Effects of Androgen Treatment on Growth in Patients with 5-α-Reductase Type 2 Deficiency.

BACKGROUND: Patients with 5-α-reductase type 2 deficiency (5αRD2) require androgen treatment for the growth of normal male external genitalia. Since limited research has been conducted on the effects of androgen treatment on height in individuals with 5αRD2, we investigated the effect of androgen treatment on bone age (BA) and the height status in children with 5αRD2. METHODS: Of the 19 participants who were followed up for an average of 10.6 years, 12 received androgen treatment. BA and height standard deviation scores (SDS) were compared between the treatment and non-treatment groups, as well as between the dihydrotestosterone (DHT) and testosterone enanthate (TE) treatment groups. RESULTS: Despite the above-average height of the 19 patients with 5αRD2, the height SDS relative to BA (htSDS-BA) was below average, particularly in the androgen treatment group. DHT treatment did not lead to an increase in BA or htSDS-BA, whereas TE treatment resulted in BA advancement and decreased htSDS-BA, especially in the prepubertal period. CONCLUSIONS: DHT treatment is more favorable for height than TE treatment in patients with 5αRD2, particularly during the prepubertal period. Therefore, age and the type of androgen used should be carefully considered to minimize the risk of height reduction in these patient groups.

The Genotype-Phenotype Correlation in Human 5α-Reductase Type 2 Deficiency: Classified and Analyzed from a SRD5A2 Structural Perspective.

The phenotype of the 5α-reductase type 2 deficiency (5αRD2) by the SRD5A2 gene mutation varies, and although there have been many attempts, the genotype-phenotype correlation still has not yet been adequately evaluated. Recently, the crystal structure of the 5α-reductase type 2 isozyme (SRD5A2) has been determined. Therefore, the present study retrospectively evaluated the genotype-phenotype correlation from a structural perspective in 19 Korean patients with 5αRD2. Additionally, variants were classified according to structural categories, and phenotypic severity was compared with previously published data. The p.R227Q variant, which belongs to the NADPH-binding residue mutation category, exhibited a more masculine phenotype (higher external masculinization score) than other variants. Furthermore, compound heterozygous mutations with p.R227Q mitigated phenotypic severity. Similarly, other mutations in this category showed mild to moderate phenotypes. Conversely, the variants categorized as structure-destabilizing and small to bulky residue mutations showed moderate to severe phenotypes, and those categorized as catalytic site and helix-breaking mutations exhibited severe phenotypes. Therefore, the SRD5A2 structural approach suggested that a genotype-phenotype correlation does exist in 5αRD2. Furthermore, the categorization of SRD5A2 gene variants according to the SRD5A2 structure facilitates the prediction of the severity of 5αRD2 and the management and genetic counseling of patients affected by it.

Distribution of Corynebacterium Species and Comparative Results of Diagnostic Methods for Identifying Corynebacterium in Experimental Mice in Korea.

The genus Corynebacterium, composed of Gram-positive diphtheroid rod-shaped bacteria, induces severe diseases, such as Corynebacterium-associated hyperkeratosis and pseudotuberculosis, in immunodeficient mice. We isolated and identified a total of 165 strains of Corynebacterium species from experimental mice in Korean laboratories, diagnosed using several methods. When identified based on molecular methods, namely, 16S rRNA and rpoB gene sequence analysis, the main Corynebacterium species isolated in Korean laboratory mice were C. mastitidis (44.8%, n = 74), C. bovis (25.5%, n = 42), C. lowii (21.2%, n = 35), and C. amycolatum (8.5%, n = 14). Diagnoses were also performed using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) and biochemical methods. MALDI-TOF MS yielded results that were 77.9% identical to the molecular identification results, whereas biochemical methods showed only 15.5% identical to molecular identification, partly owing to difficulties in distinguishing among C. mastitidis strains. Collectively, our findings indicate that molecular biological methods are better suited for detecting and identifying Corynebacterium species candidates isolated from mice than biochemical methods. Because of limitations associated with the use of MALDI-TOF MS, more precise results will be obtained by complementing this approach with other methods when used for rapid identification testing.

TGF-ß1 Receptor Inhibitor SB525334 Attenuates the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells via the TGF-ß1 Signaling Pathway.

We investigated the effect of SB525334 (TGF-ß receptor type 1 (TßRI) inhibitor) on the epithelial to mesenchymal transition (EMT) signaling pathway in human peritoneal mesothelial cells (HPMCs) and a peritoneal fibrosis mouse model. In vitro experiments were performed using HPMCs. HPMCs were treated with TGF-ß1 and/or SB525334. In vivo experiments were conducted with male C57/BL6 mice. The 0.1% chlorhexidine gluconate (CG) was intraperitoneally injected with or without SB52534 administration by oral gavage. Mice were euthanized after 28 days. EMT using TGF-ß1-treated HPMCs included morphological changes, cell migration and invasion, EMT markers and collagen synthesis. These pathological changes were reversed by co-treatment with SB525334. CG injection was associated with an increase in peritoneal fibrosis and thickness, which functionally resulted in an increase in the glucose absorption via peritoneum. Co-treatment with SB525334 attenuated these changes. The levels of EMT protein markers and immunohistochemical staining for fibrosis showed similar trends. Immunofluorescence staining for EMT markers showed induction of transformed cells with both epithelial and mesenchymal cell markers, which decreased upon co-treatment with SB525334. SB525334 effectively attenuated the TGF-ß1-induced EMT in HPMCs. Cotreatment with SB525334 improved peritoneal thickness and fibrosis and recovered peritoneal membrane function in a peritoneal fibrosis mouse model.

Effects of TGF-ß1 Receptor Inhibitor GW788388 on the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells.

We investigated the effectiveness of the transforming growth factor beta-1 (TGF-ß) receptor inhibitor GW788388 on the epithelial to mesenchymal transition (EMT) using human peritoneal mesothelial cells (HPMCs) and examined the effectiveness of GW788388 on the peritoneal membrane using a peritoneal fibrosis mouse model. HPMCs were treated with TGF-ß with or without GW788388. Animal experiments were conducted on male C57/BL6 mice. Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate. GW788388 was administered by once-daily oral gavage. The morphological change, cell migration, and invasion resulted from TGF-ß treatment, but these changes were attenuated by cotreatment with GW788388. TGF-ß-treated HPMCs decreased the level of the epithelial cell marker and increased the levels of the mesenchymal cell markers. Cotreatment with GW788388 reversed these changes. Phosphorylated Smad2 and Smad3 protein levels were stimulated with TGF-ß and the change was attenuated by cotreatment with GW788388. For the peritoneal fibrosis mice, thickness and collagen deposition of parietal peritoneum was increased, but this change was attenuated by cotreatment with GW788388. GW788388, an orally available potent TGF-ß receptor type 1 inhibitor, effectively attenuated TGF-ß-induced EMT in HPMCs. Cotreatment with GW788388 improved peritoneal thickness and fibrosis, and recovered peritoneal membrane function in a peritoneal fibrosis mouse model.

Jejunogastric intussusception prone to misdiagnosis as gastric cancer.

The authors report a case of a 78-year-old female with a history of gastric surgery 35 years ago. She was initially misdiagnosed as gastric cancer bleeding and underwent an emergency laparotomy under the diagnosis of jejunogastric intussusception (JGI), 23 hours after the onset of symptoms. We also reviewed 116 JGI case reports and analyzed clinical features and outcomes. Compared to the past, diagnosis of JGI is easier with diagnostic examinations such as an endoscopy, computed tomography, and the upper gastrointestinal series. And a good prognosis can be expected with proper fluid resuscitation and surgical reduction, even if the symptoms persist more than 48 hours.

Factors Associated with Operation Time of Laparoscopic Gastric Wedge Resection for Gastric Subepithelial Tumors.

Purpose: Gastric subepithelial tumor (GST) is a disease entity that includes all gastric subepithelial lesions. The oncologically safe surgical technique is complete resection with adequate resection margins. Most of the studies about laparoscopic gastric wedge rsection (LGWR) in GST focus on oncologic curability or surgical effectiveness. However, studies on the factors associated with the operation time are rare. Therefore, this study was conducted to analyze and compare the factors associated with the operation time of LGWR. Methods: From 2010 to 2019, 145 consecutive patients undergoing LGWR were reviewed retrospectively. Clinical characteristics of GST and operation time were analyzed and compared. Results: A total of 145 patients was enrolled and reviewed. There were 59 males (40.7%) and 86 females (59.3%) with a mean age of 53.6 years and mean body mass index (BMI) of 23.9 kg/m2. Mean tumor size was 2.9 cm and mean operation time was 66.0 minutes. In statistically, the mean operation time showed significant association with tumor size, BMI, longitudinal tumor location and tumor location between lesser and greater curvature. In multivariate analysis, tumor size, BMI and longitudinal classification of tumor location are statistically significant. Conclusion: A shorter operation time is expected when there is a small tumor, low BMI and mid portion of the stomach GST. Preoperative evaluation for tumor size and body weight is important. In patients with large GST, obesity and both end stomach GST, we think that pre-operative preparation for long operation time should be considered.

Clinicopathologic features of remnant gastric cancer after curative distal gastrectomy according to previous reconstruction method: a retrospective cohort study.

BACKGROUND: Survival rate of patients treated for gastric cancer has increased due to early detection and improvements of surgical technique and chemotherapy. Increase in survival rate has led to an increase in the risk for remnant gastric cancer (RGC). The purpose of this study was to investigate clinicopathologic features of RGC according to previous reconstruction method and factors affecting the interval from previous curative distal gastrectomy for gastric cancer to RGC occurrence. METHODS: Medical records of patients diagnosed with RGC at Yeungnam University Medical Center from January 2000 to December 2017 who had a history of distal gastrectomy with D2 LN dissection due to gastric cancer were reviewed retrospectively. RESULTS: Forty-eight patients were enrolled in this study. The mean interval of 48 RGC patients was 105.6 months (8.8 years). RGC after Billroth II reconstruction recurred more often at anastomosis site than RGC after Billroth I reconstruction (p = 0.001). The mean interval of RGC after Billroth I reconstruction was 67 months, shorter than 119 months of RGC after Billroth II reconstruction (p = 0.003). On the contrary, interval showed no difference according to stage of previous gastric cancer, remnant gastric cancer, or sex (p = 0.810, 0.145, and 0.372, respectively). CONCLUSIONS: RGC after Billroth I reconstruction tends to arise earlier at non-anastomosis site than RGC after Billroth II. Therefore, we should examine non-anastomosis site carefully from the beginning of surveillance after gastric cancer surgery with Billroth I reconstruction for better outcome.

Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial.

BACKGROUND: The CLASSIC trial was done to compare adjuvant capecitabine plus oxaliplatin versus observation after D2 gastrectomy for patients with stage II or III gastric cancer. The planned interim analysis of CLASSIC (median follow-up 34 months) showed that adjuvant capecitabine plus oxaliplatin significantly improved disease-free survival, the primary endpoint, compared with observation after D2 gastrectomy. We report the 5-year follow-up data from the trial. METHODS: CLASSIC was a phase 3, randomised, open-label study done at 35 cancer centres, medical centres, and hospitals in China, South Korea, and Taiwan. Patients with stage II-IIIB gastric cancer who underwent curative D2 gastrectomy were randomly assigned (1:1) after surgery to receive adjuvant chemotherapy with capecitabine and oxaliplatin (eight 3-week cycles of oral capecitabine 1000 mg/m(2) twice daily on days 1-14 plus intravenous oxaliplatin 130 mg/m(2) on day 1) for 6 months or observation alone. Randomisation was stratified by country and disease stage with a permuted block (size four) design. Neither patients nor investigators were masked to treatment assignment. The primary outcome was 3-year disease-free survival in the intention-to-treat population. This analysis presents the final preplanned assessment of outcomes after 5 years. The study is registered with ClinicalTrials.gov, NCT00411229. FINDINGS: We enrolled 1035 patients: 520 were randomly assigned to adjuvant capecitabine and oxaliplatin, and 515 to observation. Median follow-up for this analysis in the intention-to-treat population was 62·4 months (IQR 54-70). 139 (27%) patients had disease-free survival events in the adjuvant capecitabine and oxaliplatin group versus 203 (39%) patients in the observation group (stratified hazard ratio [HR] 0·58, 95% CI 0·47-0·72; p<0·0001). Estimated 5-year disease-free survival was 68% (95% CI 63-73) in the adjuvant capecitabine and oxaliplatin group versus 53% (47-58) in the observation alone group. By the clinical cutoff date, 103 patients (20%) had died in the adjuvant capecitabine and oxaliplatin group versus 141 patients (27%) in the observation group (stratified HR 0·66, 95% CI 0·51-0·85; p=0·0015). Estimated 5-year overall survival was 78% (95% CI 74-82) in the adjuvant capecitabine and oxaliplatin group versus 69% (64-73) in the observation group. Adverse event data were not collected after the primary analysis. INTERPRETATION: Adjuvant treatment with capecitabine plus oxaliplatin after D2 gastrectomy should be considered for patients with operable stage II or III gastric cancer. FUNDING: F Hoffmann La-Roche and Sanofi.

Analysis of microsatellite instability, protein expression and methylation status of hMLH1 and hMSH2 genes in gastric carcinomas.

BACKGROUND/AIMS: Microsatellite instability (MSI) is a manifestation of a defective DNA mismatch repair system. It is caused by germline mutations of mismatch repair genes or CpG islands hypermethylation. The majority of cancers of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome have MSI+ phenotype. The colorectal cancers show distinctive clinicopathological characteristics and prognoses according to the MSI status. However, there is a wide variety of results between MSI and clinicopathological parameters in gastric carcinomas. METHODOLOGY: Five hundred and twenty-one surgically resected gastric carcinomas were studied and the correlation with clinicopathological parameters, MSI status by using five microsatellite markers, expression of hMLH1 and hMSH2 protein by immunohistochemical stain, and methylation of hMLH1 and hMSH2 by methylation-specific polymerase chain reaction was analyzed. RESULTS: There were 50 (9.6%) high-frequency MSI (MSI-H) cases. The MSI-H gastric carcinomas were associated with older age, expanding type by Ming's classification, lymphatic invasion, tumor multiplicity, losses of hMLH1 and hMSH2 protein expressions. The methylation frequency of hMLH1 was 75.5% in MSI-H gastric carcinomas. CONCLUSIONS: Our results suggest that epigenetic inactivation of hMLH1 might play a role in the carcinogenesis of MSI-H gastric carcinomas. The immunohistochemical stain for hMLH1 protein expression could be used in routine diagnostic methods for predicting MSI status.

A solution to the stochastic point location problem in metalevel nonstationary environments.

This paper reports the first known solution to the stochastic point location (SPL) problem when the environment is nonstationary. The SPL problem involves a general learning problem in which the learning mechanism (which could be a robot, a learning automaton, or, in general, an algorithm) attempts to learn a "parameter," for example, lambda*, within a closed interval. However, unlike the earlier reported results, we consider the scenario when the learning is to be done in a nonstationary setting. For each guess, the environment essentially informs the mechanism, possibly erroneously (i.e., with probability p), which way it should move to reach the unknown point. Unlike the results available in the literature, we consider the fascinating case when the point sought for is itself stochastically moving (which is modeled as follows). The environment communicates with an intermediate entity (referred to as the teacher/oracle) about the point itself, i.e., advising where it should go. The mechanism that searches for the point in turn receives responses from the teacher/oracle, which directs how it should move. Therefore, the point itself, in the overall setting, is moving, i.e., delivering possibly incorrect information about its location to the teacher/oracle. This in turn means that the "environment" is itself nonstationary, which implies that the advice of the teacher/oracle is both uncertain and changing with time-rendering the problem extremely fascinating. The heart of the strategy we propose involves discretizing the space and performing a controlled random walk on this space. Apart from deriving some analytic results about our solution, we also report the simulation results that demonstrate the power of the scheme, and state some potential applications.

On using prototype reduction schemes to optimize kernel-based fisher discriminant analysis.

Fisher's linear discriminant analysis (LDA) is a traditional dimensionality reduction method that has been proven to be successful for decades. Numerous variants, such as the kernel-based Fisher discriminant analysis (KFDA), have been proposed to enhance the LDA's power for nonlinear discriminants. Although effective, the KFDA is computationally expensive, since the complexity increases with the size of the data set. In this correspondence, we suggest a novel strategy to enhance the computation for an entire family of the KFDAs. Rather than invoke the KFDA for the entire data set, we advocate that the data be first reduced into a smaller representative subset using a prototype reduction scheme and that the dimensionality reduction be achieved by invoking a KFDA on this reduced data set. In this way, data points that are ineffective in the dimension reduction and classification can be eliminated to obtain a significantly reduced kernel matrix K without degrading the performance. Our experimental results demonstrate that the proposed mechanism dramatically reduces the computation time without sacrificing the classification accuracy for artificial and real-life data sets.

On utilizing search methods to select subspace dimensions for kernel-based nonlinear subspace classifiers.

In Kernel-based Nonlinear Subspace (KNS) methods, the subspace dimensions have a strong influence on the performance of the subspace classifier. In order to get a high classification accuracy, a large dimension is generally required. However, if the chosen subspace dimension is too large, it leads to a low performance due to the overlapping of the resultant subspaces and, if it is too small, it increases the classification error due to the poor resulting approximation. The most common approach is of an ad hoc nature, which selects the dimensions based on the so-called cumulative proportion computed from the kernel matrix for each class. In this paper, we propose a new method of systematically and efficiently selecting optimal or near-optimal subspace dimensions for KNS classifiers using a search strategy and a heuristic function termed the Overlapping criterion. The rationale for this function has been motivated in the body of the paper. The task of selecting optimal subspace dimensions is reduced to finding the best ones from a given problem-domain solution space using this criterion as a heuristic function. Thus, the search space can be pruned to very efficiently find the best solution. Our experimental results demonstrate that the proposed mechanism selects the dimensions efficiently without sacrificing the classification accuracy.

Enhancing prototype reduction schemes with recursion: a method applicable for "large" data sets.

Most of the prototype reduction schemes (PRS), which have been reported in the literature, process the data in its entirety to yield a subset of prototypes that are useful in nearest-neighbor-like classification. Foremost among these are the prototypes for nearest neighbor classifiers, the vector quantization technique, and the support vector machines. These methods suffer from a major disadvantage, namely, that of the excessive computational burden encountered by processing all the data. In this paper, we suggest a recursive and computationally superior mechanism referred to as adaptive recursive partitioning (ARP)_PRS. Rather than process all the data using a PRS, we propose that the data be recursively subdivided into smaller subsets. This recursive subdivision can be arbitrary, and need not utilize any underlying clustering philosophy. The advantage of ARP_PRS is that the PRS processes subsets of data points that effectively sample the entire space to yield smaller subsets of prototypes. These prototypes are then, in turn, gathered and processed by the PRS to yield more refined prototypes. In this manner, prototypes which are in the interior of the Voronoi spaces, and thus ineffective in the classification, are eliminated at the subsequent invocations of the PRS. We are unaware of any PRS that employs such a recursive philosophy. Although we marginally forfeit accuracy in return for computational efficiency, our experimental results demonstrate that the proposed recursive mechanism yields classification comparable to the best reported prototype condensation schemes reported to-date. Indeed, this is true for both artificial data sets and for samples involving real-life data sets. The results especially demonstrate that a fair computational advantage can be obtained by using such a recursive strategy for "large" data sets, such as those involved in data mining and text categorization applications.