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2.  Age Patterns of Geriatric Disease Incidences in the U.S. Elderly Population: Medicare-Based Analysis 
To utilize the Medicare Files of Service Use (MFSU) to evaluate patterns in the incidence of aging-related diseases in the U.S. elderly population.
Age-specific incidence rates of nineteen aging-related diseases were evaluated with the National Long Term Care Survey (NLTCS) and the Surveillance, Epidemiology, and End Results (SEER) Registry data both linked to MSUF (NLTCS-M and SEER-M, respectively), using a developed algorithm for individual date at onset evaluation.
A random sample from the entire U.S. elderly population (Medicare beneficiaries) was used in NLTCS, and 26% of U.S. population is covered by the SEER Registry data.
34,077 individuals from NLTCS-M and 2,154,598 from SEER-M.
Individual medical histories were reconstructed using information on diagnoses coded in MFSU, dates of medical services/procedures, and Medicare enrollment/disenrollment.
The majority of diseases (e.g., prostate cancer, asthma, diabetes) had a monotonic decline (or decline following short period of increase) in incidence with age. A monotonic increase of incidence with age with a subsequent leveling off and decline was observed for myocardial infarction, stroke, heart failure, ulcer, and Alzheimer’s disease. An inverted U-shaped age pattern was detected for lung and colon carcinomas, Parkinson’s disease, and renal failure. The results obtained from the NLTCS-M and SEER-M were in agreement (excluding an excess for circulatory diseases in the NLTCS-M). A sensitivity analysis proved the stability of the evaluated incidence rates.
The developed computational approaches applied to the nationally representative Medicare-based datasets allows reconstruction of age patterns of disease incidence in the U.S. elderly population at the national level with unprecedented statistical accuracy and stability with respect to systematic biases.
PMCID: PMC3288526  PMID: 22283485
Medicare; chronic disease onset; comorbidity
3.  Evaluating the Number of Stages in Development of Squamous Cell and Adenocarcinomas across Cancer Sites Using Human Population-Based Cancer Modeling 
PLoS ONE  2012;7(5):e37430.
Adenocarcinomas (ACs) and squamous cell carcinomas (SCCs) differ by clinical and molecular characteristics. We evaluated the characteristics of carcinogenesis by modeling the age patterns of incidence rates of ACs and SCCs of various organs to test whether these characteristics differed between cancer subtypes.
Methodology/Principal Findings
Histotype-specific incidence rates of 14 ACs and 12 SCCs from the SEER Registry (1973–2003) were analyzed by fitting several biologically motivated models to observed age patterns. A frailty model with the Weibull baseline was applied to each age pattern to provide the best fit for the majority of cancers. For each cancer, model parameters describing the underlying mechanisms of carcinogenesis including the number of stages occurring during an individual’s life and leading to cancer (m-stages) were estimated. For sensitivity analysis, the age-period-cohort model was incorporated into the carcinogenesis model to test the stability of the estimates. For the majority of studied cancers, the numbers of m-stages were similar within each group (i.e., AC and SCC). When cancers of the same organs were compared (i.e., lung, esophagus, and cervix uteri), the number of m-stages were more strongly associated with the AC/SCC subtype than with the organ: 9.79±0.09, 9.93±0.19 and 8.80±0.10 for lung, esophagus, and cervical ACs, compared to 11.41±0.10, 12.86±0.34 and 12.01±0.51 for SCCs of the respective organs (p<0.05 between subtypes). Most SCCs had more than ten m-stages while ACs had fewer than ten m-stages. The sensitivity analyses of the model parameters demonstrated the stability of the obtained estimates.
A model containing parameters capable of representing the number of stages of cancer development occurring during individual’s life was applied to the large population data on incidence of ACs and SCCs. The model revealed that the number of m-stages differed by cancer subtype being more strongly associated with ACs/SCCs histotype than with organ/site.
PMCID: PMC3358315  PMID: 22629394
4.  Transitional Probability-Based Model for HPV Clearance in HIV-1-Positive Adolescent Females 
PLoS ONE  2012;7(1):e30736.
HIV-1-positive patients clear the human papillomavirus (HPV) infection less frequently than HIV-1-negative. Datasets for estimating HPV clearance probability often have irregular measurements of HPV status and risk factors. A new transitional probability-based model for estimation of probability of HPV clearance was developed to fully incorporate information on HIV-1-related clinical data, such as CD4 counts, HIV-1 viral load (VL), highly active antiretroviral therapy (HAART), and risk factors (measured quarterly), and HPV infection status (measured at 6-month intervals).
Methodology and Findings
Data from 266 HIV-1-positive and 134 at-risk HIV-1-negative adolescent females from the Reaching for Excellence in Adolescent Care and Health (REACH) cohort were used in this study. First, the associations were evaluated using the Cox proportional hazard model, and the variables that demonstrated significant effects on HPV clearance were included in transitional probability models. The new model established the efficacy of CD4 cell counts as a main clearance predictor for all type-specific HPV phylogenetic groups. The 3-month probability of HPV clearance in HIV-1-infected patients significantly increased with increasing CD4 counts for HPV16/16-like (p<0.001), HPV18/18-like (p<0.001), HPV56/56-like (p = 0.05), and low-risk HPV (p<0.001) phylogenetic groups, with the lowest probability found for HPV16/16-like infections (21.60±1.81% at CD4 level 200 cells/mm3, p<0.05; and 28.03±1.47% at CD4 level 500 cells/mm3). HIV-1 VL was a significant predictor for clearance of low-risk HPV infections (p<0.05). HAART (with protease inhibitor) was significant predictor of probability of HPV16 clearance (p<0.05). HPV16/16-like and HPV18/18-like groups showed heterogeneity (p<0.05) in terms of how CD4 counts, HIV VL, and HAART affected probability of clearance of each HPV infection.
This new model predicts the 3-month probability of HPV infection clearance based on CD4 cell counts and other HIV-1-related clinical measurements.
PMCID: PMC3265500  PMID: 22292027
5.  Cancer Risk and Behavioral Factors, Comorbidities, and Functional Status in the US Elderly Population 
ISRN Oncology  2011;2011:415790.
About 80% of all cancers are diagnosed in the elderly and up to 75% of cancers are associated with behavioral factors. An approach to estimate the contribution of various measurable factors, including behavior/lifestyle, to cancer risk in the US elderly population is presented. The nationally representative National Long-Term Care Survey (NLTCS) data were used for measuring functional status and behavioral factors in the US elderly population (65+), and Medicare Claims files linked to each person from the NLTCS were used for estimating cancer incidence. The associations (i.e., relative risks) of selected factors with risks of breast, prostate, lung and colon cancers were evaluated and discussed. Behavioral risk factors significantly affected cancer risks in the US elderly. The most influential of potentially preventable risk factors can be detected with this approach using NLTCS-Medicare linked dataset and for further deeper analyses employing other datasets with detailed risk factors description.
PMCID: PMC3197174  PMID: 22084731
6.  Medical Cost Trajectories and Onsets of Cancer and NonCancer Diseases in US Elderly Population 
Time trajectories of medical costs-associated with onset of twelve aging-related cancer and chronic noncancer diseases were analyzed using the National Long-Term Care Survey data linked to Medicare Service Use files. A special procedure for selecting individuals with onset of each disease was developed and used for identification of the date at disease onset. Medical cost trajectories were found to be represented by a parametric model with four easily interpretable parameters reflecting: (i) prediagnosis cost (associated with initial comorbidity), (ii) cost of the disease onset, (iii) population recovery representing reduction of the medical expenses associated with a disease since diagnosis was made, and (iv) acquired comorbidity representing the difference between post- and pre diagnosis medical cost levels. These parameters were evaluated for the entire US population as well as for the subpopulation conditional on age, disability and comorbidity states, and survival (2.5 years after the date of onset). The developed approach results in a family of new forecasting models with covariates.
PMCID: PMC3115464  PMID: 21687557
7.  Efficient Downregulation of Multiple mRNA Targets with a Single shRNA-Expressing Lentiviral Vector 
Plasmid  2010;63(3):143-149.
Gene silencing based on RNA interference is widely used in fundamental research and in practical applications. However, a commonly incomplete functional suppression represents a serious drawback of this technology. We describe a series of lentiviral vectors each containing a single or multiple shRNA expression cassette(s) driven by a RNA polymerase III specific promoter and localized within the 3′-LTR of the lentiviral DNA backbone. The vectors also contain an antibiotic-resistance gene that allows positive selection of recipient cells. The combined expression of three different shRNAs specific to a single mRNA was shown to improve dramatically the level of mRNA inhibition, while the use of three different RNA polymerase III specific promoters avoids the loss of shRNA expression cassettes through the homologous recombination. The vector system was used for successful simultaneous suppression of three related SESN1, SESN2 and SESN3 genes, which suggests its particular value for testing phenotypes of functionally redundant genes.
PMCID: PMC2849729  PMID: 20064551
multiplex shRNA expression; lentiviral vectors; RNAi mediated gene silencing
9.  Dynamic Determinants of Longevity and Exceptional Health 
It is well known from epidemiology that values of indices describing physiological state in a given age may influence human morbidity and mortality risks. Studies of connection between aging and life span suggest a possibility that dynamic properties of age trajectories of the physiological indices could also be important contributors to morbidity and mortality risks. In this paper we use data on longitudinal changes in body mass index, diastolic blood pressure, pulse pressure, pulse rate, blood glucose, hematocrit, and serum cholesterol in the Framingham Heart Study participants, to investigate this possibility in depth. We found that some of the variables describing individual dynamics of the age-associated changes in physiological indices influence human longevity and exceptional health more substantially than the variables describing physiological state. These newly identified variables are promising targets for prevention aiming to postpone onsets of common elderly diseases and increase longevity.
PMCID: PMC2952789  PMID: 20953403
10.  Homeostatic functions of the p53 tumor suppressor: regulation of energy metabolism and antioxidant defense 
Seminars in cancer biology  2008;19(1):32-41.
The p53 tumor suppressor plays pivotal role in the organism by supervising strict compliance of individual cells to needs of the whole organisms. It has been widely accepted that p53 acts in response to stresses and abnormalities in cell physiology by mobilizing the repair processes or by removing the diseased cells through initiating the cell death programs. Recent studies, however, indicate that even under normal physiological conditions certain activities of p53 participate in homeostatic regulation of metabolic processes and that these activities are important for prevention of cancer. These novel functions of p53 help to align metabolic processes with the proliferation and energy status, to maintain optimal mode of glucose metabolism and to boost the energy efficient mitochondrial respiration in response to ATP deficiency. Additional activities of p53 in non-stressed cells tune up the antioxidant defense mechanisms reducing the probability of mutations caused by DNA oxidation under conditions of daily stresses. The deficiency in the p53-mediated regulation of glycolysis and mitochondrial respiration greatly accounts for the deficient respiration of the predominance of aerobic glycolysis in cancer cells (the Warburg effect), while the deficiency in the p53-modulated antioxidant defense mechanisms contributes to mutagenesis and additionally boosts the carcinogenesis process.
PMCID: PMC2646792  PMID: 19101635
11.  The antioxidant function of the p53 tumor suppressor 
Nature medicine  2005;11(12):1306-1313.
It is widely accepted that the p53 tumor suppressor restricts abnormal cells by induction of growth arrest, or by triggering apoptosis. Here we show that in addition p53 protects the genome from oxidation by reactive oxygen species (ROS), a major cause for DNA damage and genetic instability. In the absence of severe stresses relatively low levels of p53 are sufficient for up-regulation of several antioxidant genes, which is associated with a decrease in intracellular ROS. Down-regulation of p53 results in excessive oxidation of DNA, increased mutation rate, and karyotype instability, which are prevented by incubation with antioxidant N-acetylcysteine (NAC). Dietary supplementation with NAC prevents frequent lymphomas characteristic to p53 knockout mice, and slows down growth of xenografts from A549 cells with p53 inhibited by siRNA. Our results provide novel paradigm for a non-restrictive tumor suppressor function of p53 and highlight potential importance of antioxidants in prophylactics and treatment of cancer.
PMCID: PMC2637821  PMID: 16286925
12.  Androgen regulates apoptosis induced by TNFR family ligands via multiple signaling pathways in LNCaP 
Oncogene  2005;24(45):6773-6784.
It has been suggested in many studies that combined treatment with chemotherapeutic agents and apoptosis-inducing ligands belonging to TNFR family is a more effective strategy for cancer treatment. However, the role of androgen regulation of TNFR family-induced apoptosis in prostate cancer is poorly understood. In this study, we investigated the dose-dependent effects of androgen on TNF-α and TRAIL-mediated apoptosis in LNCaP. To investigate the interaction between the androgen receptor (AR) and the caspase-2 gene, chromatin immunoprecipitation analysis was used, and we are the first to identify that AR interacts in vivo with an androgen-responsive elements in intron 8 of caspase-2 gene. We have found that DHT inhibited apoptosis in dose-dependent manner. There is a direct, androgen-dependent correlation between the levels of activated Akt and caspase activation after treatment with TNF-α and TRAIL. We have also found that there are at least two different regulatory mechanisms of p53 expression by androgen: at the gene and protein levels. At the same time, the level of AR was found to be higher in LNCaP-si-p53 compared to LNCaP-mock cells. These data indicate that there is a mutual regulation of expression between p53 and AR. Our study suggests that androgen-dependent outcome of apoptotic treatment can occur, at least in part, via the caspase-2, Akt and p53-mediated pathways.
PMCID: PMC1361275  PMID: 16007156
androgen; androgen receptor; Akt; p53; caspase-2; apoptosis
13.  Transcription of mammalian mRNAs by a novel nuclear RNA polymerase of mitochondrial origin 
Nature  2005;436(7051):735-739.
It is commonly known that transcription of eukaryotic genes is carried out by three nuclear RNA polymerases of which RNA polymerase II is thought to be solely responsible for the synthesis of mRNAs1. Here we show that transcription of some mRNAs in humans and rodents is mediated by a previously unknown single-polypeptide nuclear RNA polymerase (spRNAP-IV). The spRNAP-IV is expressed from an alternative transcript of the mitochondrial RNA polymerase (mtRNAP) gene (POLRMT). The RNAP IVSP lacks 262 N-terminal amino acids of mtRNAP, including the mitochondrial-targeting signal, and localizes to the nucleus. Transcription by spRNAP-IV is resistant to the RNA-polymease II inhibitor α-amanitin but sensitive to siRNA specific for the POLRMT gene. The promoters for spRNAP-IV differ substantially from those utilized by RNAP-II, do not respond to transcriptional enhancers, and contain a common functional sequence motif.
PMCID: PMC1352165  PMID: 16079853

Results 1-13 (13)