Biomedical subjects

Lang Li

Publications and source records attributed to Lang Li.

35 records · Page 2Linked to original sources

PubMed2005

Discover true association rates in multi-protein complex proteomics data sets.

Experimental processes to collect and process proteomics data are increasingly complex, while the computational methods to assess the quality and significance of these data remain unsophisticated. These challenges have led to many biological oversights and computational misconceptions. We developed a complete empirical Bayes model to analyze multi-protein complex (MPC) proteomics data derived from peptide mass spectrometry detections of purified protein complex pull-down experiments. Our model considers not only bait-prey associations, but also prey-prey associations missed in previous work. Using our model and a yeast MPC proteomics data set, we estimated that there should be an average of 28 true associations per MPC, almost ten times as high as was previously estimated. For data sets generated to mimic a real proteome, our model achieved on average 80% sensitivity in detecting true associations, as compared with the 3% sensitivity in previous work, while maintaining a comparable false discovery rate of 0.3%.

Algorithms↗

PubMed2005

[Distribution of Fas and FasL in the central nervous system of adult rhesus].

OBJECTIVE: To investigate the distribution of Fas and FasL in the CNS of adult rhesus. METHODS: Frozen sections were incubated in polyclonal anti-Fas and anti-FasL antibody by the immunohistochemical SP method. RESULTS: The Fas and FasL immunopositive neurons were observed in many areas. Fas immunoreactivity could be seen in the cytoplasm and processes of Purkinje cells and in the brain stem nuclei, including vestibular nucleus, dorsal nucleus of vagus and spinal nucleus of trigeminal nerve. FasL immunopositive neurons were observed in cerebral cortex, especially in pyramidal neurons of lamina I and V, cerebellar nuclei, diencephalon, and brain stem nuclei involving pontine nucleus, vestibular nucleus, cochlear nucleus, spinal nucleus of trigeminal nerve, hypoglossal nucleus, nucleus ambiguous and reticular formation. Fas and FasL immunoreactivity mainly distributed in motor neurons of spinal ventral horn and neural fibers and glia cells in white matter. They all took on brown staining in the cytoplasm and process. CONCLUSION: The distribution profiles of Fas and FasL in various areas of CNS indicate that they may fill some roles in the immune and physical function of the aforesaid anatomic

Animals↗

PubMed2004

Association between the CYP3A5 genotype and blood pressure.

We tested the hypothesis that the presence of a CYP3A5*1 allele is associated with increases in blood pressure in 2 studies of subjects with a total of 683 participants. The first study involving 271 subjects was part of a longitudinal study conducted at Indiana University Medical Center that consisted of 2 phases. The first phase studied the relationship of salt sensitivity with blood pressure, whereas the second phase, conducted approximately 26 years later, studied the relationship between blood pressure, carbohydrate intolerance, and vascular compliance in the same subjects. The second study was a cross-sectional evaluation of 412 normotensive and hypertensive subjects conducted at the University of California San Diego. The second study (Mantel-Haenszel chi(2) test; P=0.05) showed that a greater proportion of black participants with poor blood pressure control had CYP3A5*1/*1 genotype. Evaluation of the untreated blood pressure from phase 1 of the first study showed that the blacks with CYP3A5*3/*3 (146+/-35 mm Hg) had a higher systolic blood pressure than those with the *1/*3 (119+/-14.1 mm Hg; P=0.0006) and *1/*1 (125+/-17.4 mm Hg; P=0.009) genotypes. For blacks in study 2, the CYP3A5*1 allele was more common in hypertensives (Fisher exact test; P=0.025) than normotensives. In whites there was no association between CYP3A5 genotype and blood pressure in either study. We conclude that although untreated blood pressure may be higher in blacks with the CYP3A5*3/*3 genotype, the CYP3A5*1 allele may be associated with hypertension that is more refractory to treatment in this ethnic group.

Alleles↗

PubMed2004

QT analysis: a complex answer to a 'simple' problem.

Prolongation of the QT interval on a surface electrocardiogram is a biomarker for a potentially life-threatening arrhythmia. It is used by drug developers and regulatory agencies as a measure of drug safety. Heart rate or RR interval (the inverse of heart rate) correction of the QT interval is necessary because of the QT interval shortening that accompanies physiologic decreases in the RR interval. When a drug alters the RR interval, it is important to distinguish a QT change that is due to a drug effect versus an artefact of a heart rate change. A two-step off-drug subject-specific QT correction analysis is discussed. At the first step, a linear mixed model based only on the placebo (off-drug) RR/QT data produces a correction coefficient that can be applied to a generic formula, and QT intervals are corrected for heart rate on both placebo and treatment period data using that formula. At step two, the heart rate corrected QT interval (QTc) is then compared between placebo and treatment groups at a pre-specified heart rate (usually 60 bpm) based on another linear mixed model. This two-step QT analysis implicitly assumes the slope of log(QT) versus log(RR) is unchanged by drug. Practically, it is important to understand how much this assumption can bias the QT prolongation estimates if it is not valid. We propose a one-step off-on-drug subject-specific QT correction analysis that would pool placebo and treatment period RR/QT data and derive different subject specific coefficients for the treatment and placebo data based on a linear mixed model, which can avoid the unchanged slope assumption. It is also a known unbiased and the most efficient method. The applications of both methods are demonstrated through the QT analysis of haloperidol, a neuroleptic known to prolong QTc. Both theoretical and empirical results show that, although the two-step off-drug QT correction analysis is biased, the bias is small in the case of haloperidol (0.1-0.2 ms). The two-step off-drug QT correction analysis is shown to be almost as efficient as our one-step off- and on-drug QT analysis.

Adult↗

PubMed2004

Nuclear factor-kappaB is constitutively activated in prostate cancer in vitro and is overexpressed in prostatic intraepithelial neoplasia and adenocarcinoma of the prostate.

PURPOSE: The transcription factor nuclear factor-kappaB (NF-kappaB) promotes the production of angiogenic, antiapoptotic, and prometastatic factors that are involved in carcinogenesis. EXPERIMENTAL DESIGN: Electromobility gel shift assays were used to evaluate NF-kappaB DNA binding in vitro. The functional relevance of NF-kappaB DNA binding was assessed by both cDNA array analyses and proliferation assays of prostate cancer cells with and without exposure to an NF-kappaB inhibitor, parthenolide. Immunohistochemistry staining for the p65 NF-kappaB subunit was used to determine the frequency and location of NF-kappaB in 97 prostatectomy specimens. The amount of staining was quantified on a 0-3+ scale. RESULTS: An electromobility gel shift assay confirmed the presence of NFkappaB DNA binding in all four prostate cancer cell lines tested. The binding was inhibited by parthenolide, and this agent also decreased multiple gene transcripts under the control of NF-kappaB and inhibited proliferation of prostate cancer cells. The staining results revealed overexpression of p65 in the prostatic intraepithelial neoplasia and cancer compared with the benign epithelium. Specifically, there was a predominance of 1+ and 2+ with no 3+ staining in benign epithelium, whereas there was only 2+ and 3+ staining (30 and 70%, respectively) in the cancerous areas. These differences were statistically different. There was no correlation with tumor grade or stage. CONCLUSIONS: NF-kappaB is constitutively activated in prostate cancer and functionally relevant in vitro. Immunohistochemistry of human prostatectomy specimens demonstrated overexpression of the active subunit of NF-kappaB, p65, and that this occurs at an early stage in the genesis of prostate cancer. This work supports the rationale for targeting NF-kappaB for the prevention and/or treatment of prostate cancer.

Adenocarcinoma↗

PubMed2004

Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status.

BACKGROUND: Coactivator-associated arginine methyltransferase 1 (CARM1) is a transcriptional coactivator of the androgen receptor (AR). It is involved in the regulation of the biologic functions of the AR. It remains to be determined whether CARM1 is involved in prostatic carcinogenesis. METHODS: The expression of CARM1 in normal prostate epithelium, high-grade prostatic intraepithelial neoplasia (PIN), and prostate carcinoma tissue was examined in 66 previously untreated patients with prostate carcinomas, as well as 12 patients with hormone-independent prostate carcinoma, using immunohistochemical methods. RESULTS: Cell staining was observed in the cytoplasm and the nucleus. In 66 patients without previous hormonal treatment, the percentage of cells that stained positively for CARM1 in benign prostate tissue specimens (mean values: cytoplasm, 23%; nucleus, 16%) was statistically significantly less than the percentage of positively stained cells in PIN (mean values: cytoplasm, 56%; nucleus, 30%; P < 0.001) and in prostatic adenocarcinoma specimens (mean values: cytoplasm, 79%; nucleus, 53%; P < 0.001). The difference between adenocarcinoma and PIN also was statistically significant (P < 0.001). The staining intensity for CARM1 was significantly lower in benign prostate tissue specimens compared with PIN and prostatic adenocarcinoma specimens (P < 0.001). In the 12 patients with androgen-independent prostatic adenocarcinoma, the expression of CARM1 was significantly increased when compared with patients without previous hormonal treatment. Expression of CARM1 was not correlated with age, Gleason score sum, pathologic stage, lymph node metastasis, extraprostatic extension, surgical margin status, vascular invasion, or perineural invasion. CONCLUSIONS: The authors found that overexpression of CARM1 was involved in the development of prostate carcinoma as well as androgen-independent prostate carcinoma. Since CARM1 is functionally different from most other transcriptional coactivators of the AR, it may serve as a new target for the treatment of hormone-independent prostate carcinoma.

Adenocarcinoma↗

PubMed2004

Heterogeneity of Gleason grade in multifocal adenocarcinoma of the prostate.

BACKGROUND: The Gleason grading system uniquely combines data from different areas of carcinoma in the same prostate specimen. Prostatic adenocarcinoma often is multifocal, and different Gleason grades may be present in different foci. The current study was undertaken to compare the Gleason grades of individual adenocarcinoma foci in a given specimen with the overall Gleason grades (primary and secondary) of that specimen. METHODS: Data were obtained from 115 consecutive radical prostatectomy specimens via whole-mount processing and complete sectioning. Diagrams were constructed by tracing the outline of each whole-mount section, and tumor maps subsequently were generated. The largest focus was considered the index tumor. Each prostatectomy specimen was assigned primary and secondary Gleason grades, and each tumor focus was assigned its own primary and secondary Gleason grades. Tumor volume was measured using the grid method. RESULTS: Two or more adenocarcinoma foci were present in 87% of all specimens (2 foci, n = 20; 3 foci, n = 33; 4 foci, n = 17; 5 foci, n = 13; > 5 foci, n = 17). Specimens (n = 15) containing a single tumor were excluded from further analysis. Among the remaining specimens (n = 100), all tumor foci had Gleason grades that were the same as the corresponding overall Gleason grades in only 9 cases (9%). The Gleason score (i.e., the sum of the primary and secondary grades) of the index tumor was correlated with the overall Gleason score in 68% of specimens. The primary grade of the index tumor was the same as the overall primary grade in 97 specimens, whereas the secondary grade of the index tumor was the same as the overall secondary grade in only 68 specimens. The primary and secondary grades of the index tumor, compared with the overall Gleason primary and secondary grades, were reversed in 17 specimens. CONCLUSIONS: The findings of the current study demonstrated the histologic heterogeneity of multifocal prostate malignancies. Although the Gleason grading system was used to determine an overall score for prostate carcinoma within a specimen, the scores of individual tumors, including index tumors, often did not agree with this overall score. These findings may have implications with respect to future biomarker and tissue array studies.

Adenocarcinoma↗

PubMed2004

Loss of 14-3-3sigma in prostate cancer and its precursors.

PURPOSE: The 14-3-3 family proteins are highly conserved over many mammalian species. The sigma isoform (also called HME-1 or stratifin) is expressed in epithelial cells. Loss of 14-3-3sigma is associated with failure to arrest the cell cycle at the G(2)-M phase checkpoint after DNA damage that leads to increased G(2)-type chromosomal aberrations. The role of 14-3-3sigma in prostatic carcinogenesis is uncertain. EXPERIMENTAL DESIGN: We studied one hundred and eleven specimens of invasive prostate adenocarcinoma with paired, adjacent high-grade prostatic intraepithelial neoplasia and normal prostate epithelium. Immunohistochemistry was used to detect the expression of 14-3-3sigma. The findings were correlated with various clinical pathological parameters. RESULTS: 14-3-3sigma is ubiquitously expressed at high levels in normal prostate epithelium. Its expression is significantly decreased in prostatic intraepithelial neoplasia and prostatic adenocarcinoma. Ninety percent of samples of prostatic intraepithelial neoplasia had no or low 14-3-3sigma expression. Ninety-seven percent of invasive adenocarcinomas had no or low 14-3-3sigma expression. In most specimens (90%), suppression of 14-3-3sigma expression occurred during the development of prostatic intraepithelial neoplasia from normal epithelium. CONCLUSIONS: Our data suggest that loss of 14-3-3sigma contributes to the development of prostate adenocarcinoma. 14-3-3sigma expression is significantly decreased during the progression of normal prostatic epithelium to prostatic intraepithelial neoplasia and invasive cancer.

14-3-3 Proteins↗

PubMed2004

PC cell-derived growth factor expression in prostatic intraepithelial neoplasia and prostatic adenocarcinoma.

PURPOSE: PCDGF (PC cell-derived growth factor), also called progranulin, is a M(r) 88000 glycoprotein precursor of granulin. It is a novel growth factor that stimulates cell proliferation, confers epithelial tumorigenesis, and promotes tumor invasion. Here we investigate the potential of PCDGF as a therapeutic target for prostate cancer. EXPERIMENTAL DESIGN: We studied the expression of PCDGF in invasive prostate cancer, adjacent high-grade prostatic intraepithelial neoplasia (PIN), and benign prostate tissue from 99 human prostate specimens. The level of PCDGF expression was correlated with various clinicopathological characteristics. RESULTS: Normal prostate tissue did not express (53/99), or expressed low levels (46/99) of PCDGF. In the 46 normal prostate specimens that expressed PCDGF, most of them had less than 10% of cells expressing PCDGF. PCDGF expression could be detected in more than 50% of cells in all specimens of PIN and invasive prostate cancer. The expression of PCDGF in normal prostate tissue was much less intense and in a smaller fraction of cells than in PIN and invasive adenocarcinoma (P < 0.0001). There was no correlation of PCDGF expression with age, Gleason score, pathological stage, status of lymph node metastasis, extraprostatic extension, perineural invasion, surgical margins, and vascular invasion. CONCLUSIONS: Our data suggest that the induction of PCDGF expression occurs during the development of PIN. PCDGF may be a new molecular target for the treatment and prevention of prostate cancer.

Adenocarcinoma↗

PubMed2004

Selecting pre-screening items for early intervention trials of dementia--a case study.

Our goal was to review and extend statistical methods for discriminating between normal subjects and those with dementia or cognitive impairment. We compared six different methods to one constructed by expert opinion, in their brevity and predictive power. The methods include logistic regression and neural networks, with standard and least absolute shrinkage and selection operator (LASSO) variable selection, as well as decision trees with and without boosting. These methods were applied to the baseline data of a subgroup of subjects in a dementia study, using their screening interview items to predict their clinical diagnosis of normal or non-normal (cognitively impaired or demented). The derived models were then validated on a different subgroup of subjects in the same study who had the screening and clinical diagnosis two to five years later. Performance of different models was compared based on their sensitivity and specificity in the validation sample. Generally, the six statistical methods performed slightly to moderately better than the expert-opinion model. Neural networks generally performed better than the logistic and decision tree models. LASSO improved the performance of logistic and neural network models, but it eliminated few input variables in the neural network. The single decision tree performed at least as well as the standard logistic model, and with fewer items, making it an attractive pre-screening tool. Using the boosting option for decision trees did not substantially improve the performance. We recommend that for each situation, different methods of classification should be attempted to obtain optimal results for a given purpose.

Black or African American↗

PubMed2004

A population pharmacokinetic model with time-dependent covariates measured with errors.

We propose a population pharmacokinetic (PK) model with time-dependent covariates measured with errors. This model is used to model S-oxybutynin's kinetics following an oral administration of Ditropan, and allows the distribution rate to depend on time-dependent covariates blood pressure and heart rate, which are measured with errors. We propose two two-step estimation methods: the second-order two-step method with numerical solutions of differential equations (2orderND), and the second-order two-step method with closed form approximate solutions of differential equations (2orderAD). The proposed methods are computationally easy and require fitting a linear mixed model at the first step and a nonlinear mixed model at the second step. We apply the proposed methods to the analysis of the Ditropan data, and evaluate their performance using a simulation study. Our results show that the 2orderND method performs well, while the 2orderAD method can yield PK parameter estimators that are subject to considerable biases.

Biometry↗

PubMed2003

High-level expression of EphA2 receptor tyrosine kinase in prostatic intraepithelial neoplasia.

EphA2 is a transmembrane receptor tyrosine kinase that is overexpressed in many carcinomas. Specific targeting of EphA2 with monoclonal antibodies is sufficient to inhibit the growth, migration and invasiveness of aggressive cancers in animal models. Using immunohistochemical analyses, we measured the expression of EphA2 in prostatic adenocarcinoma, high-grade prostatic intraepithelial neoplasia, and adjacent benign prostate tissue from ninety-three radical prostatectomy specimens. These results were related to multiple clinical and pathologicalcharacteristics. The fraction of cells staining positively with EphA2 in benign prostatic epithelium (mean, 12%) was significantly lower than that in high-grade prostatic intraepithelial neoplasia (mean, 67%, P < 0.001) and prostatic adenocarcinoma (mean, 85%, P < 0.001). Moreover, the intensity of EphA2 immunoreactivity in prostatic adenocarcinoma was significantly higher than in benign prostatic tissue (P < 0.001) or high-grade prostatic intraepithelial neoplasia (P < 0.001). Benign prostatic epithelium showed weak or no immunoreactivity for EphA2 in all cases examined. Whereas EphA2 immunoreactivity related to neoplastic transformation, it did not correlate with other clinical and pathological parameters examined. Our data suggest that EphA2 levels increase as prostatic epithelial cells progress toward a more aggressive phenotype. Progressively higher levels of EphA2 in high-grade prostatic intraepithelial neoplasia and prostatic carcinoma are consistent with recent evidence that EphA2 functions as a powerful oncogene. Moreover, the presence of high levels of EphA2 in these cells suggests opportunities for prostate cancer prevention and treatment.

Adenocarcinoma↗

PubMed2003

Diabetes mellitus increases the in vivo activity of cytochrome P450 2E1 in humans.

AIMS: Cytochrome P450 2E1 (CYP2E1) is thought to activate a number of protoxins, and has been implicated in the development of liver disease. Increased hepatic expression of CYP2E1 occurs in rat models of diabetes but it is unclear whether human diabetics display a similar up-regulation. This study was designed to test the hypothesis that human diabetics experience enhanced CYP2E1 expression. METHODS: The pharmacokinetics of a single dose of chlorzoxazone (500 mg), used as an index of hepatic CYP2E1 activity, was determined in healthy subjects (n = 10), volunteers with Type I (n = 13), and Type II (n = 8) diabetes mellitus. Chlorzoxazone and 6-hydroxychlorzoxazone in serum and urine were analysed by high-performance liquid chromatography. The expression of CYP2E1 mRNA in peripheral blood mononuclear cells was quantified by reverse transcriptase-polymerase chain reaction. RESULTS: The mean +/- s.d. (90% confidence interval of the difference) chlorzoxazone area under the plasma concentration-time curve was significantly (P </= 0.05) reduced in obese Type II diabetics (15.7 +/- 11.3 micro g h ml-1; 9, 22) compared with healthy subjects (43.5 +/- 16.9 micro g h ml-1; 16, 40) and Type I diabetics (32.8 +/- 9.2 micro g h ml-1; 9, 25). There was a significant two-fold increase in the oral clearance of chlorzoxazone in obese Type II diabetics compared with healthy volunteers and Type I diabetics. The protein binding of chlorzoxazone was not significantly different between the three groups. In contrast, Type 1 diabetics and healthy volunteers demonstrated no difference in the oral clearance of chlorzoxazone. The urinary recovery of 6-hydroxychlorzoxazone as a percentage of the administered dose was not different between healthy, Type I and obese Type II diabetics. The elimination half-life of chlorzoxazone did not differ between the three groups. CYP2E1 mRNA was significantly elevated in Type I and obese Type II diabetics compared with healthy volunteers. The oral clearance of chlorzoxazone, elimination half-life, Tmax, and Cmax were not significantly influenced by weight, body mass index, serum glucose, serum cholesterol, or glycosylated haemoglobin. CONCLUSIONS: There was a marked increase in hepatic CYP2E1 activity in obese Type II diabetics as assessed by chlorzoxazone disposition. Increased expression of CYP2E1 mRNA in peripheral blood mononuclear cells was found in both types of diabetes mellitus. Adverse hepatic events associated with Type II diabetes may be in part a result of enhanced CYP2E1 expression and activity.

Adolescent↗

PubMed2003

Variability of heart rate correction methods for the QT interval.

AIMS: To compare variability of heart rate-corrected QT intervals (QTc) using three different methods in a study of low-dose oral haloperidol. METHODS: In a randomized, double-blind, placebo-controlled, crossover trial, we studied QT interval pharmacodynamics of single doses of oral haloperidol (10 mg) in 16 healthy subjects. Heart rate correction of the QT interval was performed using Bazett's, Fridericia's and subject-specific correction methods. The subject-specific correction was performed using linear mixed modelling of placebo period QT vs RR data from each study subject. RESULTS: The subject-specific correction, in the form of QTc = QT/RRalpha, yielded a correction term alpha (slope of the log-transformed QT vs RR relationship) that ranged from 0.23 to 0.38 in individual subjects, i.e. the fixed correction term alpha = 0.5 of Bazett's correction was outside and the fixed correction term alpha = 0.33 of Fridericia's correction inside the range of individual values. The mean absolute slope of the QTcvs RR regression line using the subject-specific correction was significantly lower than the mean slopes obtained using either Bazett's or Fridericia's corrections. All three methods revealed a statistically significant greater mean QTc on haloperidol than on placebo at 10 h post-drug administration. The mean QT (95% CI) was 421.6 (410.8, 432.4), and 408.4 (398.6, 417.8) on haliperidol and placebo, respectively, using the subject-specific correction method (P = 0.0053). The mean QTc (95% CI) was 425.4 (414.3, 436.5) and 403.1 (394.3, 411.9) on haliperidol and placebo, respectively, using Bazett's correction (P = 1.7 x 10-5) and 423.1 (412.6, 433.6) and 408.2 (398.6, 417.8) on haliperidol and placebo, respectively, using Fridericia's correction (P = 7.7 x 10-4). Raw P-values were calculated using a paired t-test. Bonferroni-corrected P-values were calculated by multiplying the raw P-values by 13. CONCLUSION: Haloperidol caused a statistically significant mean QTc prolongation using the three correction methods. The QTc intervals were less dependent on RR intervals using the subject-specific method, thus decreasing the possibility of over- or under-correction. The interindividual QTc changes from baseline varied significantly depending on the method of correction used.

Administration, Oral↗

PubMed2003

[c-jun expression in spared dorsal root ganglion following partial dorsal root rhizotomy and acupuncture].

OBJECTIVE: To investigate the change of c-jun expression in spared dorsal root ganglion (DRG) following partial dorsal root rhizotomy and acupuncture. METHODS: Fifteen adult cats were divided into three groups with five cats in every group--sham operation, operation, and acupuncture following operation respectively. Animals of operation group were subjected to unilateral root rhizotomy (L1-L5, L7-S2 DRGs were sectioned, L6 DRG was spared). Electro-needling was performed alternatively at two sets of acupoints, including Zusanli and Xuanzhong, Futu and Sanyinjiao, located in the distribution area of spinal nerve L6 on the operated side, 30 min everyday for 7 days following unilateral root rhizotomy. The animals of sham operation group experienced only skin and muscle incisions. On the 7th day after operation, all animals were sacrificed. The L6 DRG on the disposal side of each animal was taken and made into frozen sections 20 micrograms in thickness. The sections were stained under the same condition using specific c-jun antibody (1:1000, Santa Cruz) by immunohistochemistry ABC method. The distribution and number as well as immunoreactive level of c-jun positive neurons in DRG were observed and measured. RESULTS: In the L6 DRG of sham operation group, only parts of neurons were stained. In contrast, the number of positive neurons and immunoreactive level for c-jun increased significantly in operation group (P < 0.05). Compared with the operation group, the operation plus acupuncture group had higher c-jun immunoreactive level of neurouns, but its number of c-jun positive neurons didn't change markedly. CONCLUSION: Partial dorsal root rhizotomy leads to the up-regulation of c-jun expression in neurons of spared DRG, and acupuncture enhances the up-regulation.

Animals↗

PubMed2002

Combined shock-wave and immunogene therapy of mouse melanoma and renal carcinoma tumors.

The effects of ultrasonic shock waves (SW), recombinant interleukin-12 (rIL-12) protein and DNA plasmids coding for interleukin-12 (pIL-12) were investigated on progression of mouse B16 melanoma and RENCA renal carcinoma tumors. Tumor cells were implanted and grown on the hind legs of syngeneic mice. Before treatment, mice were anesthetized and the tumor region was shaved and depilated. Air bubbles at 10% of tumor volume and an equal volume of phosphate buffered saline (PBS), either with rIL-12 or pIL-12 were injected into the tumor. SW treatment consisted of 500 SWs (7.4-MPa peak negative pressure) from a spark-gap lithotripter. Tumor volume was measured every other day and tumor growth was statistically modeled. SW treatment augmented by air injection induced a tumor growth delay for a few days immediately after exposure. Intratumor rIL-12 injection enhanced the SW effect on tumor progression, to the extent that a statistically significant increase in survival was realized in both tumor models. pIL-12 injection alone, which is known to produce some gene transfer, provided no detectable tumor-growth reduction. The combination of SW and pIL-12 injection provided a statistically significant reduction in tumor growth relative to SW alone for both tumor models. IL-12 expression due to SW-induced gene transfer was confirmed in ELISA assays. This research demonstrates a potentiality for further development of ultrasound (US)-enhanced cancer gene therapy.

Animals↗

PubMed2002

Estimation and inference for a spline-enhanced population pharmacokinetic model.

This article is motivated by an application where subjects were dosed three times with the same drug and the drug concentration profiles appeared to be the lowest after the third dose. One possible explanation is that the pharmacokinetic (PK) parameters vary over time. Therefore, we consider population PK models with time-varying PK parameters. These time-varying PK parameters are modeled by natural cubic spline functions in the ordinary differential equations. Mean parameters, variance components, and smoothing parameters are jointly estimated by maximizing the double penalized log likelihood. Mean functions and their derivatives are obtained by the numerical solution of ordinary differential equations. The interpretation of PK parameters in the model and its flexibility are discussed. The proposed methods are illustrated by application to the data that motivated this article. The model's performance is evaluated through simulation.

Biometry↗