Role of Exosomal miRNA in Bladder Cancer: A Promising Liquid Biopsy Biomarker.

Bladder cancer (BCa) is the most prevalent neoplasia of the urinary tract. Unfortunately, limited improvements in effective BCa management have meant that it remains a challenging disease. Cystoscopy has been the gold standard for BCa diagnosis and surveillance for over two centuries but is an invasive and expensive approach. Recently, liquid biopsy has been identified as a promising field of cancer research, due to its noninvasiveness and ease of sampling. Liquid biopsy samples could provide comprehensive information regarding the genetic landscape of cancer and could track genomic evolution of the disease over time. Exosomes, which contain RNAs, DNAs, and proteins, are a potential source of tumor biomarkers in liquid biopsy samples. In particular, exosomal miRNAs (exomiRs) hold great promise as biomarkers for tumor development and progression. In this review, we provide an overview of liquid biopsy biomarkers, with a particular focus on the use of exomiRs as biomarkers of cancer, and summarize their clinical implications for BCa. Finally, we discuss the future perspectives of these biomarkers in cancer research.

Urinary cell-free microRNA biomarker could discriminate bladder cancer from benign hematuria.

The most common symptom of bladder cancer (BC) is hematuria. However, not all patients with hematuria are diagnosed with BC. Here, we explored a novel method to discriminate BC from hematuria under nonmalignant conditions by measuring differences in urinary cell-free microRNA (miRNA) expression between patients with BC and those with hematuria. A multicenter study was performed using 543 urine samples obtained from the National Biobank of Korea, including 326 BC, 174 hematuria and 43 pyuria without cancer. The urinary miR-6124 to miR-4511 ratio was considerably higher in BC than in hematuria or pyuria, and enabled the discrimination of BC from patients with hematuria at a sensitivity of >90% (p < 0.001). Conclusively, the proposed noninvasive diagnostic tool based on the expression ratio of urinary cell-free miR-6124 to miR-4511 can reduce unnecessary cystoscopies in patients with hematuria undergoing evaluation for BC, with a minimal loss in sensitivity for detecting cancer.

Chitosan-Polypyrrole Fiber for Strain Sensor.

A chitosan/polypyrrole composited fiber as bio-compatible materials for artificial muscles is investigated. The chitosan/polypyrrole fiber (CPF) is fabricated by in-situ chemical polymerization of pyrrole monomer solution using FeCl3 as an oxidant. The electrical resistivity of the fiber is changed according to the strain variation applied to the both ends of the specimen. The sensor built by using the CPF has a higher gauge factor (4) compared to conventional metal strain gauges (~2) indicating a suitable material for delicate force control in sensing work.

Effect of sagittal allograft position on coronal extrusion in lateral meniscus allograft transplantation.

PURPOSE: This study assessed the incidence of graft extrusion on the sagittal plane on magnetic resonance imaging (MRI) and evaluated the correlation between the sagittal position of the allograft and coronal graft extrusion. METHODS: The study involved 99 patients who underwent lateral meniscus allograft transplantation (LMAT) for knees that had undergone total meniscectomy and 50 sex- and age-matched control patients who underwent MRI for evaluation of knee pain and had no intra-articular lesions. Graft extrusion and sagittal graft position parameters, including the distance from the articular cartilage center to the anterior meniscus (CAMD), the distance from the articular cartilage center to the posterior meniscus, the distance from the anterior articular cartilage margin to the anterior horn (ACMD), or the distance from the posterior articular cartilage margin to the posterior horn, were assessed on immediate postoperative MRI studies (2 days after surgery) and compared between the LMAT and control groups. In the LMAT group, correlations between graft extrusion and MRI parameters were analyzed, and multiple linear regression analysis was performed to identify predictors of graft extrusion. RESULTS: The mean CAMD and mean ACMD were significantly greater and the mean distance from the articular cartilage center to the posterior meniscus and the mean distance from the posterior articular cartilage margin to the posterior horn were significantly smaller in the LMAT group than in the normal control group (P < .001 for each). CAMD (r = 0.294, P = .015) and ACMD (r = 0.244, P = .041) correlated with relative extrusion, and CAMD (r = 0.288, P = .013) correlated with absolute extrusion. CAMD was the only predictor independently associated with both absolute (ß = 0.248, P = .013) and relative (ß = 0.244, P = .015) extrusion. CONCLUSIONS: Transplanted lateral meniscal allografts were located more anteriorly on the sagittal plane than normal lateral menisci. More anterior allograft placement correlated with a greater degree of graft extrusion on the coronal plane. LEVEL OF EVIDENCE: Level III, retrospective case-control study.

IL-28A/IL-10Rß axis promotes angiogenesis via eNOS/AKT signaling and AP-1/NF-κB/MMP-2 network by regulating HSP70-1 expression.

INTRODUCTION: Angiogenesis plays a significant role in the development of tumor progression and inflammatory diseases. The role of IL-28A in angiogenesis and its precise regulatory mechanisms remain rarely elucidated. OBJECTIVES: We report the novel regulatory role of IL-28A in physiological angiogenesis. The study aimed to elucidate the regulatory mechanisms involved in IL-28A-mediated angiogenesis and identify key genes associated with IL-28A-induced angiogenic responses. METHODS: To know the effect of IL-28A on angiogenesis, HUVECs were applied to perform proliferation, migration, invasion, tube formation, immunoblot, and EMSA. Gene expression changes in HUVECs following IL-28A treatment were analyzed by NGS. The functional role of HSP70-1 and IL-10Rß in IL-28A-induced angiogenic responses was evaluated using PCR and siRNA knockdown. Animal studies were conducted by aortic ring ex vivo assays, Matrigel plug in vivo assays, and immunochemistry using HSP70-1 knockout and transgenic mice models. The efficacy of IL-28A in angiogenesis was confirmed in a hind-limb ischemia model. RESULTS: Autocrine/paracrine actions in HUVECs regulated IL-28A protein expression. Exogenous IL-28A increased the proliferation of HUVECs via eNOS/AKT and ERK1/2 signaling. IL-28A treatment promoted migration, invasion, and capillary tube formation of HUVECs through induction of the AP-1/NF-κB/MMP-2 network, which was associated with eNOS/AKT and ERK1/2 signaling. The efficacy of IL-28A-induced angiogenic potential was confirmed by aortic ring and Matrigel plug assay. HSP70-1 was identified as an IL-28A-mediated angiogenic effector gene using bioinformatics. Knockdown of HSP70-1 abolished angiogenic responses and eNOS/AKT signaling in IL-28A-treated HUVECs. IL-28A-induced microvessel sprouting formation was testified in HSP70-1-deficient and HSP70-1 transgenic mice. Flow recovery in hind-limb ischemia mice was accelerated by IL-28A injection. Finally, ablation of the IL-10Rß gene impeded the angiogenic responses and eNOS/AKT signaling stimulated by IL-28A in HUVECs. CONCLUSION: HSP70-1 drives the progression of angiogenesis by the IL-28A/IL-10Rß axis via eNOS/AKT signaling and the AP-1/NF-κB/MMP-2 network.

The TREK2 Channel Is Involved in the Proliferation of 253J Cell, a Human Bladder Carcinoma Cell.

Bladder cancer is the seventh most common cancer in men that smoke, and the incidence of disease increases with age. The mechanism of occurrence has not yet been established. Potassium channels have been linked with cell proliferation. Some two-pore domain K(+) channels (K2P), such as TASK3 and TREK1, have recently been shown to be overexpressed in cancer cells. Here we focused on the relationship between cell growth and the mechanosensitive K2P channel, TREK2, in the human bladder cancer cell line, 253J. We confirmed that TREK2 was expressed in bladder cancer cell lines by Western blot and quantitative real-time PCR. Using the patch-clamp technique, the mechanosensitive TREK2 channel was recorded in the presence of symmetrical 150 mM KCl solutions. In 253J cells, the TREK2 channel was activated by polyunsaturated fatty acids, intracellular acidosis at -60 mV and mechanical stretch at -40 mV or 40 mV. Furthermore, small interfering RNA (siRNA)-mediated TREK2 knockdown resulted in a slight depolarization from -19.9 mV±0.8 (n=116) to -8.5 mV±1.4 (n=74) and decreased proliferation of 253J cells, compared to negative control siRNA. 253J cells treated with TREK2 siRNA showed a significant increase in the expression of cell cycle boundary proteins p21 and p53 and also a remarkable decrease in protein expression of cyclins D1 and D3. Taken together, the TREK2 channel is present in bladder cancer cell lines and may, at least in part, contribute to cell cycle-dependent growth.

Changes in magnetic resonance imaging signal intensity of transplanted meniscus allografts are not associated with clinical outcomes.

PURPOSE: To evaluate changes in intrameniscal signal intensity (IMSI) of transplanted allografts during the first year after meniscus allograft transplantation (MAT) by use of serial magnetic resonance imaging, as well as to analyze the relation between IMSI and clinical outcome. METHODS: This prospective study involved 43 patients who underwent MAT between 2006 and 2007 after diagnosis of total or subtotal meniscectomized knees. The mean patient age at the time of surgery was 35.8 years (range, 17 to 46 years). Allografts were assessed by conventional magnetic resonance imaging performed at 6 weeks and 3, 6, and 12 months after MAT. The ratio of the signal intensity of the transplanted meniscus allograft to that of the control normal meniscus in the ipsilateral knee was calculated to obtain a standardized signal intensity value. IMSI was assessed in terms of postoperative time and location (anterior v posterior horn). The Lysholm score was used to evaluate knee function. RESULTS: The IMSI of transplanted allograft menisci was higher than that for nontransplanted menisci at all 4 postoperative time points (P < .01). The anterior horn allograft IMSI was greater than the posterior horn allograft IMSI at all time points (P < .01). The allograft IMSI increased starting 3 months postoperatively for the anterior horn (F(3,40) = 7.5, P < .01) and 6 months postoperatively for the posterior horn (F(3,40) = 9.2, P < .01). These increases were maintained to the final assessment at 1 year postoperatively. No correlation was found between IMSI and postoperative Lysholm score. CONCLUSIONS: Transplanted allograft menisci had higher signal intensities than normal menisci. Signal intensity was higher for the anterior horn than the posterior horn throughout the first postoperative year. Signal intensity increased over time, and this increase was maintained at 1 year postoperatively. However, signal intensity was not related to clinical outcome. LEVEL OF EVIDENCE: Level II, development of diagnostic criteria based on analysis of consecutive patients, applying a universally recognized gold standard.

Predictors of degenerative medial meniscus extrusion: radial component and knee osteoarthritis.

PURPOSE: the purpose of this study was to determine the effect of a radial tear on degenerative medial meniscus posterior horn tear extrusion and to identify predictors of medial meniscus extrusion. METHODS: we reviewed the records of 102 knees with medial meniscus posterior horn tears and degeneration that underwent a partial meniscectomy. Tears were classified as root (n = 17) and non-root (n = 85) tears, or as radial (n = 46) and non-radial (n = 56) tears. Groups were compared in terms of absolute and relative meniscal extrusion, and the proportion of knees with major (> 3 mm) extrusion. Multiple regression analysis was used to identify predictors of extrusion. RESULTS: the radial group had greater mean absolute (4 ± 1 vs. 3 ± 1 mm, P = 0.001) and relative (31 ± 11 vs. 23 ± 12%, P = 0.031) extrusion than the non-radial group. The radial group also had a greater proportion of major extrusions than the non-radial group (74% vs. 26%; P = 0.016). In contrast, the root tear and non-root tear groups were similar in terms of mean absolute (3 ± 1 vs. 3 ± 1 mm, P = n.s.) and relative (30 ± 7 vs. 26 ± 13%; P = n.s.) extrusion and in terms of proportion with major extrusions (59 vs. 55%; P = n.s.). Extrusion was found to be associated with a similar strength with both the presence of a radial component and the preoperative Kellgren-Lawrence grade. CONCLUSION: meniscal extrusion was greater and more severe in knees with a radial tear component than in knees without a radial component. The incidence and degree of major extrusion was similar in knees with root tears and non-root tears. A radial component and knee osteoarthritis severity were similarly predictive of absolute and relative extrusion. Meniscal extrusion in osteoarthritic knees was associated not only with degenerative meniscal tear but also with osteoarthritis severity. Therefore, arthroscopic meniscal procedures, especially meniscal repair, should be cautiously considered in patients with meniscal extrusion.

High-flexion total knee arthroplasty improves flexion of stiff knees.

PURPOSE: High-flexion knee prosthesis designs are generally thought to be of benefit only in patients with a satisfactory preoperative flexion angle. The aim of the study was to evaluate whether high-flexion designs were indeed worthless in osteoarthritis patients with severe preoperative flexion limitation. METHODS: The postoperative maximum flexion was compared in osteoarthritis patients with a preoperative maximum flexion of 100° or less, using LPS and LPS-flex implants (NexGen®; Zimmer, Warsaw, IN) in total knee arthroplasties. Data on 39 knees in the LPS group and 41 in the LPS-flex group, with a minimum of 2 years of follow-up, were reviewed retrospectively, focused on the postoperative maximum flexion. RESULTS: Two years after operation, the LPS-flex group had a mean postoperative maximum flexion of 131±10° (range, 105-140°), which was significantly higher than the 121±12° (range, 95-140°) in the LPS group (P<0.001). In the LPS-flex group, about half of the knees (n=18, 44%) could achieve a maximum flexion of 140° postoperatively, but in the LPS group only five knees (13%) achieved a maximum flexion of 140°. CONCLUSION: Despite a different period of the operation between groups, this study suggested that osteoarthritis patients with severe preoperative flexion limitation could achieve more postoperative gain in flexion when a high-flexion prosthesis was used, compared to the flexion obtained using a standard prosthesis.

No impact of severe varus deformity on clinical outcome after posterior stabilized total knee arthroplasty.

PURPOSE: Severe varus deformity may lead to premature failure of total knee arthroplasties (TKAs) because of technical difficulties associated with satisfactory alignment and good ligament balance. The aim of the study was to assess whether preoperative varus severity would affect the longevity, clinical outcomes, and complication rates of TKAs. METHODS: From a prospectively collected database, we assessed outcomes in 168 knees that underwent primary TKAs using a single posterior stabilized design. These included 86 knees with mild preoperative deformity (varus mechanical tibiofemoral angle≤5°) and 82 knees with severe preoperative deformity (varus angle≥15°). Survivorship was analyzed by a life-table method. Clinical outcomes were also compared, including Knee Society knee and functional scores and complication rates. RESULTS: The postoperative tibiofemoral angle of the mild varus group was 7.1°±2.5°, whereas that of the severe varus group was 6.4°±2.5° (n.s.). There were no significant differences in terms of perioperative complications. Both groups showed the same cumulative survival rate, with absence of mechanical failure, of 98% at 7 years without difference (n.s.). There were no significant between-group differences of clinical parameters throughout the each follow-up period. CONCLUSION: The knees with preoperative severe varus deformity were achieved the results comparable to those in knees with mild varus deformity, as determined by survival rate and clinical results. These data suggest that preoperative severe varus deformities can be successfully managed and do not have any detrimental effect on the longevity and clinical outcomes after a modern posterior stabilized TKA.

Urinary microRNA-1913 to microRNA-3659 expression ratio as a non-invasive diagnostic biomarker for prostate cancer.

PURPOSE: MicroRNAs (miRNAs) are small non-coding RNAs and are involved in the development, proliferation, and pathogenesis of prostate cancer (PCa). Urinary miRNAs are promising non-invasive biomarkers for PCa diagnosis because of their stability in urine. Here, we evaluated the diagnostic value of urinary miR-1913 to miR-3659 ratio in PCa patients and benign prostate hyperplasia (BPH) controls. MATERIALS AND METHODS: Candidate miRNAs were identified from urinary microarray data and tested by real-time PCR. The urinary miR-1913 to miR-3659 expression ratio was selected and tested in 83 urine samples (44 PCa and 39 BPH) to confirm its validity as a non-invasive diagnostic biomarker for PCa. RESULTS: The expression ratio of urinary miR-1913 to miR-3659 was significantly higher in PCa than in BPH (p=0.002) and showed a higher area under the receiver operating characteristic curve than prostate-specific antigen (PSA; 0.821 vs. 0.518) in patients within the PSA gray zone (tPSA: 3-10 ng/mL), with sensitivity of 75.0% and specificity of 78.6% (p=0.003). CONCLUSIONS: The urinary miR-1913 to miR-3659 expression ratio was increased in PCa and may serve as a useful supplemental biomarker to PSA for the diagnosis of PCa, particularly in patients within the PSA gray zone.

Collagen type VI­α1 and 2 repress the proliferation, migration and invasion of bladder cancer cells.

The bladder cancer (BCa) microenvironment comprises heterogeneous tumor cell populations, the surrounding stroma and the extracellular matrix (ECM). Collagen, the scaffold of the tumor microenvironment, regulates ECM remodeling to promote tumor infiltration, angiogenesis, invasion and migration. The present study examined how collagen type VI­α (COL6A) 1 and 2 function during BCa pathogenesis and progression, with the aim of facilitating the development of precision therapeutics, risk stratification and molecular diagnosis. COL6A1 and COL6A2 mRNA expression in non­muscle invasive BCa (NMIBC) and MIBC tissue samples was measured using reverse transcription­quantitative PCR. In addition, the tumor­suppressive effects of COL6A1 and COL6A2 in human BCa EJ cells (MGH­U1) were assessed. Compared with normal controls, COL6A1 and COL6A2 mRNA expression was downregulated in both NMIBC and MIBC tissue samples (P<0.05, respectively). COL6A1 and COL6A2 effectively inhibited the proliferation of human BCa EJ cells (MGH­U1) and induced cell cycle arrest at the G1 phase. Additionally, COL6A1 and COL6A2 served roles in MAPK and AKT signaling by increasing p38 MAPK phosphorylation and decreasing AKT phosphorylation. Finally, COL6A1 and COL6A2 inhibited wound healing and invasion by suppressing the activity of matrix metalloproteinase (MMP)­2 and MMP­9. In conclusion, COL6A1 and COL6A2 may act as classical collagens by forming a physical barrier to inhibit BCa tumor growth and invasion.

Predictive value of progression-related gene classifier in primary non-muscle invasive bladder cancer.

BACKGROUND: While several molecular markers of bladder cancer prognosis have been identified, the limited value of current prognostic markers has created the need for new molecular indicators of bladder cancer outcomes. The aim of this study was to identify genetic signatures associated with disease prognosis in bladder cancer. RESULTS: We used 272 primary bladder cancer specimens for microarray analysis and real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. Microarray gene expression analysis of randomly selected 165 primary bladder cancer specimens as an original cohort was carried out. Risk scores were applied to stratify prognosis-related gene classifiers. Prognosis-related gene classifiers were individually analyzed with tumor invasiveness (non-muscle invasive bladder cancer [NMIBC] and muscle invasive bladder cancer [MIBC]) and prognosis. We validated selected gene classifiers using RT-PCR in the original (165) and independent (107) cohorts. Ninety-seven genes related to disease progression among NMIBC patients were identified by microarray data analysis. Eight genes, a progression-related gene classifier in NMIBC, were selected for RT-PCR. The progression-related gene classifier in patients with NMIBC was closely correlated with progression in both original and independent cohorts. Furthermore, no patient with NMIBC in the good-prognosis signature group experienced cancer progression. CONCLUSIONS: We identified progression-related gene classifier that has strong predictive value for determining disease outcome in NMIBC. This gene classifier could assist in selecting NMIBC patients who might benefit from more aggressive therapeutic intervention or surveillance.

Evaluation of the TEST 1 erythrocyte sedimentation rate system and intra- and inter-laboratory quality control using new latex control materials.

BACKGROUND: The erythrocyte sedimentation rate (ESR) test has been considered to be a simple procedure, not requiring quality control (QC). However, QC is essential for accuracy and precision. We evaluated the TEST 1 ESR system and performed QC procedures using newly developed latex control materials in three hospitals. METHODS: Using tripotassium ethylenediaminetetraacetic acid blood samples (n=184), we compared TEST 1 ESR values with Westergren ESR data and evaluated intra-assay precision. Three levels of latex control materials were used to assess inter-assay precision. Reference range assessment was done using samples from 220 healthy individuals. Inter-laboratory QC with latex control materials in three hospitals was performed. RESULTS: Correlation between TEST 1 ESR and Westergren ESR results was good (p<0.001). Intra-assay precision [coefficients of variation (CV) 6.6%-21.7%] with patient samples and inter-assay precision (CV 0.0%-6.8%) with latex control materials were satisfactory. The reference ranges of 2-10 mm/h for males and 2-19 mm/h for females were established. Inter-laboratory QC data with latex control materials in three hospitals demonstrated good accuracy and satisfactory precision (CV 0.0%-14.4%). CONCLUSIONS: Our results demonstrate that the TEST 1 QC is reliable and the latex control materials are valuable for inter-laboratory proficiency testing.

A novel tumor suppressing gene, ARHGAP9, is an independent prognostic biomarker for bladder cancer.

Screening for genes or markers relevant to bladder cancer (BC) tumorigenesis and progression is of vital clinical significance. The present study used reverse-transcription quantitative PCR reaction assays to examine the expression of mRNA encoding Rho GTPase-activating protein 9 (ARHGAP9) in BC tissue samples and to determine whether ARHGAP9 is an independent prognostic biomarker for non-muscle invasive BC (NMIBC) and muscle invasive BC (MIBC). The results revealed that the downregulation of ARHGAP9 expression in the tissue of patients with NMIBC or MIBC was significantly associated with a poor prognosis. In patients with NMIBC, a high expression of ARHGAP9 was significantly associated with prolonged recurrence-free survival, whereas in MIBC patients, it was significantly associated with an increased progression-free and cancer-specific survival. The risk of cancer-specific death was 2.923 times higher (95% confidence interval, 1.192-7.163) when ARHGAP9 levels were decreased. In conclusion, lower expressions of ARHGAP9 correlated with BC prognosis, indicating that it may be a useful marker for guiding treatment application.

Hypersensitivity to RF fields emitted from CDMA cellular phones: a provocation study.

With the number of cellular phone users rapidly increasing, there is a considerable amount of public concern regarding the effects that electromagnetic fields (EMFs) from cellular phones have on health. People with self-attributed electromagnetic hypersensitivity (EHS) complain of subjective symptoms such as headaches, insomnia, and memory loss, and attribute these symptoms to radio frequency (RF) radiation from cellular phones and/or base stations. However, EHS is difficult to diagnose because it relies on a person's subjective judgment. Various provocation studies have been conducted on EHS caused by Global System for Mobile Communications (GSM) phones in which heart rate and blood pressure or subjective symptoms were investigated. However, there have been few sham-controlled provocation studies on EHS with Code Division Multiple Access (CDMA) phones where physiological parameters, subjective symptoms, and perception of RF radiation for EHS and non-EHS groups were simultaneously investigated. In this study, two volunteer groups of 18 self-reported EHS and 19 non-EHS persons were tested for both sham and real RF exposure from CDMA cellular phones with a 300 mW maximum exposure that lasted half an hour. We investigated not only the physiological parameters such as heart rate, respiration rate, and heart rate variability (HRV), but also various subjective symptoms and the perception of EMF. In conclusion, RF exposure did not have any effects on physiological parameters or subjective symptoms in either group. As for EMF perception, there was no evidence that the EHS group better perceived EMF than the non-EHS group.

Intra-Oral Factors Influencing Halitosis in Young Women.

OBJECTIVES: The aim of this research was to determine intra-oral factors that affect halitosis in young women. METHODS: This study was performed between March 2014 to May 2014, and included 35 women in their 20s with good oral health. Correlation and logistic regression analyses were performed to investigate the change in halitosis immediately, and 1 hour after scaling. RESULTS: In both oral gas (OG) and extraoral gas (EG) groups, halitosis was reduced after scaling compared to before scaling. The logistic regression analysis of oral state factors in OG showed that as oral fluid [odds ratio (OR) = 0.792, p = 0.045] and dental plaque (OR = 0.940, p = 0.016) decreased by 1 unit, the OR in the OG group decreased (> 50). In addition, as glucose levels in the oral cavity (OR = 1.245, p = 0.075) and tongue coating index (OR = 2.912, p = 0.064) increased by 1 unit, the OR in the OG group increased (> 50). Furthermore, in the EG group, as oral fluid (OR = 0.66, p = 0.01) and dental plaque (OR = 0.95, p = 0.04) decreased, the OR in the EG group decreased (> 50) significantly. CONCLUSION: To control halitosis, it is necessary to increase oral fluid and decrease the amount of tongue plaque. Furthermore, maintaining a healthy oral environment, aided by regular scaling and removal of dental plaque, may significantly control halitosis.

Biomarker for the Prediction of Major Adverse Cardiac Events in Patients with Non-ST-Segment Elevation Myocardial Infarction.

N-terminal pro-brain natriuretic peptide (NT-proBNP) is a well-known biomarker for the diagnosis and prognosis of heart failure, and is directly associated with myocardial dysfunction. We evaluated the prognostic value of NT-proBNP for major adverse cardiac events (MACEs) among patients with non-ST-segment elevation myocardial infarction (NSTEMI) from the Korea Acute Myocardial Infarction Registry during their mid-term follow-up period. In this paper, we analyzed NT-proBNP according to various MACE and level of NT-proBNP. We used multivariate logistic regression to determine the risk factors according to MACE type and NT-proBNP levels, and to identify the cutoff value for each MACE by using the receiver operating characteristic (ROC) curve. NT-proBNP was a significant variable among cardiac deaths (p = 0.016), myocardial infarction (p = 0.000), and coronary artery bypass grafting (CABG) (p = 0.000) in patients with MACE compared with those without MACE. Two-vessel coronary artery disease (CAD) (p = 0.037) and the maximum creatinine kinase (max-CK) (p = 0.031) produced significant results in repeat percutaneous coronary intervention. The area under the ROC curve was found to be statistically significant for cardiac death and CABG. NT-proBNP is a useful predictor for 12-month MACEs among patients with NSTEMI and in those with heart failure. We propose that a new index incorporating NT-proBNP, max-CK, and CAD vessel will be useful as a prognostic indicator of MACEs in the future.

Transcriptomic features of primary prostate cancer and their prognostic relevance to castration-resistant prostate cancer.

Although various mechanisms of castration-resistant prostate cancer (CRPC) have been discovered, reliable biomarkers for monitoring CRPC progression are lacking. We sought to identify molecules that predict the progression of advanced prostate cancer (AdvPC) into CRPC. The study used primary-site samples (N=45 for next-generation sequencing (NGS); N=243 for real-time polymerase chain reaction) from patients with prostate cancer (PC). Five public databases containing microarray data of AdvPC and CRPC samples were analyzed. The NGS data showed that each progression step in PC associated with distinct gene expression profiles. Androgen receptor (AR) associated with tumorigenesis, advanced progression, and progression into CRPC. Analysis of the paired and unpaired AdvPC and CRPC samples in the NGS cohort showed that 15 genes associated with progression into CRPC. This was validated by cohort-1 and public database analyses. Analysis of the third cohort with AdvPC showed that higher serine peptidase inhibitor, Kazal type 1 (SPINK1) and lower Sp8 transcription factor (SP8) expression associated with progression into CRPC (log-rank test, both P<0.05). Multivariate regression analysis showed that higher SPINK1 (Hazard Ratio (HR)=4.506, 95% confidence intervals (CI)=1.175-17.29, P=0.028) and lower SP8 (HR=0.199, 95% CI=0.063-0.632, P=0.006) expression independently predicted progression into CRPC. Gene network analysis showed that CRPC progression may be mediated through the AR-SPINK1 pathway by a HNF1A-based gene network. Taken together, our results suggest thatSPINK1 and SP8 may be useful for classifying patients with AdvPC who have a higher risk of progressing to CRPC.

Expression levels of FGFR3 as a prognostic marker for the progression of primary pT1 bladder cancer and its association with mutation status.

The present study examined the utility of fibroblast growth factor receptor 3 (FGFR3) mutation status and gene expression as a prognostic marker in primary pT1 bladder cancer (BC). A total of 120 patients with primary pT1 BC were enrolled. FGFR3 mutation status was determined by direct sequencing and FGFR3 mRNA expression level was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. The results were compared with the clinicopathological parameters, and the prognostic value of FGFR3 was evaluated by Kaplan-Meier analysis and a multivariate Cox regression test. FGFR3 mutations were identified in 48/120 (40.0%) patients with pT1 BC. FGFR3 mRNA expression level was significantly higher in those with BC harboring FGFR3 mutations (P<0.001). Low FGFR3 expression level was associated with high-grade tumors and cancer progression (P=0.006 and P=0.001), whereas FGFR3 mutation status was not associated with cancer progression. Kaplan-Meier analysis revealed a similar result (log-rank, P<0.001). Multivariate analysis identified low FGFR3 expression level (odds ratio, 3.300; 95% confidence interval, 1.310-8.313; P=0.011) as an independent predictor of cancer progression. Stratification by exon site of FGFR3 mutations yielded significant differences in mRNA expression level. None of the patients with BC harboring FGFR3 mutations in exon 9 demonstrated disease progression. The mRNA expression level of the FGFR3 gene may be used to precisely identify subsets of patients with pT1 BC that have a relatively better prognosis. The prognostic influences of FGFR3 mutations may be modulated by the exon site of FGFR3 mutations.