Natural Selection Signatures in the Hondo and Ryukyu Japanese Subpopulations.

Natural selection signatures across Japanese subpopulations are under-explored. Here we conducted genome-wide selection scans with 622,926 single nucleotide polymorphisms for 20,366 Japanese individuals, who were recruited from the main-islands of Japanese Archipelago (Hondo) and the Ryukyu Archipelago (Ryukyu), representing two major Japanese subpopulations. The integrated haplotype score (iHS) analysis identified several signals in one or both subpopulations. We found a novel candidate locus at IKZF2, especially in Ryukyu. Significant signals were observed in the major histocompatibility complex region in both subpopulations. The lead variants differed and demonstrated substantial allele frequency differences between Hondo and Ryukyu. The lead variant in Hondo tags HLA-A*33:03-C*14:03-B*44:03-DRB1*13:02-DQB1*06:04-DPB1*04:01, a haplotype specific to Japanese and Korean. While in Ryukyu, the lead variant tags DRB1*15:01-DQB1*06:02, which had been recognized as a genetic risk factor for narcolepsy. In contrast, it is reported to confer protective effects against type 1 diabetes and human T lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis. The FastSMC analysis identified 8 loci potentially affected by selection within the past 20-150 generations, including 2 novel candidate loci. The analysis also showed differences in selection patterns of ALDH2 between Hondo and Ryukyu, a gene recognized to be specifically targeted by selection in East Asian. In summary, our study provided insights into the selection signatures within the Japanese and nominated potential sources of selection pressure.

Neutropenia related to an azathioprine metabolic disorder induced by an inosine triphosphate pyrophosphohydrolase (ITPA) gene mutation in a patient with PR3-ANCA-positive microscopic polyangiitis
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A 68-year-old Japanese man was monitored for chronic kidney disease (CKD), with unknown primary disease starting in 2014. His serum creatinine (sCr) was stable at ~ 2.5 mg/dL for ~ 2 years. Two weeks before admission, he had bloody sputum, and sCr increased to 4.63 mg/dL. Soon after admission, the patient developed a high fever with pigment spots on the legs. A kidney biopsy was performed. The kidney specimens showed necrotizing and crescentic glomerulonephritis without granuloma formation. An additional blood-sampling test revealed high titers of PR3-ANCA, and we diagnosed PR3-ANCA-positive microscopic polyangiitis (MPA). Treatment with intravenous steroid pulse therapy and intermittent pulse intravenous cyclophosphamide therapy was started for remission induction. With these treatments, sCr improved to ~ 3.0 mg/dL. Azathioprine (AZA) was added for remission-maintenance therapy. Three days later, the dose of AZA was increased from 50 to 100 mg/day, and the number of neutrophils decreased to 30/µL. After withdrawal of AZA, neutrophil levels gradually recovered. We suspected that an abnormal metabolism of AZA was responsible for the neutropenia. Therefore, we analyzed three AZA metabolism-associated genes for mutations: thiopurine S-methyltransferase (TPMT), inosine triphosphate pyrophosphohydrolase (ITPA), and nucleoside diphosphate linked moiety X-type motif 15 (NUDT15), and we identified ITPA 94C>A mutation. This was a rare case of PR3-positive MPA with AZA-induced severe neutropenia that was possibly due to an ITPA gene mutation. This case suggests that ITPA gene mutation is related to the adverse reactions of AZA in Japanese patients. We have to pay attention to severe neutropenia when we use AZA, especially in Asian patients with CKD.
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Outcomes of surgical treatment for osteochondritis dissecans of the elbow: evaluation by lesion location.

BACKGROUND: For treatment of advanced elbow osteochondritis dissecans (OCD), we have used surgical treatment. Although favorable treatment outcomes have been reported for centrally located OCD, treatment outcomes are generally questionable and the choice of surgical method is controversial for laterally located OCD. Our purpose was to evaluate the treatment outcomes based on lesion location. METHODS: The patients were 30 young (mean age, 14 years) male athletes who underwent surgical treatment of elbow OCD and were monitored for more than 1 year. Osteochondral autografts harvested from the knee were transplanted to centralized (13 patients) or lateral localized (9 patients) OCD lesions. For lateral widespread (8 patients) OCD lesions, a detached osteochondral fragment was fixed using small osteochondral plugs. When the remaining cartilage defect was large after fragment fixation, a large-sized osteochondral plug was transplanted to the defect. Treatment outcomes were evaluated by the Japanese Orthopaedic Association score, elbow range of motion (ROM), and radiographic findings. RESULTS: The Japanese Orthopaedic Association score significantly improved in patients with centralized, lateral localized, and lateral widespread types of OCD. ROM significantly improved in patients with centralized and lateral localized, and they returned to playing sports within 6 months. However, patients with lateral widespread OCD exhibited no significant ROM improvement, and returning to sports was difficult for 3 patients because of poor osseous integration of the fixed osteochondral fragment. CONCLUSIONS: Osteochondral autograft transplantation provided favorable outcomes for centralized and lateral localized elbow OCD lesions. However, for lateral widespread OCD lesions, reconstruction of the entire capitellar lesion area may be necessary.

RNF213 Variants, Vasospastic Angina, and Risk of Fatal Myocardial Infarction.

Importance: Vasospastic angina (VSA) is vasospasm of the coronary artery and is particularly prevalent in East Asian populations. However, the specific genetic architecture for VSA at genome-wide levels is not fully understood. Objective: To identify genetic factors associated with VSA. Design, Setting, and Participants: This was a case-control genome-wide association study of VSA. Data from Biobank Japan (BBJ; enrolled patients from 2002-2008 and 2013-2018) were used, and controls without coronary artery disease (CAD) were enrolled. Patients from the BBJ were genotyped using arrays or a set of arrays. Patients recruited between 2002 and 2005 were classified within the first dataset, and those recruited between 2006 and 2008 were classified within the second dataset. To replicate the genome-wide association study in the first and second datasets, VSA cases and control samples from the latest patients in the BBJ recruited between 2013 and 2018 were analyzed in a third dataset. Exposures: Single-nucleotide variants associated with VSA. Main Outcomes and Measures: Cases with VSA and controls without CAD. Results: A total of 5720 cases (mean [SD] age, 67 [10] years; 3672 male [64.2%]) and 153 864 controls (mean [SD] age, 62 [15] years; 77 362 male [50.3%]) in 3 datasets were included in this study. The variants at the RNF213 locus showed the strongest association with VSA across the 3 datasets (odds ratio [OR], 2.34; 95% CI, 1.99-2.74; P = 4.4 × 10-25). Additionally, rs112735431, an Asian-specific rare deleterious variant (p.Arg4810Lys) experimentally shown to be associated with reduced angiogenesis and a well-known causal risk for Moyamoya disease was the most promising candidate for a causal variant explaining the association. The effect size of rs112735431 on VSA was distinct from that of other CADs. Furthermore, homozygous carriers of rs112735431 showed an association with VSA characterized by a large effect estimate (OR, 18.34; 95% CI, 5.15-65.22; P = 7.0 × 10-6), deviating from the additive model (OR, 4.35; 95% CI, 1.18-16.05; P = .03). Stratified analyses revealed that rs112735431 exhibited a stronger association in males (χ21 = 7.24; P = .007) and a younger age group (OR, 3.06; 95% CI, 2.24-4.19), corresponding to the epidemiologic features of VSA. In the registry, carriers without CAD of the risk allele rs112735431 had a strikingly high mortality rate due to acute myocardial infarction during the follow-up period (hazard ratio, 2.71; 95% CI, 1.57-4.65; P = 3.3 × 10-4). As previously reported, a possible overlap between VSA and Moyamoya disease was not found. Conclusions and Relevance: Results of this study suggest that vascular cell dysfunction mediated by variants in the RNF213 locus may promote coronary vasospasm, and the presence of the risk allele could serve as a predictive factor for the prognosis.

Decoding triancestral origins, archaic introgression, and natural selection in the Japanese population by whole-genome sequencing.

We generated Japanese Encyclopedia of Whole-Genome/Exome Sequencing Library (JEWEL), a high-depth whole-genome sequencing dataset comprising 3256 individuals from across Japan. Analysis of JEWEL revealed genetic characteristics of the Japanese population that were not discernible using microarray data. First, rare variant-based analysis revealed an unprecedented fine-scale genetic structure. Together with population genetics analysis, the present-day Japanese can be decomposed into three ancestral components. Second, we identified unreported loss-of-function (LoF) variants and observed that for specific genes, LoF variants appeared to be restricted to a more limited set of transcripts than would be expected by chance, with PTPRD as a notable example. Third, we identified 44 archaic segments linked to complex traits, including a Denisovan-derived segment at NKX6-1 associated with type 2 diabetes. Most of these segments are specific to East Asians. Fourth, we identified candidate genetic loci under recent natural selection. Overall, our work provided insights into genetic characteristics of the Japanese population.

A genome-wide association study identifies a locus associated with knee extension strength in older Japanese individuals.

Sarcopenia is a common skeletal muscle disease in older people. Lower limb muscle strength is a good predictive value for sarcopenia; however, little is known about its genetic components. Here, we conducted a genome-wide association study (GWAS) for knee extension strength in a total of 3452 Japanese aged 60 years or older from two independent cohorts. We identified a significant locus, rs10749438 which is an intronic variant in TACC2 (transforming acidic coiled-coil-containing 2) (P = 4.2 × 10-8). TACC2, encoding a cytoskeleton-related protein, is highly expressed in skeletal muscle, and is reported as a target of myotonic dystrophy 1-associated splicing alterations. These suggest that changes in TACC2 expression are associated with variations in muscle strength in older people. The association was consistently observed in young and middle-aged subjects. Our findings would shed light on genetic components of lower limb muscle strength and indicate TACC2 as a potential therapeutic target for sarcopenia.

Improved genetic prediction of the risk of knee osteoarthritis using the risk factor-based polygenic score.

BACKGROUND: Polygenic risk score (PRS) analysis is used to predict disease risk. Although PRS has been shown to have great potential in improving clinical care, PRS accuracy assessment has been mainly focused on European ancestry. This study aimed to develop an accurate genetic risk score for knee osteoarthritis (OA) using a multi-population PRS and leveraging a multi-trait PRS in the Japanese population. METHODS: We calculated PRS using PRS-CS-auto, derived from genome-wide association study (GWAS) summary statistics for knee OA in the Japanese population (same ancestry) and multi-population. We further identified risk factor traits for which PRS could predict knee OA and subsequently developed an integrated PRS based on multi-trait analysis of GWAS (MTAG), including genetically correlated risk traits. PRS performance was evaluated in participants of the Nagahama cohort study who underwent radiographic evaluation of the knees (n = 3,279). PRSs were incorporated into knee OA integrated risk models along with clinical risk factors. RESULTS: A total of 2,852 genotyped individuals were included in the PRS analysis. The PRS based on Japanese knee OA GWAS was not associated with knee OA (p = 0.228). In contrast, PRS based on multi-population knee OA GWAS showed a significant association with knee OA (p = 6.7 × 10-5, odds ratio (OR) per standard deviation = 1.19), whereas PRS based on MTAG of multi-population knee OA, along with risk factor traits such as body mass index GWAS, displayed an even stronger association with knee OA (p = 5.4 × 10-7, OR = 1.24). Incorporating this PRS into traditional risk factors improved the predictive ability of knee OA (area under the curve, 74.4% to 74.7%; p = 0.029). CONCLUSIONS: This study showed that multi-trait PRS based on MTAG, combined with traditional risk factors, and using large sample size multi-population GWAS, significantly improved predictive accuracy for knee OA in the Japanese population, even when the sample size of GWAS of the same ancestry was small. To the best of our knowledge, this is the first study to show a statistically significant association between the PRS and knee OA in a non-European population. TRIAL REGISTRATION: No. C278.

Androgen receptor binding sites enabling genetic prediction of mortality due to prostate cancer in cancer-free subjects.

Prostate cancer (PrCa) is the second most common cancer worldwide in males. While strongly warranted, the prediction of mortality risk due to PrCa, especially before its development, is challenging. Here, we address this issue by maximizing the statistical power of genetic data with multi-ancestry meta-analysis and focusing on binding sites of the androgen receptor (AR), which has a critical role in PrCa. Taking advantage of large Japanese samples ever, a multi-ancestry meta-analysis comprising more than 300,000 subjects in total identifies 9 unreported loci including ZFHX3, a tumor suppressor gene, and successfully narrows down the statistically finemapped variants compared to European-only studies, and these variants strongly enrich in AR binding sites. A polygenic risk scores (PRS) analysis restricting to statistically finemapped variants in AR binding sites shows among cancer-free subjects, individuals with a PRS in the top 10% have a strongly higher risk of the future death of PrCa (HR: 5.57, P = 4.2 × 10-10). Our findings demonstrate the potential utility of leveraging large-scale genetic data and advanced analytical methods in predicting the mortality of PrCa.

Genetic insights into ossification of the posterior longitudinal ligament of the spine.

Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis are primarily unknown. The relationship between OPLL and comorbidities, especially type 2 diabetes (T2D) and high body mass index (BMI), has been the focus of attention; however, no trait has been proven to have a causal relationship. We conducted a meta-analysis of genome-wide association studies (GWASs) using 22,016 Japanese individuals and identified 14 significant loci, 8 of which were previously unreported. We then conducted a gene-based association analysis and a transcriptome-wide Mendelian randomization approach and identified three candidate genes for each. Partitioning heritability enrichment analyses observed significant enrichment of the polygenic signals in the active enhancers of the connective/bone cell group, especially H3K27ac in chondrogenic differentiation cells, as well as the immune/hematopoietic cell group. Single-cell RNA sequencing of Achilles tendon cells from a mouse Achilles tendon ossification model confirmed the expression of genes in GWAS and post-GWAS analyses in mesenchymal and immune cells. Genetic correlations with 96 complex traits showed positive correlations with T2D and BMI and a negative correlation with cerebral aneurysm. Mendelian randomization analysis demonstrated a significant causal effect of increased BMI and high bone mineral density on OPLL. We evaluated the clinical images in detail and classified OPLL into cervical, thoracic, and the other types. GWAS subanalyses identified subtype-specific signals. A polygenic risk score for BMI demonstrated that the effect of BMI was particularly strong in thoracic OPLL. Our study provides genetic insight into the etiology and pathogenesis of OPLL and is expected to serve as a basis for future treatment development.

Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

Accurate magnetic field imaging using nanodiamond quantum sensors enhanced by machine learning.

Nanodiamonds can be excellent quantum sensors for local magnetic field measurements. We demonstrate magnetic field imaging with high accuracy of 1.8 [Formula: see text]T combining nanodiamond ensemble (NDE) and machine learning without any physical models. We discover the dependence of the NDE signal on the field direction, suggesting the application of NDE for vector magnetometry and the improvement of the existing model. Our method enhances the NDE performance sufficiently to visualize nano-magnetism and mesoscopic current and expands the applicability of NDE in arbitrarily shaped materials, including living organisms. This accomplishment bridges machine learning to quantum sensing for accurate measurements.

Role of Lysine-Specific Demethylase 1 in Metabolically Integrating Osteoclast Differentiation and Inflammatory Bone Resorption Through Hypoxia-Inducible Factor 1α and E2F1.

OBJECTIVE: Hypoxia occurs in tumors, infections, and sites of inflammation, such as in the affected joints of patients with rheumatoid arthritis (RA). It alleviates inflammatory responses and increases bone resorption in inflammatory arthritis by enhancing osteoclastogenesis. The mechanism by which the hypoxia response is linked to osteoclastogenesis and inflammatory bone resorption is unclear. This study was undertaken to evaluate whether the protein lysine-specific demethylase 1 (LSD1) metabolically integrates inflammatory osteoclastogenesis and bone resorption in a state of inflammatory arthritis. METHODS: LSD1-specific inhibitors and gene silencing with small interfering RNAs were used to inhibit the expression of LSD1 in human osteoclast precursor cells derived from CD14-positive monocytes, with subsequent assessment by RNA-sequencing analysis. In experimental mouse models of arthritis, inflammatory osteolysis, or osteoporosis, features of accelerated bone loss and inflammatory osteolysis were analyzed. Furthermore, in blood samples from patients with RA, cis-acting expression quantitative trait loci (cis-eQTL) were analyzed for association with the expression of hypoxia-inducible factor 1α (HIF-1α), and associations between HIF-1α allelic variants and extent of bone erosion were evaluated. RESULTS: In human osteoclast precursor cells, RANKL induced the expression of LSD1 in a mechanistic target of rapamycin-dependent manner. Expression of LSD1 was higher in synovium from RA patients than in synovium from osteoarthritis patients. Inhibition of LSD1 in human osteoclast precursors suppressed osteoclast differentiation. Results of transcriptome analysis identified several LSD1-mediated hypoxia and cell-cycle pathways as key genetic pathways involved in human osteoclastogenesis. Furthermore, HIF-1α protein, which is rapidly degraded by the proteasome in a normoxic environment, was found to be expressed in RANKL-stimulated osteoclast precursor cells. Induction of LSD1 by RANKL stabilized the expression of HIF-1α protein, thereby promoting glycolysis, in conjunction with up-regulation of the transcription factor E2F1. Analyses of cis-eQTL revealed that higher HIF-1α expression was associated with increased bone erosion in patients with RA. Inhibition of LSD1 decreased pathologic bone resorption in mice, both in models of accelerated osteoporosis and models of arthritis and inflammatory osteolysis. CONCLUSION: LSD1 metabolically regulates osteoclastogenesis in an energy-demanding inflammatory environment. These findings provide potential new therapeutic strategies targeting osteoclasts in the management of inflammatory arthritis, including in patients with RA.

Serum type IV collagen level is predictive for esophageal varices in patients with severe alcoholic disease.

AIM: To determine factors predictive for esophageal varices in severe alcoholic disease (SAD). METHODS: Abdominal ultrasonography (US) was performed on 444 patients suffering from alcoholism. Forty-four patients found to have splenomegaly and/ or withering of the right liver lobe were defined as those with SAD. SAD patients were examined by upper gastrointestinal (UGI) endoscopy for the presence of esophageal varices. The existence of esophageal varices was then related to clinical variables. RESULTS: Twenty-five patients (56.8%) had esophageal varices. A univariate analysis revealed a significant difference in age and type IV collagen levels between patients with and without esophageal varices. A logistic regression analysis identified type IV collagen as the only independent variable predictive for esophageal varices (P = 0.017). The area under the curve (AUC) for type IV collagen as determined by the receiver operating characteristic (ROC) for predicting esophageal varices was 0.78. CONCLUSION: This study suggests that the level of type IV collagen has a high diagnostic accuracy for the detection of esophageal varices in SAD.

The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions.

The neurohypophyseal peptide [Arg(8)]-vasopressin (AVP) exerts major physiological actions through three distinct receptor isoforms designated V1a, V1b, and V2. Among these three subtypes, the vasopressin V1b receptor is specifically expressed in pituitary corticotrophs and mediates the stimulatory effect of vasopressin on ACTH release. To investigate the functional roles of V1b receptor subtypes in vivo, gene targeting was used to create a mouse model lacking the V1b receptor gene (V1bR-/-). Under resting conditions, circulating concentrations of ACTH and corticosterone were lower in V1bR-/- mice compared with WT mice (V1bR+/+). The normal increase in circulating ACTH levels in response to exogenous administration of AVP was impaired in V1bR-/- mice, while corticotropin-releasing hormone-stimulated ACTH release in the V1bR-/- mice was not significantly different from that in the V1bR+/+ mice. AVP-induced ACTH release from primary cultured pituitary cells in V1bR-/- mice was also blunted. Furthermore, the increase in ACTH after a forced swim stress was significantly suppressed in V1bR-/- mice. Our results clearly demonstrate that the V1b receptor plays a crucial role in regulating hypothalamic-pituitary-adrenal axis activity. It does this by maintaining ACTH and corticosterone levels, not only under stress but also under basal conditions.

Charge transfer induced enhancement of near-IR two-photon absorption of 5,15-bis(azulenylethynyl) zinc(II) porphyrins.

Intramolecular charge transfer in 5,15-bis(azulenylethynyl) substituted zinc(ii) porphyrin leads to a significant enhancement of two-photon absorption at near-IR region, which has been investigated by femtosecond Z-scan method.

Serum intercellular adhesion molecule-1 in patients with nonalcoholic steatohepatitis: comparison with alcoholic hepatitis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) includes both nonalcoholic fatty liver (FL) and nonalcoholic steatohepatitis (NASH). It has previously been reported that alcoholic hepatitis, which shows morphological findings similar to that of NASH, leads to the onset of endotoxinemia and to an increase in the production of tumor necrosis factor-alpha (TNF-alpha) and/or interleukin-1 (IL-1) from macrophages. Tumor necrosis factor-alpha and IL-1 induce strong expression of intercellular adhesion molecule-1 (ICAM-1) of the cell membranes of hepatocytes and/or sinusoidal endothelial cells, resulting in increased serum ICAM-1 levels in our previous study. In this study, we clarified the significance of serum ICAM-1 levels in patients with NAFLD, and especially in NASH. METHODS: Thirty-three obese patients of NAFLD (FL: n=14, NASH: n=19) with no habit of drinking, 20 cases of alcoholic liver diseases (alcoholic hepatitis; ASH: n=10, alcoholic hepatic fibrosis; HF: n=10), and 10 healthy individuals were studied. Serum ICAM-1 concentrations were analyzed by enzyme-linked immunoassay in patients with NAFLD and alcoholic liver diseases. Potential factors were assessed for increase in serum ICAM-1 and a diagnostic tool for NASH including ICAM-1 levels, C-reactive protein (CRP), white blood cell count, aspartate aminotransferase, alanine aminotransferase, gamma-gluatmyl transferase, total cholesterol, triglyceride, type-IV collagen, body mass index, homeostasis model assessment (HOMA-IR), and existence of high blood pressure. RESULTS: The serum ICAM-1 level was significantly higher in the patients with NASH than in the patients with FL, and in the normal subjects. The serum ICAM-1 level was also significantly higher in the patients with ASH. The serum ICAM-1 level in the patients with ASH was remarkably high compared with that of the patients with NASH. No significant difference in serum ICAM-1 levels was found between the patients with NASH and those with HF. The serum ICAM-1 level was significantly higher in patients with high blood pressure than in those without high blood pressure in NAFLD. A multivariate analysis using multiple logistic regression showed that high blood pressure and GGTP were the significant factors contributing to high serum ICAM-1 levels, while highly sensitive CRP and ICAM-1 were the significant factors for the diagnosis of NASH. CONCLUSIONS: The serum ICAM-1 concentration is increased in patients with NASH. The serum level of ICAM-1 in patients with NAFLD may be a useful marker for the diagnosis of NASH.

Endoscopic submucosal dissection for an atypical small verrucous carcinoma: a case report.

BACKGROUND: Esophageal verrucous carcinoma is a rare variant of esophageal squamous cell carcinoma. In most cases, verrucous carcinoma presents as an exophytic, slow-growing mass with an extensive superficial growth pattern. Symptoms often include an insidious onset of dysphagia resulting in weight loss. In a patient presenting with super early-stage verrucous carcinoma, we were able to eliminate the aberration using endoscopic submucosal dissection. CASE PRESENTATION: An asymptomatic 68-year-old Asian man was found to have an abnormality in his esophagus. The abnormality was discovered, by chance, in a barium study for a health checkup. Esophagogastroduodenoscopy revealed a 1-centimeter polypoid lesion covered with squamous epithelium. Biopsies showed squamous high-grade intraepithelial neoplasia. An endoscopic submucosal dissection was performed and the histopathological findings showed a well-differentiated squamous cell carcinoma with hyperkeratosis with a church spire configuration. These features are consistent with the growth pattern of verrucous carcinoma. CONCLUSIONS: Verrucous carcinoma can manifest as a small mass with nonclinical symptoms and endoscopic submucosal dissection is useful as a curative treatment. We must consider that verrucous carcinoma can manifest as appearance of a polyp that is not papillary or warty-like with and without extensive superficial growth appearance.

Formation of acrylamide in a processed food model system, and examination of inhibitory conditions.

Acrylamide (AAm) is formed from asparagine (Asn) and reducing sugar during cooking of foods at high temperature. We examined the formation of AAm in a model system using a glass fiber filter paper, and looked for suitable conditions for inhibiting AAm formation. In frying, the formation rate was about 10 times that in a moistureless oven. Increase of frying temperature and frying time increased AAm formation when the residual moisture was 5% or less. AAm increased with increasing amount of glucose (Glc) addition up to 1:1 with respect to Asn, but then decreased. On the other hand, in the case of fructose, as the amount added was increased, AAm increased accordingly. The AAm formation rate with respect to Asn increased when valine (Val) was co-present in a Glc and Asn reaction system. Cysteine and lysine inhibited the AAm formation rate. Pathways for the formation of AAm are proposed.

Cytologic features of sarcomatoid carcinoma of the urinary bladder: a case report.

Sarcomatoid carcinoma of the urinary bladder is a rare entity, whose histogenesis and biological behavior remain controversial. The cytological literature on sarcomatoid carcinoma in voided urine is very scarce. Clinically, the diagnosis of this tumor can be made by computed tomography (CT), magnetic resonance imaging (MRI), cytology, and biopsy material. In this study, cytology, histopathology, and radiological imaging were employed in order to reach a diagnosis of sarcomatoid carcinoma. CT imaging showed increased thickness of the bladder wall associated to a polypoid mass. MRI showed a 4-cm sized, broadly necked polypoid mass with calcification and ulceration at the right side of the bladder wall. T2W1 imaging showed low signal. Voided urinary cytology showed a scattered cellular presentation. The tumor cells had a high nucleo- cytoplasmic ratio, with elongated cytoplasm with faint with indistinct cytoplasm border. The nucleus was oval to round, with large and irregular nucleoli and irregular nuclear membrane. These tumor cells were positive for cytokeratin (CKAE1/AE3), vimentin, p53, carcinoembryonic antigen (CEA), α1-smooth muscle actin (SMA) by the immunoperoxidase staining. Histopathology showed spindle-shaped and clumped large tumor cells with abundant cytoplasm. Mitotic figures were frequently seen and varied from area to area (50% of the tumor cells were positive for MIB1).