ABSTRACT
Introduction: Postorgasmic illness syndrome (POIS) is rare and includes a cluster of physical and cognitive symptoms that occur after ejaculation. The pathogenesis and effective treatments remain unclear. Aim: This study aimed to characterize the symptomatology of POIS, study the allergic response of autologous semen in patients and controls, and evaluate the effects of desensitization therapy. Methods: The clinical characteristics of 24 Chinese patients with POIS were analyzed. Skin prick tests, intracutaneous tests, and specific IgE detection were performed with autologous semen. Five patients were desensitized via subcutaneous injections of autologous semen. Outcomes: Evaluated outcomes included the clinical features of POIS; scores of the Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS), and visual analog scale (VAS) of symptoms; skin reactions; desensitization with diluted autologous seminal fluid; and the IgE reactivity patterns of immunoblotting and enzyme-linked immunosorbent assay in vitro. Results: The most common symptom cluster was the general cluster, and the most prevalent symptoms were extreme fatigue and inattention. A total of 66.67% (14/21) of the patients had no symptoms or milder symptoms after nocturnal emission than after intercourse or masturbation. Of the patients, 87.5% (21/24) had psychiatric symptoms and 53.85% (7/13) had abnormal sex hormone levels. The SAS and SDS scores of the high and low VAS groups were significantly higher than those of the control group. Pearson analysis showed that the correlation coefficient between the SAS and VAS was 0.607 (P < .01) and that between the SDS and VAS was 0.490 (P < .05). The patients and healthy donors all had positive intracutaneous test results with their own semen, negative skin prick test results, and no IgE specific to autologous semen. Most patients (4/5) did not achieve ideal therapeutic effects with desensitization. Clinical Implications: Allergy is not the main pathogenesis of POIS, and desensitization with autologous semen is not effective for most patients. Strengths and Limitations: This project included the largest number of patients with POIS in China and assessed the allergic response to autologous semen and the effect of desensitization therapy. There is no objective method for evaluating the efficacy of desensitization with autologous semen. Conclusions: IgE-mediated semen allergy is not the main pathogenesis of POIS, and there is a positive chance that POIS is related to psychological factors. Most patients do not respond to desensitization with autologous semen, and POIS treatment should be individualized, especially in cases with uncertain causes.
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OBJECTIVE: Waist circumference, waist-to-hip ratio and waist-to-height ratio, which are the indicators or measures of abdominal adiposity, have long been hypothesized to increase the risk of stroke; yet evidence accumulated till date is not conclusive. Here, we conducted a dose-response meta-analysis to summarize evidences of the association between these measures of abdominal adiposity and the risk of stroke. METHODS: PubMed and Web of Science databases were searched from inception to May 2015. Two investigators independently conducted the study selection and data extraction. Dose-response relationships were assessed by the generalized least squares trend estimation, while the summary effect estimates were evaluated by the use of fixed- or random-effect models. Subgroup and sensitivity analyses were performed to assess the potential sources of heterogeneity and the robustness of the pooled estimation. Publication bias of the literature was evaluated using Begg's and Egger's test. RESULTS: Altogether 15 prospective cohort studies were identified in this study. The summary of relative risks (95% confidence intervals) of stroke for the highest versus the lowest categories was 1.28 (1.18-1.40) for waist circumference, 1.32 (1.21-1.44) for waist-to-hip ratio, and 1.49 (1.24-1.78) for waist-to-height ratio. For a 10-cm increase in waist circumference, the relative risk of stroke increased by 10%; for a 0.1-unit increase in waist-to-hip ratio, the relative risk increased by 16%; and for a 0.05-unit increase in waist-to-height ratio, the relative risk increased by 13%. There was evidence of a nonlinear association between waist-to-hip ratio and stroke risk, Pnonlinearity=0.028. CONCLUSION: Findings from our meta-analysis indicated that waist circumference, waist-to-hip ratio, and waist-to-height ratio were positively associated with the risk of stroke, particularly ischemic stroke.
Subject(s)
Abdominal Fat , Stroke/etiology , Humans , Risk Factors , Waist Circumference , Waist-Hip RatioABSTRACT
PURPOSE: To assess the efficacy and safety of the novel sodium glucose co-transporter 2 (SGLT2) inhibitor-canagliflozin for type 2 diabetes (T2DM). METHODS: A search of Medline (1946-January 2014), Embase (1950-January 2014), and The Cochrane Library for randomized controlled trials of canagliflozin compared to placebo or active comparator in T2DM was performed. Clinical Trials website and unpublished U.S. Food and Drug Administration data were also searched. RESULTS: Ten trials including 6,701 patients were analyzed. Compared with placebo, canagliflozin produced absolute reductions in glycated hemoglobin A1c levels when used as monotherapy (weighted mean difference (WMD) -1.08%, 95% confidence interval (CI) [-1.25 to -0.90], p < 0.00001) or add-on treatment (WMD -0.73%, 95%CI [-0.84 to -0.61], p < 0.00001). When compared with other active comparators, canagliflozin significantly reduced HbA1c by -0.21% (WMD, 95%CI [-0.33 to -0.08], p = 0.001). Canagliflozin led to greater body weight loss (vs. placebo, WMD -2.81 kg, 95%CI [-3.26 to -2.37]; vs. active comparators, WMD -3.49 kg, 95%CI [-4.86 to -2.12]). Hypoglycemia with canagliflozin was similar to placebo or sitagliptin, and was lower than glimepiride (risk ratio (RR) 0.15, 95%CI [0.10 to 0.22]). Genital tract infections were more common with canagliflozin (vs. placebo, RR 3.76, 95%CI [2.23 to 6.35]; vs. active comparators, RR 4.95, 95%CI [3.25 to 7.52]). Similar incidences of urinary tract infections were noted with canagliflozin compared with control groups. CONCLUSION: Canagliflozin led to improvements in reducing glycated hemoglobin A1c levels and body weight with low risk of hypoglycemia in patients with T2DM. Common adverse effects including genital tract infections and osmotic diuresis-related AEs were identified and reviewed. Risks of cardiovascular events are even less certain, and more data on long-term effects are needed.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glucosides/therapeutic use , Hypoglycemic Agents/therapeutic use , Thiophenes/therapeutic use , Canagliflozin , Diabetes Mellitus, Type 2/physiopathology , Glucosides/adverse effects , Glucosides/pharmacology , Glycated Hemoglobin/metabolism , Humans , Hypoglycemia/chemically induced , Hypoglycemia/epidemiology , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/pharmacology , Sodium-Glucose Transporter 2 Inhibitors , Thiophenes/adverse effects , Thiophenes/pharmacologyABSTRACT
In order to search for alternative agents to overcome chemoresistance during the treatment of ovarian cancer, this study aimed to examine the anticancer effects and action mechanism of salinomycin, a selective inhibitor of cancer stem cells, on cisplatin-resistant human ovarian cancer cell lines in vitro and in vivo. The concentration- (0.01-200 µM) and timedependent (24-72 h) growth inhibitory effects of salinomycin were observed in the ovarian cancer cell lines OV2008, C13, A2780, A2780-cp, SKOV3 and OVCAR3, by measuring cell viability using the resazurin reduction assay. The IC50 (24 h) range of salinomycin on the six cell lines was found to be 1.7-7.4 µM. After cisplatin-resistant C13 cells were treated with salinomycin, the percentage of apoptotic cells determined by flow cytometry was significantly increased, in a concentration- and timedependent manner. However, no cell cycle arrest was detected in the G1/G0, S and G2/M phases in the salinomycintreated and control cells. The Bio-Plex phosphoprotein 5-plex assay (Akt, IκB-α, ERK1/2, JNK and p38 MAPK) demonstrated a marked time- and concentrationdependent increase in the phosphorylation of p38 MAPK, subsequent to salinomycin treatment. Moreover, salinomycin significantly suppressed tumor growth in a tumor xenograft model. These findings suggested that salinomycin efficiently inhibits the cisplatin-resistant human ovarian cancer cell line growth through the induction of apoptosis, potentially associated with the p38 MAPK activation.
Subject(s)
Cisplatin/administration & dosage , Drug Resistance, Neoplasm/genetics , Ovarian Neoplasms/drug therapy , Pyrans/administration & dosage , p38 Mitogen-Activated Protein Kinases/genetics , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Drug Resistance, Neoplasm/drug effects , Female , Flow Cytometry , Humans , Mice , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/genetics , Xenograft Model Antitumor Assays , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
MicroRNAs (miRNAs) are a class of small noncoding RNAs whose expression changes are associated with cancer development and invasion. We hypothesized that miR-10b and miR-373, which are increased in lymphatic metastatic tissues, could be directly assayed in the plasma and used to detect the lymph node status of breast cancer patients. Between November 2009 and January 2012, 35 breast ductal carcinoma patients with lymph node metastasis (N patients), 25 ductal carcinoma patients without lymph node metastasis (N(0) patients), and ten healthy female donors were enrolled in the study. Circulating miR-10b and miR-373 were determined in preoperative plasma samples by reverse transcription quantitative real-time PCR assay. In preliminary tests, the plasma levels of circulating miR-10b and miR-373 were found to be significantly higher in ten breast cancer patients with lymph node metastasis compared to ten N(0) patients and ten normal donors (P < 0.01). On validation analysis, the median value level of miR-10b in the 35 N patients was 4.44-fold (P < 0.01) increased, and miR-373 was 4.38-fold (P < 0.01) increased in comparison to the 25 N(0) patients. MiR-10b was used for differentiation of N patients from N(0) patients; the odds ratio was 2.19, and the value of the area under the receiver-operating curve (AUC) was 0.80, with sensitivity of 71 % and specificity of 72 %. For miR-373, the odds ratio was 2.62, and the AUC was 0.84, with sensitivity of 68 % and specificity of 89 %. A combination of the two circulating miRNAs further enhanced the sensitivity to 72 % and the specificity to 94.3 %. Our data suggest that circulating miRNA-10b and miRNA-373 are potential biomarkers for detecting the lymph node status of breast cancer.
Subject(s)
Breast Neoplasms/blood , Breast Neoplasms/genetics , Lymphatic Metastasis , MicroRNAs/blood , Adult , Aged , Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/blood , Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/pathology , Female , Gene Expression Regulation, Neoplastic , Humans , Lymph Nodes/pathology , Middle AgedABSTRACT
Cluster of differentiation 133 (CD133) is recognized as a stem cell marker for normal and cancerous tissues. Using cell culture and realtime fluorescent polymerase chain reaction, CD133 expression was analyzed in osteosarcoma tissue and Saos2 cell lines. In addition, cancer stem cellrelated gene expression in the Saos2 cell line was determined to explore the mechanisms underlying tumorigenesis and high drug resistance in osteosarcoma. CD133+ cells were found to be widely distributed in various types of osteosarcoma tissue. Following cell culture, cells entered the G2/M and S cell cycle stages from G0/G1. Levels of CD133+ cells decreased to normal levels rapidly over the course of cell culture. Colony forming efficiency was higher in the CD133+ compared with the CD133 subpopulation of Saos2 cells. Expression levels of stem cellrelated genes, including multidrug resistance protein 1 (MDR1) and sex determining region Ybox 2 (Sox2) in the CD133+ subpopulation of cells were found to be significantly higher compared with the CD133 subpopulation. These observations indicate that CD133+ Saos2 cells exhibit stem cell characteristics, including low abundance, quiescence and a high potential to undergo differentiation, as well as expression of key stem cell regulatory and drug resistance genes, which may cause osteosarcoma and high drug resistance.
Subject(s)
Antigens, CD/metabolism , Glycoproteins/metabolism , Peptides/metabolism , AC133 Antigen , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Cell Differentiation , Cell Line, Tumor , Cell Proliferation , Drug Resistance, Neoplasm , Humans , Interphase , Neoplastic Stem Cells/metabolism , Osteosarcoma/metabolism , Osteosarcoma/pathology , SOXB1 Transcription Factors/metabolismABSTRACT
This study investigated the anticancer effect and mechanism of salinomycin, a selective inhibitor of cancer stem cell, on human ovarian cancer cell line OV2008 in vitro and in vivo. The growth inhibitory effect of salinomycin on ovarian cancer cell line OV2008 was determined by measuring cell viability using the resazurin reduction assay. Apoptotic nuclear morphology was visualized by 4,6-diamino-2-phenylindole staining technique. The percentages of apoptotic cells and cell cycle parameters were detected by flow cytometry. The activity of p38 mitogen-activated protein kinase (p38 MAPK) was analyzed by Bio-Plex phosphoprotein assay. In vivo activity of salinomycin was assayed through tumor growth. Salinomycin caused concentration- (0.01-200 µM) and time-dependent (24-72 h) growth inhibitory effects in OV2008. Cell nuclear morphology observations showed that salinomycin-treated OV2008 cells displayed typical apoptotic characteristics. Salinomycin significantly increased the percentages of apoptotic cells in OV2008, showing a concentration- and time-dependent manner. There was no cell cycle arrest in the G1/G0, S, and G2/M phases between salinomycin-treated cells and control cells. Salinomycin also enhanced the phosphorylation of p38 MAPK. Moreover, salinomycin significantly inhibited the growth of the ovarian xenograft tumors. Salinomycin exhibited significant growth inhibition and induction of apoptosis in the human ovarian cancer cell line OV2008. The data suggested that salinomycin-induced apoptosis in OV2008 might be associated with activating p38 MAPK and merits further investigations.
Subject(s)
Anti-Bacterial Agents/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Proliferation/drug effects , Ovarian Neoplasms/metabolism , Pyrans/pharmacology , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Blotting, Western , Female , Flow Cytometry , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Phosphorylation/drug effects , Signal Transduction/drug effects , Tumor Cells, CulturedABSTRACT
BACKGROUND: Invasion and metastasis are two important hallmarks of malignant tumors caused by complex genetic and epigenetic alterations. The present study investigated the contribution of aberrant methylation profiles of cancer related genes, APC, BIN1, BMP6, BRCA1, CST6, ESR-b, GSTP1, P14 (ARF), P16 (CDKN2A), P21 (CDKN1A), PTEN, and TIMP3, in the matched axillary lymph node metastasis in comparison to the primary tumor tissue and the adjacent normal tissue from the same breast cancer patients to identify the potential of candidate genes methylation as metastatic markers. METHODS: The quantitative methylation analysis was performed using the SEQUENOM's EpiTYPER™ assay which relies on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). RESULTS: The quantitative DNA methylation analysis of the candidate genes showed higher methylation proportion in the primary tumor tissue than that of the matched normal tissue and the differences were significant for the APC, BIN1, BMP6, BRCA1, CST6, ESR-b, P16, PTEN and TIMP3 promoter regions (P<0.05). Among those candidate methylated genes, APC, BMP6, BRCA1 and P16 displayed higher methylation proportion in the matched lymph node metastasis than that found in the normal tissue (P<0.05). The pathway analysis revealed that BMP6, BRCA1 and P16 have a role in prevention of neoplasm metastasis. CONCLUSIONS: The results of the present study showed methylation heterogeneity between primary tumors and metastatic lesion. The contribution of aberrant methylation alterations of BMP6, BRCA1 and P16 genes in lymph node metastasis might provide a further clue to establish useful biomarkers for screening metastasis.
Subject(s)
Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , DNA Methylation , Lymph Nodes/pathology , Adult , Aged , Aged, 80 and over , Breast Neoplasms/metabolism , CpG Islands , Female , Gene Expression Profiling , Humans , Lymphatic Metastasis , Middle Aged , Neoplasm Staging , Promoter Regions, Genetic , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolismABSTRACT
BACKGROUND: Alterations of mitochondrial DNA (mtDNA) have been found in cancer patients, therefore informative mtDNA mutations could serve as biomarkers for the disease. MATERIALS AND METHODS: The two hypervariable regions HVR1 and HVR2 in the D-Loop region were sequenced in ten paired tissue and plasma samples from breast cancer patients. RESULTS: MtDNA mutations were found in all patients' samples, suggesting a 100% detection rate. Examining germline mtDNA mutations, a total of 85 mutations in the D-loop region were found; 31 of these mutations were detected in both tissues and matched plasma samples, the other 54 germline mtDNA mutations were found only in the plasma samples. Regarding somatic mtDNA mutations, a total of 42 mutations in the D-loop region were found in breast cancer tissues. CONCLUSION: Somatic mtDNA mutations in the D-loop region were detected in breast cancer tissues but not in the matched plasma samples, suggesting that more sensitive methods will be needed for such detection to be of clinical utility.
Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , DNA, Mitochondrial/genetics , Mutation , Aged , Breast Neoplasms/diagnosis , DNA/metabolism , DNA Primers/genetics , DNA, Mitochondrial/metabolism , Female , Germ-Line Mutation , Humans , Middle Aged , Mitochondria/metabolism , Protein Structure, TertiaryABSTRACT
BACKGROUND: The contribution of aberrant DNA methylation in silencing of tumor suppressor genes (TSGs) and microRNAs has been investigated. Since these epigenetic alterations are reversible, it became of interest to determine the effects of the 5-aza-2'-deoxycytidine (DAC) demethylation therapy in breast cancer at different molecular levels. METHODS AND FINDINGS: Here we investigate a synoptic model to predict complete DAC treatment effects at the level of genes, microRNAs and proteins for several human breast cancer lines. The present study assessed an effective treatment dosage based on the cell viability, cytotoxicity, apoptosis and methylation assays for the investigated cell lines. A highly aggressive and a non-aggressive cell line were investigated using omics approaches such as MALDI-TOF MS, mRNA- and microRNA expression arrays, 2-D gel electrophoresis and LC-MS-MS. Complete molecular profiles including the biological interaction and possible early and late systematic stable or transient effects of the methylation inhibition were determined. Beside the activation of several epigenetically suppressed TSGs, we also showed significant dysregulation of some important oncogenes, oncomiRs and oncosuppressors miRNAs as well as drug tolerance genes/miRNAs/proteins. CONCLUSIONS: In the present study, the results denote some new molecular DAC targets and pathways based on the chemical modification of DNA methylation in breast cancer. The outlined approach might prove to be useful as an epigenetic treatment model also for other human solid tumors in the management of cancer patients.
Subject(s)
Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , DNA Methylation , Epigenesis, Genetic , MicroRNAs/physiology , Antimetabolites, Antineoplastic/pharmacology , Apoptosis , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Blotting, Western , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation , Decitabine , Electrophoresis, Gel, Two-Dimensional , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Gene Silencing , Humans , Oligonucleotide Array Sequence Analysis , Promoter Regions, Genetic/genetics , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
BACKGROUND: Circulating cell-free (ccf) DNA in blood has been suggested as a potential biomarker in many conditions regarding early diagnosis and prognosis. However, misdiagnosis can result due to the limited DNA resources in Biobank's plasma samples or insufficient DNA targets from a predominant DNA background in genetic tests. This study explored several strategies for an efficient DNA extraction to increase DNA amount from limited plasma input. METHODS: Ccf plasma DNA was extracted with three different methods, a phenol-chloroform-isoamylalcohol (PCI) method, a High Pure PCR Template Preparation Kit method and a method used for single cell PCR in this group. Subsequently, the total DNA was measured by Nanodrop and the genome equivalents (GE) of the GAPDH housekeeping gene and MTATP 8 gene were measured using a multiplex real-time quantitative PCR for the quantitative assessment of nDNA and mtDNA. RESULTS: Instead of 400-800 µL (routine input in the laboratory), 50 µLof plasma input enabled the extraction of ccf DNA sufficient for quantitative analysis. Using the PCI method and the kit method, both nDNA and mtDNA could be successfully detected in plasma samples, but nDNA extracted using protocol for single cell PCR was not detectable in 25% of plasma samples. In comparison to the other two methods, the PCI method showed lower DNA purity, but higher concentrations and more GE of nDNA and mtDNA. CONCLUSIONS: The PCI method was more efficient than the other two methods in the extraction of ccf DNA in plasma. Limited plasma is available for ccf DNA analysis.
Subject(s)
Cell Nucleus/chemistry , Clinical Chemistry Tests/methods , DNA, Mitochondrial , DNA/chemistry , Blood Specimen Collection , DNA/blood , DNA, Mitochondrial/blood , HumansABSTRACT
Both genetic and epigenetic alterations can control the progression of cancer. Genetic alterations are impossible to reverse, while epigenetic alterations are reversible. This advantage suggests that epigenetic modifications should be preferred in therapy applications. DNA methyltransferases and histone deacetylases have become the primary targets for studies in epigenetic therapy. Some DNA methylation inhibitors and histone deacetylation inhibitors are approved by the US Food and Drug Administration as anti-cancer drugs. Therefore, the uses of epigenetic targets are believed to have great potential as a lasting favorable approach in treating breast cancer.
Subject(s)
Breast Neoplasms/genetics , Epigenomics , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methylation/drug effects , Female , Histone Deacetylase Inhibitors/therapeutic use , HumansABSTRACT
In the course of the search for new biomarkers, circulating cell-free DNA (ccf-DNA) has become a popular target of interest. An elevated level of ccf-DNA has been detected in the circulation of cancer patients in comparison with healthy controls. Since ccf-DNA in cancer patients often bears similar genetic and epigenetic features to the related tumor DNA, there is evidence that some of the ccf-DNA originates from tumoral tissue. This, and the fact that ccf-DNA can easily be isolated from the circulation and other body fluids of patients, makes it a promising candidate as a non-invasive biomarker of cancer. Yet ccf-DNA-based cancer tests have not come to fruitful clinical applications. This review evaluates the potential of ccf-DNA alterations as a biomarker for cancer management by addressing the question of how large the gap between ccf-DNA and the ideal cancer biomarker is.
Subject(s)
Biomarkers, Tumor/blood , DNA/blood , Biomarkers, Tumor/genetics , DNA/genetics , Epigenesis, Genetic , Humans , Microsatellite Repeats/geneticsABSTRACT
PURPOSE: To identify cancer-linked genes, Sjöblom et al. and Wood et al. performed a genome-wide mutation screening in human breast and colorectal cancers. 140 CAN-genes were found in breast cancer, which in turn contained overall 334 mutations. These mutations could prove useful for diagnostic and therapeutic purposes. METHODS: We used a MALDI-TOF MS 40-plex assay for testing 40 loci within 21 high-ranking breast cancer CAN-genes. To confirm mutations, we performed single-plex assays and sequencing. RESULTS: In general, the mutation rate of the analyzed loci in our sample cohort was very low. No mutation from the 40 loci analyzed could be found in the 6 cell lines. In tissue samples, a single breast cancer tissue sample showed heterozygosity at locus c.5834G>A within the ZFYVE26 gene (Zinc finger FYVE domain-containing gene 26). CONCLUSIONS: Sjöblom et al./Wood et al. already showed that the vast majority of CAN-genes are mutated at very low frequency. Due to the fact that we only found one mutation in our cohort, we therefore assume that at the selected loci, mutations might be low-frequency events and therefore, more rarely detectable. However, further evaluation of the CAN-gene mutations in larger cohorts should be the aim of further studies.
Subject(s)
Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Colorectal Neoplasms/genetics , Mutation , Nuclear Pore Complex Proteins/genetics , Polymorphism, Single Nucleotide , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Adult , Carcinoma, Ductal, Breast/genetics , Carcinoma, Medullary/genetics , Cell Line, Tumor , DNA, Neoplasm/genetics , Female , Genotype , Humans , Middle Aged , Polymerase Chain Reaction , Predictive Value of TestsABSTRACT
Even though there are a lot of options in treating gynecological malignancies, ovarian cancer still remains a leading cause of death. Diagnosis at an early stage is the most important determinant of survival. Current diagnostic tools applied at clinics have had very limited success in early detection. Discovery of new diagnostic biomarkers/panels for early diagnosis of ovarian cancer is one of the main challenges of modern medicine. With the progress of techniques in genomics and proteomics, numerous molecular biomarkers/panels were identified and showed promise for ovarian cancer diagnosis, but still need further validation. This article summarizes various types of markers investigated by different strategies/technologies for the ovarian cancer diagnosis at present, including gene-, protein-based and emerging ovarian cancer indicators (such as microRNA-, metabolite-based). Before biomarker tests are translated for routine use, more researches, such as retrospective and prospective clinical trials, are needed to evaluate the overall clinical utility of the tests.
Subject(s)
Biomarkers, Tumor/analysis , Ovarian Neoplasms/diagnosis , Early Detection of Cancer , Female , Humans , Mutation , Ovarian Neoplasms/geneticsABSTRACT
BACKGROUND: Aberrant DNA methylation patterns might be used as a biomarker for diagnosis and management of cancer patients. METHODS AND FINDINGS: To achieve a gene panel for developing a breast cancer blood-based test we quantitatively assessed the DNA methylation proportion of 248 CpG sites per sample (total of 31,248 sites in all analyzed samples) on 10 candidate genes (APC, BIN1, BMP6, BRCA1, CST6, ESR-b, GSTP1, P16, P21 and TIMP3). The number of 126 samples consisting of two different cohorts was used (first cohort: plasma samples from breast cancer patients and normal controls; second cohort: triple matched samples including cancerous tissue, matched normal tissue and serum samples). In the first cohort, circulating cell free methylated DNA of the 8 tumor suppressor genes (TSGs) was significantly higher in patients with breast cancer compared to normal controls (P<0.01). In the second cohort containing triple matched samples, seven genes showed concordant hypermethylated profile in tumor tissue and serum samples compared to normal tissue (P<0.05). Using eight genes as a panel to develop a blood-based test for breast cancer, a sensitivity and specificity of more than 90% could be achieved in distinguishing between tumor and normal samples. CONCLUSIONS: Our study suggests that the selected TSG panel combined with the high-throughput technology might be a useful tool to develop epigenetic based predictive and prognostic biomarker for breast cancer relying on pathologic methylation changes in tumor tissue, as well as in circulation.
Subject(s)
Breast Neoplasms/diagnosis , DNA Methylation , Gene Regulatory Networks , Genes, Tumor Suppressor , Breast Neoplasms/genetics , Case-Control Studies , CpG Islands , DNA, Neoplasm/blood , Female , Genes, Neoplasm , Humans , Sensitivity and SpecificityABSTRACT
Umbilical cord blood (UCB) is a valuable alternative source of hematopoietic stem cells (HSCs). It has unique advantages of easy procurement, absence of risk to donors, low risk of transmitting infections, immediate availability, greater tolerance of human leukocyte antigen (HLA) disparity, and lower incidence of inducing severe graft-versus-host disease (GVHD). In the last several years, these features of UCB permit the field of UCB transplantation (UCBT) to move at a faster pace for both children and adults with malignancies and nonmalignancies. However, new strategies and novel developments are expected to improve engraftment and reconstitution, and to enable in utero transplantation for early therapy, as well as to allow the therapy for a wide spectrum of human diseases.
Subject(s)
Cord Blood Stem Cell Transplantation/trends , Fetal Blood/cytology , Hematopoietic Stem Cells/physiology , Adult , Animals , Cord Blood Stem Cell Transplantation/methods , Cord Blood Stem Cell Transplantation/statistics & numerical data , Fetal Blood/physiology , Hematologic Neoplasms/therapy , Humans , Immunologic Deficiency Syndromes/therapy , Metabolic Diseases/therapyABSTRACT
Ovarian cancer remains a leading cause of death from gynecological malignancy. Early diagnosis is the most important determinant of survival. Current diagnostic tools have had very limited success in early detection. In recent years, the advancing techniques for proteomics have accelerated the discovery of ovarian cancer biomarkers. Numerous proteomics-based molecular biomarkers/panels have been identified and hold great potential for diagnostic applications, but they need further development and validation. This article reviews recently published data on the diagnosis of ovarian cancer with proteomics, including the major proteomics technologies and promising strategies for biomarker discovery and development.
Subject(s)
Biomarkers, Tumor/metabolism , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/metabolism , Proteomics , Early Diagnosis , Female , HumansABSTRACT
DNA methylation is an epigenetic regulation mechanism of genomic function, and aberrant methylation pattern has been found to be a common event in many diseases and human cancers. A large number of cancer studies have been focused on identification of methylation changes as biomarkers (i.e., breast cancer). However, still clinical use of them is very limited because of lack of specificity and sensitivity for diagnostic test. This highlights the critical need for specific primer and probe design to avoid false-positive detection of methylation profiling. The guideline and online web tools that are introduced in this paper might help to perform a successful experiment and to develop specific diagnosis biomarkers by designing right primer pair and probe prior to experimental step.
ABSTRACT
The present study investigated promoter hypermethylation of TP53 regulatory pathways providing a potential link between epigenetic changes and mitochondrial DNA (mtDNA) alterations in breast cancer patients lacking a TP53 mutation. The possibility of using the cancer-specific alterations in serum samples as a blood-based test was also explored. Triple-matched samples (cancerous tissues, matched adjacent normal tissues and serum samples) from breast cancer patients were screened for TP53 mutations, and the promoter methylation profile of P14(ARF), MDM2, TP53 and PTEN genes was analyzed as well as mtDNA alterations, including D-loop mutations and mtDNA content. In the studied cohort, no mutation was found in TP53 (DNA-binding domain). Comparison of P14(ARF) and PTEN methylation patterns showed significant hypermethylation levels in tumor tissues (P < 0.05 and <0.01, respectively) whereas the TP53 tumor suppressor gene was not hypermethylated (P < 0.511). The proportion of PTEN methylation was significantly higher in serum than in the normal tissues and it has a significant correlation to tumor tissues (P < 0.05). mtDNA analysis revealed 36.36% somatic and 90.91% germline mutations in the D-loop region and also significant mtDNA depletion in tumor tissues (P < 0.01). In addition, the mtDNA content in matched serum was significantly lower than in the normal tissues (P < 0.05). These data can provide an insight into the management of a therapeutic approach based on the reversal of epigenetic silencing of the crucial genes involved in regulatory pathways of the tumor suppressor TP53. Additionally, release of significant aberrant methylated PTEN in matched serum samples might represent a promising biomarker for breast cancer.