James Brody - Academia.edu (original) (raw)

Papers by James Brody

Research paper thumbnail of Identification of the protein Zibra, its genomic organization, regulation, and expression in breast cancer cells

Experimental Cell Research, May 1, 2004

Research paper thumbnail of Electrochemiluminescence as a tool for microscopy at the nanoscale

SPIE Proceedings, 2004

The particular form of electrochemiluminescence (ECL) used for analytical assays relies upon the ... more The particular form of electrochemiluminescence (ECL) used for analytical assays relies upon the discovery that tris(2,2-bipyridyl)ruthenium(II) (Ru(bpy) 2+ 3) emits a 620 nm photon when adjacent to an electrode held at about one volt relative to Ag/AgCl. This reaction occurs within nanometers of the electrode. The enormous economic investment in nanoscale lithography tools is leading to tools capable of routinely producing 32 nm features by 2009. We propose that these two technologies could be combined to produce a nanoscale microscopy system. We constructed a macroscopic test-bed and performed tests on it to explore the feasibility of such a system. We tested an ECL solution containing 1 mM Ru(bpy) 2+ 3 0.2 mM ammonium oxalate monohydrate in a 0.1 M ammonium acetate buffer at pH 5.0. Using this solution, we found that the ECL light was most intense at an applied voltage of 1.6 Volts, that the effect had excellent reproducibility and that the time to reach maximum intensity was several seconds after applying a voltage.

Research paper thumbnail of Genetic Risk Score for Predicting Schizophrenia Using Human Chromosomal-Scale Length Variation

Studies indicate that schizophrenia has a genetic component, however it cannot be isolated to a s... more Studies indicate that schizophrenia has a genetic component, however it cannot be isolated to a single gene. We aimed to determine how well one could predict that a person will develop schizophrenia based on their germ line genetics. We compared 1129 people from the UK Biobank dataset who had a diagnosis of schizophrenia to an equal number of age matched people drawn from the general UK Biobank population. For each person, we constructed a profile consisting of numbers. Each number characterized the length of segments of chromosomes. We tested several machine learning algorithms to determine which was most effective in predicting schizophrenia and if any improvement in prediction occurs by breaking the chromosomes into smaller chunks. We found that the stacked ensemble, performed best with an area under the receiver operating characteristic curve (AUC) of 0.545 (95% CI 0.539-0.550). We noted an increase in the AUC by breaking the chromosomes into smaller chunks for analysis. Using S...

Research paper thumbnail of Additional file 2: of Laboratory tests as short-term correlates of stroke

The Relative Risk (with confidence intervals), the correlations computed between different tests,... more The Relative Risk (with confidence intervals), the correlations computed between different tests, the description and range of observed values for each test. (XLSX 48 kb)

Research paper thumbnail of Additional file 1: Table S1. of Laboratory tests as short-term correlates of stroke

Racial/ethnic distribution of patients in the dataset. Table S2. Correlations between different l... more Racial/ethnic distribution of patients in the dataset. Table S2. Correlations between different laboratory tests. (PDF 277 kb)

Research paper thumbnail of A genetic risk score for glioblastoma multiforme based on copy number variations

Cancer Treatment and Research Communications, 2021

Glioblastoma multiforme is the most common form of brain cancer. Several lines of evidence sugges... more Glioblastoma multiforme is the most common form of brain cancer. Several lines of evidence suggest that glioblastoma multiforme has a genetic basis. A genetic test that could identify people who are at high risk of developing glioblastoma multiforme could improve our understanding of this form of brain cancer. Using the Cancer Genome Atlas (TCGA) dataset, we found common germ line DNA copy number variations in the TCGA population. We tested whether different sets of these germ line DNA copy number variations could effectively distinguish patients with glioblastoma multiforme from others in the TCGA dataset. We used a gradient boosting machine, a machine learning classification algorithm, to classify TCGA patients solely based on a set of germline DNA copy number variations. We found that this machine learning algorithm could classify TCGA glioblastoma multiforme patients from the other TCGA patients with an area under the curve (AUC) of the receiver operating characteristic curve (AUC=0.875). Grouped into quintiles, the highest ranked quintile by the machine learning algorithm had an odds ratio of 3.78 (95% CI 3.25-4.40) higher than the average odds ratio and about 40 (95% CI 20-70) times higher than the lowest quintile. The identification of an effective germ line genetic test to stratify risk of developing glioblastoma multiforme should lead to a better understanding of how this cancer forms. This result might ultimately lead to better treatments of glioblastoma multiforme.

Research paper thumbnail of A genetic risk score using human chromosomal-scale length variation can predict schizophrenia

Scientific Reports, 2021

Studies indicate that schizophrenia has a genetic component, however it cannot be isolated to a s... more Studies indicate that schizophrenia has a genetic component, however it cannot be isolated to a single gene. We aimed to determine how well one could predict that a person will develop schizophrenia based on their germ line genetics. We compared 1129 people from the UK Biobank dataset who had a diagnosis of schizophrenia to an equal number of age matched people drawn from the general UK Biobank population. For each person, we constructed a profile consisting of numbers. Each number characterized the length of segments of chromosomes. We tested several machine learning algorithms to determine which was most effective in predicting schizophrenia and if any improvement in prediction occurs by breaking the chromosomes into smaller chunks. We found that the stacked ensemble, performed best with an area under the receiver operating characteristic curve (AUC) of 0.545 (95% CI 0.539–0.550). We noted an increase in the AUC by breaking the chromosomes into smaller chunks for analysis. Using S...

Research paper thumbnail of Genetic risk score for ovarian cancer based on chromosomal-scale length variation

IntroductionTwin studies indicate that a substantial fraction of ovarian cancers should be predic... more IntroductionTwin studies indicate that a substantial fraction of ovarian cancers should be predictable from genetic testing. Genetic risk scores can stratify women into different classes of risk. Higher risk women can be treated or screened for ovarian cancer, which should reduce overall death rates due to ovarian cancer. However, current ovarian cancer genetic risk scores, based on SNPs, do not work that well. We developed a genetic risk score based on structural variation, quantified by variations in the length of chromosomes.MethodsWe evaluated this genetic risk score using data collected by The Cancer Genome Atlas. From this dataset, we synthesized a dataset of 414 women who had ovarian serous carcinoma and 4225 women who had no form of ovarian cancer. We characterized each woman by 22 numbers, representing the length of each chromosome in their germ line DNA. We used a gradient boosting machine, a machine learning algorithm, to build a classifier that can predict whether a woma...

Research paper thumbnail of Analysis of copy number variation from germline DNA can predict individual cancer risk

BACKGROUND: Twin studies suggest that inherited factors are responsible for a substantial portion... more BACKGROUND: Twin studies suggest that inherited factors are responsible for a substantial portion of many different forms of cancer. However, most of these inherited factors have yet to be identified. Most analyses of genome wide association data focus on the additive effects of single nucleotide polymorphisms found in germline DNA. The objective of this study is to test whether germline DNA copy number variation data can be used to predict whether a person will develop cancer. METHODS: We tested this objective using data compiled by The Cancer Genome Atlas (TCGA) project. The TCGA data consisted of information on DNA copy number variation extracted from the peripheral blood of 8,821 different patients, each of whom had one of 32 different types of cancer. We used a machine-learning algorithm to test how well we could classify whether or not a patient had a certain cancer based solely on this data. RESULTS: We found that all 32 different types of cancer tested could be predicted bet...

Research paper thumbnail of Laboratory tests as short-term correlates of stroke

BMC neurology, Jan 21, 2016

The widespread adoption of electronic health records provides new opportunities to better predict... more The widespread adoption of electronic health records provides new opportunities to better predict which patients are likely to suffer a stroke. Using electronic health records, we assessed the correlation of different laboratory tests to future occurrences of a stroke. We examined the electronic health records of 2.4 million people over a two year time span. These records contained 26,964 diagnoses of stroke. Using Cox regression analysis, we measured whether any one of 1796 different laboratory tests were effectively correlated with a future diagnosis of stroke. We identified 38 different laboratory tests that had significant short-term (two year) prognostic value for a future diagnosis of stroke. For each of the 38 laboratory tests we also compiled the Kaplan-Meier survival curve, and relative risk ratio that the test confers. Several dozen laboratory tests are effective short-term correlates of stroke.

Research paper thumbnail of The Age Specific Incidence Anomaly Suggests that Cancers Originate During Development

Biophysical Reviews and Letters, 2014

The accumulation of genetic alterations causes cancers. Since this accumulation takes time, the i... more The accumulation of genetic alterations causes cancers. Since this accumulation takes time, the incidence of most cancers is thought to increase exponentially with age. However, careful measurements of the age-specific incidence show that the specific incidence for many forms of cancer rises with age to a maximum, and then decreases. This decrease in the age-specific incidence with age is an anomaly. Understanding this anomaly should lead to a better understanding of how tumors develop and grow. Here we derive the shape of the age-specific incidence, showing that it should follow the shape of a Weibull distribution. Measurements indicate that the age-specific incidence for colon cancer does indeed follow a Weibull distribution. This analysis leads to the interpretation that for colon cancer two subpopulations exist in the general population: a susceptible population and an immune population. Colon tumors will only occur in the susceptible population. This analysis is consistent with...

Research paper thumbnail of Prominent microscopic effects in microfabricated fluidic analysis systems

SPIE Proceedings, 1997

Microfabricated fluidic systems allow complex chemical analyses to be performed on sub-nanoliter ... more Microfabricated fluidic systems allow complex chemical analyses to be performed on sub-nanoliter volumes of sample. Compared to macroscopic systems, these devices offer many advantages, including the promise of performing some analytical functions more rapidly and on smaller samples. However, miniaturization of analytic instruments is not simply a matter of reducing their size. At small scales, different effects become more prominent,

Research paper thumbnail of <title>New assay for multiple single molecule enzyme kinetics</title>

Imaging, Manipulation, and Analysis of Biomolecules and Cells: Fundamentals and Applications III, 2005

Research paper thumbnail of <title>Using poly(ethylene glycol) silane to prevent protein adsorption in microfabricated silicon channels</title>

Micro- and Nanofabricated Structures and Devices for Biomedical Environmental Applications, 1998

ABSTRACT

Research paper thumbnail of Reverse Engineering the Yeast RNR1 Transcriptional Control System

PLoS ONE, 2010

Transcription is controlled by multi-protein complexes binding to short non-coding regions of gen... more Transcription is controlled by multi-protein complexes binding to short non-coding regions of genomic DNA. These complexes interact combinatorially. A major goal of modern biology is to provide simple models that predict this complex behavior. The yeast gene RNR1 is transcribed periodically during the cell cycle. Here, we present a pilot study to demonstrate a new method of deciphering the logic behind transcriptional regulation. We took regular samples from cell cycle synchronized cultures of Saccharomyces cerevisiae and extracted nuclear protein. We tested these samples to measure the amount of protein that bound to seven different 16 base pair sequences of DNA that have been previously identified as protein binding locations in the promoter of the RNR1 gene. These tests were performed using surface plasmon resonance. We found that the surface plasmon resonance signals showed significant variation throughout the cell cycle. We correlated the protein binding data with previously published mRNA expression data and interpreted this to show that transcription requires protein bound to a particular site and either five different sites or one additional sites. We conclude that this demonstrates the feasibility of this approach to decipher the combinatorial logic of transcription.

Research paper thumbnail of Similarities in the Age-Specific Incidence of Colon and Testicular Cancers

PLoS ONE, 2013

Colon cancers are thought to be an inevitable result of aging, while testicular cancers are thoug... more Colon cancers are thought to be an inevitable result of aging, while testicular cancers are thought to develop in only a small fraction of men, beginning in utero. These models of carcinogenesis are, in part, based upon age-specific incidence data. The specific incidence for colon cancer appears to monotonically increase with age, while that of testicular cancer increases to a maximum value at about 35 years of age, then declines to nearly zero by the age of 80. We hypothesized that the agespecific incidence for these two cancers is similar; the apparent difference is caused by a longer development time for colon cancer and the lack of age-specific incidence data for people over 84 years of age. Here we show that a single distribution can describe the age-specific incidence of both colon carcinoma and testicular cancer. Furthermore, this distribution predicts that the specific incidence of colon cancer should reach a maximum at about age 90 and then decrease. Data on the incidence of colon carcinoma for women aged 85-99, acquired from SEER and the US Census, is consistent with this prediction. We conclude that the age specific data for testicular cancers and colon cancers is similar, suggesting that the underlying process leading to the development of these two forms of cancer may be similar.

Research paper thumbnail of A theory of the cancer age-specific incidence data based on extreme value distributions

AIP Advances, 2012

The incidence of cancers varies with age, if normalized this is called the age-specific incidence... more The incidence of cancers varies with age, if normalized this is called the age-specific incidence. A mathematical model that describes this variation should provide a better understanding of how cancers develop. We suggest that the age-specific incidence should follow an extreme value distribution, based on three widely accepted assumptions: (1) a tumor develops from a single cell, (2) many potential tumor progenitor cells exist in a tissue, and (3) cancer is diagnosed when the first of these many potential tumor cells develops into a tumor. We tested this by comparing the predicted distribution to the age-specific incidence data for colon and prostate carcinomas collected by the Surveillance, Epidemiology and End Results network of 17 cancer registries. We found that colon carcinoma age-specific incidence data is consistent with an extreme value distribution, while prostate carcinomas age-specific incidence data generally follows the distribution. This model indicates that both colon and prostate carcinomas only occur in a subset of the population (22% for prostate and 13.5% for colon.) Because of their very general nature, extreme value distributions might be applicable to understanding other chronic human diseases.

Research paper thumbnail of Age-Specific Incidence Data Indicate Four Mutations Are Required for Human Testicular Cancers

PLoS ONE, 2011

Normal human cells require a series of genetic alterations to undergo malignant transformation. D... more Normal human cells require a series of genetic alterations to undergo malignant transformation. Direct sequencing of human tumors has identified hundreds of mutations in tumors, but many of these are thought to be unnecessary and a result of, rather than a cause of, the tumor. The exact number of mutations to transform a normal human cell into a tumor cell is unknown. Here I show that male gonadal germ cell tumors, the most common form of testicular cancers, occur after four mutations. I infer this by constructing a mathematical model based upon the multi-hit hypothesis and comparing it to the age-specific incidence data. This result is consistent with the multi-hit hypothesis, and implies that these cancers are genetically or epigenetically predetermined at birth or an early age.

Research paper thumbnail of Parallel Routes of Human Carcinoma Development: Implications of the Age-Specific Incidence Data

PLoS ONE, 2009

The multi-stage hypothesis suggests that cancers develop through a single defined series of genet... more The multi-stage hypothesis suggests that cancers develop through a single defined series of genetic alterations. This hypothesis was first suggested over 50 years ago based upon age-specific incidence data. However, recent molecular studies of tumors indicate that multiple routes exist to the formation of cancer, not a single route. This parallel route hypothesis has not been tested with age-specific incidence data. To test the parallel route hypothesis, I formulated it in terms of a mathematical equation, confirmed this equation with computer simulations, then tested whether this equation was consistent with age-specific incidence data compiled by the Surveillance Epidemiology and End Results (SEER) cancer registries since 1973. I used the chi-squared goodness of fit test to measure consistency. I found that the age-specific incidence data from most human carcinomas, including those of the colon, lung, prostate, and breast were consistent with the parallel route hypothesis. However, this hypothesis is only consistent if an immune sub-population exists, one that will never develop carcinoma. Furthermore, breast carcinoma has two distinct forms of the disease, and one of these occurs at significantly different rates in different racial groups. I conclude that the parallel route hypothesis is consistent with the age-specific incidence data only if carcinoma occurs in a distinct sub population.

Research paper thumbnail of Diversity in the Activity of Individual Enzymes

Current Pharmaceutical Biotechnology, 2005

Although the structure of an enzyme is often depicted as static, it is dynamic. Hence, a populati... more Although the structure of an enzyme is often depicted as static, it is dynamic. Hence, a population of chemically identical enzymes has not one, but a distribution of structures at any moment in time. Does this have an effect on the activity of the enzyme? This article reviews experiments designed to test the hypothesis that this distribution of structures results in a distribution of enzyme activities. The experiments reviewed here use different enzymes, falvin adenine dinucleotide, P-galactosidase, alkaline phosphatase, exonuclease I, lactate dehydrogenase I, a-chymotrypsin. the 20s proteasome, and horseradish peroxidase. All experiments come to the same conclusion, when measured individually, apparently identical enzymes show a distribution in rates of activity.

Research paper thumbnail of Identification of the protein Zibra, its genomic organization, regulation, and expression in breast cancer cells

Experimental Cell Research, May 1, 2004

Research paper thumbnail of Electrochemiluminescence as a tool for microscopy at the nanoscale

SPIE Proceedings, 2004

The particular form of electrochemiluminescence (ECL) used for analytical assays relies upon the ... more The particular form of electrochemiluminescence (ECL) used for analytical assays relies upon the discovery that tris(2,2-bipyridyl)ruthenium(II) (Ru(bpy) 2+ 3) emits a 620 nm photon when adjacent to an electrode held at about one volt relative to Ag/AgCl. This reaction occurs within nanometers of the electrode. The enormous economic investment in nanoscale lithography tools is leading to tools capable of routinely producing 32 nm features by 2009. We propose that these two technologies could be combined to produce a nanoscale microscopy system. We constructed a macroscopic test-bed and performed tests on it to explore the feasibility of such a system. We tested an ECL solution containing 1 mM Ru(bpy) 2+ 3 0.2 mM ammonium oxalate monohydrate in a 0.1 M ammonium acetate buffer at pH 5.0. Using this solution, we found that the ECL light was most intense at an applied voltage of 1.6 Volts, that the effect had excellent reproducibility and that the time to reach maximum intensity was several seconds after applying a voltage.

Research paper thumbnail of Genetic Risk Score for Predicting Schizophrenia Using Human Chromosomal-Scale Length Variation

Studies indicate that schizophrenia has a genetic component, however it cannot be isolated to a s... more Studies indicate that schizophrenia has a genetic component, however it cannot be isolated to a single gene. We aimed to determine how well one could predict that a person will develop schizophrenia based on their germ line genetics. We compared 1129 people from the UK Biobank dataset who had a diagnosis of schizophrenia to an equal number of age matched people drawn from the general UK Biobank population. For each person, we constructed a profile consisting of numbers. Each number characterized the length of segments of chromosomes. We tested several machine learning algorithms to determine which was most effective in predicting schizophrenia and if any improvement in prediction occurs by breaking the chromosomes into smaller chunks. We found that the stacked ensemble, performed best with an area under the receiver operating characteristic curve (AUC) of 0.545 (95% CI 0.539-0.550). We noted an increase in the AUC by breaking the chromosomes into smaller chunks for analysis. Using S...

Research paper thumbnail of Additional file 2: of Laboratory tests as short-term correlates of stroke

The Relative Risk (with confidence intervals), the correlations computed between different tests,... more The Relative Risk (with confidence intervals), the correlations computed between different tests, the description and range of observed values for each test. (XLSX 48 kb)

Research paper thumbnail of Additional file 1: Table S1. of Laboratory tests as short-term correlates of stroke

Racial/ethnic distribution of patients in the dataset. Table S2. Correlations between different l... more Racial/ethnic distribution of patients in the dataset. Table S2. Correlations between different laboratory tests. (PDF 277 kb)

Research paper thumbnail of A genetic risk score for glioblastoma multiforme based on copy number variations

Cancer Treatment and Research Communications, 2021

Glioblastoma multiforme is the most common form of brain cancer. Several lines of evidence sugges... more Glioblastoma multiforme is the most common form of brain cancer. Several lines of evidence suggest that glioblastoma multiforme has a genetic basis. A genetic test that could identify people who are at high risk of developing glioblastoma multiforme could improve our understanding of this form of brain cancer. Using the Cancer Genome Atlas (TCGA) dataset, we found common germ line DNA copy number variations in the TCGA population. We tested whether different sets of these germ line DNA copy number variations could effectively distinguish patients with glioblastoma multiforme from others in the TCGA dataset. We used a gradient boosting machine, a machine learning classification algorithm, to classify TCGA patients solely based on a set of germline DNA copy number variations. We found that this machine learning algorithm could classify TCGA glioblastoma multiforme patients from the other TCGA patients with an area under the curve (AUC) of the receiver operating characteristic curve (AUC=0.875). Grouped into quintiles, the highest ranked quintile by the machine learning algorithm had an odds ratio of 3.78 (95% CI 3.25-4.40) higher than the average odds ratio and about 40 (95% CI 20-70) times higher than the lowest quintile. The identification of an effective germ line genetic test to stratify risk of developing glioblastoma multiforme should lead to a better understanding of how this cancer forms. This result might ultimately lead to better treatments of glioblastoma multiforme.

Research paper thumbnail of A genetic risk score using human chromosomal-scale length variation can predict schizophrenia

Scientific Reports, 2021

Studies indicate that schizophrenia has a genetic component, however it cannot be isolated to a s... more Studies indicate that schizophrenia has a genetic component, however it cannot be isolated to a single gene. We aimed to determine how well one could predict that a person will develop schizophrenia based on their germ line genetics. We compared 1129 people from the UK Biobank dataset who had a diagnosis of schizophrenia to an equal number of age matched people drawn from the general UK Biobank population. For each person, we constructed a profile consisting of numbers. Each number characterized the length of segments of chromosomes. We tested several machine learning algorithms to determine which was most effective in predicting schizophrenia and if any improvement in prediction occurs by breaking the chromosomes into smaller chunks. We found that the stacked ensemble, performed best with an area under the receiver operating characteristic curve (AUC) of 0.545 (95% CI 0.539–0.550). We noted an increase in the AUC by breaking the chromosomes into smaller chunks for analysis. Using S...

Research paper thumbnail of Genetic risk score for ovarian cancer based on chromosomal-scale length variation

IntroductionTwin studies indicate that a substantial fraction of ovarian cancers should be predic... more IntroductionTwin studies indicate that a substantial fraction of ovarian cancers should be predictable from genetic testing. Genetic risk scores can stratify women into different classes of risk. Higher risk women can be treated or screened for ovarian cancer, which should reduce overall death rates due to ovarian cancer. However, current ovarian cancer genetic risk scores, based on SNPs, do not work that well. We developed a genetic risk score based on structural variation, quantified by variations in the length of chromosomes.MethodsWe evaluated this genetic risk score using data collected by The Cancer Genome Atlas. From this dataset, we synthesized a dataset of 414 women who had ovarian serous carcinoma and 4225 women who had no form of ovarian cancer. We characterized each woman by 22 numbers, representing the length of each chromosome in their germ line DNA. We used a gradient boosting machine, a machine learning algorithm, to build a classifier that can predict whether a woma...

Research paper thumbnail of Analysis of copy number variation from germline DNA can predict individual cancer risk

BACKGROUND: Twin studies suggest that inherited factors are responsible for a substantial portion... more BACKGROUND: Twin studies suggest that inherited factors are responsible for a substantial portion of many different forms of cancer. However, most of these inherited factors have yet to be identified. Most analyses of genome wide association data focus on the additive effects of single nucleotide polymorphisms found in germline DNA. The objective of this study is to test whether germline DNA copy number variation data can be used to predict whether a person will develop cancer. METHODS: We tested this objective using data compiled by The Cancer Genome Atlas (TCGA) project. The TCGA data consisted of information on DNA copy number variation extracted from the peripheral blood of 8,821 different patients, each of whom had one of 32 different types of cancer. We used a machine-learning algorithm to test how well we could classify whether or not a patient had a certain cancer based solely on this data. RESULTS: We found that all 32 different types of cancer tested could be predicted bet...

Research paper thumbnail of Laboratory tests as short-term correlates of stroke

BMC neurology, Jan 21, 2016

The widespread adoption of electronic health records provides new opportunities to better predict... more The widespread adoption of electronic health records provides new opportunities to better predict which patients are likely to suffer a stroke. Using electronic health records, we assessed the correlation of different laboratory tests to future occurrences of a stroke. We examined the electronic health records of 2.4 million people over a two year time span. These records contained 26,964 diagnoses of stroke. Using Cox regression analysis, we measured whether any one of 1796 different laboratory tests were effectively correlated with a future diagnosis of stroke. We identified 38 different laboratory tests that had significant short-term (two year) prognostic value for a future diagnosis of stroke. For each of the 38 laboratory tests we also compiled the Kaplan-Meier survival curve, and relative risk ratio that the test confers. Several dozen laboratory tests are effective short-term correlates of stroke.

Research paper thumbnail of The Age Specific Incidence Anomaly Suggests that Cancers Originate During Development

Biophysical Reviews and Letters, 2014

The accumulation of genetic alterations causes cancers. Since this accumulation takes time, the i... more The accumulation of genetic alterations causes cancers. Since this accumulation takes time, the incidence of most cancers is thought to increase exponentially with age. However, careful measurements of the age-specific incidence show that the specific incidence for many forms of cancer rises with age to a maximum, and then decreases. This decrease in the age-specific incidence with age is an anomaly. Understanding this anomaly should lead to a better understanding of how tumors develop and grow. Here we derive the shape of the age-specific incidence, showing that it should follow the shape of a Weibull distribution. Measurements indicate that the age-specific incidence for colon cancer does indeed follow a Weibull distribution. This analysis leads to the interpretation that for colon cancer two subpopulations exist in the general population: a susceptible population and an immune population. Colon tumors will only occur in the susceptible population. This analysis is consistent with...

Research paper thumbnail of Prominent microscopic effects in microfabricated fluidic analysis systems

SPIE Proceedings, 1997

Microfabricated fluidic systems allow complex chemical analyses to be performed on sub-nanoliter ... more Microfabricated fluidic systems allow complex chemical analyses to be performed on sub-nanoliter volumes of sample. Compared to macroscopic systems, these devices offer many advantages, including the promise of performing some analytical functions more rapidly and on smaller samples. However, miniaturization of analytic instruments is not simply a matter of reducing their size. At small scales, different effects become more prominent,

Research paper thumbnail of <title>New assay for multiple single molecule enzyme kinetics</title>

Imaging, Manipulation, and Analysis of Biomolecules and Cells: Fundamentals and Applications III, 2005

Research paper thumbnail of <title>Using poly(ethylene glycol) silane to prevent protein adsorption in microfabricated silicon channels</title>

Micro- and Nanofabricated Structures and Devices for Biomedical Environmental Applications, 1998

ABSTRACT

Research paper thumbnail of Reverse Engineering the Yeast RNR1 Transcriptional Control System

PLoS ONE, 2010

Transcription is controlled by multi-protein complexes binding to short non-coding regions of gen... more Transcription is controlled by multi-protein complexes binding to short non-coding regions of genomic DNA. These complexes interact combinatorially. A major goal of modern biology is to provide simple models that predict this complex behavior. The yeast gene RNR1 is transcribed periodically during the cell cycle. Here, we present a pilot study to demonstrate a new method of deciphering the logic behind transcriptional regulation. We took regular samples from cell cycle synchronized cultures of Saccharomyces cerevisiae and extracted nuclear protein. We tested these samples to measure the amount of protein that bound to seven different 16 base pair sequences of DNA that have been previously identified as protein binding locations in the promoter of the RNR1 gene. These tests were performed using surface plasmon resonance. We found that the surface plasmon resonance signals showed significant variation throughout the cell cycle. We correlated the protein binding data with previously published mRNA expression data and interpreted this to show that transcription requires protein bound to a particular site and either five different sites or one additional sites. We conclude that this demonstrates the feasibility of this approach to decipher the combinatorial logic of transcription.

Research paper thumbnail of Similarities in the Age-Specific Incidence of Colon and Testicular Cancers

PLoS ONE, 2013

Colon cancers are thought to be an inevitable result of aging, while testicular cancers are thoug... more Colon cancers are thought to be an inevitable result of aging, while testicular cancers are thought to develop in only a small fraction of men, beginning in utero. These models of carcinogenesis are, in part, based upon age-specific incidence data. The specific incidence for colon cancer appears to monotonically increase with age, while that of testicular cancer increases to a maximum value at about 35 years of age, then declines to nearly zero by the age of 80. We hypothesized that the agespecific incidence for these two cancers is similar; the apparent difference is caused by a longer development time for colon cancer and the lack of age-specific incidence data for people over 84 years of age. Here we show that a single distribution can describe the age-specific incidence of both colon carcinoma and testicular cancer. Furthermore, this distribution predicts that the specific incidence of colon cancer should reach a maximum at about age 90 and then decrease. Data on the incidence of colon carcinoma for women aged 85-99, acquired from SEER and the US Census, is consistent with this prediction. We conclude that the age specific data for testicular cancers and colon cancers is similar, suggesting that the underlying process leading to the development of these two forms of cancer may be similar.

Research paper thumbnail of A theory of the cancer age-specific incidence data based on extreme value distributions

AIP Advances, 2012

The incidence of cancers varies with age, if normalized this is called the age-specific incidence... more The incidence of cancers varies with age, if normalized this is called the age-specific incidence. A mathematical model that describes this variation should provide a better understanding of how cancers develop. We suggest that the age-specific incidence should follow an extreme value distribution, based on three widely accepted assumptions: (1) a tumor develops from a single cell, (2) many potential tumor progenitor cells exist in a tissue, and (3) cancer is diagnosed when the first of these many potential tumor cells develops into a tumor. We tested this by comparing the predicted distribution to the age-specific incidence data for colon and prostate carcinomas collected by the Surveillance, Epidemiology and End Results network of 17 cancer registries. We found that colon carcinoma age-specific incidence data is consistent with an extreme value distribution, while prostate carcinomas age-specific incidence data generally follows the distribution. This model indicates that both colon and prostate carcinomas only occur in a subset of the population (22% for prostate and 13.5% for colon.) Because of their very general nature, extreme value distributions might be applicable to understanding other chronic human diseases.

Research paper thumbnail of Age-Specific Incidence Data Indicate Four Mutations Are Required for Human Testicular Cancers

PLoS ONE, 2011

Normal human cells require a series of genetic alterations to undergo malignant transformation. D... more Normal human cells require a series of genetic alterations to undergo malignant transformation. Direct sequencing of human tumors has identified hundreds of mutations in tumors, but many of these are thought to be unnecessary and a result of, rather than a cause of, the tumor. The exact number of mutations to transform a normal human cell into a tumor cell is unknown. Here I show that male gonadal germ cell tumors, the most common form of testicular cancers, occur after four mutations. I infer this by constructing a mathematical model based upon the multi-hit hypothesis and comparing it to the age-specific incidence data. This result is consistent with the multi-hit hypothesis, and implies that these cancers are genetically or epigenetically predetermined at birth or an early age.

Research paper thumbnail of Parallel Routes of Human Carcinoma Development: Implications of the Age-Specific Incidence Data

PLoS ONE, 2009

The multi-stage hypothesis suggests that cancers develop through a single defined series of genet... more The multi-stage hypothesis suggests that cancers develop through a single defined series of genetic alterations. This hypothesis was first suggested over 50 years ago based upon age-specific incidence data. However, recent molecular studies of tumors indicate that multiple routes exist to the formation of cancer, not a single route. This parallel route hypothesis has not been tested with age-specific incidence data. To test the parallel route hypothesis, I formulated it in terms of a mathematical equation, confirmed this equation with computer simulations, then tested whether this equation was consistent with age-specific incidence data compiled by the Surveillance Epidemiology and End Results (SEER) cancer registries since 1973. I used the chi-squared goodness of fit test to measure consistency. I found that the age-specific incidence data from most human carcinomas, including those of the colon, lung, prostate, and breast were consistent with the parallel route hypothesis. However, this hypothesis is only consistent if an immune sub-population exists, one that will never develop carcinoma. Furthermore, breast carcinoma has two distinct forms of the disease, and one of these occurs at significantly different rates in different racial groups. I conclude that the parallel route hypothesis is consistent with the age-specific incidence data only if carcinoma occurs in a distinct sub population.

Research paper thumbnail of Diversity in the Activity of Individual Enzymes

Current Pharmaceutical Biotechnology, 2005

Although the structure of an enzyme is often depicted as static, it is dynamic. Hence, a populati... more Although the structure of an enzyme is often depicted as static, it is dynamic. Hence, a population of chemically identical enzymes has not one, but a distribution of structures at any moment in time. Does this have an effect on the activity of the enzyme? This article reviews experiments designed to test the hypothesis that this distribution of structures results in a distribution of enzyme activities. The experiments reviewed here use different enzymes, falvin adenine dinucleotide, P-galactosidase, alkaline phosphatase, exonuclease I, lactate dehydrogenase I, a-chymotrypsin. the 20s proteasome, and horseradish peroxidase. All experiments come to the same conclusion, when measured individually, apparently identical enzymes show a distribution in rates of activity.