Biomedical subjects

Gang Zheng

Publications and source records attributed to Gang Zheng.

At least 19 recordsLinked to original sources

PubMed2025

From Diagnosis, Therapy Decision-Making to Genetic Risk Assessment: The Impact of ctDNA Testing on Comprehensive Cancer Management-A Case Report.

Circulating tumor DNA (ctDNA) testing is a minimally invasive alternative to tissue biopsy and is ideal for inaccessible tumors or limited samples. It captures tumor heterogeneity over time and different anatomic locations, unlike the static snapshot provided by a biopsy. In this report, we describe a 68-year-old female with an initial diagnosis of metastatic pancreatic adenocarcinoma (a pancreas head mass with multiple bilateral lung nodules). Mutation profiling of the pancreatic mass biopsy using a comprehensive cancer next-generation sequencing (NGS) panel was unsuccessful due to insufficient tissue. Consequently, ctDNA testing using a pan-cancer NGS panel was performed, and an EGFR p.L858R variant at 2.15% was identified. Interestingly, this activating variant is highly specific to non-small cell lung cancer (NSCLC), which raised the possibility of a synchronous tumor unrelated to the pancreatic mass. Immunohistochemistry showed the EGFR variant in station 7 lymph nodes but not in pancreatic biopsy tissue, supporting the inference that the variant originated from the lung mass. Droplet digital PCR on the limited pancreatic biopsy identified a KRAS p.Q61 variant, which was absent by ctDNA testing, suggesting a pancreatic primary with low ctDNA levels. In addition to diagnosing a primary lung cancer, ctDNA testing guided treatment decisions. With a primary EGFR p.L858R-mutant NSCLC, osimertinib was administered, resulting in a partial response within 10 months. In addition, given the synchronous primary pancreatic adenocarcinoma, germline testing was performed, revealing a CDKN2A p.I49T variant consistent with melanoma-pancreatic cancer syndrome, prompting comprehensive cancer surveillance and familial testing. This case illustrates how ctDNA testing enabled a comprehensive evaluation by clarifying the diagnosis, identifying actionable biomarkers, and facilitating genetic risk assessment, ultimately having a significant impact on the patient's clinical management.

Humans↗

PubMed2006

On estimation of the variance in Cochran-Armitage trend tests for genetic association using case-control studies.

The Cochran-Armitage trend test has been used in case-control studies for testing genetic association. As the variance of the test statistic is a function of unknown parameters, e.g. disease prevalence and allele frequency, it must be estimated. The usual estimator combining data for cases and controls assumes they follow the same distribution under the null hypothesis. Under the alternative hypothesis, however, the cases and controls follow different distributions. Thus, the power of the trend tests may be affected by the variance estimator used. In particular, the usual method combining both cases and controls is not an asymptotically unbiased estimator of the null variance when the alternative is true. Two different estimates of the null variance are available which are consistent under both the null and alternative hypotheses. In this paper, we examine sample size and small sample power performance of trend tests, which are optimal for three common genetic models as well as a robust trend test based on the three estimates of the variance and provide guidelines for choosing an appropriate test.

Case-Control Studies↗

PubMed2006

Robust trend tests for genetic association using matched case-control design.

Trend tests for genetic association using a matched case-control design are studied, which allows for a variable number of controls per case. However, the tests depend on the scores based on the underlying genetic model, thus it may result in substantial loss of power when the model is misspecified. Since the mode of inheritance may be unknown for complex diseases, robust trend tests in matched case-control studies are developed. Simulation is conducted to compare the trend tests and the robust trend tests under various genetic models. The results are applied to detect candidate-gene association using an example from a case-control aetiologic study of sarcoidosis.

Black People↗

PubMed2006

Photodynamic therapy agent with a built-in apoptosis sensor for evaluating its own therapeutic outcome in situ.

Identifying the extent of apoptosis in cells or tissues after cancer therapy in real time would be a powerful firsthand tool for assessing therapeutic outcome. We combined therapeutic and imaging functions in one agent, choosing photodynamic therapy (PDT) as an appropriate cancer treatment modality. This agent induces photodamage in irradiated cells and simultaneously identifies apoptotic cells by near-infrared fluorescence. This photodynamic therapy agent with a built-in apoptosis sensor (PDT-BIAS) contains a fluorescent photosensitizer used as an anticancer drug, connected to a fluorescence quencher by a caspase-3 cleavable peptide linker. We demonstrated that cleavage of the peptide linker by caspase-3, one of the executioner caspases involved in apoptosis, results in a detectable increase of fluorescence in solution and in cancer cells after PDT treatment. The apoptosis involvement and drug effectiveness were confirmed by Apoptag and cell viability (MTT) assays supporting the ability of PDT-BIAS to induce and image apoptosis in situ.

Apoptosis↗

PubMed2006

Micellar partitioning and its effects on Henry's law constants of chlorinated solvents in anionic and nonionic surfactant solutions.

Micellar partitioning of volatile chlorinated hydrocarbons in surfactant solutions and its effects on vapor-liquid equilibrium is fundamental to the overall design and implementation of surfactant-enhanced aquifer remediation. Surfactant micelles greatly enhance contaminant recovery from the subsurface; however, the reduced volatility of organic compounds compromises the aboveground treatment of surfactant-laden wastewaters using air-stripping process. Batch equilibrium tests were performed to acquire micellar partition coefficients (Km) and apparent Henry's law constants (H*) of three prominent groundwater contaminants (tetrachloroethylene, trichloroethylene, cis-dichlorethylene) in the presence of two anionic surfactants (sodium dodecyl sulfate, SDS; sodium dodecylbenzene sulfonate, SDBS) and two nonionic surfactants (Triton X-100 and Tween 80). The H* values were significantly reduced in the presence of all four surfactants over their critical micelle concentrations (cmc's). On a cmc basis, the anionic surfactant SDS had the greatest effect on H*, followed by SDBS, Triton X-100, and Tween 80. Anionic surfactants decreased H* to an order of magnitude lower than nonionic surfactants, although nonionic surfactants decreased the H* at concentrations significantly lower than the anionic surfactants due to their lower cmc's. Nonionic surfactants present higher Km and molar solubilization ratio than anionic surfactants. Tetrachloroethylene has the highest Km values among three chlorinated solvents, which agrees well with the hydrophobicity (Kow) of these chemicals. An empirical correlation between log Km and log Kow is developed on the basis of data from this study and the Km values reported for a number of chlorinated and nonchlorinated hydrocarbons. Equilibrium data were also tested against three sets of models that describe the partitioning of volatile compounds in vapor-water-micelle phases. Applications of these models in experimentally determining Km from batch vapor-water equilibrium data are discussed.

Anions↗

PubMed2006

Low-density lipoprotein nanoparticles as magnetic resonance imaging contrast agents.

Low-density lipoproteins (LDLs) are a naturally occurring endogenous nanoplatform in mammalian systems. These nanoparticles (22 nm) specifically transport cholesterol to cells expressing the LDL receptor (LDLR). Several tumors overexpress LDLRs presumably to provide cholesterol to sustain a high rate of membrane synthesis. Amphiphilic gadolinium (Gd)-diethylenetriaminepentaacetic acid chelates have been incorporated into the LDL to produce a novel LDLR-targeted magnetic resonance imaging (MRI) contrast agent. The number of Gd chelates per LDL particle ranged between 150 and 496 Gd(III). In vitro studies demonstrated that Gd-labeled LDL retained a similar diameter and surface charge as the native LDL particle. In addition, Gd-labeled LDL retained selective cellular binding and uptake through LDLR-mediated endocytosis. Finally, Gd-labeled LDLs exhibited significant contrast enhancement 24 hours after administration in nude mice with human hepatoblastoma G2 xenografts. Thus, Gd-labeled LDL demonstrates potential use as a targeted MRI contrast agent for in vivo tumor detection.

Animals↗

PubMed2006

[Development of a predicting model of survival rates for patients with salivary adenoid cystic carcinoma].

OBJECTIVE: To establish a predicting model of survival rates and to evaluate the weighted contributions of each key prognostic factor of the patients with salivary adenoid cystic carcinoma (SACC). METHODS: One hundred and eighteen follow-up cases with SACC were analyzed for the survival study with retrospective cohort method. Ten possible clinical and pathologic factors were selected. A multivariate analysis was performed by Cox proportional hazard model and prognostic index (PI) was calculated. According to the PI, all cases were divided into three risk subgroups respectively: lower, intermediate and higher risk subgroups. Ten-year survival rate and median survival time were calculated and the predicting models of survival rates were established. RESULTS: The significant prognostic factors influencing the survival rate were age at diagnosis, clinical presentation, TNM clinical stage, treatment, surgical margins (P < 0.05). The predicting formula was PI = 0.031X(2) + 0.665X(5) + 0.420X(6)-0.576X(7) + 0.999X(10). According to the value of PI, the prognosis of the patients was significantly different among the three subgroups (P < 0.05). In the three risk subgroups, 10-year survival rates were 83.56%, 31.45% and 11.20% respectively, the median survival time was 18 years, 7 years and 4 years respectively. CONCLUSIONS: The established predicting model of survival rates can predict the prognosis of the patients with SACC.

Adolescent↗

PubMed2005

Robust trend tests for genetic association in case-control studies using family data.

We studied a trend test for genetic association between disease and the number of risk alleles using case-control data. When the data are sampled from families, this trend test can be adjusted to take into account the correlations among family members in complex pedigrees. However, the test depends on the scores based on the underlying genetic model and thus it may have substantial loss of power when the model is misspecified. Since the mode of inheritance will be unknown for complex diseases, we have developed two robust trend tests for case-control studies using family data. These robust tests have relatively good power for a class of possible genetic models. The trend tests and robust trend tests were applied to a dataset of Genetic Analysis Workshop 14 from the Collaborative Study on the Genetics of Alcoholism.

Alcoholism↗

PubMed2005

Selection of single-nucleotide polymorphisms in disease association data.

We studied several methods for selecting single-nucleotide polymorphisms (SNPs) in a disease association study. Two major categories for analytical strategy are the univariate and the set selection approaches. The univariate approach evaluates each SNP marker one at a time, while the set selection approach tests disease association of a set of SNP markers simultaneously. We examined various test statistics that can be utilized in testing disease association and also reviewed several multiple testing procedures that can properly control the family-wise error rates when the univariate approach is applied to multiple markers. The set association methods were then briefly reviewed. Finally, we applied these methods to the data from Collaborative Study on the Genetics of Alcoholism (COGA).

Databases, Genetic↗

PubMed2005

Robust genomic control for association studies.

Population-based case-control studies are a useful method to test for a genetic association between a trait and a marker. However, the analysis of the resulting data can be affected by population stratification or cryptic relatedness, which may inflate the variance of the usual statistics, resulting in a higher-than-nominal rate of false-positive results. One approach to preserving the nominal type I error is to apply genomic control, which adjusts the variance of the Cochran-Armitage trend test by calculating the statistic on data from null loci. This enables one to estimate any additional variance in the null distribution of statistics. When the underlying genetic model (e.g., recessive, additive, or dominant) is known, genomic control can be applied to the corresponding optimal trend tests. In practice, however, the mode of inheritance is unknown. The genotype-based chi (2) test for a general association between the trait and the marker does not depend on the underlying genetic model. Since this general association test has 2 degrees of freedom (df), the existing formulas for estimating the variance factor by use of genomic control are not directly applicable. By expressing the general association test in terms of two Cochran-Armitage trend tests, one can apply genomic control to each of the two trend tests separately, thereby adjusting the chi (2) statistic. The properties of this robust genomic control test with 2 df are examined by simulation. This genomic control-adjusted 2-df test has control of type I error and achieves reasonable power, relative to the optimal tests for each model.

Case-Control Studies↗

PubMed2005

Acetylation and alternative splicing regulate ZNF76-mediated transcription.

We previously showed that ZNF76 is a general transcription repressor targeting TATA-binding protein (TBP), through a process regulated by sumoylation [G. Zheng, Y.C. Yang, ZNF76, a novel transcriptional repressor targeting TATA-binding protein, is modulated by sumoylation, J. Biol. Chem. 279 (2004) 42410-42421]. In this study, two additional regulatory mechanisms for ZNF76 were identified. ZNF76 is acetylated by p300 and deacetylated by HDAC1, and acetylation of ZNF76 leads to its loss of sumoylation and attenuation of TBP interaction. Consistent with their physical antagonism, acetylation, and sumoylation play opposite roles in regulating the transactivation of ZNF76. Besides acetylation and sumoylation, ZNF76 is also regulated through mRNA splicing: two isoforms of ZNF76 have different abilities of interacting with TBP. Our study shows that ZNF76, a TBP-interacting transcriptional modulator, is regulated by both lysine modifications and alternative splicing.

Acetylation↗

PubMed2005

Rerouting lipoprotein nanoparticles to selected alternate receptors for the targeted delivery of cancer diagnostic and therapeutic agents.

We report that a lipoprotein-based nanoplatform generated by conjugating tumor-homing molecules to the protein components of naturally occurring lipoproteins reroutes them from their normal lipoprotein receptors to other selected cancer-associated receptors. Multiple copies of these targeting moieties may be attached to the same nanoparticle, or a variety of different targeting moieties can be attached. Such a diverse set of tumor-homing molecules could be used to create a variety of conjugated lipoproteins as multifunctional, biocompatible nanoplatforms with a broad application to both cancer imaging and treatment. The same principle can be applied to imaging and treatment of other diseases and for monitoring specific tissues. To validate this concept, we prepared a low-density lipoprotein (LDL)-based folate receptor (FR)-targeted agent by conjugating folic acid to the Lys residues of the apolipoprotein B (apoB)-100 protein. To demonstrate the ability of the lipoprotein-based nanoplatform to deliver surface-loaded and core-loaded payloads, the particles were labeled either with the optical reporter 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine that was intercalated in the phospholipid monolayer or with the lipophilic photodynamic therapy agent, tetra-t-butyl-silicon phthalocyanine bisoleate, that was reconstituted into the lipid core. Cellular localization of the labeled LDL was monitored by confocal microscopy and flow cytometry in FR-overexpressing KB cells, in FR-nonexpressing CHO and HT-1080 cells, and in LDL receptor-overexpressing HepG2 cells. These studies demonstrate that the folic acid conjugation to the Lys side-chain amino groups blocks binding to the normal LDL receptor and reroutes the resulting conjugate to cancer cells through their FRs.

Animals↗

PubMed2005

Sumoylation and acetylation play opposite roles in the transactivation of PLAG1 and PLAGL2.

PLAG1 (pleomorphic adenoma gene 1) and PLAGL2 (PLAG-like 2) are oncogenes involved in various malignancies. Thus the study of their regulatory mechanisms may lead to identification of novel therapeutic targets. In this study, we provide supporting evidence that sumoylation and acetylation regulate functions of PLAG1 and PLAGL2. A conserved transcriptional repression domain exists in both PLAG1 and PLAGL2, whose activity depends on the presence of three sumoylation motifs and an intact sumoylation pathway. In vivo sumoylation assays confirmed that lysines 244, 263, and 353 of PLAG1 and lysines 250, 269, and 356 of PLAGL2 are indeed sumoylation sites. Further study showed that sumoylation inhibits PLAG1-induced IGF-II expression in reporter assays. The repression mediated by sumoylation may be partially explained by its effect on the cellular localization of PLAG1 and PLAGL2, because sumoylation-deficient but not wild-type PLAG1 and PLAGL2 concentrate in the nucleolus. PLAG1 and PLAGL2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by HDAC7. Interestingly, the sumoylation-deficient mutant of PLAGL2 is acetylated at a lower level than its wild-type counterpart, suggesting that some of the lysine residues may be targets for both modifications. Finally, mutation of three lysine residues in sumoylation motifs significantly impairs the transformation ability of PLAG1 and PLAGL2, suggesting the essential roles of these sites in the oncogenic potential of PLAG proteins. Taken together, the activities of PLAG1 and PLAGL2 are tightly modulated by both sumoylation and acetylation, which have opposite effects on their transactivation. To our knowledge, this is the first demonstration that oncoproteins can be regulated by both sumoylation and acetylation.

Acetylation↗

PubMed2005

Linkage disequilibrium mapping of quantitative-trait Loci by selective genotyping.

The principles of linkage disequilibrium mapping of dichotomous diseases can be well applied to the mapping of quantitative-trait loci through the method of selective genotyping. In 1999, M. Slatkin considered a truncation selection (TS) approach. We propose in this report an extended TS approach and an extreme-rank-selection (ERS) approach. The properties of these selection approaches are studied analytically. By using a simulation study, we demonstrate that both the extended TS approach and the ERS approach provide remarkable improvements over Slatkin's original TS approach.

Genotype↗

PubMed2005

The impact of diagnostic error on testing genetic association in case-control studies.

In case-control studies, subjects in the case group may be recruited from suspected patients who are diagnosed positively with disease. While many statistical methods have been developed for measurement error or misclassification of exposure variables in epidemiological studies, no studies have been reported on the effect of errors in diagnosing disease on testing genetic association in case-control studies. We study the impact of using the original Cochran-Armitage trend test assuming no diagnostic error when, in fact, cases and controls may be clinically diagnosed by an imperfect gold standard or a reference test. The type I error, sample size and asymptotic power of trend tests are examined under a family of genetic models in the presence of diagnostic error. The empirical powers of the trend tests are also compared by simulation studies under various genetic models.

Case-Control Studies↗

PubMed2005

On averaging power for genetic association and linkage studies.

A power calculation is crucial in planning genetic studies. In genetic association studies, the power is often calculated using the expected number of individuals with each genotype calculated from an assumed allele frequency under Hardy-Weinberg equilibrium. Since the allele frequency is often unknown, the number of individuals with each genotype is random and so a power calculation assuming a known allele frequency may be incorrect. Ambrosius et al. recently showed that the power ignoring this randomness may lead to studies with insufficient power and proposed averaging the power due to the randomness. We extend the method of averaging power in two directions. First, for testing association in case-control studies, we use the Cochran-Armitage trend test and find that the time needed for calculating the averaged power is much reduced compared to the chi-square test with two degrees of freedom studied by Ambrosius et al. A real study is used for illustration of the method. Second, we extend the method to linkage analysis, where the number of identical-by-descent alleles shared by siblings is random. The distribution of identical-by-descent numbers depends on the underlying genetic model rather than the allele frequency. The robust test for linkage analysis is also examined using the averaged powers. We also recommend a sensitivity analysis when the true allele frequency or the number of identical-by-descent alleles is unknown.

Case-Control Studies↗

PubMed2005

Comparison of maximum statistics for hypothesis testing when a nuisance parameter is present only under the alternative.

In many practical problems, a hypothesis testing involves a nuisance parameter which appears only under the alternative hypothesis. Davies (1977, Biometrika 64, 247-254) proposed the maximum of the score statistics over the whole range of the nuisance parameter as a test statistic for this type of hypothesis testing. Freidlin, Podgor, and Gastwirth (1999, Biometrics 55, 883-886) studied two other simpler maximum test statistics, the maximum of the score statistics at two extreme points of the nuisance parameter, and the maximum of the score statistics at three points of the nuisance parameter including the two extreme points. In this article, we compare the powers of these three maximum-type statistics in the context of three genetic problems.

Biometry↗

PubMed2005

Genomic control for association studies under various genetic models.

Case-control studies are commonly used to study whether a candidate allele and a disease are associated. However, spurious association can arise due to population substructure or cryptic relatedness, which cause the variance of the trend test to increase. Devlin and Roeder derived the appropriate variance inflation factor (VIF) for the trend test and proposed a novel genomic control (GC) approach to estimate VIF and adjust the test statistic. Their results were derived assuming an additive genetic model and the corresponding VIF is independent of the candidate allele frequency. We determine the appropriate VIFs for recessive and dominant models. Unlike the additive test, the VIFs for the optimal tests for these two models depend on the candidate allele frequency. Simulation results show that, when the null loci used to estimate the VIF have allele frequencies similar to that of the candidate gene, the GC tests derived for recessive and dominant models remain optimal. When the underlying genetic model is unknown or the null loci and candidate gene have quite different allele frequencies, the GC tests derived for the recessive or dominant models cannot be used while the GC test derived for the additive model can be.

Biometry↗