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This study aims to evaluate the relationship between the cyclooxygenase 2 ( COX2 ) G1195A (rs689465) polymorphism and the risk of prostate cancer in a Japanese population and the associations between COX2 polymorphisms and clinicopathological characteristics, including Gleason grade and prostate-specific antigen (PSA) grade. We recruited 134 patients with prostate cancer and 86 healthy controls matched for age and smoking status. The COX2 G1195A polymorphism status was determined by polymerase chain reaction and restriction fragment length polymorphism analysis. Genotype distributions ( p  = 0.028) and allelic frequencies ( p  = 0.014) differed significantly between prostate cancer and control groups in terms of the COX2 G1195A polymorphism (Pearson’s χ 2 test). Logistic regression analysis of case and control outcomes showed an odds ratio between the GG and AA genotypes of 3.15 (95 % confidence interval = 1.27–8.08, p  = 0.014), indicating an increased risk of prostate cancer associated with the AA genotype. Subset analysis revealed no significant associations between this polymorphism and clinicopathological characteristics of prostate cancer. This study demonstrated a relationship between the COX2 G1195A variant and prostate cancer risk. This polymorphism may merit further investigation as a potential genomic marker for the early detection of prostate cancer. Our results support the hypothesis that rs689465 influences susceptibility to prostate cancer; however, prostate cancer progression was not associated with rs689465 in a Japanese population.

MET, a c-met proto-oncogene product and hepatocyte growth factor (HGF) receptor, is known to play an important role in cancer progression, including bone metastasis. In a previous study, we reported increased expression of MET and matriptase, a novel activator of HGF, in bone metastasis. In this study, we employed a mouse model of renal cell carcinoma (RCC) bone metastasis to clarify the significance of the HGF/MET signaling axis and the regulator of HGF activator inhibitor type-2 (HAI-2). Luciferase-transfected 786-O cells were injected into the left cardiac ventricle of mice to prepare the mouse model of bone metastasis. The formation of bone metastasis was confirmed by whole-body bioluminescent imaging, and specimens were extracted. Expression of HGF/MET-related molecules was analyzed. Based on the results, we produced HAI-2 stable knockdown 786-O cells, and analyzed invasiveness and motility. Expression of HGF and matriptase was increased in bone metastasis compared with the control, while that of HAI-2 was decreased. Furthermore, we confirmed increased phosphorylation of MET in bone metastasis. The expression of matriptase was upregulated, and both invasiveness and motility were increased significantly by knockdown of HAI-2. The significance of ligand-dependent MET activation in RCC bone metastasis is considered, and HAI-2 may be an important regulator in this system.

In renal cell carcinoma patients with inferior vena cava (IVC) extension, the difficulty of resection increases with the degree of venous extension, which in turn increases the risk of perioperative morbidity and mortality. In addition, the degree of IVC occlusion and associated bland thrombus are reported to be important factors in the choice of operative procedure and in the risk of perioperative complications. Therefore, presurgical treatment to decrease the extent of tumor thrombus would be of significant benefit. Three renal cell carcinoma patients with IVC extension were treated presurgically with axitinib at our institution between September 2012 and November 2013. All patients received axitinib at an initial dose of 5 mg twice daily for 12 weeks. Objective response to treatment was assessed with enhanced computed tomography at 4 and 12 weeks, and therapeutic value was evaluated. Level of inferior vena cava thrombus, according to the classification of Neves et al., and degree of occlusion, according to the classification of Blute et al., were evaluated. Drug-related adverse events and perioperative complications were also investigated. Reduction in primary tumor size was observed in all cases. Two patients showed shortening of tumor thrombus, and a patient with complete occlusion of the IVC by tumor thrombus showed substantial improvement. No grade 3 or greater adverse events and no perioperative complications were observed during treatment. Axitinib may have benefits as a presurgical treatment for renal cell carcinoma patients with IVC extension.

Background and objectivesPompe disease is reportedly less prevalent in Japan than in neighbouring countries, raising a possibility that some patients may be overlooked. Therefore, all muscle biopsy samples received at our institute were screened for Pompe disease to determine the accuracy of the disease prevalence.MethodsThe acid α-glucosidase (GAA) activity was assayed using 10 µm frozen muscle sections from 2408 muscle biopsies received between July 2015 and January 2018. Genetic analysis was performed for samples with decreased activity. The number of myopathologically diagnosed patients was retrospectively assessed.ResultsThe GAA activity was distributed similarly to previous results from dried blood spot screening. GAA activity measured using muscle sections corresponded to that measured using muscle blocks. Of 163 patients with GAA activity <3 nmol/hour/mg protein, 43 (26%) patients had homozygous pseudodeficiency alleles in GAA (p.G576S and p.E689K). In the retrospective analysis, the number of patients diagnosed with Pompe disease via muscle biopsies decreased to zero over time.DiscussionMuscle pathology is an accurate method to diagnose Pompe disease. It is unlikely that a significant number of patients with Pompe disease are overlooked. Pathological variants were rare, and the majority carried a pseudodeficiency allele, which further supports our conclusion.

Lysosomal associated membrane protein 2 ( LAMP2 ) is physiologically implicated in autophagy. A genetic LAMP2 defect causes Danon disease, which consists of two major phenotypes of myopathy and cardiomyopathy. In addition, arteriopathy may manifest on rare occasions but the pathological basis remains unknown. We encountered two Danon families that developed small-vessel vasculopathy in the coronary or cerebral arteries. To investigate the underlying mechanisms, we characterized the biological features of LAMP-2–deficient mice and cultured cells. LAMP-2–deficient mice at 9–24 months of age showed medial thickening with luminal stenosis due to proliferation of vascular smooth muscle cells (VSMC) in muscular arteries. Ultrastructural analysis of VSMC revealed various autophagic vacuoles scattered throughout the cytoplasm, suggesting impaired autophagy of long-lived metabolites and degraded organelles ( i . e ., mitochondria). The VSMC in Lamp2 null mice expressed more vimentin but less α-smooth muscle actin (α-SMA), indicating a switch from contractile to synthetic phenotype. Silencing of LAMP2 in cultured human brain VSMC showed the same phenotypic transition with mitochondrial fragmentation, enhanced mitochondrial respiration, and overproduction of reactive oxygen species (ROS). These findings indicate that LAMP-2 deficiency leads to arterial medial hypertrophy with the phenotypic conversion of VSMC, resulting from age-dependent accumulation of cellular waste generated by aberrant autophagy.

Among the autophagic vacuolar myopathies (AVMs), a subgroup is characterized pathologically by unusual autophagic vacuoles with sarcolemmal features (AVSF) and includes Danon disease and X-linked myopathy with excessive autophagy. The diagnostic importance and detailed morphologic features of AVSF in different AVMs have not been well established, and the mechanism of AVSF formation is not known. To address these issues, we have performed detailed histologic studies of myopathies with AVSF and other AVMs. In Danon disease and related AVMs, at the light microscopic level, autophagic vacuoles appeared to be accumulations of lysosomes, which, by electron microscopy consisted of clusters of autophagic vacuoles, indicative of autolysosomes. Some autolysosomes were surrounded by membranes with sarcolemmal proteins, acetylcholinesterase activity, and basal lamina. In Danon disease, the number of fibers with AVSF increased linearly with age while the number with autolysosomal accumulations decreased slightly, suggesting that AVSF are produced secondarily in response to autolysosomes. Most of the AVSF form enclosed spaces, indicating that the vacuolar membranes may be formed in situ rather than through sarcolemmal indentation. This unique intracytoplasmic membrane structure was not found in other AVMs. In conclusion, AVSF with acetylcholinesterase activity are autolysosomes surrounded by secondarily generated intracytoplasmic sarcolemma-like structure and delineates a subgroup of AVMs.

Among the autophagic vacuolar myopathies (AVMs), a subgroup is characterized pathologically by unusual autophagic vacuoles with sarcolemmal features (AVSF) and includes Danon disease and X-linked myopathy with excessive autophagy. The diagnostic importance and detailed morphologic features of AVSF in different AVMs have not been well established, and the mechanism of AVSF formation is not known. To address these issues, we have performed detailed histologic studies of myopathies with AVSF and other AVMs. In Danon disease and related AVMs, at the light microscopic level, autophagic vacuoles appeared to be accumulations of lysosomes, which, by electron microscopy consisted of clusters of autophagic vacuoles, indicative of autolysosomes. Some autolysosomes were surrounded by membranes with sarcolemmal proteins, acetylcholinesterase activity, and basal lamina. In Danon disease, the number of fibers with AVSF increased linearly with age while the number with autolysosomal accumulations decreased slightly, suggesting that AVSF are produced secondarily in response to autolysosomes. Most of the AVSF form enclosed spaces, indicating that the vacuolar membranes may be formed in situ rather than through sarcolemmal indentation. This unique intracytoplasmic membrane structure was not found in other AVMs. In conclusion, AVSF with acetylcholinesterase activity are autolysosomes surrounded by secondarily generated intracytoplasmic sarcolemma-like structure and delineates a subgroup of AVMs.