Cinnamon bark extract suppresses metastatic dissemination of cancer cells through inhibition of glycolytic metabolism.

Metastasis is responsible for approximately 90% of cancer-associated mortality and proceeds through multiple steps. Several herbal medicines are reported to inhibit primary tumor growth, but the suppressor effects of the medicines on metastasis progression are still not fully elucidated. Here we report that cinnamon bark extract (CBE) has a suppressor effect on metastatic dissemination of cancer cells. Through a phenotypic screening using zebrafish embryos, CBE was identified to interfere with the gastrulation progression of zebrafish embryos, of which the molecular mechanisms are conserved in metastasis progression. A Boyden chamber assay showed that CBE decreased cell motility and invasion of MDA-MB-231 human breast cancer cells without affecting their cell viability. Furthermore, CBE suppressed metastatic dissemination of the cells in a zebrafish xenotransplantation model. Quantitative metabolome analyses revealed that the productions of glucose-6-phosphate (G6P) and fructose 6-phosphate which are intermediate metabolites of glycolytic metabolism were interrupted in CBE-treated cells. qPCR and western-blotting analyses revealed that CBE-treated cells showed decreased expression of hexokinase 2 (HK2) which yields G6P. Pharmacological inhibition of HK2 with 2-deoxy-D-glucose suppressed cell invasion and migration of the cells without affecting their cell viability. Taken together, CBE suppresses metastatic dissemination of cancer cells through inhibition of glycolysis metabolism.

Psoitis and multiple venous thromboses caused by Panton Valentine Leukocidin-positive methicillin-sensitive Staphylococcus aureus in a 12-year-old girl: A case report.

Panton Valentine Leukocidin (PVL) is one of the many toxins produced by Staphylococcus aureus. In Japan, PVL-positive S. aureus strains are mainly methicillin-resistant S. aureus (MRSA). Data regarding PVL-positive methicillin-sensitive S. aureus (MSSA) are scarce. In this report, we describe a case of severe infection by PVL-positive MSSA. A 12-year-old healthy girl was admitted with high fever and pain in the lower back. Computed tomography revealed a diagnosis of psoitis and multiple venous thromboses. Blood cultures obtained after admission revealed infection with MSSA. Her fever continued despite adequate antibiotic therapy. On the fifth hospitalization day, she developed bladder dysfunction, and an abscess was noted near the third lumbar vertebra. She underwent an emergency operation and recovered. Bacterial analyses revealed that the causative MSSA was a PVL-producing single variant of ST8 (related to USA300clone), of sequence type 2149. PVL is known to cause platelet activation. This case demonstrates the need for detailed analyses of the causative strain of bacteria in cases of S. aureus infection with deep vein thrombosis, even in cases of known MSSA infection.

Variation in bradyrhizobial NopP effector determines symbiotic incompatibility with Rj2-soybeans via effector-triggered immunity.

Genotype-specific incompatibility in legume-rhizobium symbiosis has been suggested to be controlled by effector-triggered immunity underlying pathogenic host-bacteria interactions. However, the rhizobial determinant interacting with the host resistance protein (e.g., Rj2) and the molecular mechanism of symbiotic incompatibility remain unclear. Using natural mutants of Bradyrhizobium diazoefficiens USDA 122, we identified a type III-secretory protein NopP as the determinant of symbiotic incompatibility with Rj2-soybean. The analysis of nopP mutations and variants in a culture collection reveal that three amino acid residues (R60, R67, and H173) in NopP are required for Rj2-mediated incompatibility. Complementation of rj2-soybean by the Rj2 allele confers the incompatibility induced by USDA 122-type NopP. In response to incompatible strains, Rj2-soybean plants activate defense marker gene PR-2 and suppress infection thread number at 2 days after inoculation. These results suggest that Rj2-soybeans monitor the specific variants of NopP and reject bradyrhizobial infection via effector-triggered immunity mediated by Rj2 protein.

Congenital left ventricular aneurysm coexisting with left ventricular non-compaction in a newborn.

Described herein is the case of a rare combination of congenital left ventricular (LV) aneurysm and left ventricular non-compaction (LVNC) in a newborn. The patient developed refractory heart failure soon after birth and died at 5 months of age. The etiology of both congenital LV aneurysm and LVNC seems to be maldevelopment of the ventricular myocardium during early fetal life. Treatment should be individually tailored depending on clinical severity, and treatment options are limited. Given that this combination of congenital LV aneurysm and LVNC is significantly associated with poor prognosis, it appears that patients with congenital LV aneurysm and LVNC are candidates for early, aggressive intervention, including surgical aneurysmectomy and evaluation for transplantation. It is important to be aware of this combination of congenital LV aneurysm and LVNC, and to make earlier decisions on therapeutic strategy.

A novel mutation of ribosomal protein S10 gene in a Japanese patient with diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is an inherited bone marrow disease. The condition is characterized by anemia that usually presents during infancy or early childhood and congenital malformation. Several reports show that DBA is associated with mutations in the ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7. Recently, 5 and 12 patients with mutations in RPS10 and RPS26, respectively, were identified in a cohort of 117 DBA probands. Therefore, we screened the DBA patients who were negative for mutations in these DBA genes for mutations in RPS10 and RPS26. The present case report describes the identification of the first Japanese DBA patient with a novel mutation in RPS10.

Molecular pathogenesis in Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a congenital anemia and a broad spectrum of developmental abnormalities that presents soon after birth. The anemia is due to a failure of erythropoiesis with normal platelet and myeloid lineages. Approximately 10-20% of DBA cases are inherited. Genetic studies have identified heterozygous mutations in at least one of eight ribosomal protein genes in up to 50% of cases. Mutations in RPL5 and RPL11 are at a high risk for developing malformation. Especially, mutations in RPL5 are associated with multiple physical abnormalities, including cleft lip/plate and thumb and heart anomalies. Recently, the 5q- syndrome, a subtype of myelodysplastic syndrome characterized by a defect in erythroid differentiation, is caused by a somatically acquired deletion of chromosome 5q, which results in haploinsufficiency of RPS14. These data indicate that abnormalities in ribosome function are broadly implicated in both congenital and acquired bone marrow failure syndrome in humans.

Biopsy-proven myocardial sequels in Kawasaki disease with giant coronary aneurysms.

BACKGROUND: Although most Kawasaki disease with giant coronary aneurysms is asymptomatic, conventional investigations might not identify previous lesions, or all Kawasaki disease with giant aneurysms at risk of future myocardial lesions. We evaluated the long-term histopathology of the myocardium, especially of intramural small vessels in asymptomatic Kawasaki disease with giant aneurysms. METHOD: The initial study comprised 16 consecutive Kawasaki patients - male-to-female ratio was 12:4 - aged from 2 to 12 years, and in the subsequent study, the same patients were aged from 4.9 to 16 years. Endomyocardial biopsies were histopathologically evaluated. Microangiopathies, mitochondrial abnormalities, and loss or disarray of myofibrils were compared by electron microscopy. RESULTS: The incidence of histopathological abnormalities such as degeneration, hypertrophy, and inflammatory cell infiltration was quite high in the initial study, and inflammatory cell infiltration, interstitial fibrosis, and disarray were very noticeable at follow-up biopsies. The area of fibrous tissue was significantly higher in patients administered with intravenous immunoglobulin at follow-up biopsies. Electron microscopy showed microangiopathies including microthrombi within intramural small vessels in some patients at follow-up biopsies. The sites of the coronary aneurysms did not seem to have an impact on the biopsy findings, suggesting that the underlying pathophysiology is related to the original disease process. CONCLUSIONS: Whether the abnormalities were due to direct myocardial injury, chronic ischaemia, repeated small-vessel thrombosis, or other problems associated only with biopsies, is difficult to determine. However, this subgroup had residual abnormal lesions in the myocardium. Follow-up should be more aggressive in this group of patients to identify myocardial damage that could be asymptomatic.

Mutations in the ribosomal protein genes in Japanese patients with Diamond-Blackfan anemia.

BACKGROUND: Diamond-Blackfan anemia is a rare, clinically heterogeneous, congenital red cell aplasia: 40% of patients have congenital abnormalities. Recent studies have shown that in western countries, the disease is associated with heterozygous mutations in the ribosomal protein (RP) genes in about 50% of patients. There have been no studies to determine the incidence of these mutations in Asian patients with Diamond-Blackfan anemia. DESIGN AND METHODS: We screened 49 Japanese patients with Diamond-Blackfan anemia (45 probands) for mutations in the six known genes associated with Diamond-Blackfan anemia: RPS19, RPS24, RPS17, RPL5, RPL11, and RPL35A. RPS14 was also examined due to its implied involvement in 5q- syndrome. RESULTS: Mutations in RPS19, RPL5, RPL11 and RPS17 were identified in five, four, two and one of the probands, respectively. In total, 12 (27%) of the Japanese Diamond-Blackfan anemia patients had mutations in ribosomal protein genes. No mutations were detected in RPS14, RPS24 or RPL35A. All patients with RPS19 and RPL5 mutations had physical abnormalities. Remarkably, cleft palate was seen in two patients with RPL5 mutations, and thumb anomalies were seen in six patients with an RPS19 or RPL5 mutation. In contrast, a small-for-date phenotype was seen in five patients without an RPL5 mutation. CONCLUSIONS: We observed a slightly lower frequency of mutations in the ribosomal protein genes in patients with Diamond-Blackfan anemia compared to the frequency reported in western countries. Genotype-phenotype data suggest an association between anomalies and RPS19 mutations, and a negative association between small-for-date phenotype and RPL5 mutations.

Combined therapy of enalapril and losartan attenuates histologic progression in immunoglobulin A nephropathy.

BACKGROUND: It has been reported that combined therapy of angiotensin converting enzyme inhibitor and angiotensin receptor blocker significantly decreases proteinuria in immunoglobulin A (IgA) nephropathy. However, histologic alterations following the therapy have not been reported. METHODS: A total of nine Japanese children with severe proteinuric IgA nephropathy who received a prompt immunosuppressive therapy were enrolled the study, four of whom received a combined therapy of angiotensin converting enzyme inhibitor, enalapril and angiotensin receptor blocker, losartan (Group A), while the remaining five did not (Group B). All underwent renal biopsy before and approximately 12 months after the first renal biopsy. RESULTS: At presentation, urine protein excretion and the histologic indices of mean activity index, mean chronicity index and tubulointerstitial scores did not show a statistical difference between the two groups: Group A (2.6 +/- 0.6 g/day; mean activity index, 5.0 +/- 1.0; mean chronicity index, 5.0 +/- 1.0; tubulointerstitial scores, 4.3 +/- 1.0) and Group B (2.2 +/- 0.6 g/day; mean activity index, 4.8 +/- 0.8; mean chronicity index, 4.8 +/- 1.3; tubulointerstitial scores, 3.6 +/- 0.5, respectively). All had normal blood pressure and renal function. Urine protein excretion and the activity index decreased at the second renal biopsy, while the chronicity index and the tubulointerstitial scores slightly increased or remained unchanged. In comparison with Group B, a significant suppression in increasing the chronicity index and the tubulointerstitial scores obtained at the second renal biopsy were observed in Group A [Group A: 4.3 +/- 1.2 and 3.0 +/- 0.0, respectively, vs Group B: 6.0 +/- 0.7 and 4.4 +/- 0.9, respectively (P < 0.05)]. One patient in Group B developed chronic renal insufficiency thereafter. CONCLUSIONS: Although only a small number of patients were examined, these clinical findings suggest that a combined therapy of enalapril and losartan may attenuate histologic progression in at least a proportion of patients with severe proteinuric IgA nephropathy.