3K inhibition synergistically downregulates MYC protein levels and induces apoptosis in "double-hit" (DH) diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, CUDC-907, a small-molecule dual-acting inhibitor of both class I and II HDACs and class I PI3Ks, effectively suppresses the growth and survival of MYC-altered or MYC-dependent cancer cells, such as DH DLBCL and BRD-NUT fusion-positive NUT midline carcinoma (NMC) cells, and MYC protein downregulation is an early event induced by CUDC-907 treatment. Consistently, the antitumor activity of CUDC-907 against multiple MYC-driven cancer types was also demonstrated in animal models, including DLBCL and NMC xenograft models, Myc transgenic tumor syngeneic models, and MYC-amplified solid tumor patient-derived xenograft (PDX) models. Our findings suggest that dual function HDAC and PI3K inhibitor CUDC-907 is an effective agent targeting MYC and thus may be developed as potential therapy for MYC-dependent cancers. Mol Cancer Ther; 16(2); 285-99. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0390DOI Listing
February 2017

Estrogen Drives Cellular Transformation and Mutagenesis in Cells Expressing the Breast Cancer-Associated R438W DNA Polymerase Lambda Protein.

Mol Cancer Res 2016 11 12;14(11):1068-1077. Epub 2016 Sep 12.

Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.

Repair of DNA damage is critical for maintaining the genomic integrity of cells. DNA polymerase lambda (POLL/Pol λ) is suggested to function in base excision repair (BER) and nonhomologous end-joining (NHEJ), and is likely to play a role in damage tolerance at the replication fork. Here, using next-generation sequencing, it was discovered that the POLL rs3730477 single-nucleotide polymorphism (SNP) encoding R438W Pol λ was significantly enriched in the germlines of breast cancer patients. Expression of R438W Pol λ in human breast epithelial cells induces cellular transformation and chromosomal aberrations. The role of estrogen was assessed as it is commonly used in hormone replacement therapies and is a known breast cancer risk factor. Interestingly, the combination of estrogen treatment and the expression of the R438W Pol λ SNP drastically accelerated the rate of transformation. Estrogen exposure produces 8-oxoguanine lesions that persist in cells expressing R438W Pol λ compared with wild-type (WT) Pol λ-expressing cells. Unlike WT Pol λ, which performs error-free bypass of 8-oxoguanine lesions, expression of R438W Pol λ leads to an increase in mutagenesis and replicative stress in cells treated with estrogen. Together, these data suggest that individuals who carry the rs3730477 POLL germline variant have an increased risk of estrogen-associated breast cancer.

Implications: The Pol λ R438W mutation can serve as a biomarker to predict cancer risk and implicates that treatment with estrogen in individuals with this mutation may further increase their risk of breast cancer. Mol Cancer Res; 14(11); 1068-77. ©2016 AACR.
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http://dx.doi.org/10.1158/1541-7786.MCR-16-0209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107123PMC
November 2016

Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors.

Cancer Cell 2016 Mar;29(3):255-269

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

Using transgenic mouse models, cell line-based functional studies, and clinical specimens, we show that cyclin D1/CDK4 mediate resistance to targeted therapy for HER2-positive breast cancer. This is overcome using CDK4/6 inhibitors. Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC1 activity. This relieves feedback inhibition of upstream EGFR family kinases, resensitizing tumors to EGFR/HER2 blockade. Consequently, dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of TSC2 phosphorylation and hence mTORC1/S6K/S6RP activity. The suppression of both Rb and S6RP enhances G1 arrest and a phenotype resembling cellular senescence. In vivo, CDK4/6 inhibitors sensitize patient-derived xenograft tumors to HER2-targeted therapies and delay tumor recurrence in a transgenic model of HER2-positive breast cancer.
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http://dx.doi.org/10.1016/j.ccell.2016.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794996PMC
March 2016

Immune Signatures Following Single Dose Trastuzumab Predict Pathologic Response to PreoperativeTrastuzumab and Chemotherapy in HER2-Positive Early Breast Cancer.

Clin Cancer Res 2016 07 3;22(13):3249-59. Epub 2016 Feb 3.

Case Western Reserve University School of Medicine, Cleveland, Ohio.

Purpose: Recent data suggest that intrinsic subtype and immune cell infiltration may predict response to trastuzumab-based therapy. We studied the interaction between these factors, changes in immune signatures following brief exposure to trastuzumab, and achievement of pathologic complete response (pCR) to subsequent preoperative trastuzumab and chemotherapy in HER2-positive breast cancer.

Experimental Design: In patients enrolled on two multicenter trials (03-311 and 211B), tumor core biopsies were obtained at baseline and after brief exposure to single-agent trastuzumab or nab-paclitaxel. Gene expression profiles were assessed to assign PAM50 subtypes, measure immune cell activation, and were correlated with response.

Results: The pCR rate was significantly higher in HER2-enriched tumors in the Discovery, 03-311 (36%, P = 0.043) dataset, as compared with other subtypes, which validated in 211B (50%, P = 0.048). Significant increases in a signature of immune cell admixture (Immune Index) were observed only following brief exposure to trastuzumab in HER2-enriched tumors (Discovery/03-311, P = 0.05; Validation/211B, P = 0.02). Increased Immune Index was predictive of response after brief exposure (03-311, P = 0.03; 211B, P = 0.04), but not at baseline, in addition to increased expression of a CD4(+) follicular helper T-cell signature (03-311, P = 0.05; 211B, P = 0.04). Brief exposure to trastuzumab significantly increased gene expression of the T-cell marker PD-1 in HER2-enriched tumors (Discovery/03-311, P = 0.045) and PD-1 positivity by IHC (Validation/211B, P = 0.035).

Conclusions: Correlations between pCR rates, increases in Immune Index and markers of T-cell activity following brief exposure to trastuzumab in HER2-enriched tumors provide novel insights into the interaction between tumor biology, antitumor immunity, and response to treatment, and suggest potential clinically useful biomarkers in HER2(+) breast cancers. Clin Cancer Res; 22(13); 3249-59. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439498PMC
July 2016

Phase 1b study of the mammalian target of rapamycin inhibitor sirolimus in combination with nanoparticle albumin-bound paclitaxel in patients with advanced solid tumors.

Cancer 2015 Jun 3;121(11):1817-26. Epub 2015 Feb 3.

Department of Medical Oncology, Case Western University, Cleveland, Ohio.

Background: The optimal weekly oral dose of sirolimus and intravenous nanoparticle albumin-bound paclitaxel (nab-paclitaxel) were evaluated.

Methods: A phase 1b study was performed to evaluate escalating doses of oral sirolimus (5-60 mg) on days 2, 9, and 16 with intravenous nab-paclitaxel (100 mg/m(2) ) on days 1, 8, and 15 in a 28-day cycle. A run-in treatment of nab-paclitaxel (day -14) and sirolimus (day -7) was administered for pharmacokinetic and pharmacodynamic assessments. Clinical trial endpoints included dose-limiting toxicities (DLTs), maximum tolerated doses, and response rates. Pharmacodynamics included immunohistochemistry for phosphatase and tensin homolog, mammalian target of rapamycin (mTOR), AKT, phosphorylated AKT, S6K1, and phosphorylated S6K1; exploratory gene expression analysis; and [(18) F]fludeoxyglucose (FDG) positron emission tomography.

Results: Twenty-three patients with advanced solid tumors were treated. Fifteen patients had prior taxane therapy. Twenty-two patients were evaluable for responses. One patient had a complete response, and 5 patients had a partial response (3 confirmed). DLTs were seen in 1 patient each at 10 (grade 3 dyspnea/hypoxia) and 40 mg (grade 4 leukopenia/neutropenia) and in 2 patients at 60 mg (grade 3 fatigue and grade 4 pericardial effusion). Patients with higher expression of posttreatment AKT and a greater decline in FDG activity were more likely to have a treatment response or stable disease.

Conclusions: Sirolimus showed an acceptable safety profile at a weekly dose of 40 mg with weekly intravenous nab-paclitaxel at 100 mg/m(2) on days 1, 8, and 15 every 28 days. The posttreatment AKT score and changes in FDG activity may have roles as early predictors of responses to mTOR inhibitors.
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http://dx.doi.org/10.1002/cncr.29254DOI Listing
June 2015

Immune-priming of the tumor microenvironment by radiotherapy: rationale for combination with immunotherapy to improve anticancer efficacy.

Am J Clin Oncol 2015 Feb;38(1):90-7

*Bristol-Myers Squibb Company, Princeton, NJ †Memorial Sloan-Kettering Cancer Center, New York, NY.

A clear contribution of the immune system to eradication of tumors has been supported by recent developments in the field of immunotherapy. Durable clinical responses obtained after treatment with immunomodulatory agents such as ipilimumab (Yervoy) and anti-PD-1 antibody (BMS-936558), have established that harnessing the immune response against chemoresistant tumors can result in their complete eradication. However, only a subset of patients benefit from these therapeutic approaches. Accumulating evidence suggests that tumors with a preexisting active immune microenvironment might have a better response to immunotherapy. In a number of preclinical and clinical studies, many cytotoxic agents elicit changes within tumors and their microenvironment that may make these malignant cells more sensitive to an efficient immune cell attack. Therefore, it is plausible that combining immunotherapy with standard anticancer therapies such as chemotherapy or radiotherapy will provide synergistic antitumor effects. Despite a large collection of preclinical data, the immune mechanisms that might contribute to the efficacy of conventional cytotoxic therapies and their combinations with immunotherapeutic approaches have not yet been extensively studied in the clinical setting and warrant further investigation. This review will focus on current knowledge of the immunomodulatory effects of one such cytotoxic treatment, radiotherapy, and explore different pathways by which its combination with immunomodulatory antibodies might contribute toward more efficacious antitumor immunity.
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http://dx.doi.org/10.1097/COC.0b013e3182868ec8DOI Listing
February 2015

Extended lifespan and reduced adiposity in mice lacking the FAT10 gene.

Proc Natl Acad Sci U S A 2014 Apr 24;111(14):5313-8. Epub 2014 Mar 24.

Departments of Genetics, Pediatrics, Pathology, and Immunobiology, Yale University School of Medicine, New Haven, CT 06520.

The HLA-F adjacent transcript 10 (FAT10) is a member of the ubiquitin-like gene family that alters protein function/stability through covalent ligation. Although FAT10 is induced by inflammatory mediators and implicated in immunity, the physiological functions of FAT10 are poorly defined. We report the discovery that FAT10 regulates lifespan through pleiotropic actions on metabolism and inflammation. Median and overall lifespan are increased 20% in FAT10ko mice, coincident with elevated metabolic rate, preferential use of fat as fuel, and dramatically reduced adiposity. This phenotype is associated with metabolic reprogramming of skeletal muscle (i.e., increased AMP kinase activity, β-oxidation and -uncoupling, and decreased triglyceride content). Moreover, knockout mice have reduced circulating glucose and insulin levels and enhanced insulin sensitivity in metabolic tissues, consistent with elevated IL-10 in skeletal muscle and serum. These observations suggest novel roles of FAT10 in immune metabolic regulation that impact aging and chronic disease.
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http://dx.doi.org/10.1073/pnas.1323426111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986194PMC
April 2014

Molecular phenotypes in triple negative breast cancer from African American patients suggest targets for therapy.

PLoS One 2013 18;8(11):e71915. Epub 2013 Nov 18.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States of America ; Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany.

Triple negative breast cancer (TNBC) is characterized by high proliferation, poor differentiation and a poor prognosis due to high rates of recurrence. Despite lower overall incidence African American (AA) patients suffer from higher breast cancer mortality in part due to the higher proportion of TNBC cases among AA patients compared to European Americans (EA). It was recently shown that the clinical heterogeneity of TNBC is reflected by distinct transcriptional programs with distinct drug response profiles in preclinical models. In this study, gene expression profiling and immunohistochemistry were used to elucidate potential differences between TNBC tumors of EA and AA patients on a molecular level. In a retrospective cohort of 136 TNBC patients, a major transcriptional signature of proliferation was found to be significantly upregulated in samples of AA ethnicity. Furthermore, transcriptional profiles of AA tumors showed differential activation of insulin-like growth factor 1 (IGF1) and a signature of BRCA1 deficiency in this cohort. Using signatures derived from the meta-analysis of TNBC gene expression carried out by Lehmann et al., tumors from AA patients were more likely of basal-like subtypes whereas transcriptional features of many EA samples corresponded to mesenchymal-like or luminal androgen receptor driven subtypes. These results were validated in The Cancer Genome Atlas mRNA and protein expression data, again showing enrichment of a basal-like phenotype in AA tumors and mesenchymal subtypes in EA tumors. In addition, increased expression of VEGF-activated genes together with elevated microvessel area determined by the AQUA method suggest that AA patients exhibit higher tumor vascularization. This study confirms the existence of distinct transcriptional programs in triple negative breast cancer in two separate cohorts and that these programs differ by racial group. Differences in TNBC subtypes and levels of tumor angiogenesis in AA versus EA patients suggest that targeted therapy choices should be considered in the context of race.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071915PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832509PMC
July 2014

Translating next generation sequencing to practice: opportunities and necessary steps.

Mol Oncol 2013 Aug 15;7(4):743-55. Epub 2013 May 15.

Philips Research North America, Briarcliff Manor, NY 10510, USA.

Next-generation sequencing (NGS) approaches for measuring RNA and DNA benefit from greatly increased sensitivity, dynamic range and detection of novel transcripts. These technologies are rapidly becoming the standard for molecular assays and represent huge potential value to the practice of oncology. However, many challenges exist in the transition of these technologies from research application to clinical practice. This review discusses the value of NGS in detecting mutations, copy number changes and RNA quantification and their applications in oncology, the challenges for adoption and the relevant steps that are needed for translating this potential to routine practice.
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http://dx.doi.org/10.1016/j.molonc.2013.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528427PMC
August 2013

PAM50 proliferation score as a predictor of weekly paclitaxel benefit in breast cancer.

Breast Cancer Res Treat 2013 Apr 20;138(2):457-66. Epub 2013 Feb 20.

Department of Medical Oncology, Instituto de Investigación Sanitaria Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain.

To identify a group of patients who might benefit from the addition of weekly paclitaxel to conventional anthracycline-containing chemotherapy as adjuvant therapy of node-positive operable breast cancer. The predictive value of PAM50 subtypes and the 11-gene proliferation score contained within the PAM50 assay were evaluated in 820 patients from the GEICAM/9906 randomized phase III trial comparing adjuvant FEC to FEC followed by weekly paclitaxel (FEC-P). Multivariable Cox regression analyses of the secondary endpoint of overall survival (OS) were performed to determine the significance of the interaction between treatment and the (1) PAM50 subtypes, (2) PAM50 proliferation score, and (3) clinical and pathological variables. Similar OS analyses were performed in 222 patients treated with weekly paclitaxel versus paclitaxel every 3 weeks in the CALGB/9342 and 9840 metastatic clinical trials. In GEICAM/9906, with a median follow up of 8.7 years, OS of the FEC-P arm was significantly superior compared to the FEC arm (unadjusted HR = 0.693, p = 0.013). A benefit from paclitaxel was only observed in the group of patients with a low PAM50 proliferation score (unadjusted HR = 0.23, p < 0.001; and interaction test, p = 0.006). No significant interactions between treatment and the PAM50 subtypes or the various clinical-pathological variables, including Ki-67 and histologic grade, were identified. Finally, similar OS results were obtained in the CALGB data set, although the interaction test did not reach statistical significance (p = 0.109). The PAM50 proliferation score identifies a subset of patients with a low proliferation status that may derive a larger benefit from weekly paclitaxel.
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http://dx.doi.org/10.1007/s10549-013-2416-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608881PMC
April 2013

Hypoxia-induced protein CAIX is associated with somatic loss of BRCA1 protein and pathway activity in triple negative breast cancer.

Breast Cancer Res Treat 2012 Nov 14;136(1):67-75. Epub 2012 Sep 14.

School of Medicine, Yale University, 310 Cedar Street, New Haven, CT 06520, USA.

The purpose of this study is to explore the relationship between tumor hypoxia assessed by CA IX protein expression and loss of BRCA1 function in triple negative breast cancer (TNBC). Protein expression of CA IX and BRCA1 was evaluated by AQUA™ technology on two breast cancer cohorts: an unselected cohort of 637 breast cancer patients and a TNBC cohort of 120 patients. Transcriptional profiling was performed on FFPE samples from the TNBC cohort to evaluate a gene expression signature associated with BRCA1 mutation (van't Veer et al., Nature 415(6871):530-536, 2002). CA IX is expressed in 7 % of the unselected breast cancer cohort and in 25 % of the TNBCs and is significantly associated with the triple negative phenotype. CA IX protein expression and BRCA1 protein expression are inversely correlated in both cohorts. Patients expressing high levels of CA IX show significantly worse overall survival (p = 0.02). Importantly, high CA IX protein expression occurs in patients who show the BRCA1 mutant signature and low levels of BRCA1 protein. These data suggest that elevated CA IX protein in TNBC is associated with a BRCA1 mutant signature and loss of BRCA1 function. CA IX may be a useful biomarker to identify triple negative patients with defective homologous recombination, who might benefit from PARP inhibitor therapy.
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http://dx.doi.org/10.1007/s10549-012-2232-0DOI Listing
November 2012

DNA polymerase β variant Ile260Met generates global gene expression changes related to cellular transformation.

Mutagenesis 2012 Nov 21;27(6):683-91. Epub 2012 Aug 21.

Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.

Maintenance of genomic stability is essential for cellular survival. The base excision repair (BER) pathway is critical for resolution of abasic sites and damaged bases, estimated to occur 20,000 times in cells daily. DNA polymerase β (Pol β) participates in BER by filling DNA gaps that result from excision of damaged bases. Approximately 30% of human tumours express Pol β variants, many of which have altered fidelity and activity in vitro and when expressed, induce cellular transformation. The prostate tumour variant Ile260Met transforms cells and is a sequence-context-dependent mutator. To test the hypothesis that mutations induced in vivo by Ile260Met lead to cellular transformation, we characterized the genome-wide expression profile of a clone expressing Ile260Met as compared with its non-induced counterpart. Using a 1.5-fold minimum cut-off with a false discovery rate (FDR) of <0.05, 912 genes exhibit altered expression. Microarray results were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and revealed unique expression profiles in other clones. Gene Ontology (GO) clusters were analyzed using Ingenuity Pathways Analysis to identify altered gene networks and associated nodes. We determined three nodes of interest that exhibited dysfunctional regulation of downstream gene products without themselves having altered expression. One node, peroxisome proliferator-activated protein γ (PPARG), was sequenced and found to contain a coding region mutation in PPARG2 only in transformed cells. Further analysis suggests that this mutation leads to dominant negative activity of PPARG2. PPARG is a transcription factor implicated to have tumour suppressor function. This suggests that the PPARG2 mutant may have played a role in driving cellular transformation. We conclude that PPARG induces cellular transformation by a mutational mechanism.
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http://dx.doi.org/10.1093/mutage/ges034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3611876PMC
November 2012

Tcf7 is an important regulator of the switch of self-renewal and differentiation in a multipotential hematopoietic cell line.

PLoS Genet 2012 8;8(3):e1002565. Epub 2012 Mar 8.

Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.

A critical problem in biology is understanding how cells choose between self-renewal and differentiation. To generate a comprehensive view of the mechanisms controlling early hematopoietic precursor self-renewal and differentiation, we used systems-based approaches and murine EML multipotential hematopoietic precursor cells as a primary model. EML cells give rise to a mixture of self-renewing Lin-SCA+CD34+ cells and partially differentiated non-renewing Lin-SCA-CD34- cells in a cell autonomous fashion. We identified and validated the HMG box protein TCF7 as a regulator in this self-renewal/differentiation switch that operates in the absence of autocrine Wnt signaling. We found that Tcf7 is the most down-regulated transcription factor when CD34+ cells switch into CD34- cells, using RNA-Seq. We subsequently identified the target genes bound by TCF7, using ChIP-Seq. We show that TCF7 and RUNX1 (AML1) bind to each other's promoter regions and that TCF7 is necessary for the production of the short isoforms, but not the long isoforms of RUNX1, suggesting that TCF7 and the short isoforms of RUNX1 function coordinately in regulation. Tcf7 knock-down experiments and Gene Set Enrichment Analyses suggest that TCF7 plays a dual role in promoting the expression of genes characteristic of self-renewing CD34+ cells while repressing genes activated in partially differentiated CD34- state. Finally a network of up-regulated transcription factors of CD34+ cells was constructed. Factors that control hematopoietic stem cell (HSC) establishment and development, cell growth, and multipotency were identified. These studies in EML cells demonstrate fundamental cell-intrinsic properties of the switch between self-renewal and differentiation, and yield valuable insights for manipulating HSCs and other differentiating systems.
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http://dx.doi.org/10.1371/journal.pgen.1002565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297581PMC
September 2012

Favorable outcome associated with an IGF-1 ligand signature in breast cancer.

Breast Cancer Res Treat 2012 May;133(1):321-31

Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520-8034, USA.

The insulin-like growth factor (IGF) axis is fundamentally important in cell growth, development and cancer. We used genomic technologies to better characterize the activity of the IGF axis in human breast cancer and to identify predictors of response to IGF targeted therapies. Analysis of the gene expression patterns and pathway analysis in 204 clinically annotated primary breast cancers were performed and compared to levels of mRNA for IGF ligands and receptors. Pathway activation scores were calculated by Pearson correlation (+1, -1). Network analysis was performed using Ingenuity software. IGF-1 ligand levels were strongly negatively correlated (P < 10⁻⁶) with a published IGF-IR activation signature.A signature of high IGF-1 ligand was associated with better prognosis (P = 0.025-1.5 x 10⁻⁸) in several public datasets. Pathway analysis revealed upregulation of pathways associated with breast differentiation (adipocyte growth factors, PPAR-gamma) and down-regulation of proliferation pathways (AKT/MAPK) in the IGF-1 ligand high group. Of note, the IGF-1 ligand signature was anti-correlated with IGFIR receptor levels (P = 0.07). In conclusion, a breast tumor-derived signature of high IGF-1 ligand is associated with favorable outcome, in contrast to a previously reported IGF-IR activation signature. The prognostic value of the IGF-I ligand signature is validated in three independent datasets. These signatures should be applied in study of IGF1-R targeted therapy.
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http://dx.doi.org/10.1007/s10549-012-1952-5DOI Listing
May 2012

Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1.

Proc Natl Acad Sci U S A 2011 Aug 25;108(33):13379-86. Epub 2011 Jul 25.

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Aberrations in epigenetic processes, such as histone methylation, can cause cancer. Retinoblastoma binding protein 2 (RBP2; also called JARID1A or KDM5A) can demethylate tri- and dimethylated lysine 4 in histone H3, which are epigenetic marks for transcriptionally active chromatin, whereas the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor promotes H3K4 methylation. Previous studies suggested that inhibition of RBP2 contributed to tumor suppression by the retinoblastoma protein (pRB). Here, we show that genetic ablation of Rbp2 decreases tumor formation and prolongs survival in Rb1(+/-) mice and Men1-defective mice. These studies link RBP2 histone demethylase activity to tumorigenesis and nominate RBP2 as a potential target for cancer therapy.
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http://dx.doi.org/10.1073/pnas.1110104108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158206PMC
August 2011

NFBD1/MDC1 regulates Cav1 and Cav2 independently of DNA damage and p53.

Mol Cancer Res 2011 Jun 6;9(6):766-81. Epub 2011 May 6.

Yale University, 333 Cedar Street, P.O. Box 208023, New Haven, CT 06520, USA.

NFBD1/MDC1 is involved in DNA damage checkpoint signaling and DNA repair. NFBD1 binds to the chromatin component γH2AX at sites of DNA damage, causing amplification of ataxia telangiectasia-mutated gene (ATM) pathway signaling and recruitment of DNA repair factors. Residues 508-995 of NFBD1 possess transactivation activity, suggesting a possible role of NFBD1 in transcription. Furthermore, NFBD1 influences p53-mediated transcription in response to adriamycin. We sought to determine the role of NFBD1 in ionizing radiation (IR)-responsive transcription and if NFBD1 influences transcription independently of p53. Using microarray analysis, we identified genes altered upon NFBD1 knockdown. Surprisingly, most NFBD1 regulated genes are regulated in both the absence and presence of IR, thus pointing toward a novel function for NFBD1 outside of the DNA damage response. Furthermore, NFBD1 knockdown regulated genes mostly independent of p53 knockdown. These genes are involved in pathways including focal adhesion signaling, carbohydrate metabolism, and insulin signaling. We found that CAV1 and CAV2 mRNA and protein levels are reduced by both NFBD1 knockdown and knockout independently of IR and p53. NFBD1-depleted cells exhibit some similar phenotypes to Cav1-depleted cells. Furthermore, like Cav1-depletion, NFBD1 shRNA increases Erk phosphorylation. Thus, Cav1 could act as a mediator of the DNA-damage independent effects of NFBD1 in mitogenic signaling.
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http://dx.doi.org/10.1158/1541-7786.MCR-10-0317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901581PMC
June 2011

MicroRNA signatures differentiate melanoma subtypes.

Cell Cycle 2011 Jun 1;10(11):1845-52. Epub 2011 Jun 1.

Yale University School of Medicine, New Haven, CT, USA.

Melanoma is an aggressive cancer that is highly resistance to therapies once metastasized. We studied microRNA (miRNA) expression in clinical melanoma subtypes and evaluated different miRNA signatures in the background of gain of function somatic and inherited mutations associated with melanoma. Total RNA from 42 patient derived primary melanoma cell lines and three independent normal primary melanocyte cell cultures was evaluated by miRNA array. MiRNA expression was then analyzed comparing subtypes and additional clinicopathologic criteria including somatic mutations. The prevalence and association of an inherited variant in a miRNA binding site in the 3'UTR of the KRAS oncogene, referred to as the KRAS-variant, was also evaluated. We show that seven miRNAs, miR-142-3p, miR-486, miR-214, miR-218, miR-362, miR-650 and miR-31, were significantly correlated with acral as compared to non-acral melanomas (p < 0.04). In addition, we discovered that the KRAS-variant was enriched in non-acral melanoma (25%), and that miR-137 under expression was significantly associated with melanomas with the KRAS-variant. Our findings indicate that miRNAs are differentially expressed in melanoma subtypes and that their misregulation can be impacted by inherited gene variants, supporting the hypothesis that miRNA misregulation reflects biological differences in melanoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233487PMC
http://dx.doi.org/10.4161/cc.10.11.15777DOI Listing
June 2011

A 3'-untranslated region KRAS variant and triple-negative breast cancer: a case-control and genetic analysis.

Lancet Oncol 2011 Apr 22;12(4):377-86. Epub 2011 Mar 22.

Department of Therapeutic Radiology, Yale University, New Haven, CT 06880, USA.

Background: We previously identified a functional variant in a let-7 microRNA (miRNA) complementary site in the 3'-untranslated region of the KRAS oncogene (rs61764370) which is associated with cancer. We aimed to investigate the association of this KRAS variant with breast cancer and tumour biology.

Methods: We assessed frequency distributions of the KRAS variant in 415 patients with histologically confirmed breast cancer and 457 controls from Connecticut, USA (study group 1) and association of this variant with breast-cancer subtypes in 690 Irish women with known oestrogen receptor (ER), progesterone receptor (PR), and HER2 statuses, and 360 controls (study group 2). We pooled data for study groups 1 and 2 with a cohort of 140 women with triple-negative breast cancer and 113 controls to assess the association of the KRAS variant with triple-negative breast cancer risk, and genome-wide mRNA and specific miRNA expression in patients with triple-negative breast cancer.

Findings: Although frequency distributions of the KRAS variant in study group 1 did not differ between all genotyped individuals, eight (33%) of 24 premenopausal women with ER/PR-negative cancer had the KRAS variant, compared with 27 (13%) of 201 premenopausal controls (p=0.015). In study group 2, the KRAS variant was significantly enriched in women with triple-negative breast cancer (19 [21%] of 90 cases) compared with 64 (13%) of 478 for luminal A, 13 (15%) of 87 for luminal B, and two (6%) of 35 for HER2-positive subgroups (p=0.044). Multivariate analysis in the pooled study groups showed that the KRAS variant was associated with triple-negative breast cancer in premenopausal women (odds ratio 2.307, 95% CI 1.261-4.219, p=0.0067). Gene-expression analysis of triple-negative breast-cancer tumours suggested that KRAS-variant positive tumours have significantly altered gene expression, and are enriched for the luminal progenitor and BRCA1 deficiency signatures. miRNA analysis suggested reduced levels of let-7 miRNA species in KRAS-variant tumours.

Interpretation: The KRAS variant might be a genetic marker for development of triple-negative breast cancer in premenopausal women, and altered gene and miRNA expression signatures should enable molecular and biological stratification of patients with this subgroup of breast cancer.

Funding: US National Institutes of Health.
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http://dx.doi.org/10.1016/S1470-2045(11)70044-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488438PMC
April 2011

Valproic acid antagonizes the capacity of other histone deacetylase inhibitors to activate the Epstein-barr virus lytic cycle.

J Virol 2011 Jun 16;85(11):5628-43. Epub 2011 Mar 16.

Department of Molecular Biophysics, Yale University School of Medicine, New Haven, CT 06520-8064, USA.

Diverse stimuli reactivate the Epstein-Barr virus (EBV) lytic cycle in Burkitt lymphoma (BL) cells. In HH514-16 BL cells, two histone deacetylase (HDAC) inhibitors, sodium butyrate (NaB) and trichostatin A (TSA), and the DNA methyltransferase inhibitor azacytidine (AzaCdR) promote lytic reactivation. Valproic acid (VPA), which, like NaB, belongs to the short-chain fatty acid class of HDAC inhibitors, fails to induce the EBV lytic cycle in these cells. Nonetheless, VPA behaves as an HDAC inhibitor; it causes hyperacetylation of histone H3 (J. K. Countryman, L. Gradoville, and G. Miller, J. Virol. 82:4706-4719, 2008). Here we show that VPA blocked the induction of EBV early lytic proteins ZEBRA and EA-D in response to NaB, TSA, or AzaCdR. The block in lytic activation occurred prior to the accumulation of BZLF1 transcripts. Reactivation of EBV in Akata cells, in response to anti-IgG, and in Raji cells, in response to tetradecanoyl phorbol acetate (TPA), was also inhibited by VPA. MS-275 and apicidin, representing two additional classes of HDAC inhibitors, and suberoylanilide hydroxamic acid (SAHA) reactivated EBV in HH514-16 cells; this activity was also inhibited by VPA. Although VPA potently blocked the expression of viral lytic-cycle transcripts, it did not generally block the transcription of cellular genes and was not toxic. The levels and kinetics of specific cellular transcripts, such as Stat3, Frmd6, Mad1, Sepp1, c-fos, c-jun, and egr1, which were activated by NaB and TSA, were similar in HH514-16 cells treated with VPA. When combined with NaB or TSA, VPA did not inhibit the activation of these cellular genes. Changes in cellular gene expression in response to VPA, NaB, or TSA were globally similar as assessed by human genome arrays; however, VPA selectively stimulated the expression of some cellular genes, such as MEF2D, YY1, and ZEB1, that could repress the EBV lytic cycle. We describe a novel example of functional antagonism between HDAC inhibitors.
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http://dx.doi.org/10.1128/JVI.02659-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094991PMC
June 2011

GPHMM: an integrated hidden Markov model for identification of copy number alteration and loss of heterozygosity in complex tumor samples using whole genome SNP arrays.

Nucleic Acids Res 2011 Jul 11;39(12):4928-41. Epub 2011 Mar 11.

Department of Electronic Science and Technology, University of Science and Technology of China.

There is an increasing interest in using single nucleotide polymorphism (SNP) genotyping arrays for profiling chromosomal rearrangements in tumors, as they allow simultaneous detection of copy number and loss of heterozygosity with high resolution. Critical issues such as signal baseline shift due to aneuploidy, normal cell contamination, and the presence of GC content bias have been reported to dramatically alter SNP array signals and complicate accurate identification of aberrations in cancer genomes. To address these issues, we propose a novel Global Parameter Hidden Markov Model (GPHMM) to unravel tangled genotyping data generated from tumor samples. In contrast to other HMM methods, a distinct feature of GPHMM is that the issues mentioned above are quantitatively modeled by global parameters and integrated within the statistical framework. We developed an efficient EM algorithm for parameter estimation. We evaluated performance on three data sets and show that GPHMM can correctly identify chromosomal aberrations in tumor samples containing as few as 10% cancer cells. Furthermore, we demonstrated that the estimation of global parameters in GPHMM provides information about the biological characteristics of tumor samples and the quality of genotyping signal from SNP array experiments, which is helpful for data quality control and outlier detection in cohort studies.
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http://dx.doi.org/10.1093/nar/gkr014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130254PMC
July 2011

Single-lineage transcriptome analysis reveals key regulatory pathways in primitive erythroid progenitors in the mouse embryo.

Blood 2011 May 24;117(18):4924-34. Epub 2011 Jan 24.

Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.

Primitive erythroid (EryP) progenitors are the first cell type specified from the mesoderm late in gastrulation. We used a transgenic reporter to image and purify the earliest blood progenitors and their descendants from developing mouse embryos. EryP progenitors exhibited remarkable proliferative capacity in the yolk sac immediately before the onset of circulation, when these cells comprise nearly half of all cells of the embryo. Global expression profiles generated at 24-hour intervals from embryonic day 7.5 through 2.5 revealed 2 abrupt changes in transcript diversity that coincided with the entry of EryPs into the circulation and with their late maturation and enucleation, respectively. These changes were paralleled by the expression of critical regulatory factors. Experiments designed to test predictions from these data demonstrated that the Wnt-signaling pathway is active in EryP progenitors, which display an aerobic glycolytic profile and the numbers of which are regulated by transforming growth factor-β1 and hypoxia. This is the first transcriptome assembled for a single hematopoietic lineage of the embryo over the course of its differentiation.
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http://dx.doi.org/10.1182/blood-2010-10-313676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100699PMC
May 2011

Germline competency of parthenogenetic embryonic stem cells from immature oocytes of adult mouse ovary.

Hum Mol Genet 2011 Apr 14;20(7):1339-52. Epub 2011 Jan 14.

School of Life Science, Sun Yat-Sen University, Guangzhou 510275, China.

Parthenogenetic embryonic stem cells (pESCs) have been generated in several mammalian species from parthenogenetic embryos that would otherwise die around mid-gestation. However, previous reports suggest that pESCs derived from in vivo ovulated (IVO) mature oocytes show limited pluripotency, as evidenced by low chimera production, high tissue preference and especially deficiency in germline competence, a critical test for genetic integrity and pluripotency of ESCs. Here, we report efficient generation of germline-competent pESC lines (named as IVM pESCs) from parthenogenetic embryos developed from immature oocytes of adult mouse ovaries following in vitro maturation (IVM) and artificial activation. In contrast, pESCs derived from IVO oocytes show defective germline competence, consistent with previous reports. Further, IVM pESCs resemble more ESCs from fertilized embryos (fESCs) than do IVO pESCs on genome-wide DNA methylation and global protein profiles. In addition, IVM pESCs express higher levels of Blimp1, Lin28 and Stella, relative to fESCs, and in their embryoid bodies following differentiation. This may indicate differences in differentiation potentially to the germline. The mechanisms for acquisition of pluripotency and germline competency of IVM pESCs from immature oocytes remain to be determined.
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http://dx.doi.org/10.1093/hmg/ddr016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049357PMC
April 2011

Modeling the clonal heterogeneity of stem cells.

Theor Biol Med Model 2010 Nov 17;7:44. Epub 2010 Nov 17.

Department of Pathology, Pathology Informatics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

Recent experimental studies suggest that tissue stem cell pools are composed of functionally diverse clones. Metapopulation models in ecology concentrate on collections of populations and their role in stabilizing coexistence and maintaining selected genetic or epigenetic variation. Such models are characterized by expansion and extinction of spatially distributed populations. We develop a mathematical framework derived from the multispecies metapopulation model of Tilman et al (1994) to study the dynamics of heterogeneous stem cell metapopulations. In addition to normal stem cells, the model can be applied to cancer cell populations and their response to treatment. In our model disturbances may lead to expansion or contraction of cells with distinct properties, reflecting proliferation, apoptosis, and clonal competition. We first present closed-form expressions for the basic model which defines clonal dynamics in the presence of exogenous global disturbances. We then extend the model to include disturbances which are periodic and which may affect clones differently. Within the model framework, we propose a method to devise an optimal strategy of treatments to regulate expansion, contraction, or mutual maintenance of cells with specific properties.
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http://dx.doi.org/10.1186/1742-4682-7-44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998476PMC
November 2010

MicroRNA signatures differentiate uterine cancer tumor subtypes.

Gynecol Oncol 2010 Sep 9;118(3):251-7. Epub 2010 Jun 9.

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Yale University School of Medicine, New Haven, CT, USA.

Objective: Endometrial cancer (EC) is the most common gynecologic malignancy. Type I EC has a favorable prognosis, while type II ECs account for half of all treatment failures. Little knowledge of the biological differences is available to predict EC outcomes besides their pathological distinctions. MicroRNAs (miRNA) are a family of non-translated RNAs important in regulating oncogenic pathways. Mis-expression patterns of miRNAs in EC, as well as differences in miRNA expression patterns between the subtypes of EC, has not been previously evaluated. Our purpose was to identify miRNA profiles of EC subtypes, and to identify miRNAs associated with these subtypes to ultimately understand the different biological behavior between these subtypes.

Methods: Ninety-five fresh/frozen and paraffin-embedded samples of endometrial type I and II cancer, carcinosarcomas and benign endometrial samples were collected. MiRNA expression profiles were evaluated by microarray analysis. Statistical analysis was performed.

Results: Distinct miRNA signatures in tumor versus normal samples and in endometrioid vs. uterine papillary serous carcinomas exist. Additionally, carcinosarcomas have a unique miRNA signature from either the type I or II epithelial tumors.

Conclusions: We hypothesize that further understanding the miRNAs that separate these subtypes of EC will lead to biological insights into the different behavior of these tumors.
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http://dx.doi.org/10.1016/j.ygyno.2010.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918705PMC
September 2010