PAI-1 4G/5G Polymorphism Contributes to Cancer Susceptibility: Evidence from Meta-Analysis

Background

The plasminogen activator inhibitor-1 (PAI-1) is expressed in many cancer cell types and allows the modulation of cancer growth, invasion and angiogenesis. To date, studies investigated the association between a functional polymorphism in PAI-1 (4G/5G) and risk of cancer have shown inclusive results.

Methods

A meta-analysis based on 25 case-control studies was performed to address this issue. Odds ratios (OR) with corresponding 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with I² test.

Results

Overall, a significant increased risk of cancer was associated with the PAI-1 4G/4G polymorphism for the allele contrast (4G vs. 5G: OR = 1.10, CI = 1.03–1.18, I² = 49.5%), the additive genetic model (4G/4G vs. 5G/5G: OR = 1.21, CI = 1.06–1.39, I² = 51.9%), the recessive genetic model (4G/4G vs. 4G/5G+5G/5G: OR = 1.11, CI = 1.04–1.18, I² = 20.8%). In the subgroup analysis by ethnicity, the results indicated that individuals with 4G/4G genotype had a significantly higher cancer risk among Caucasians (4G/4G vs. 5G/5G: OR = 1.31, 95%CI = 1.09–1.59, I² = 59.6%; 4G/4G vs. 4G/5G: OR = 1.12, 95%CI = 1.04–1.21, I² = 3.6%; recessive model: OR = 1.12, 95%CI = 1.05–1.21, I² = 25.3%).

Conclusions

The results of the present meta-analysis support an association between the PAI-1 4G/5G polymorphism and increasing cancer risk, especially among Caucasians, and those with 4G allele have a high risk to develop colorectal cancer and endometrial cancer.     

Potentiation of Scutellarin on Human Tongue Carcinoma Xenograft by Low-Intensity Ultrasound

Scutellarin 7-O-β-d-glucuronide (scutellarin) has shown great potential as a chemotherapeutic agent for cancer treatment, but only at high dosage. Here we investigate the possibility of using low intensity ultrasound to reduce the scutellarin dosage. Ultrasound intensities of 1.0 W/cm² and 0.05 W/cm² were used for in vivo and in vitro experiments, respectively, and a very low dosage of scutellarin (15 nM) was used. Tumor-bearing Balb/c mice and SAS human-tongue squamous carcinoma cell suspensions were used for the in vivo and in vitro experiments, respectively. Each kind of subjects was divided into control, ultrasound-alone, scutellarin-alone, and combined ultrasound-scutellarin treatment groups. Only the combined treatment showed strong anticancer effects. In the in vivo case, the combined treatment significantly delayed tumor growth, initiated cellular chromatin changes (including a decrease in the number of cytoplasmic organelles and fragmentation of condensed nuclear chromatin), inhibited tumor angiogenesis and lymphangiogenesis, stopped cancer-cell proliferation, decreased MMP-2 and MMP-9 expression levels and caused cancer-cell apoptosis. In the in vitro case, the combined treatment produced cancer cell-shape irregularity in a manner seriously fractured microvilli, inhibited cancer-cell migratory and invasion activities, and induced cancer-cell apoptosis. Because the combined treatment did not increase intracellular ROS production, scutellarin is not a sonosensitizer so that the anticancer effect is not through sonodynamic therapy. Low-intensity ultrasound is merely increasing the permeability of scutellarin into cancer cells. Based on our results, one may perform localized chemotherapy using much reduced dosage of the drug with the help of low intensity ultrasound, which will greatly minimize side effects.     

Variation of Genetic Diversity in a Rapidly Expanding Population of the Greater Long-Tailed Hamster (Tscherskia triton) as Revealed by Microsatellites

Genetic diversity is essential for persistence of animal populations over both the short- and long-term. Previous studies suggest that genetic diversity may decrease with population decline due to genetic drift or inbreeding of small populations. For oscillating populations, there are some studies on the relationship between population density and genetic diversity, but these studies were based on short-term observation or in low-density phases. Evidence from rapidly expanding populations is lacking. In this study, genetic diversity of a rapidly expanding population of the Greater long-tailed hamsters during 1984–1990, in the Raoyang County of the North China Plain was studied using DNA microsatellite markers. Results show that genetic diversity was positively correlated with population density (as measured by % trap success), and the increase in population density was correlated with a decrease of genetic differentiation between the sub-population A and B. The genetic diversity tended to be higher in spring than in autumn. Variation in population density and genetic diversity are consistent between sub-population A and B. Such results suggest that dispersal is density- and season-dependent in a rapidly expanding population of the Greater long-tailed hamster. For typically solitary species, increasing population density can increase intra-specific attack, which is a driving force for dispersal. This situation is counterbalanced by decreasing population density caused by genetic drift or inbreeding as the result of small population size. Season is a major factor influencing population density and genetic diversity. Meanwhile, roads, used to be considered as geographical isolation, have less effect on genetic differentiation in a rapidly expanding population. Evidences suggest that gene flow (Nm) is positively correlated with population density, and it is significant higher in spring than that in autumn.     

A Novel PEGylated Liposome-Encapsulated SANT75 Suppresses Tumor Growth through Inhibiting Hedgehog Signaling Pathway

The Hedgehog (Hh) pathway inhibitors have shown great promise in cancer therapeutics. SANT75, a novel compound we previously designed to specially inhibit the Smoothened (SMO) protein in the Hh pathway, has greater inhibitory potency than many of commonly used Hh inhibitors. However, preclinical studies of SANT75 revealed water insolubility and acute toxicity. To overcome these limitations, we developed a liposomal formulation of SANT75 and investigated its antitumor efficacy in vitro and in vivo. We encapsulated SANT75 into PEGylated liposome and the mean particle size distribution and zeta-potential (ZP) of liposomes were optimized. Using the Shh-light2 cell and Gli-GFP or Flk-GFP transgenic reporter zebrafish, we confirmed that liposome-encapsulated SANT75 inhibited Hh activity with similar potency as the original SANT75. SANT75 encapsulated into liposome exerted strong tumor growth-inhibiting effects in vitro and in vivo. In addition, the liposomal SANT75 therapy efficiently improved the survival time of tumor-bearing mice without obvious systemic toxicity. The pathological morphology and immunohistochemistry staining revealed that liposomal SANT75 induced tumor cell apoptosis, inhibited tumor angiogenesis as assessed by CD31 and down-regulated the expression of Hh target protein Gli-1 in tumor tissues. Our findings suggest that liposomal formulated SANT75 has improved solubility and bioavailability and should be further developed as a drug candidate for treating tumors with abnormally high Hh activity.     

A Genome-Wide Scan for Breast Cancer Risk Haplotypes among African American Women

Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.     

Focused Ultrasound-Induced Blood–Brain Barrier Opening to Enhance Temozolomide Delivery for Glioblastoma Treatment: A Preclinical Study

The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment.     

PGPIPN,a Therapeutic Hexapeptide,Suppressed Human Ovarian Cancer Growth by Targeting BCL2

Bioactive peptides, either derived from nature resources or synthesized by rational design, have been demonstrated potential for therapeutic agents against numerous human diseases, including cancer. However, the mechanism of therapeutic peptides against cancer has not been well elucidated. Here we show that PGPIPN, a hexapeptide derived from bovine β-casein, inhibited the proliferation of human ovarian cancer cells line SKOV₃ as well as the primary ovarian cancer cells in vitro. Consistently, PGPIPIN also decreased tumor growth rate in xenograft ovarian cancer model mice in a dose-dependent manner. Further study demonstrated that the anti-tumor effect of PGPIPN is partially through promoting cell apoptosis by inhibiting BCL2 pathway. Thus, our study suggests that PGPIPN is a potential therapeutic agent for the treatment of ovarian cancer or other types of cancer.     

Aspirin Use and Risk of Age-Related Macular Degeneration: A Meta-Analysis

Background

Age-related macular degeneration (AMD) is the main cause of blindness and the curative options are limited. The objective of this meta-analysis was to determine the association between aspirin use and risk of AMD.

Methods

A comprehensive literature search was performed in PubMed, Embase, Web of Science, and reference lists. A meta-analysis was performed by STATA software.

Results

Ten studies involving 171729 individuals examining the association between aspirin use and risk of AMD were included. Among the included studies, 2 were randomized-controlled trials (RCTs), 4 were case-control studies and 4 were cohort studies. The relative risks (RRs) were pooled using a random-effects model. Relative risks with 95% confidence intervals (CIs) of aspirin use as a risk for AMD. The pooled RR of 10 included studies between the use of aspirin and risk of AMD was 1.09 (95% CI, 0.96–1.24). The same result was detected in early and late stage AMD subgroup analysis. In the subgroup analyses, the pooled RR of RCTs, case-control studies and cohort studies were 0.81 (95% CI, 0.64–1.02), 1.02 (95% CI, 0.92–1.14) and 1.08 (95% CI, 0.91–1.28), respectively.

Conclusions

The use of aspirin was not associated with the risk of AMD.     

Evaluating Hemorrhage in Renal Cell Carcinoma Using Susceptibility Weighted Imaging

Background

Intratumoral hemorrhage is a frequent occurrence in renal cell carcinoma and is an indicator of tumor subtype. We hypothesize that susceptibility weighted imaging (SWI) is sensitive to hemorrhage in renal cell carcinoma and can give a more diagnostic image when compared to conventional imaging techniques.

Materials and Methods

A retrospective review of 32 patients with clear cell renal cell carcinoma was evaluated. All patients underwent magnetic resonance imaging (MRI) and 22 out of 32 patients also underwent a computed tomography (CT) scan. Hemorrhage was classified into 3 different categories according to shape and distribution. Histopathology was obtained from all masses by radical nephrectomy. The ability to detect the presence of hemorrhage using CT, non-contrast conventional MRI and SWI was evaluated, and the patterns of hemorrhage were compared.

Results

Using pathologic results as the gold standard, the sensitivities of non-contrast conventional MRI, SWI and CT in detecting hemorrhage in clear cell renal cell carcinoma were 65.6%, 100% and 22.7%, respectively. Accuracy of non-contrast conventional MRI and SWI in evaluating hemorrhagic patterns were 31.3% and 100%, respectively.

Conclusion

These results demonstrate that SWI can better reveal hemorrhage and characterize the pattern more accurately than either non-contrast conventional MRI or CT. This suggests that SWI is the technique of choice for detecting hemorrhagic lesions in patients with renal cancer.