Publications

2022

Del Toro, Juan, Adam Fine, Ming-Te Wang, Alvin Thomas, Lisa Schneper, Colter Mitchell, Ronald Mincy, Sara McLanahan, and Daniel Notterman. “The Longitudinal Associations Between Paternal Incarceration and Family Well-Being: Implications for Ethnic Racial Disparities in Health..” Journal of the American Academy of Child and Adolescent Psychiatry 61.3 (2022): 423–433.

OBJECTIVE: Ethnic/racial minority children in the United States are more likely to experience father loss to incarceration than White children, and limited research has examined the health implications of these ethnic/racial disparities. Telomere length is a biomarker of chronic stress that is predictive of adverse health outcomes. This study examined whether paternal incarceration predicted telomere length shortening among offspring from childhood to adolescence, whether maternal depression mediated the link, and whether ethnicity/race moderated results.

METHOD: Research participants included 2,395 families in the Fragile Families and Child Wellbeing study, a national and longitudinal cohort study of primarily low-income families from 20 large cities in the United States. Key constructs were measured when children were on average ages 9 (2007-2010) and 15 (2014-2017).

RESULTS: Children who experienced paternal incarceration exhibited shorter telomere lengths between ages 9 and 15, and changes in maternal depression mediated this finding. Specifically, mothers who experienced a partner's incarceration were more likely to have depression between children's ages 9 and 15. In turn, increases in maternal depression between children's ages 9 and 15 predicted more accelerated telomere length shortening among children during this period. Paternal incarceration was more prevalent and frequent for ethnic/racial minority youth than for White youth.

CONCLUSION: Paternal incarceration is associated with a biomarker of chronic stress among children in low-income families. Rates of paternal incarceration were more prevalent and frequent among Black American and multiethnic/multiracial families than among White Americans. As a result, the mass incarceration crisis of the criminal justice system is likely shaping intergenerational ethnic/racial health disparities.

2021

Geronimus, Arline, John Bound, Colter Mitchell, Aresha Martinez-Cardoso, Linnea Evans, Landon Hughes, Lisa Schneper, and Daniel Notterman. “Coming up Short: Comparing Venous Blood, Dried Blood Spots & Saliva Samples for Measuring Telomere Length in Health Equity Research..” PloS one 16.8 (2021): e0255237.

BACKGROUND: Telomere length (TL) in peripheral blood mononuclear cells (PBMC) from fresh venous blood is increasingly used to estimate molecular impacts of accumulated social adversity on population health. Sometimes, TL extracted from saliva or dried blood spots (DBS) are substituted as less invasive and more scalable specimen collection methods; yet, are they interchangeable with fresh blood? Studies find TL is correlated across tissues, but have not addressed the critical question for social epidemiological applications: Do different specimen types show the same association between TL and social constructs?

METHODS: We integrate expertise in social epidemiology, molecular biology, and the statistical impact of measurement error on parameter estimates. Recruiting a diverse sample of 132 Metro-Detroit women, we measure TL for each woman from fresh blood PBMC, DBS, and saliva. Using regression methods, we estimate associations between social characteristics and TL, comparing estimates across specimen types for each woman.

RESULTS: Associations between TL and social characteristics vary by specimen type collected from the same woman, sometimes qualitatively altering estimates of the magnitude or direction of a theorized relationship. Being Black is associated with shorter TL in PBMC, but longer TL in saliva or DBS. Education is positively associated with TL in fresh blood, but negatively associated with TL using DBS.

CONCLUSION: Findings raise concerns about the use of TL measures derived from different tissues in social epidemiological research. Investigators need to consider the possibility that associations between social variables and TL may be systematically related to specimen type, rather than be valid indicators of socially-patterned biopsychosocial processes.

Mullola, Sari, Jeanne Brooks-Gunn, Marko Elovainio, Christian Hakulinen, Lisa Schneper, and Daniel Notterman. “Early Childhood Psychosocial Family Risks and Cumulative Dopaminergic Sensitizing Score: Links to Behavior Problems in U.S. 9-Year-Olds..” Journal of affective disorders 280.Pt A (2021): 432–441.

BACKGROUND: We examined, (a) whether in early childhood exposure to risky family environment in different domains (socioeconomic, mental, parenting practices, health behavior, and child-related risks) and accumulatively across various domains (cumulative risk) is associated with child's problem behavior at age 9, and (b) whether the association is more pronounced in children carrying cumulative dopaminergic sensitizing genotype or living in low-income families.

METHODS: Participants were 2,860 9-year old children (48% females; 48% Black) and their mothers from the 'Fragile Families and Child Wellbeing Study', a probability birth cohort from large U.S. cities. Mothers responded to questions on child's problem behavior (CBCL). Children responded to questions about their vandalism and substance use.

RESULTS: Cumulative family risk was associated with higher internalizing and externalizing behavior and higher vandalism and substance use. All domain-specific risk clusters were associated with higher internalizing behavior and, with the exception of child-related risk, with higher externalizing behavior. Mental health risks, risky parenting practices, and risky health behavior were associated with higher vandalism. Risky parenting practices were associated with higher substance use. The associations were robust to adjustment for cumulative dopaminergic sensitizing genotype. No G x E interactions with dopaminergic genotype and family SES were observed.

LIMITATIONS: Sample size was relatively small for genetic analysis and polygenic risk scores were not available.

CONCLUSIONS: Exposure to cumulative psychosocial family risks from early childhood is associated with early indicators of problem behavior in adolescence.

2020

Xu, Eugenia, Evan Vosburgh, Chung Wong, Laura Tang, and Daniel Notterman. “Genetic Analysis of the Cooperative Tumorigenic Effects of Targeted Deletions of Tumor Suppressors , , , and in Neuroendocrine Tumors in Mice..” Oncotarget 11.28 (2020): 2718–2739.

Genetic alterations of tumor suppressor genes (TSGs) are frequently observed to have cumulative or cooperative tumorigenic effects. We examined whether the TSGs , , and have cooperative effects in suppressing neuroendocrine tumors (NETs) in mice. We generated pairwise homozygous deletions of these four genes in insulin II gene expressing cells using the Cre-LoxP system. By monitoring growth and examining the histopathology of the pituitary (Pit) and pancreas (Pan) in these mice, we demonstrated that pRB had the strongest cooperative function with PTEN in suppressing PitNETs and had strong cooperative function with Menin and TRP53, respectively, in suppressing PitNETs and PanNETs. TRP53 had weak cooperative function with PTEN in suppressing pituitary lesions. We also found that deletion of singly led to prolactinomas in female mice, and deletion of alone led to islet hyperplasia in pancreas. Collectively, our data indicated that pRB and PTEN pathways play significant roles in suppressing PitNETs, while the Menin-mediated pathway plays a significant role in suppressing PanNETs. Understanding the molecular mechanisms of these genes and pathways on NETs will help us understand the molecular mechanisms of neuroendocrine tumorigenesis and develop effective preclinical murine models for NET therapeutics to improve clinical outcomes in humans.

Koss, Kalsea, Lisa Schneper, Jeanne Brooks-Gunn, Sara McLanahan, Colter Mitchell, and Daniel Notterman. “Early Puberty and Telomere Length in Preadolescent Girls and Mothers..” The Journal of pediatrics 222 (2020): 193–199.e5.

OBJECTIVE: To test the association between early puberty and telomere length in preadolescent girls and mothers from a large representative sample of US females.

STUDY DESIGN: We analyzed data from 1194 preadolescent girls and 2421 mothers from the Fragile Families and Child Wellbeing Study. Participants were from a population-based birth cohort (1998-2000) born in large US cities. Telomere length was assessed by quantitative polymerase chain reaction from saliva samples provided by preadolescent girls and mothers of preadolescent youth. Mothers completed a questionnaire about their child's pubertal development to determine concurrent Tanner stages and provided self-reports of her own age at menarche. Linear regression models were used to estimate the association between pubertal development (status and timing) and telomere length.

RESULTS: Early pubertal timing but not pubertal status was associated with shorter telomere length in preadolescent girls (P < .01). Early age at menarche was associated with shorter telomere length in a sample of mothers of preadolescent youth (P < .05).

CONCLUSIONS: Results provide evidence for the association between early puberty and shorter telomeres evidenced by associations in both preadolescent girls and mothers. Future research should address the limitations of this study by using longitudinal measurements of pubertal development assessed through medical examinations and repeated assessments of telomere length to capture telomere attrition.

Wong, Chung, Laura Tang, Christian Davidson, Evan Vosburgh, Wenjin Chen, David Foran, Daniel Notterman, Arnold Levine, and Eugenia Xu. “Two Well-Differentiated Pancreatic Neuroendocrine Tumor Mouse Models..” Cell death and differentiation 27.1 (2020): 269–283.

Multiple endocrine neoplasia type 1 (MEN1) is a genetic syndrome in which patients develop neuroendocrine tumors (NETs), including pancreatic neuroendocrine tumors (PanNETs). The prolonged latency of tumor development in MEN1 patients suggests a likelihood that other mutations cooperate with Men1 to induce PanNETs. We propose that Pten loss combined with Men1 loss accelerates tumorigenesis. To test this, we developed two genetically engineered mouse models (GEMMs)-MPR (Men1 Pten RIP-Cre) and MPM (Men1 Pten MIP-Cre) using the Cre-LoxP system with insulin-specific biallelic inactivation of Men1 and Pten. Cre in the MPR mouse model was driven by the transgenic rat insulin 2 promoter while in the MPM mouse model was driven by the knock-in mouse insulin 1 promoter. Both mouse models developed well-differentiated (WD) G1/G2 PanNETs at a much shorter latency than Men1 or Pten single deletion alone and exhibited histopathology of human MEN1-like tumor. The MPR model, additionally, developed pituitary neuroendocrine tumors (PitNETs) in the same mouse at a much shorter latency than Men1 or Pten single deletion alone as well. Our data also demonstrate that Pten plays a role in NE tumorigenesis in pancreas and pituitary. Treatment with the mTOR inhibitor rapamycin delayed the growth of PanNETs in both MPR and MPM mice, as well as the growth of PitNETs, resulting in prolonged survival in MPR mice. Our MPR and MPM mouse models are the first to underscore the cooperative roles of Men1 and Pten in cancer, particularly neuroendocrine cancer. The early onset of WD PanNETs mimicking the human counterpart in MPR and MPM mice at 7 weeks provides an effective platform for evaluating therapeutic opportunities for NETs through targeting the MENIN-mediated and PI3K/AKT/mTOR signaling pathways.

Notterman, Daniel, and Lisa Schneper. “Telomere Time-Why We Should Treat Biological Age Cautiously..” JAMA network open 3.5 (2020): e204352.

2019

Carcillo, Joseph, Robert Berg, David Wessel, Murray Pollack, Kathleen Meert, Mark Hall, Christopher Newth, John Lin, Allan Doctor, Tom Shanley, Tim Cornell, Rick Harrison, Athena Zuppa, Ron Reeder, Russell Banks, John Kellum, Richard Holubkov, Daniel Notterman, Michael Dean, and Eunice Network. “A Multicenter Network Assessment of Three Inflammation Phenotypes in Pediatric Sepsis-Induced Multiple Organ Failure..” Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 20.12 (2019): 1137–1146.

OBJECTIVES: Ongoing adult sepsis clinical trials are assessing therapies that target three inflammation phenotypes including 1) immunoparalysis associated, 2) thrombotic microangiopathy driven thrombocytopenia associated, and 3) sequential liver failure associated multiple organ failure. These three phenotypes have not been assessed in the pediatric multicenter setting. We tested the hypothesis that these phenotypes are associated with increased macrophage activation syndrome and mortality in pediatric sepsis.

DESIGN: Prospective severe sepsis cohort study comparing children with multiple organ failure and any of these phenotypes to children with multiple organ failure without these phenotypes and children with single organ failure.

SETTING: Nine PICUs in the Eunice Kennedy Shriver National Institutes of Child Health and Human Development Collaborative Pediatric Critical Care Research Network.

PATIENTS: Children with severe sepsis and indwelling arterial or central venous catheters.

INTERVENTIONS: Clinical data collection and twice weekly blood sampling until PICU day 28 or discharge.

MEASUREMENTS AND MAIN RESULTS: Of 401 severe sepsis cases enrolled, 112 (28%) developed single organ failure (0% macrophage activation syndrome 0/112; < 1% mortality 1/112), whereas 289 (72%) developed multiple organ failure (9% macrophage activation syndrome 24/289; 15% mortality 43/289). Overall mortality was higher in children with multiple organ and the phenotypes (24/101 vs 20/300; relative risk, 3.56; 95% CI, 2.06-6.17). Compared to the 188 multiple organ failure patients without these inflammation phenotypes, the 101 multiple organ failure patients with these phenotypes had both increased macrophage activation syndrome (19% vs 3%; relative risk, 7.07; 95% CI, 2.72-18.38) and mortality (24% vs 10%; relative risk, 2.35; 95% CI, 1.35-4.08).

CONCLUSIONS: These three inflammation phenotypes were associated with increased macrophage activation syndrome and mortality in pediatric sepsis-induced multiple organ failure. This study provides an impetus and essential baseline data for planning multicenter clinical trials targeting these inflammation phenotypes in children.

2017

Mitchell, Colter, Sara McLanahan, Lisa Schneper, Irwin Garfinkel, Jeanne Brooks-Gunn, and Daniel Notterman. “Father Loss and Child Telomere Length..” Pediatrics 140.2 (2017): e20163245. Print.
James, Sarah, Sara McLanahan, Jeanne Brooks-Gunn, Colter Mitchell, Lisa Schneper, Brandon Wagner, and Daniel Notterman. “Sleep Duration and Telomere Length in Children..” The Journal of Pediatrics S0022-3476.17 (2017): 30635–2.
Objective

To test the association between sleep duration and telomere length in a pediatric population.

Study design

We analyzed cross-sectional data for 1567 children from the age 9 study wave of the Fragile Families and Child Wellbeing Study, a population-based birth cohort of children born between 1998 and 2000 in large American cities (population >200 000). We measured telomere length using quantitative polymerase chain reaction, and children's typical nightly sleep duration was reported by their primary caregivers. Using linear regression, we estimated the association between sleep duration and telomere length both in unadjusted models and adjusting for a number of covariates.

Results

We found that children with shorter sleep durations have shorter telomeres than children with longer sleep durations. Each hour less of nightly sleep duration is associated with having telomeres that are 0.015 log-kilobases per chromosome shorter (P < .05). We found no difference in this association by race, sex, or socioeconomic status.

Conclusions

We provide preliminary evidence that children with shorter sleep durations have shorter telomeres. This finding is consistent with a broader literature indicating that suboptimal sleep duration is a risk for increased physiological stress and impaired health. Future research should address the limitations of our study design by using longitudinal study designs and telomere measurements, measuring sleep duration via polysomnography or actigraphy, and assessing the intermediate biological mechanisms of the link between sleep and telomere dynamics.

2016

Schneper, Lisa, Jeanne Brooks-Gunn, Daniel Notterman, and Stephen Suomi. “Early-Life Experiences and Telomere Length in Adult Rhesus Monkeys: An Exploratory Study..” Psychosom Med 78.9 (2016): 1066–1071.
OBJECTIVE: Child-rearing environments have been associated with morbidity in adult rhesus monkeys. We examine whether such links are also seen with leukocyte telomere length. METHODS: To determine telomere length in leukocytes, blood was collected from 11 adult female monkeys aged 7 to 10 years who had been exposed to different rearing environments between birth and 7 months. Four had been reared with their mothers in typical social groups composed of other female monkeys, their offspring, and 1 to 2 adult male monkeys. The other 7 had been reared in either small groups of peers or individual cages with extensive peer interaction daily. After 7 months, all shared a common environment. RESULTS: Telomere lengths were longer for those adults who had been reared with their mothers in social groups (median = 16.0 kb, interquartile range = 16.5-15.4) than for those who were reared without their mothers (median = 14.0 kb, interquartile range = 14.3-12.7; 2.2 kb/telomere difference, p
Traube, Chani, Elizabeth Mauer, Linda Gerber, Savneet Kaur, Christine Joyce, Abigail Kerson, Charlene Carlo, Daniel Notterman, Stefan Worgall, Gabrielle Silver, and Bruce Greenwald. “Cost Associated With Pediatric Delirium in the ICU..” Crit Care Med 44.12 (2016): e1175-e1179.
OBJECTIVE: To determine the costs associated with delirium in critically ill children. DESIGN: Prospective observational study. SETTING: An urban, academic, tertiary-care PICU in New York city. PATIENTS: Four-hundred and sixty-four consecutive PICU admissions between September 2, 2014, and December 12, 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All children were assessed for delirium daily throughout their PICU stay. Hospital costs were analyzed using cost-to-charge ratios, in 2014 dollars. Median total PICU costs were higher in patients with delirium than in patients who were never delirious ($18,832 vs $4,803; p 3 d with delirium; p
Mitchell, Colter, Lisa Schneper, and Daniel Notterman. “DNA Methylation, Early Life Environment, and Health Outcomes..” Pediatr Res 79.1-2 (2016): 212–9.
Epigenetics, and especially DNA methylation, have recently become provocative biological explanations for early-life environmental effects on later health. Despite the large increase in papers on the topic over the last few years, many questions remain with regards to the biological feasibility of this mechanism and the strength of the evidence to date. In this review, we examine the literature on early-life effects on epigenetic patterns, with special emphasis on social environmental influences. First, we review the basic biology of epigenetic modification of DNA and debate the role of early-life stressful, protective, and positive environments on gene-specific, system-specific, and whole-genome epigenetic patterns later in life. Second, we compare the epigenetic literatures of both humans and other animals and review the research linking epigenetic patterns to health in order to complete the mechanistic pathway. Third, we discuss physical environmental and social environmental effects, which have to date, generally not been jointly considered. Finally, we close with a discussion of the current state of the area's research, its future direction, and its potential use in pediatric health.

2015

Mitchell, Colter, John Hobcraft, Sara McLanahan, Jeanne Brooks-Gunn, Irwin Garfinkel, and Daniel Notterman. “Family Structure Instability, Genetic Sensitivity and Child Wellbeing.” Journal of Sociology 120.4 (2015): 1195–1225. Print.
Notterman, Daniel, and Colter Mitchell. “Epigenetics and Understanding the Impact of Social Determinants of Health..” Pediatr Clin North Am 62.5 (2015): 1227–40.
Recently, a new research agenda emphasizing interactions between social factors and health has emerged. The term social determinant of health often refers to any nonmedical factor directly influencing health. Health across the life span is strongly and adversely affected by social disadvantage. Research in epigenetics indicates that alterations in DNA methylation may provide a causal link between social adversity and health disparity. Likewise, accelerated loss of telomeres is correlated with chronic stress. Research is still required to develop an understanding of the role of epigenetics and perturbed telomere function in linking social adversity with health outcome.

2014

Cheng, YW, Hanna Pincas, Huang, Zachariah, Zeng, Daniel Notterman, Paty, and Barany. “High Incidence of LRAT Promoter Hypermethylation in Colorectal Cancer Correlates With Tumor Stage..” Medical Oncology 31.11 (2014): 254. Print.
Mitchell, Colter, John Hobcraft, Sara McLanahan, SR Siegel, Berg, Jeanne Brooks-Gunn, Irwin Garfinkel, and Daniel Notterman. “Social Disadvantage, Genetic Sensitivity, and children’s Telomere Length.” PNAS 111.16 (2014): 5944–5949.

Disadvantaged social environments are associated with adverse health outcomes. This has been attributed, in part, to chronic stress. Telomere length (TL) has been used as a biomarker of chronic stress: TL is shorter in adults in a variety of contexts, including disadvantaged social standing and depression. We use data from 40, 9-y-old boys participating in the Fragile Families and Child Wellbeing Study to extend this observation to African American children. We report that exposure to disadvantaged environments is associated with reduced TL by age 9 y. We document significant associations between low income, low maternal education, unstable family structure, and harsh parenting and TL. These effects were moderated by genetic variants in serotonergic and dopaminergic pathways. Consistent with the differential susceptibility hypothesis, subjects with the highest genetic sensitivity scores had the shortest TL when exposed to disadvantaged social environments and the longest TL when exposed to advantaged environments.

2013

Lee, Jeanne Brooks-Gunn, Sara McLanahan, Daniel Notterman, and Irwin Garfinkel. “The Great Recession, Genetic Sensitivity, and Maternal Harsh Parenting..” PNAS 110.34 (2013): 13780–13784. Print.
Giacobbe, Bongiorno-Borbone, Bernassola, Terrinoni, EK Markert, Arnold Levine, Feng, Agostini, Zolla, AF Agro, Daniel Notterman, Melino, and Peschiaroli. “p63 Regulates Glutaminase 2 Expression.” Cell Cycle 12.9 (2013): n. pag. Print.
Mitchell, Colter, Sara McLanahan, Jeanne Brooks-Gunn, Irwin Garfinkel, John Hobcraft, and Daniel Notterman. “Genetic Differential Sensitivity to Social Environments: Implications for Research..” Am J Public Health 103 Suppl 1 (2013): S102–10.
Researchers have proposed a genetic differential sensitivity to social environmental (GDSE) model positing that individuals with certain genetic makeups are more sensitive to favorable and unfavorable environmental influences than those without these genetic makeups. We discuss several issues facing researchers who want to use GDSE to examine health: (1) the need for greater theorizing about the social environment to properly understand the size and direction of environmental influences; (2) the potential for combining multiple genetic markers to measure an individual's genetic sensitivity to environmental influence; (3) how this model and exogenous shocks deal with gene-environment correlations; (4) implications of this model for public health and prevention; and (5) how life course and developmental theories may be used to inform GDSE research.

2011

Mitchell, Colter, Daniel Notterman, Jeanne Brooks-Gunn, John Hobcraft, Irwin Garfinkel, Kate Jaeger, Iulia Kotenko, and Sara McLanahan. “Role of mother’s Genes and Environment in Postpartum Depression..” Proc Natl Acad Sci U S A 108.20 (2011): 8189–93.
Most studies of human molecular genetics and social environment interactions on health have relied heavily on the classic diathesis-stress model that treats genetic variations and environments as being either "risky" or "protective." The biological susceptibility model posits that some individuals have greater genetic reactivity to stress, leading to worse outcomes in poor environments, but better outcomes in rich environments. Using a nontruncated measure of a chronic environmental stressor--socioeconomic status--measured by education, and two polymorphisms (5-HTTLPR and STin2 VNTR) of the serotonin transporter gene (5-HTT), we find strong evidence that some women are genetically more reactive to the environment, resulting in a crossover of risks of postpartum depression for the most reactive groups. We discuss how our approach and findings provide a framework for understanding some of the confusion in the gene-environment interaction literature on stress, 5-HTT, and depression.

2009

Sheffer, Bacolod, Zuk, Giardina, Hanna Pincas, Barany, Paty, William Gerald, and Daniel Notterman. “Association of Survival and Disease Progression With Chromosomal Instability: A Genomic Exploration of Colorectal Cancer..” PNAS 106 (2009): 7131–7136. Print.
Meng, R.D., C.C. Shelton, YM Li, LX Qin, Daniel Notterman, and Gary Schwartz. “Gamma-Secretase Inhibitors Abrogate Oxaliplatin-Induced Activation of the Notch-1 Signaling Pathway in Colon Cancer Cells Resulting in Enhanced Chemosensitivity..” Cancer Research 69.2 (2009): 573–582.
Postel, Edith, Zou, Daniel Notterman, and La Perle. “Double Knockout Nme1 Nme2 Mouse Model Suggests a Critical Role for NDP Kinases in Erythroid Development..” Molecular Cell Biochemistry 329 (2009): 45–50. Print.

2008

Kareddula, A., Zachariah, Daniel Notterman, and Michael Reiss. “Transforming Growth Factor- β Signaling Strength Determines Target Gene Expression Profile in Human Keratinocytes..” Journal of Epithelial Biology and Pharmacology 1 (2008): 40–50.
Cheng, Hanna Pincas, Bacolod, Schemmann, Giardina, Huang, Barral, Idress, Khan, Zeng, Rosenberg, Daniel Notterman, Ott, and Barany. “CpG Island Methylator Phenotype Associates With Low-Degree Chromosomal Abnormalities in Colorectal Cancer.” Clinical Cancer Research 14.19 (2008): 6005–6013. Print.
Bacolod, Schemmann, Giardina, Paty, Daniel Notterman, and Barany. “Emerging Paradigms in Cancer Genetics: Some Important Findings from High-Density SNP Array Studies..” Cancer Research 69.3 (2008): 723–727.
Bacolod, Schemmann, Wang, Shattock, SF Giardina, Zeng, Shia, RF Stengel, Gerry, Hoh, Kirchoff, Gold, MF Christman, Offit, WL Gerald, Daniel Notterman, Ott, Paty, and Francis Barany. “The Signatures of Autozygosity Among Patients With Colorectal Cancer.” Cancer Research 68.8 (2008): 2610–2621.
Puca, Nardinocchi, Gal, Domany, Daniel Notterman, Blandino, Givol, and D’Orazi. “Reversible Dysfunction of Wild-Type p53 Following HIPK2 Knockdown.” Cancer Research 69.10 (2008): 3703–3714.
Forslund, Zeng, Qin, Rosenberg, Ndubuisi, Gerald, Daniel Notterman, Francis Barany, and Paty. “MDM2 Gene Amplification Is Correlated to Tumor Progression But Not to the Presence of SNP309 or TP53 Mutational Status in Primary Colorectal Cancers..” Molecular Cancer Research 6.2 (2008): 205–211.

2007

Gavert, Sheffer, Raveh, Spaderna, Shtutman, Brabletz, Francis Barany, Paty, Daniel Notterman, Domany, and Ben-Ze’ev. “Expression of L1-CAM and ADAM10 in Human Colon Cancer Cells Induces Metastasis.” Cancer Research 67.16 (2007): 7703–7712.
Li, X., Liu, Qin, Joseph Tamasi, Bergenstock, Shapses, Jean, Feyen, Daniel Notterman, and Nicola Partridge. “Determination of Parathyroid hormone’s Dual Effects on Skeletal Gene Expression in Vivo by Microarray and Network Analysis..” Journal of Biological Chemistry 282.45 (2007): 33086–33097.
Hertzberg, Betts, Raimondi, Shurtleff, Schaefer, Daniel Notterman, Domany, and Izraeli. “Prediction of Chromosomal Aneuploidy from Gene Expression Data.” Genes, Chromosomes and Cancer 46.1 (2007): 75–86.

Chromosomal aneuploidy is commonly observed in neoplastic diseases and is an important prognostic marker. Here we examine how gene expression profiles reflect aneuploidy and whether these profiles can be used to detect changes in chromosome copy number. We developed two methods for detecting such changes in the gene expression profile of a single sample. The first method, fold-change analysis, relies on the availability of gene expression data from a large cohort of patients with the same disease. The expression profile of the sample is compared with that of the dataset. The second method, chromosomal relative expression analysis, is more general and requires the expression data from the tested sample only. We found that the relative expression values are stable among different chromosomes and exhibit little variation between different normal tissues. We exploited this novel finding to establish the set of reference values needed to detect changes in the copy number of chromosomes in a single sample on the basis of gene expression levels. We measured the accuracy of the performance of each method by applying them to two independent leukemia datasets. The second method was also applied to two solid tumor datasets. We conclude that chromosomal aneuploidy can be detected and predicted by analysis of gene expression profiles. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

2006

Tsafrir, Bacolod, Selvanayagam, Tsafrir, Shia, Zeng, Liu, Krier, RF Stengel, Francis Barany, WL Gerald, Phillip Paty, Domany, and Daniel Notterman. “Relationship of Gene Expression and Chromosomal Abnormalities in Colorectal Cancer.” Cancer Research 66.4 (2006): 2129–2137.

Several studies have verified the existence of multiple chromosomal abnormalities in colon cancer. However, the relationships between DNA copy number and gene expression have not been adequately explored nor globally monitored during the progression of the disease. In this work, three types of array-generated data (expression, single nucleotide polymorphism, and comparative genomic hybridization) were collected from a large set of colon cancer patients at various stages of the disease. Probes were annotated to specific chromosomal locations and coordinated alterations in DNA copy number and transcription levels were revealed at specific positions. We show that across many large regions of the genome, changes in expression level are correlated with alterations in DNA content. Often, large chromosomal segments, containing multiple genes, are transcriptionally affected in a coordinated way, and we show that the underlying mechanism is a corresponding change in DNA content. This implies that whereas specific chromosomal abnormalities may arise stochastically, the associated changes in expression of some or all of the affected genes are responsible for selecting cells bearing these abnormalities for clonal expansion. Indeed, particular chromosomal regions are frequently gained and overexpressed (e.g., 7p, 8q, 13q, and 20q) or lost and underexpressed (e.g., 1p, 4, 5q, 8p, 14q, 15q, and 18) in primary colon tumors, making it likely that these changes favor tumorigenicity. Furthermore, we show that these aberrations are absent in normal colon mucosa, appear in benign adenomas (albeit only in a small fraction of the samples), become more frequent as disease advances, and are found in the majority of metastatic samples.

Cheng, Shawber, Daniel Notterman, Phillip Paty, and Francis Barany. “Multiplexed Profiling of Candidate Genes for CpG Island Methylation Status Using a Flexible PCR LDR Universal Array Assay..” Genome Research 16.2 (2006): 282–289.

DNA methylation in CpG islands is associated with transcriptional silencing. Accurate determination of cytosine methylation status in promoter CpG dinucleotides may provide diagnostic and prognostic value for human cancers. We have developed a quantitative PCR/LDR/Universal Array assay that allows parallel evaluation of methylation status of 75 CpG dinucleotides in the promoter regions of 15 tumor suppressor genes (CDKN2B, CDKN2A, CDKN2D, CDKN1A, CDKN1B, TP53, BRCA1, TIMP3, APC, RASSF1, CDH1, MGMT, DAPK1, GSTP1, and RARB). When compared with an independent pyrosequencing method at a single promoter, the two approaches gave good correlation. In a study using 15 promoter regions and seven blinded tumor cell lines, our technology was capable of distinguishing methylation profiles that identified cancer cell lines derived from the same origins. Preliminary studies using 96 colorectal tumor samples and 73 matched normal tissues indicated CpG methylation is a gene-specific and nonrandom event in colon cancer. This new approach is suitable for clinical applications where sample quantity and purity can be limiting factors.

Lee, HJ, Liu, Goodman, Ji, Maehr, Uskokovic, Daniel Notterman, Michael Reiss, and Suh. “Gene Expression Changes Induced by a Novel Gemini Vitamin D Derivative During the Progression of Breast Cancer.” Biochemical Pharmacology 72.3 (2006): 332–343.

We investigated gene expression changes induced by a novel Gemini Vitamin D3 analog, RO-438-3582 (1α,25-dihydroxy-20S-21(3-hydroxy-3-methyl-butyl)-23-yne-26,27-hexafluoro-cholecalciferol, Ro3582), in a unique human breast MCF10 model. We used two breast epithelial cell lines from this model, namely MCF10AT1 (Ha-ras oncogene transfected MCF10A, early premalignant) and MCF10CA1a (fully malignant and metastatic derived from the MCF10AT1 line). We analyzed gene expression changes induced by Ro3582 using GeneChip technology, quantitative RT-PCR, Western blot analysis, or a gene transcription assay. Interestingly, we found distinct gene expression profile differences between Ro3582-induced response of the early premalignant MCF10AT1 and the malignant and metastatic MCF10CA1a cell lines. Moreover, while the Gemini Vitamin D3 analog Ro3582 modulated the expression of several Vitamin D target genes such as the 24-hydroxylase, CD14, osteocalcin, and osteopontin in both cell lines, Ro3582 regulated many genes involved in cell proliferation and apoptosis, cell adhesion, invasion, angiogenesis as well as cell signaling pathways, such as the BMP and TGF-β systems, differently in the two cell lines. The Gemini Vitamin D3 analog Ro3582 induced more significant gene changes in the early premalignant MCF10AT1 cells than in the malignant metastatic MCF10CA1a cells, suggesting that Gemini Vitamin D3 analogs may be more effective in preventing the progression of an early stage of breast carcinogenesis than in treating late stage breast cancer.

Wen, Yu, SF Giardina, Hamming, Jennifer Greenman, Zachariah, Bacolod, Hao Liu, Shia Jinru, Peter Amenta, Francis Barany, Phillip Paty, William Gerald, and Daniel Notterman. “GROα Is Highly Expressed in Adenocarcinoma of the Colonand Down-Regulates Fibulin-1.” Clinical Cancer Research 12.20 (2006): 5951–5959.

2005

Tsafrir, Tsafrir, Ein-Dor, Zuk, Daniel Notterman, and Domany. “Sorting Points into Neighborhoods (SPIN): Data Analysis and Visualization by Ordering Distance Matrices..” Bioinformatics 21 (2005): 2301–2308.

Summary: We introduce a novel unsupervised approach for the organization and visualization of multidimensional data. At the heart of the method is a presentation of the full pairwise distance matrix of the data points, viewed in pseudocolor. The ordering of points is iteratively permuted in search of a linear ordering, which can be used to study embedded shapes. Several examples indicate how the shapes of certain structures in the data (elongated, circular and compact) manifest themselves visually in our permuted distance matrix. It is important to identify the elongated objects since they are often associated with a set of hidden variables, underlying continuous variation in the data. The problem of determining an optimal linear ordering is shown to be NP-Complete, and therefore an iterative search algorithm with O(n3) step-complexity is suggested. By using sorting points into neighborhoods, i.e. SPIN to analyze colon cancer expression data we were able to address the serious problem of sample heterogeneity, which hinders identification of metastasis related genes in our data. Our methodology brings to light the continuous variation of heterogeneity—starting with homogeneous tumor samples and gradually increasing the amount of another tissue. Ordering the samples according to their degree of contamination by unrelated tissue allows the separation of genes associated with irrelevant contamination from those related to cancer progression.

Schaar, Lui, Sharma, Ting, Martin, Krier, Ciardella, Osman, Goodell, Daniel Notterman, and Strair. “12-O-Tetradecanoylphorbol-13-Acetate (TPA)-Induced Dual-Specificity Phosphatase Expression and AML Cell Survival..” Leukemia Research 29.10 (2005): 1171–9.

12-O-Tetradecanoylphorbol-13-acetate (TPA) is being developed as a therapeutic agent by virtue of its being a potent modulator of signal transduction in pre-clinical models of AML [Strair RK, Schaar D, Goodell L, Aisner J, Chin KV, Eid J, et al. Administration of a phorbol ester to patients with hematological malignancies: preliminary results from a phase I clinical trial of 12-O-tetradecanoylphorbol-13-acetate. Clin Cancer Res 2002;8:2512-8]. In this report, we identify a subset of primary AML samples that undergoes apoptosis after exposure to TPA and demonstrate that TPA-induced cytotoxicity is associated with modulation of the ERK signaling pathway. Analysis of mitogen-activated protein kinase (MAPK) dual-specificity phosphatases (DUSP), as potential regulators of AML cell signaling, indicates that these genes are coordinately regulated and rapidly induced by TPA in primary AML cells. Therefore, TPA-induced primary AML cytotoxicity is associated with modulation of ERK signaling which may be partially mediated by regulation of phosphatase expression.

2003

Getz, Gal, Kela, Daniel Notterman, and Domany. “Coupled Two-Way Clustering Analysis of Breast Cancer and Colon Cancer Gene Expression Data..” Bioinformatics 19.9 (2003): 1079–1089.

We present and review coupled two-way clustering, a method designed to mine gene expression data. The method identifies submatrices of the total expression matrix, whose clustering analysis reveals partitions of samples (and genes) into biologically relevant classes. We demonstrate, on data from colon and breast cancer, that we are able to identify partitions that elude standard clustering analysis

2001

Yagiela, JA, CJ Cote, Daniel Notterman, HW Karl, JA Weinberg, and McCloskey. “Adverse Sedation Events in Pediatrics.” Pediatrics 107.6 (2001): 1494.
OBJECTIVE:

Factors that contribute to adverse sedation events in children undergoing procedures were examined using the technique of critical incident analysis.

METHODOLOGY:

We developed a database that consists of descriptions of adverse sedation events derived from the Food and Drug Administration's adverse drug event reporting system, from the US Pharmacopeia, and from a survey of pediatric specialists. One hundred eighteen reports were reviewed for factors that may have contributed to the adverse sedation event. The outcome, ranging in severity from death to no harm, was noted. Individual reports were first examined separately by 4 physicians trained in pediatric anesthesiology, pediatric critical care medicine, or pediatric emergency medicine. Only reports for which all 4 reviewers agreed on the contributing factors and outcome were included in the final analysis.

RESULTS:

Of the 95 incidents with consensus agreement on the contributing factors, 51 resulted in death, 9 in permanent neurologic injury, 21 in prolonged hospitalization without injury, and in 14 there was no harm. Patients receiving sedation in nonhospital-based settings compared with hospital-based settings were older and healthier. The venue of sedation was not associated with the incidence of presenting respiratory events (eg, desaturation, apnea, laryngospasm, approximately 80% in each venue) but more cardiac arrests occurred as the second (53.6% vs 14%) and third events (25% vs 7%) in nonhospital-based facilities. Inadequate resuscitation was rated as being a determinant of adverse outcome more frequently in nonhospital-based events (57.1% vs 2.3%). Death and permanent neurologic injury occurred more frequently in nonhospital-based facilities (92.8% vs 37.2%). Successful outcome (prolonged hospitalization without injury or no harm) was associated with the use of pulse oximetry compared with a lack of any documented monitoring that was associated with unsuccessful outcome (death or permanent neurologic injury). In addition, pulse oximetry monitoring of patients sedated in hospitals was uniformly associated with successful outcomes whereas in the nonhospital-based venue, 4 out of 5 suffered adverse outcomes. Adverse outcomes despite the benefit of an early warning regarding oxygenation likely reflect lack of skill in assessment and in the use of appropriate interventions, ie, a failure to rescue the patient.

CONCLUSIONS:

This study-a critical incident analysis-identifies several features associated with adverse sedation events and poor outcome. There were differences in outcomes for venue: adverse outcomes (permanent neurologic injury or death) occurred more frequently in a nonhospital-based facility, whereas successful outcomes (prolonged hospitalization or no harm) occurred more frequently in a hospital-based setting. Inadequate resuscitation was more often associated with a nonhospital-based setting. Inadequate and inconsistent physiologic monitoring (particularly failure to use or respond appropriately to pulse oximetry) was another major factor contributing to poor outcome in all venues. Other issues rated by the reviewers were: inadequate presedation medical evaluation, lack of an independent observer, medication errors, and inadequate recovery procedures. Uniform, specialty-independent guidelines for monitoring children during and after sedation are essential. Age and size-appropriate equipment and medications for resuscitation should be immediately available regardless of the location where the child is sedated. All health care providers who sedate children, regardless of practice venue, should have advanced airway assessment and management training and be skilled in the resuscitation of infants and children so that they can successfully rescue their patient should an adverse sedation event occur.

Facer, LI Sohn, and Daniel Notterman. “Dielectric Spectroscopy: 40 Hz to 20.5 GHz in a Microfabricated Waveguide..” API 78 (2001): 996–998. Print.
Using an oligonucleotide array containing sequences complementary to approximately 3200 full-length human cDNAs and 3400 expressed sequence tags (GeneChip, Affymetrix), mRNA expression patterns were probed in 18 colon adenocarcinomas and 4 adenomas. Paired normal tissue was available and analyzed for each of the tumors. Relatively few changes in transcript expression are associated with colon cancer. Nineteen transcripts (0.48% of those detected) had at least 4-10.5-fold higher mRNA expression in carcinoma compared with paired normal samples, whereas 47 transcripts (1.3% of those detected) had at least 4-38-fold or lower expression in the tumor tissue compared with the normal samples. Some of these differences were confirmed by reverse transcription-PCR. Many of these transcripts were already known to be abnormally expressed in neoplastic tissue in general, or colon cancer in particular, and several of these differences were also observed in premalignant adenoma samples. A two-way hierarchical clustering algorithm successfully distinguished adenoma from adenocarcinoma and normal tissue, generating a phylogenetic tree that appropriately represented the clinical relationship between the three tissue types included in the analysis. This supports the concept that genome-wide expression profiling may permit a molecular classification of solid tumors.

2000

Zhao, Gish, Murphy, Yin, Notterman, Hoffman, Tom, Mack, and Levine. “The Transcriptional Program Following p53 Activation..” Cold Spring Harb Symp Quant Biol 65 (2000): 475–82. Print.
Sohn, Saleh, Facer, Beavis, Allan, and Notterman. “Capacitance Cytometry: Measuring Biological Cells One by One..” Proc Natl Acad Sci U S A 97.20 (2000): 10687–90.
Measuring the DNA content of eukaryotic cells is a fundamental task in biology and medicine. We have observed a linear relationship between the DNA content of eukaryotic cells and the change in capacitance that is evoked by the passage of individual cells across a 1-kHz electric field. This relationship is species-independent; consequently, we have developed a microfluidic technique-"capacitance cytometry"-that can be used to quantify the DNA content of single eukaryotic cells and to analyze the cell-cycle kinetics of populations of cells. Comparisons with standard flow cytometry demonstrate the sensitivity of this new technique.
Zhao, Gish, Murphy, Yin, Notterman, Hoffman, Tom, Mack, and Levine. “Analysis of p53-Regulated Gene Expression Patterns Using Oligonucleotide Arrays..” Genes Dev 14.8 (2000): 981–93. Print.
Oligonucleotide microarrays were employed to quantitate mRNA levels from a large number of genes regulated by the p53 transcription factor. Responses to DNA damage and to zinc-inducible p53 were compared for their transcription patterns in cell culture. A cluster analysis of these data demonstrates that genes induced by gamma radiation, UV radiation, and the zinc-induced p53 form distinct sets and subsets with a few genes in common to all these treatments. Cell type- or cell line-specific p53 responses were detected. When p53 proteins were induced with zinc, the kinetics of induction or repression of mRNAs from p53-responsive genes fell into eight distinct classes, five different kinetics of induction, and three different kinetics of repression. In addition, low levels of p53 in a cell induced or repressed only a subset of genes observed at higher p53 levels. The results of this study demonstrate that the nature of the p53 response in diverse mRNA species depends on the levels of p53 protein in a cell, the type of inducing agent or event, and the cell type employed. Of 6000 genes examined for p53 regulatory responses, 107 induced and 54 repressed genes fell into categories of apoptosis and growth arrest, cytoskeletal functions, growth factors and their inhibitors, extracellular matrix, and adhesion genes.

1999

Alon, Barkai, Notterman, Gish, Ybarra, Mack, and Levine. “Broad Patterns of Gene Expression Revealed by Clustering Analysis of Tumor and Normal Colon Tissues Probed by Oligonucleotide Arrays..” Proc Natl Acad Sci U S A 96.12 (1999): 6745–50. Print.
Oligonucleotide arrays can provide a broad picture of the state of the cell, by monitoring the expression level of thousands of genes at the same time. It is of interest to develop techniques for extracting useful information from the resulting data sets. Here we report the application of a two-way clustering method for analyzing a data set consisting of the expression patterns of different cell types. Gene expression in 40 tumor and 22 normal colon tissue samples was analyzed with an Affymetrix oligonucleotide array complementary to more than 6,500 human genes. An efficient two-way clustering algorithm was applied to both the genes and the tissues, revealing broad coherent patterns that suggest a high degree of organization underlying gene expression in these tissues. Coregulated families of genes clustered together, as demonstrated for the ribosomal proteins. Clustering also separated cancerous from noncancerous tissue and cell lines from in vivo tissues on the basis of subtle distributed patterns of genes even when expression of individual genes varied only slightly between the tissues. Two-way clustering thus may be of use both in classifying genes into functional groups and in classifying tissues based on gene expression.

1998

The tumor suppressor p53 has been identified as a component of a mitotic spindle checkpoint. When exposed to a spindle-disrupting drug such as nocodazole, fibroblasts derived from mice having wild-type p53 are blocked with a 4N content of DNA. Conversely, fibroblasts from p53-deficient mice become polyploid. To learn if transcriptional activation of downstream genes by p53 plays a role in this putative checkpoint, three cell lines were exposed to nocodazole. In one line, p53 protein is not expressed, while the other two cell lines over-express p53. In one of these two lines, the N-terminal transactivation domain is wild-type and in the second, this region contains a mutation that eliminates the ability of the protein to act as a transcription factor. Incubation with nocodazole of cells containing wild-type p53 results in accumulation of both 2N and 4N populations of cells. Under the same conditions, cells containing a transactivation-deficient mutant of p53 accumulate a 4N population of cells, but not a 2N population of cells. Cells entirely deficient in p53 protein become hyperdiploid, and display 8N to 16N DNA content. In all three cell lines, nocodazole elicited an initial increase in mitotic cells, but within 24 h the mitotic index returned to baseline. Expression patterns of cyclins B and D indicated that following entry into mitosis, the cells returned to a G1 state but with 4N DNA content. Subsequent re-duplication of DNA beyond 4N is prevented in cells containing either wild-type or transcriptionally inactive p53 protein. In cells entirely lacking p53 protein, DNA is re-duplicated (without an intervening mitosis) and the cells become hyperdiploid. These experiments indicate that p53 does not participate in the transient mitotic arrest that follows spindle disruption, but is essential to prevent subsequent reduplication of DNA and the resulting hyperdiploid state. This function is intact in a mutant that is transcriptionally inactive.

1997

Recent studies indicate that disruption of the E-cadherin-mediated cell-cell adhesion system is frequently associated with human cancers of epithelial origin. Reduced levels of both E-cadherin and the associated protein, alpha-catenin, have been reported in human tumors. This report describes the characterization of a human ovarian carcinoma-derived cell line (Ov2008) which expresses a novel mutant form of the alpha-catenin protein lacking the extreme N terminus of the wild-type protein. The altered form of alpha-catenin expressed in Ov2008 cells fails to bind efficiently to beta-catenin and is localized in the cytoplasm. Deletion mapping has localized the beta-catenin binding site on alpha-catenin between amino acids 46 and 149, which encompasses the same region of the protein that is deleted in the Ov2008 variant. Restoration of inducible expression of the wild-type alpha-catenin protein in these cells caused them to assume the morphology typical of an epithelial sheet and retarded their growth in vitro. Additionally, the induction of alpha-catenin expression in Ov2008 cells injected into nude mice attenuated the ability of these cells to form tumors. These observations support the classification of alpha-catenin as a growth-regulatory and candidate tumor suppressor gene.

1994

Levine, Chang, Dittmer, Notterman, Silver, Thorn, Welsh, and Wu. “The p53 Tumor Suppressor Gene..” J Lab Clin Med 123.6 (1994): 817–23. Print.

Contact

Faculty Assistant

Ellen Brindle-Clark
Thomas Laboratory, 230
ebrindle@princeton.edu
p: 609-258-5419

Notterman Lab Website
molbiolabs.princeton.edu/notterman