TEK is a novel prognostic marker for clear cell renal cell carcinoma.

OBJECTIVE: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. However, effective therapeutics for ccRCC are lacking. Novel biomarkers could provide critical information when determining prognoses for patients with ccRCC. In this study, we sought to determine if the expression of receptor tyrosine kinase (TEK) could be a potential novel prognostic biomarker for ccRCC. TEK, originally identified as an endothelial cell-specific receptor, plays an important role in the modulation of vasculogenesis and remodeling. Altered TEK expression has been observed in tumor tissues (e.g., oral squamous cell carcinomas, leukemia) and breast, gastric and thyroid cancers. However, the role of TEK in ccRCC remains unknown. PATIENTS AND METHODS: Differential TEK expression between non-metastatic (stage M0) and metastatic (stage M1) ccRCC patient cohorts was determined from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). Furthermore, TEK expression was assessed as a prognostic factor using the time-dependent area under the curve (AUC) of Uno's C-index, the AUC value of the receiver operating characteristics (ROC) at 5 years, Kaplan-Meier survival curves and multivariate analyses. RESULTS: A Kaplan-Meier curve analysis revealed that the downregulation of TEK expression was associated with a poor prognosis for patients with ccRCC with good discrimination (p<0.0001 and p=0.0044 for the TGCA and ICGC cohorts, respectively). Analyses of C-indices and receiver operating characteristic AUC values further support this discriminative ability. Moreover, multivariate analyses showed the prognostic significance of TEK expression levels (p<0.001). CONCLUSIONS: Although additional clinical investigations will be needed, our results suggest that TEK is a potential biomarker for ccRCC.

Generic velpatasvir plus sofosbuvir for hepatitis C virus infection in patients with or without human immunodeficiency virus coinfection.

BACKGROUND: Data are limited regarding the effectiveness and safety of generic velpatasvir plus sofosbuvir (VEL/SOF) for hepatitis C virus (HCV) in patients with or without human immunodeficiency virus (HIV) coinfection. AIM: To evaluate the effectiveness and safety of generic VEL/SOF-based therapy for HCV infection in patients with or without HIV coinfection in Taiwan. METHODS: Sixty-nine HIV/HCV-coinfected and 159 HCV-monoinfected patients receiving 12 weeks of generic VEL/SOF with or without ribavirin (RBV) for HCV were prospectively enrolled. The anti-viral responses and the adverse events (AEs) were compared between the two groups. The characteristics potentially related to sustained virological response 12 weeks off therapy (SVR12 ) were analysed. RESULTS: The SVR12 was achieved in 67 HIV/HCV-coinfected patients (97.1%; 95% CI: 90.0%-99.2%) and in 156 HCV-monoinfected patients (98.1%; 95% CI: 94.6%-99.4%) receiving VEL/SOF-based therapy, respectively. The SVR12 rates were comparable between HIV/HCV-coinfected and HCV-monoinfected patients, regardless of pre-specified baseline characteristics. One hundred twenty-two (53.5%) and seven (3.1%) patients had baseline resistance-associated substitutions (RASs) in HCV NS5A and NS5B regions, but the SVR12 rates were not affected by the presence or absence of RASs. One (1.4%) and five (3.1%) patients in the HIV/HCV-coinfected and HCV-monoinfected groups had serious AEs. No patient died or discontinued treatment due to AEs. The eGFR remained stable throughout the course of treatment in HIV/HCV-coinfected patients receiving anti-retroviral therapy containing tenofovir disoproxil fumarate (TDF). CONCLUSIONS: Generic VEL/SOF-based therapy is well-tolerated and provides comparably high SVR12 rates for HCV infection in patients with and without HIV coinfection.

Distant metastatic lesions in patients with differentiated thyroid carcinoma. Clinical implications of radioiodine and FDG uptake.

AIM: Many investigators have reported an inverse relationship between iodine and glucose utilization of differentiated thyroid carcinoma (DTC) according to its degree of differentiation; however, not every DTC is compatible with this phenomenon. This study was conducted to evaluate the clinical implication of iodine and glucose uptake at distant metastatic lesions in DTC patients. PATIENTS, METHODS: 64 DTC patients (women 47; mean age 49.9 ± 16.4 years) with distant metastasis who underwent post (131)I treatment whole-body scan (RxWBS) and FDG PET/CT were included in the study. Radioiodine (RAI) and FDG uptake of metastatic lesions were evaluated. TSH stimulated serum thyroglobulin (s-Tg) were obtained. RESULTS: 53 of 64 patients (82.8%) were RAI(+) group, and 37 patients (57.8%) were FDG(+) group. Patients in the RAI(-) group showed a higher rate of FDG uptake than RAI(+) group (100.0% vs. 49.1%, p = 0.002). Patients in the FDG(-) group showed a higher rate of RAI uptake than FDG(+) group (100.0% vs. 70.3%, p = 0.002). Patients with s-Tg < 100 ng/ml were frequently observed in the FDG(-)/RAI(+) group and the FDG(+)/RAI(-) group (p = 0.023). And patients with s-Tg ≥ 500 ng/ml were more frequently observed in the FDG(+)/RAI(+) group, compared with the FDG(+)/RAI(-) group (p = 0.036). Reduced disease-specific survival (DSS) was observed in patients with RAI(-) (p = 0.003), FDG(+) (p = 0.006), SUVmax > 3.6 (p<0.001), and s-Tg > 75.8 ng/ml (p = 0.009). In multivariate analysis, only a SUVmax > 3.6 was significantly predictive of DSS (p = 0.006). CONCLUSION: An inverse relationship between RAI and FDG uptake, flip-flop phenomenon, was observed in patients with metastatic lesions of DTC. Reduced disease-specific survival was observed in patients with FDG(+), RAI(-) in metastatic lesions, or high s-Tg value.

Preoperative risk stratification using (18)F-FDG PET/CT in women with endometrial cancer.

UNLABELLED: The aim of this study is to evaluate the usefulness of (18)F-FDG PET/CT for preoperative stratification of high-risk and low-risk carcinomas in patients with endometrial cancer. PATIENTS, METHODS: 60 women (mean age 53.8±9.9 years) with endometrial cancer, who underwent (18)F-FDG PET/CT for preoperative staging work-up, followed by primary cytoreductive surgery, were enrolled in this study. Maximum and mean standardized uptake values (SUVmax, SUVmean) of endometrial tumors were measured, and compared with the various clinicopathologic findings obtained after surgery. Tumour aggressiveness was classified as high-risk and low-risk carcinomas. Patients with stage I or II, endometrioid adenocarcinoma, histologic grade 1 or 2, invasion of less than half of the myometrium, maximum tumor size less than 2.0 cm, and absence of cervical invasion and lymphovascular space involvement (LVSI) were classified as the low-risk carcinoma group. The remaining patients were classified as the high-risk carcinoma group. RESULTS: In univariate analysis, SUVmax of the primary endometrial tumor was significantly higher in patients who were in a postmenopausal state (p=0.047), large (>2 cm) primary tumor (p<0.001), nonendometrioid subtype (p=0.024), invasion of more than half of the myometrium (p=0.020), or LVSI (p=0.004). SUVmax differed significantly according to FIGO stage (p=0.013) and histologic grade (p<0.001). In multivariate analysis, FIGO stage, histologic grade, LVSI, and maximum tumor size demonstrated a significant association with SUVmax (p<0.001; r=0.843, r(2)=0.711). SUVmean showed similar results. Forty-one (68.3%) patients were diagnosed postoperatively as high-risk and 19 patients (31.7%) as low-risk carcinoma. Patients with high-risk carcinoma (12.1±6.1) showed significantly higher SUVmax than patients with low-risk carcinoma (5.8±2.8, p<0.001). The optimal SUVmax cut-off value of 8.7, determined by ROC analysis, revealed 75.6% sensitivity, 89.5% specificity, and 81.7% accuracy for risk stratification. CONCLUSION: High-risk endometrial cancer might be differentiated by means of higher SUVmax from low-risk endometrial cancer. (18)F-FDG FDG PET/CT can be applied preoperatively for stratification of risk in patients with endometrial cancer.

Can (18)F-FDG PET/CT predict recurrence in patients with cutaneous malignant melanoma?

UNLABELLED: The AIM of this study was to evaluate the prognostic significance of maximum standardized uptake value (SUVmax) of primary cutaneous malignant melanoma (CMM) lesions by (18)F-FDG positron emission tomography/computerized tomography (PET/CT) in terms of recurrence. PATIENTS, METHODS: 37 CMM patients (17 men, mean age: 61.7 ± 13.6 years) that underwent PET/CT at presentation were enrolled in this study. Recurrence was determined by histological confirmation or by radiological and clinical follow-up for at least 8 months after curative surgery. Clinical variables such as age, sex, clinical stage, and primary lesion location, thickness, and ulceration, and SUVmax values were analyzed with respect to their usefulness for predicting recurrence. RESULTS: SUVmax was found to be significantly higher in patients with ulceration of primary lesion of CMM (p = 0.004) and in patients with a stage ≥ III (p < 0.000). Patients that experience recurrence had a significantly higher mean SUVmax value (4.9 ± 2.9) than patients who did not (2.1 ± 1.5, p = 0.024). ROC analysis showed that a SUVmax cut-off value 2.2 had high sensitivity (88.9%) and specificity (67.9%) for predicting recurrence. Kaplan-Meier analysis identified ulceration of primary lesion (p = 0.034), stage ≥ III (p = 0.019) and SUVmax ≥ 2.2 (p = 0.002) as predictors of recurrence. However, Cox proportional-hazards analysis showed that only SUVmax (p = 0.025, relative risk 11.063) significantly predicted recurrence. CONCLUSION: Preoperative SUVmax of primary lesion was found to be the most potent predictor of recurrence in CMM patient. Patients with high SUV max of primary lesion should be followed meticulously for recurrence.

Flow cytometric evaluation on the age-dependent changes of testicular DNA contents in rats.

An age-dependent cellular change of DNA contents in the testis of Sprague-Dawley rats was investigated by flow-cytometric method. Testicular cell suspensions at the age of 4, 5, 6, 7, 8, 10, 12, 16 and 26 weeks were prepared and stained with propidium iodide. The relative proportions in the number of mature and immature haploid (1n), diploid (2n), S-phase and tetraploid (4n) cells were calculated. The proportion in the number of mature haploid cells was sharply increased to the age of 10 weeks (about 38%), thereafter increased slightly to the level of 42% at the age of 26 weeks. The proportion of immature haploid cells was dramatically increased to the age of 6 weeks, then maintained at the level of 20 to 30% thereafter. The proportion of diploid cells was 64% at the age of 4 weeks, then decreased gradually through the age of 26 weeks. The proportion of S-phase cells was increased to the age of 4 weeks, then maintained at a plateau level to the age of 26 weeks. The proportion of tetraploid cells were about 26% at the age of 4 weeks, then decreased gradually to the age of 26 weeks. These results suggest that the proportions of testicular cells may depend on the age of the rat and that the flow cytometric method may be useful in the evaluation of the spermatogenic status with regard to accuracy and sensitivity.

Effect of ethylene glycol monoethyl ether on the spermatogenesis in pubertal and adult rats.

The effects of ethylene glycol monoethyl ether (EGEE) on testicular cell populations in pubertal (5 weeks old) and adult (9 weeks old) male rats were investigated by a flow cytometric method. A total of 50 rats (in number, 25 pubertal and 25 adult rats) was divided into 5 experimental groups including 0 (control), 50, 100, 200, and 400 mg EGEE/kg of body weight. The animals were administered by gavage for 4 weeks. In adult rats, the treatment of EGEE at the dose of 400 mg/kg of body weight decreased significantly the populations of haploid, while it increased those of diploid and tetraploid cells. In pubertal rats, the treatment of EGEE at the dose of 400 mg/kg of body weight caused only minimal changes in the relative percent of testicular cell types. These results suggest that the effects of EGEE on testicular function in pubertal rats appear to be less pronounced than in adult rats.

Hybrid supervisory control using recurrent fuzzy neural network for tracking periodic inputs.

A hybrid supervisory control system using a recurrent fuzzy neural network (RFNN) is proposed to control the mover of a permanent magnet linear synchronous motor (PMLSM) servo drive for the tracking of periodic reference inputs. First, the field-oriented mechanism is applied to formulate the dynamic equation of the PMLSM. Then, a hybrid supervisory control system, which combines a supervisory control system and an intelligent control system, is proposed to control the mover of the PMLSM for periodic motion. The supervisory control law is designed based on the uncertainty bounds of the controlled system to stabilize the system states around a predefined bound region. Since the supervisory control law will induce excessive and chattering control effort, the intelligent control system is introduced to smooth and reduce the control effort when the system states are inside the predefined bound region. In the intelligent control system, the RFNN control is the main tracking controller which is used to mimic a idea control law and a compensated control is proposed to compensate the difference between the idea control law and the RFNN control. The RFNN has the merits of fuzzy inference, dynamic mapping and fast convergence speed, In addition, an online parameter training methodology, which is derived using the Lyapunov stability theorem and the gradient descent method, is proposed to increase the learning capability of the RFNN. The proposed hybrid supervisory control system using RFNN can track various periodic reference inputs effectively with robust control performance.

Recurrent neural network control for LCC-resonant ultrasonic motor drive.

A newly designed driving circuit for the traveling wave-type ultrasonic motor (USM), which consists of a push-pull DC-DC power converter and a two-phase voltage source inverter using one inductance and two capacitances (LCC) resonant technique, is presented in this study. Moreover, because the dynamic characteristics of the USM are difficult to obtain and the motor parameters are time varying, a recurrent neural network (RNN) controller is proposed to control the USM drive system. In the proposed controller, the dynamic backpropagation algorithm is adopted to train the RNN on-line using the proposed delta adaptation law. Furthermore, to guarantee the convergence of tracking error, analytical methods based on a discrete-type Lyapunov function are proposed to determine the varied learning rates for the training of the RNN. Finally, the effectiveness of the RNN-controlled USM drive system is demonstrated by some experimental results.

Evidence for nm23 RNA overexpression, DNA amplification and mutation in aggressive childhood neuroblastomas.

Reduced expression of nm23 RNAs/proteins has been associated previously with high tumor metastatic potential. In contrast, we report that regional (state III) and metastatic (stage IV) childhood neuroblastomas exhibit elevated nm23 RNA levels as compared with localized tumors. Elevated neuroblastoma nm23 RNA levels were associated with significant reductions in patient survival in the overall (n = 75) and N-myc non-amplified (n = 61) portion of the cohort. Amplification of the chromosomal nm23-H1 gene was observed in 6/18 stage III and IV tumors; amplification of nm23-H2 was not demonstrated. Genomic amplification of nm23-H1 was associated with increased tumor nm23 RNA expression and reduced patient survival. Single-strand conformational polymorphism (SSCP) analysis was performed on seven neuroblastomas. Minor subpopulations of cDNAs exhibiting altered mobility were apparent in both nm23-H1 and nm23-H2 translated regions of stage III and IV tumors, suggestive of mutations. Confirmation of the SSCP data was provided by direct sequencing of nm23-H2 in a stage IV tumor, revealing a leucine to valine mutation at position 48. The data indicate that molecular alterations to nm23 other than its reduced expression can be associated with tumor aggressiveness, and provide the first evidence for nm23 mutation in a human cancer.

Characterization of human glucocerebrosidase from different mutant alleles.

Human cDNA was mutagenized to duplicate six naturally occurring mutations in the gene for glucocere-brosidase. The mutant genes were expressed in NIH 3T3 cells. The abnormal human enzymes were purified by immunoaffinity chromatography and characterized. The Asn370----Ser mutant protein differed from normal enzyme in its inhibition by both conduritol B epoxide and glucosphingosine demonstrating that the 370 mutant enzyme has an abnormal catalytic site. In addition, the 370 mutant enzyme is less activated by saposin C, but more stimulated by phosphatidylserine than the wild type enzyme. The Arg463----Cys mutant protein was normal with respect to conduritol B epoxide and glucosphingosine inhibition, but was less activated by both saposin C and phosphatidylserine. The Arg120----Gln mutant protein was catalytically inactive. The Leu444----Pro, the pseudopattern, and the Pro415----Arg mutants appear to have reduced amounts of enzyme protein in cells. The studies demonstrated that mutations in the gene for glucocerebrosidase have different effects on the catalytic activity and stability of the enzyme.

Sequence of two alleles responsible for Gaucher disease.

Enzymatically amplified RNA transcripts were used to analyze the full coding region of the glucocerebrosidase gene from Gaucher disease patients. Two previously undescribed mutations were identified. One mutation consists of a single-base substitution in three different codons: codon 444, Leu (CTG) to Pro (CCG); codon 456, Ala (GCT) to Pro (CCT); and codon 460, Val (GTG) to Val (GTC). This mutant is called "pseudo pattern" (psi) because it is identical in sequence to a small region of the pseudogene in exon 10 (Horowitz et al., 1989). The other new mutation is a single-base substitution (C to T) resulting in the substitution of Cys for Arg in codon 463. These mutations in the human gene were duplicated in wild-type cDNA and expressed in 3T3 cells. The human mutant proteins were isolated by immunoaffinity and shown to have altered enzymatic properties demonstrating the causality of these two allelic mutations for Gaucher disease.