Prediction of clinically significant prostate cancer through urine metabolomic signatures: A large-scale validated study.

PURPOSE: Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk. METHODS: Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC). RESULTS: In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS. CONCLUSION: This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.

Effects of ABT-737 combined with irradiation treatment on uterine cervical cancer cells.

The aim of the present study was to examine the role of ABT-737, an inhibitor of B-cell lymphoma 2 (Bcl-2), in enhancing the effect of irradiation on uterine cervical cancer. Based on The Cancer Genomic Atlas (TCGA), Bcl-2 mRNA expression was associated with the Tumor-Node-Metastasis stage of cervical cancer. Therefore, it was hypothesized that Bcl-2 inhibition may decrease the progression of cervical cancer. ABT-737 was added to irradiation treatment to evaluate its effectiveness in inhibiting cancer cell progression. SiHa and CaSki cervical cancer cells were selected for in vitro assays. Patients with advanced stage III uterine cancer had slightly increased mRNA expression levels of Bcl-2 compared with patients with stage I cancer, although the difference was not significant. ABT-737 and radiation administration induced a synergistic cytotoxic effect based on the MTT assay and flow cytometry results, where an increase in apoptosis was observed. The apoptotic percentages were significantly increased in the cells treated with a combination of ABT-737 and irradiation. Loss of mitochondrial membrane potential and gain of reactive oxygen species (ROS) were detected by flow cytometry in CaSki and SiHa cells treated with ABT-737 and radiation. Additionally, the protein expression levels of the cleaved forms of poly ADP ribose polymerase and caspase-7 were increased following the combined treatment. In conclusion, ABT-737 and irradiation may induce apoptosis via loss of mitochondrial membrane potential and a ROS-dependent apoptotic pathway in CaSki and SiHa cells. The present study indicates that ABT-737 may be a potential irradiation adjuvant when treating cervical cancer.

Clinical implication of voltage-dependent anion channel 1 in uterine cervical cancer and its action on cervical cancer cells.

Two-dimensional gel electrophoresis and liquid chromatography-tandem mass spectrometry were performed to investigate the influence of human nonmetastatic clone 23 type 1 (nm23-H1), a metastasis-associated gene on proteomic alterations in cancer cells of the uterine cervix. It was validated by RT-PCR and Western blot analysis. The expression of voltage-dependent anion channel 1 (VDAC1) was increased in nm23-H1 gene silenced SiHa or CaSki cervical cancer cells. The clinical implication was shown that cervical cancer tissues with positive VDAC1 immunoreactivity exhibited deep stromal invasion (>10 mm in depth) and large tumor size (> 4 cm in diameter). Cervical cancer patients with positive VDAC1 immunoreactivity displayed higher recurrence and poorer overall survival than those with negative VDAC1. Silencing of VDAC1 reduced cell proliferation and migratory ability. Mitochondrial membrane potential was decreased and reactive oxygen species generation was increased in the VDAC1 gene-silenced cervical cancer cells. Cell cycle progression and autophagy were not changed in VDAC1 silencing cells. The cytotoxicity of cisplatin was significantly enhanced by knockdown of cellular VDAC1 and the compounds that interfere with hexokinase binding to VDAC. Therapeutic strategies may be offered using VDAC1 as a target to reduce cell growth and migration, enhance the synergistic therapeutic efficacy of cisplatin and reduce cisplatin dose-limiting toxicity.

Single-Nucleotide Polymorphisms and Haplotypes of Intercellular Adhesion Molecule-1 in Uterine Cervical Carcinogenesis in Taiwanese Women.

The association of intercellular adhesion molecule 1 (ICAM-1) genetic polymorphisms with uterine cervical carcinogenesis has seldom been reported. Therefore, the aim of this study was to investigate the association of single-nucleotide polymorphisms (SNPs) and haplotypes of ICAM-1 with cervical tumorigenesis in Taiwanese women. Four hundred forty four women, including 91 with cervical invasive cancer, 63 with precancerous lesions, and 290 normal controls, were recruited. The genotypic distribution of 4 SNPs of ICAM-1, rs5498 (A1548G), rs5491 (K56M), rs281432 (C8823G), and rs3093030 (C-286T) was determined using real-time polymerase chain reactions and genotyping. Compared to homozygous wild CC, heterozygous CG, homozygous mutant GG, or genotypes with CG/GG display increased risks or a tendency of precancerous lesions or invasive cancer with strong power in rs281432. The homozygotic mutant alleles TT in rs3093030 and homozygotic mutant alleles GG in rs5498 were associated with a higher risk of invasive cancer and precancerous lesions, respectively, but with lower power. The CG/TA/TG haplotypes of ICAM-1 SNPs rs3093030 and rs5498 exhibited a tendency to increase susceptibility to precancerous lesions and invasive cancer. In conclusion, Taiwanese women with ICAM-1 SNP rs281432 and haplotypes CG/TA/TG of rs3093030 and rs5498 are associated with uterine cervical carcinogenesis.

The expression of ribonucleotide reductase M2 in the carcinogenesis of uterine cervix and its relationship with clinicopathological characteristics and prognosis of cancer patients.

BACKGROUND: To investigate the implication of ribonucleotide reductase M2 (RRM2) in the carcinogenesis of uterine cervix and its relationship with clinicopathological characteristics and prognosis of cancer patients. METHODOLOGY AND PRINCIPAL FINDINGS: The impact of RRM2 on cell viability was investigated in SiHa cervical cancer cells after RRM2 knockdown and the addition of cisplatin, which induces inter- and intra-strand DNA crosslinks. RRM2 immunoreactivity was evaluated by semi-quantitative H score among 29 normal, 30 low-grade dysplasia, 30 high-grade dysplasia and 103 invasive cancer tissue specimens of the uterine cervix, using tissue microarrays. RRM2 was then correlated with the clinicopathological variables of cervical cancer and patient survival. A greater toxic effect on cell viability using cisplatin was reflected by the greater reduction in RRM2 protein expression in SiHa cells. The RRM2 expression in cancer tissues was higher than that in high-grade dysplasia, low-grade dysplasia or normal cervical tissues. RRM2 upregulation was correlated with deep stromal invasion, large tumors and parametrial invasion and predicted poor survival. CONCLUSIONS: RRM2 is a new molecular marker for the diagnosis and clinical outcomes of cervical cancer. It is involved in cervical carcinogenesis and predicts poor survival, and may be a potential therapeutic target including in cisplatin treatment.

New markers in pelvic inflammatory disease.

Pelvic inflammatory disease (PID) is a common infection in women of reproductive age. However, diagnosis of PID can be difficult due to the wide variation in the symptoms and signs, ranging from subtle or mild symptoms to severe pain in the lower abdomen. Clinical diagnosis alone has only 87% sensitivity and 50% specificity. Therefore, identifying biological factors that are useful for early diagnosis and correlating their expression with the severity of PID could provide significant benefits to women suffering from PID. Pentraxin 3 (PTX3), E-cadherin, myeloperoxidase, stromal cell-derived factor 1 (SDF-1) and the matrix metalloproteinase-9 (MMP-9)/MMP-2 ratio are potential candidates for detecting PID reliably. As PID is often subtle, highly sensitive PID detection methods are needed to promote the prevention of severe sequelae. Growth arrest-specific 6 (Gas6), in combination with its soluble tyrosine kinase receptor, sAxl, could elevate the sensitivity to 92%, which was higher than all other markers tested. Moreover, PTX3, D-dimer and YKL-40 concentrations can predict the clinical course of PID. Although single nucleotide polymorphisms of biomarker genes are not associated with the development of PID, myeloperoxidase SNP -463 G/A and SDF-1 SNP 801 G/A may affect the aggravated expression of their biomarkers in PID.