Kyung Chul Moon

Theranostic Probe Based on Lanthanide-Doped Nanoparticles for Simultaneous In Vivo Dual-Modal Imaging and Photodynamic Therapy

Dual-modal in vivo tumor imaging and photodynamic therapy using hexagonal NaYF(4):Yb,Er/NaGdF(4) core-shell upconverting nanoparticles combined with a photosensitizer, chlorin e6, is reported. Tumors can be clearly observed not only in the upconversion luminescence image but also in the magnetic resonance image. In vivo photodynamic therapy by systemic administration is demonstrated under 980 nm irradiation.

Hypermethylation of CpG island loci and hypomethylation of LINE-1 and Alu repeats in prostate adenocarcinoma and their relationship to clinicopathological features.

Promoter CpG island hypermethylation is an important carcinogenic event in prostate adenocarcinoma. Regardless of tissue type, human cancers have in common both focal CpG island hypermethylation and global genomic hypomethylation. The present study evaluated CpG island loci hypermethylation and LINE‐1 and Alu repeat hypomethylation in prostate adenocarcinoma, analysed the relationship between them, and correlated these findings with clinicopathological features. We examined 179 cases of prostate adenocarcinoma and 30 cases of benign prostate hypertrophy for the methylation status of 22 CpG island loci and the methylation levels of LINE‐1 and Alu repeats using methylation‐specific polymerase chain reaction and combined bisulphite restriction analysis, respectively. The following 16 CpG island loci were found to display cancer‐related hypermethylation: RASSF1A, GSTP1, RARB, TNFRSF10C, APC, BCL2, MDR1, ASC, TIG1, RBP1, COX2, THBS1, TNFRSF10D, CD44, p16, and RUNX3. Except for the last four CpG island loci, hypermethylation of each of the remaining 12 CpG island loci displayed a close association with one or more of the prognostic parameters (ie preoperative serum prostate specific antigen level, Gleason score sum, and clinical stage). Prostate adenocarcinoma with hypermethylation of each of ASC, COX2, RARB, TNFRSF10C, MDR1, TIG1, RBP1, NEUROG1, RASSF1A, and GSTP1 showed a significantly lower methylation level of Alu or LINE‐1 than prostate adenocarcinoma without hypermethylation. In addition, hypomethylation of Alu or LINE‐1 was closely associated with one or more of the above prognostic parameters. These data suggest that in tumour progression a close relationship exists between CpG island hypermethylation and the hypomethylation of repetitive elements, and that CpG island hypermethylation and DNA hypomethylation contribute to cancer progression. Copyright

BRAF and KRAS mutations in prostatic adenocarcinoma.

Constitutive activation of the kinase cascade involving RAS, RAF, MEK and ERK is common to human cancers, and mutations of KRAS and BRAF are mutually exclusive and serve as alternatives to activate the RAS/RAF/ERK signaling pathway. RAS mutations are known to occur in prostate adenocarcinomas, but little is known about BRAF mutations in these tumors. In the present study, BRAF and KRAS mutations were characterized in 206 prostate adenocarcinomas by enhanced PCR‐RFLP and direct sequencing. The identified KRAS and BRAF mutations were then analyzed with respect to preoperative serum PSA levels, Gleason scores and tumor stages. Mutations in codon 600 of BRAF were identified in 21 (10.2%) of 206 prostate adenocarcinomas. KRAS mutations in codons 12 or 13 were found in 15 (7.3%) of 206 prostate adenocarcinomas. However, no tumor specimen contained both BRAF and KRAS mutations. Prostate adenocarcinomas with a BRAF mutation tended to show higher preoperative serum PSA levels, Gleason scores and tumor stages than prostate adenocarcinomas with a KRAS mutation. The results obtained show that BRAF mutations are as uncommon as KRAS mutations in prostate adenocarcinoma. Although BRAF and KRAS are members of the same RAS/ERK signaling pathway, prostate adenocarcinomas with a BRAF mutation showed clinicopathologic features that differed from those of prostate adenocarcinoma with a KRAS mutation.

Segmental Enhancement Inversion at Biphasic Multidetector CT: Characteristic Finding of Small Renal Oncocytoma

PURPOSE To retrospectively determine the usefulness of segmental enhancement inversion during the corticomedullary phase (CMP) and early excretory phase (EEP) of biphasic multidetector computed tomography (CT) in differentiating small renal oncocytoma from renal cell carcinoma (RCC). MATERIALS AND METHODS This retrospective study was institutional review board approved; informed consent was waived. Between January 2004 and December 2006, 98 patients with pathologically confirmed renal masses smaller than 4 cm (10 renal oncocytomas and 88 RCCs) were included in this study. Segmental enhancement inversion was defined as follows: In a mass with two segments showing different degrees of enhancement during CMP, the relatively highly enhanced segment became less enhanced during EEP, whereas the less-enhanced segment during CMP became highly enhanced during EEP. Two experienced radiologists retrospectively assessed the presence of segmental inversion in all masses and measured attenuation with consensus. The Fisher exact test was used to determine the significance of segmental enhancement inversion in differentiating small renal oncocytoma from RCC. RESULTS Eight of 10 renal oncocytomas and only one of 88 RCCs showed segmental inversion during CMP and EEP, which significantly differentiated small renal oncocytomas and RCCs (P < .0001). For differentiating oncocytoma from RCC, segmental inversion was found to have a sensitivity of 80% (eight of 10), a specificity of 99% (87 of 88), a positive predictive value of 89% (eight of nine), and a negative predictive value of 98% (87 of 89). The mean values of the attenuation differences shown by two segments during CMP and EEP were 62.75 HU +/- 36.96 (standard deviation) and -36.88 HU +/- 20.02, respectively. CONCLUSION Segmental enhancement inversion during CMP and EEP was found to be a characteristic enhancement pattern of small renal oncocytoma at biphasic multidetector CT and it may help in differentiating small oncocytoma from RCC. SUPPLEMENTAL MATERIAL http://radiology.rsnajnls.org/cgi/content/full/2522081180/DC1.

TMPRSS2-ERG Gene Fusion and Clinicopathologic Characteristics of Korean Prostate Cancer Patients

OBJECTIVES To survey the status of TMPRSS2-ERG fusion in Korean prostate cancer patients, we assessed the differences in clinicopathologic characteristics and biochemical recurrence according to TMPRSS2-ERG fusion status. METHODS The incidence of the TMPRSS2-ERG fusion gene was evaluated via fluorescence in situ hybridization (FISH) using ERG break-apart probes in 254 prostate cancer tissues resected by radical prostatectomy, and analyses of clinicopathologic parameters and biochemical recurrence were conducted. RESULTS The fusion rate of the TMPRSS2-ERG gene was 20.9% (53/254). TMPRSS2-ERG gene fusion was identified more frequently in patients with low Gleason grade (primary Gleason pattern ≤ 3 or sum of Gleason score ≤ 7, P = .015 and .027). Patients with large cribriform glands in Gleason pattern 4 harbored a rare TMPRSS2-ERG fusion gene compared with patients without large cribriform glands (P = .027). The incidence of biochemical recurrence did not differ according to TMPRSS2-ERG fusion gene status (P = .598). CONCLUSIONS ERG gene aberration did not correlate with biochemical recurrence of prostate cancers in Korean patients. Lower Gleason grade demonstrated higher rates of TMPRSS2-ERG fusion compared with high-grade tumors, including those demonstrating a large cribriform glands pattern. Prostate cancer with large cribriform glands revealed rare TMPRSS2-ERG gene fusion.

Risk factors for consequent kidney impairment and differential impact of liver transplantation on renal function

BACKGROUND Chronic kidney disease (CKD) develops frequently after liver transplantation (LTx), and it is important to identify and correct risk factors that negatively affect kidney function. Risk factors have not been well evaluated in Asian countries where hepatitis B virus (HBV) infection is a dominant cause. METHODS Four hundred thirty-one Korean recipients who underwent LTx between 1997 and 2008 were analysed. CKD was defined as a sustained decrease in estimated glomerular filtration rate (eGFR) of <60 (mL/min/1.73 m(2)) for at least three consecutive months using an abbreviated Modification in Renal Disease (MDRD) formula. RESULTS Eighty percent of the patients had HBV-related underlying diseases. The recipients whose pretransplant eGFR had been low (<30 mL/min/1.73 m(2)) improved their renal function after LTx, but significant functional decline occurred in recipients whose pretransplant eGFR was high (>or=60 mL/min/1.73 m(2)). A multivariate Cox regression analysis revealed that the overall risk of CKD development (eGFR < 60 mL/min/1.73 m(2)) was associated with old age of recipients, cyclosporine, posttransplant acute renal failure (ARF), cause [calcineurin inhibitor (CNI) nephrotoxicity] and severity of posttransplant ARF, low pretransplant eGFR, pretransplant hepatorenal syndrome, pretransplant proteinuria, high Child-Pugh score and high Model for End-Stage Renal Disease (MELD) score. Especially in recipients whose pre-operative eGFR was high (>or=60 mL/min/1.73 m(2)), rapid progression of kidney disease was associated with high tacrolimus level, non-HBV disease, posttransplant ARF, cause (CNI nephrotoxicity) and severity of posttransplant ARF and Child-Pugh score. CNI toxicity and focal segmental sclerosis, but not immune-complex disease, were revealed as significant contributors to CKD after LTx in HBV recipients. CONCLUSION Judicious use of CNIs should be applied to liver recipients to prevent kidney dysfunction.

Genomic hypomethylation and CpG island hypermethylation in prostatic intraepithelial neoplasm.

Altered DNA methylation in cancer cells is characterized by focal CpG island hypermethylation and diffuse genomic hypomethylation. Both types of aberrant methylation are frequently found in human prostate adenocarcinoma (PCa). Prostatic intraepithelial neoplasm (PIN), a precursor lesion of PCa, has been demonstrated to contain CpG island hypermethylation, but little is known about the role of DNA hypomethylation. We analyzed the methylation status at 12 CpG island loci and at two repetitive DNA elements (LINE-1 and SAT2) from normal prostate (n = 20), PIN (n = 25), and PCa (n = 35) tissues using MethyLight assay or combined bisulfite restriction analysis. The methylation levels in LINE-1 and SAT2 decreased with progression of lesion types from normal prostate to PIN to PCa (P < 0.05), whereas promoter CpG island loci displayed increased methylation. Ten genes were found to be hypermethylated in a cancer-specific manner and were further analyzed in another set of PCa tissues (n = 64). The number of methylated genes was closely associated with TNM stage, Gleason sum, and preoperative serum PSA levels (P = 0.020, 0.073, 0.033, respectively). These results suggest that genomic hypomethylation and CpG island hypermethylation, common among PCas, are early events in prostate carcinogenesis and may be implicated in the development of PIN.

Familial focal segmental glomerulosclerosis associated with an ACTN4 mutation and paternal germline mosaicism.

Mutations in the ACTN4 gene cause focal segmental glomerulosclerosis (FSGS), which shows autosomal dominant inheritance (Online Mendelian Inheritance in Man No. 603278, FSGS1). Most patients with a diagnosis of FSGS1 show a mild to moderate degree of proteinuria during adolescence or later, and some patients gradually progress to end-stage renal disease. Here, we report a familial case of FSGS1 in which 2 affected siblings showed unusual clinical, pathological, and genetic features. Both patients presented with full-blown rapidly progressing nephrotic syndrome in early childhood. Renal pathological findings were of an FSGS collapsing variant and FSGS not otherwise specified. A novel ACTN4 mutation, p.Ser262Phe, was detected in the patients, and their father was found to have a germline mosaicism for the mutation. In addition, these siblings also had a heterozygous p.Thr5Met substitution in NPHS1, which encodes nephrin, although the functional significance of this substitution is unclear. This is the third clinical report of FSGS1 and the first case report of germline mosaicism confirmed in patients with hereditary podocyte disorders. FSGS1 may have widely variable clinical and pathological phenotypes and therefore should be considered in young children with full-blown and rapidly progressing nephrotic syndrome. The possibility of germline mosaicism makes interpretation of molecular diagnoses and genetic counseling more difficult.

The frequency and clinical significance of intra-uterine infection and inflammation in patients with placenta previa and preterm labor and intact membranes.

OBJECTIVE Histologic placental and/or intra-amniotic inflammation is frequently documented during ascending intra-uterine infections in patients with preterm labor and intact membranes. Placenta previa can be a clinical situation that shows the successive schema of histologic placental and intra-amniotic inflammation during the process of ascending intra-uterine infections. However, a paucity of information exists about the frequency and clinical significance of intra-uterine infections and inflammation in patients with placenta previa and preterm labor and intact membranes. The purpose of this study was to examine this issue. STUDY DESIGN Amniocentesis was performed on 42 patients with placenta previa and preterm labor and intact membranes (gestational age <37 weeks). Amniotic fluid (AF) was cultured for aerobic and anaerobic bacteria and genital mycoplasmas, and AF white blood cell (WBC) count and matrix metalloproteinase-8 (MMP-8) concentrations were determined. The diagnosis of intra-amniotic inflammation was made in patients with an elevated AF MMP-8 (> or =23 ng/ml). Non-parametric statistics were used for analysis. RESULTS 1) Intra-amniotic inflammation was present in 16.7% (7/42), proven AF infection in 4.9% (2/41), and histologic chorioamnionitis in 19.0% (8/42) of patients with placenta previa and preterm labor; 2) Patients with intra-amniotic inflammation had significantly higher rates of a positive AF culture, histologic chorioamnionitis, funisitis, and a shorter interval-to-delivery than those without intra-amniotic inflammation (p<0.05 for each); 3) Among patients with histologic chorioamnionitis, inflammation of the choriodecidua, which was exposed to the cervical canal, existed in all cases (8/8), but inflammation of the chorionic plate existed in 63% of patients (5/8); 4) Patients with inflammation of the chorionic plate had significantly higher median AF MMP-8 concentrations and WBC counts, and higher rates of intra-amniotic inflammation than those in whom inflammation was restricted to choriodecidua (p<0.05 for each). CONCLUSIONS Placental inflammation was present in 19.0% and intra-amniotic inflammation was present in 16.7% of patients with placenta previa and preterm labor and intact membranes. The intra-amniotic inflammatory response was stronger when inflammation was present in the chorionic plate and choriodecidua, than when it was restricted to the choriodecidua only, which was exposed to the cervical canal in placenta previa.

Simultaneous Detection of Dual Prostate Specific Antigens Using Surface-Enhanced Raman Scattering-Based Immunoassay for Accurate Diagnosis of Prostate Cancer

Accurate analysis of specific biomarkers in clinical serum is essential for early diagnosis and treatment of cancer. Here, a surface-enhanced Raman scattering (SERS)-based immunoassay, using magnetic beads and SERS nano tags, was developed for the determination of free to total (f/t) prostate specific antigen (PSA) ratio to improve the diagnostic performance of prostate cancer. To assess the clinical applicability of the proposed method, SERS-based assays for the simultaneous detection of dual PSA markers, free PSA (f-PSA) and complexed PSA (c-PSA), were performed for clinical samples in the gray zone between 4.0 and 10.0 ng/mL. Our assay results for f/t PSA ratio showed a good linear correlation with those measured using the electrochemiluminescence (ECL) system installed in the clinical laboratory of the University Hospital. In addition, the simultaneous assay provided better precision than parallel assays for the detection of f-PSA and c-PSA in 13 clinical serum samples. Therefore, our SERS-based assay for simultaneous detection of dual PSA markers in clinical fluids has strong potential for application in the accurate diagnosis of prostate cancer.