Search

Introduction: Regucalcin plays a multifunctional role in the regulation of cellular function including metabolism, signaling process, and transcriptional activity in maintaining cell homeostasis. Downregulated expression or activity of regucalcin contributes to the development of malignancies in various types of human cancer. Survival of cancer patients, including metastatic prostate cancer, is prolonged with high expression of regucalcin in the tumor tissues. Methods: We elucidate whether extracellular regucalcin conquers the growth, migration, invasion, and adhesion of metastatic human prostate cancer PC-3 and DU-145 cells. Results: Extracellular regucalcin (0.1, 1, and 10 nM) of physiologic levels (1 nM at human serum) inhibited colony formation and growth of PC-3 and DU-145 cells, while it did not have an effect on cell death. Repressive effects of extracellular regucalcin on the proliferation were not exhibited by the presence of inhibitors of the cell cycle, intracellular signaling process, and transcriptional activity, suggesting that the signals of extracellular regucalcin are transmitted to block cell growth. Furthermore, extracellular regucalcin (0.1, 1, or 10 nM) inhibited migration, invasion, and adhesion of PC-3 and DU-145 cells. Mechanistically, extracellular regucalcin (10 nM) decreased the levels of various signaling proteins including Ras, posphatidylinositol-3 kinase, mitogen-activated protein kinase, mechanistic target of rapamycin, RSK-2, caveolin-1, and integrin β1 in PC-3 cells. Discussion and Conclusion: Thus, extracellular regucalcin may play a suppressive role in growth, migration, invasion, and adhesion, which are involved in the metastatic activity of human prostate cancer cells, via affecting diverse signaling processes. This study may provide a new strategy in preventing metastatic prostate cancer with exogenous regucalcin. [ABSTRACT FROM AUTHOR]

Background: Despite reports of a link between human papillomavirus (HPV) infection and mechanistic target of rapamycin (mTOR) signaling activation, the role of the mTOR pathway, especially raptor and rictor, in HPV-related head and neck cancer is still unclear. The aim of the present study was to elucidate the role of the mTOR pathway in HPV-related oropharyngeal squamous cell carcinoma (OPSCC).Methods: The present study involved two strategies. The first was to investigate the activity of mTOR and mTOR-related complexes in high-risk HPV-positive (UM-SCC47 and CaSki) and HPV-negative (SCC-4 and SAS) cancer cell lines. The second was to elucidate mTOR complex expression in 80 oropharyngeal cancer tissues and to examine the relationship between mTOR complex expression and survival in patients with OPSCC.Results: The UM-SCC47 and CaSki cell lines showed high gene and protein expression of raptor. They also exhibited G1/S and G2/M phase cell cycle arrest following 24 h incubation with 6 μM temsirolimus, a rapamycin analog, and temsirolimus administration inhibited their growth. HPV-related OPSCC samples showed high gene and protein expression of raptor and rictor compared with HPV-unrelated OPSCC. In addition, HPV-related OPSCC patients with high raptor and rictor expression tended to have a worse prognosis than those with low or medium expression.Conclusions: These results suggest that raptor and rictor have important roles in HPV-related OPSCC and that temsirolimus is a potential therapeutic agent for patients with HPV-related OPSCC. This is the first report to reveal the overexpression of raptor and rictor in HPV-related OPSCC. [ABSTRACT FROM AUTHOR]

Flavones are the most dominant type of flavonoids isolated from the roots of Scutellaria baicalensis (Radix Scutellariae), which is a traditional medicinal plant in East Asian countries, including China, Japan and Korea. Most of the flavones are derivatives with methoxyl and hydroxyl groups, and they include baicalein, baicalin, chrysin, norwogonin, oroxylin A and wogonin. Baicalein possesses anti-cancer activities against a wide spectrum of human cancer cells by inducing apoptosis and cell cycle arrest, and by inhibiting angiogenesis, metastasis and inflammation. Some examples of the effects of baicalein on apoptosis, cell cycle arrest and metastasis are presented with discussion on the molecular targets and pathways. Studies on the structure-activity relationships of flavonoid cytotoxicity towards human cancer cells show that the potent cytotoxic activities of baicalein can be attributed to its -OH groupsat C5, C6 and C7 (triple hydroxylation) of ring A, carbonyl group at C4 of ring C, and C2-C3 double bond of ring C. Studies on structural modifications of baicalein have shown that the configurations at C6 of ring A are critical factors influencing its anti-proliferative activity. Considering the remarkable anti-cancer properties, the future prospects for developing baicalein into an anti-cancer drug are promising. [ABSTRACT FROM AUTHOR]

SUMMARY A new species of benthic marine dinoflagellate, Pyramidodinium spinulosum Horiguchi, Moriya, Pinto & Terada is described from the deep (36 m) seafloor off Mageshima Island, Kagoshima Prefecture, Japan in the subtropical region of the northwest Pacific. The life cycle of the dinoflagellate consists of a dominant, attached, dome-shaped, vegetative form and short-lasting, motile cell. Asexual reproduction takes place by the formation of two motile cells within each non-motile cell. The released motile cells swim only for a short period and transform directly into the dome-shaped vegetative form. The duration of the cell cycle varies and can be extremely long, ranging 5-38 days under culture conditions. The non-motile cell is enclosed by a cell wall and its surface is covered with many (80 -130) spines of various length. The dinoflagellate is photosynthetic and contains many (more than 50) discoidal chloroplasts. Phylogenetic analysis reveals that the dinoflagellate is closely related to the type species of the genus Pyramidodinium, P. atrofuscum which also possesses a dominant, attached, non-motile form. However, P. spinulosum can be clearly distinguished from P. atrofuscum by the cell shape (dome-shaped vs. pyramid-shaped) and surface ornamentation (spines vs. wart-like processes) of the non-motile form. Based on these morphological differences together with molecular evidence, it was concluded that this organism from a deep water sand sample should be described as a second species of the genus Pyramidodinium, P. spinulosum. [ABSTRACT FROM AUTHOR]

The ichthyotoxic genus Pseudochattonella forms recurrent extensive blooms in coastal waters in Japan, New Zealand and Northern Europe. It comprises of two morphologically similar species, P. verruculosa and P. farcimen, which complicates visual species identification and enumeration of live and fixed material. Primers designed previously could not quantitatively distinguish species in mixed assemblages. To address this issue we developed two primer sets: one revealed itself to be genus specific for Pseudochattonella and the other species-specific for P. verruculosa. By subtracting cell estimates for P. verruculosa from combined results we could calculate cell numbers for P. farcimen. This approach has overcome the challenges posed by the very limited sequence availability and low gene variability between the two species. The qPCR assay was extensively tested for specificity, efficiency and sensitivity over an entire growth cycle in both single and mixed assemblages. Comparison of cell abundance estimates obtained by qPCR assay and microscopy showed no statistically significant difference until stationary and death phases. The assay was also tested on environmental samples collected during a small Pseudochattonella bloom in Denmark in March-April 2015. It was impossible to distinguish P. farcimen and P. verruculosa by light microscopy but qPCR showed both species were present. The two methods provided nearly identical cell numbers but the assay provided discrimination and enumeration of both species. [ABSTRACT FROM AUTHOR]

The article reports on the developments at the International Symposium on "Ran and the Cell Cycle," on October 2-5, 2005, in Awaji Yumebutai, Japan. Topics discussed include: a historical perspective on the development of the Ran field; Ran-associated proteins in the cell cycle; and a comprehensive systems biology analysis of the nuclear protein import pathway.

Tubular response, including phenotypic changes against a variety of injuries, is an initial event that promotes tubulointerstitial injuries. Using the progressive kidney disease model of rat adriamycin (ADR) nephrosis, the present study focused on the cell cycle activation and phenotypic changes that occur in the tubuli in early tubulointerstitial injury in ADR nephrosis. At 12 weeks, experimental animals developed overt nephrosis with tubulointerstitial injury, which correlated well with the degree of proteinuria and incidence of glomerulosclerosis. Initial pathology of the tubuli showed a slight dilatation of tubuli, which tended to occur in individual nephrons. Immunohistochemistry demonstrated that vimentin-positive tubuli and osteopontin (OPN)-positive tubuli were associated mostly with proliferating cell nuclear antigen expression. Protein levels of OPN in the renal cortex were correlated with the level of proteinuria by western blotting. Vimentin- and OPN-expressing tubuli were tightly associated with a peritubular influx of α-smooth muscle actin (SMA)-positive cells or ED-1-positive cells. In addition, we found thrombomodulin+ / TUNEL+ (dUTP-biotin nick-end labeling) peritubular endothelial cells and ED-1+ /α-SMA+ cells at an early stage among interstitial inflammatory cells. These results suggest that cell cycle activation in tubular cells forms the background for the phenotypic tubular changes that are involved in chronic tubulointerstitial injury in ADR nephrosis. [ABSTRACT FROM AUTHOR]

The article focuses on the evaluation of infraspecific differences in Cytotella comta populations in the Fuji five lakes and lake Ashino-Ko in Japan. The populations in Lake Shoji-ko in spring, those in Lakes Shoji-ko in early summer and Sai-ko, and those in the other lakes are distinguished from each other by the morphological appearance. Two populations in spring in both Lakes Yamanaka-ko and Ashino-ko are sympatric and they differ in the cycle of reproduction. The differences in the cell types among lakes and the operation of an annual cell cycle could be identified morphologically in the natural population.

Anaplastic lymphoma kinase (ALK), a receptor-type tyrosine kinase, is involved in the pathogenesis of several cancers. ALK has been targeted with small molecule inhibitors for the treatment of different cancers, but absolute success remains elusive. In the present study, the effects of ALK inhibitors on M phase progression were evaluated. Crizotinib, ceritinib, and TAE684 suppressed proliferation of neuroblastoma SH-SY5Y cells in a concentration-dependent manner. At approximate IC50 concentrations, these inhibitors caused misorientation of spindles, misalignment of chromosomes and reduction in autophosphorylation. Similarly, knockdown of ALK caused M phase delay, which was rescued by re-expression of ALK. Time-lapse imaging revealed that anaphase onset was delayed. The monopolar spindle 1 (MPS1) inhibitor, AZ3146, and MAD2 knockdown led to a release from inhibitor-induced M phase delay, suggesting that spindle assembly checkpoint may be activated in ALK-inhibited cells. H2228 human lung carcinoma cells that express EML4-ALK fusion showed M phase delay in the presence of TAE684 at about IC50 concentrations. These results suggest that ALK plays a role in M phase regulation and ALK inhibition may contribute to the suppression of cell proliferation in ALK-expressing cancer cells. [ABSTRACT FROM AUTHOR]

Background: Despite reports of a link between human papillomavirus (HPV) infection and mechanistic target of rapamycin (mTOR) signaling activation, the role of the mTOR pathway, especially raptor and rictor, in HPV-related head and neck cancer is still unclear. The aim of the present study was to elucidate the role of the mTOR pathway in HPV-related oropharyngeal squamous cell carcinoma (OPSCC)., Methods: The present study involved two strategies. The first was to investigate the activity of mTOR and mTOR-related complexes in high-risk HPV-positive (UM-SCC47 and CaSki) and HPV-negative (SCC-4 and SAS) cancer cell lines. The second was to elucidate mTOR complex expression in 80 oropharyngeal cancer tissues and to examine the relationship between mTOR complex expression and survival in patients with OPSCC., Results: The UM-SCC47 and CaSki cell lines showed high gene and protein expression of raptor. They also exhibited G1/S and G2/M phase cell cycle arrest following 24 h incubation with 6 μM temsirolimus, a rapamycin analog, and temsirolimus administration inhibited their growth. HPV-related OPSCC samples showed high gene and protein expression of raptor and rictor compared with HPV-unrelated OPSCC. In addition, HPV-related OPSCC patients with high raptor and rictor expression tended to have a worse prognosis than those with low or medium expression., Conclusions: These results suggest that raptor and rictor have important roles in HPV-related OPSCC and that temsirolimus is a potential therapeutic agent for patients with HPV-related OPSCC. This is the first report to reveal the overexpression of raptor and rictor in HPV-related OPSCC.

Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS-PDC) is a disappearing neurodegenerative disorder of apparent environmental origin formerly hyperendemic among Chamorros of Guam-USA, Japanese residents of the Kii Peninsula, Honshu Island, Japan and Auyu-Jakai linguistic groups of Papua-Indonesia on the island of New Guinea. The most plausible etiology is exposure to genotoxins in seed of neurotoxic cycad plants formerly used for food and/or medicine. Primary suspicion falls on methylazoxymethanol (MAM), the aglycone of cycasin and on the non-protein amino acid β-N-methylamino-L-alanine, both of which are metabolized to formaldehyde. Human and animal studies suggest: (a) exposures occurred early in life and sometimes during late fetal brain development, (b) clinical expression of neurodegenerative disease appeared years or decades later, and (c) pathological changes in various tissues indicate the disease was not confined to the CNS. Experimental evidence points to toxic molecular mechanisms involving DNA damage, epigenetic changes, transcriptional mutagenesis, neuronal cell-cycle reactivation and perturbation of the ubiquitin-proteasome system that led to polyproteinopathy and culminated in neuronal degeneration. Lessons learned from research on ALS-PDC include: (a) familial disease may reflect common toxic exposures across generations, (b) primary disease prevention follows cessation of exposure to culpable environmental triggers; and (c) disease latency provides a prolonged period during which to intervene therapeutically. Exposure to genotoxic chemicals ("slow toxins") in the early stages of life should be considered in the search for the etiology of ALS-PDC-related neurodegenerative disorders, including sporadic forms of ALS, progressive supranuclear palsy and Alzheimer's disease., (Copyright © 2020. Published by Elsevier B.V.)

Saccular intracranial aneurysms are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with approximately 832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (OR) = 1.22, P = 1.1 x 10(-12)), STARD13-KL on 13q13.1 (OR = 1.20, P = 2.5 x 10(-9)) and a gene-rich region on 10q24.32 (OR = 1.29, P = 1.2 x 10(-9)). We also confirmed prior associations near SOX17 (8q11.23-q12.1; OR = 1.28, P = 1.3 x 10(-12)) and CDKN2A-CDKN2B (9p21.3; OR = 1.31, P = 1.5 x 10(-22)). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting the proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair.

Background: DNA topoisomerase II alpha (topo II alpha) is associated with active cell proliferation of mammalian cells. Topo II alpha overexpression has been reported in a number of human malignancies and is considered to be related to their biological behaviors., Materials and Methods: We examined the expression of topo II alpha immunohistochemically in 136 cases of human esophageal squamous cell carcinoma, 10 foci of squamous dysplasia and 10 non-pathologic squamous epithelium. We calculated the labeling index (LI) or the percentage of immunopositive cells for Topo II alpha and Ki67, and Topo II alpha LI/Ki67 LI (T/K ratio). These findings were then correlated with clinicopathological features of the patients including their clinical outcome., Results: Both topo II alpha and Ki67 immunoreactivity were detected in the nuclei. A significant positive correlation was obtained between Topo II alpha and Ki67 LIs in all the specimens examined. Topo II alpha LI and T/K ratio were 24.5 +/- 8.0% and 1.04 +/- 0.64 for carcinoma, 19.1 +/- 15.2% and 0.68 +/- 0.29 for dysplasia and 14.0 +/- 14.1% and 0.55 +/- 0.17 for non-pathologic epithelium, respectively. Topo II alpha LI and T/K ratio in carcinoma cases were significantly higher than those of normal epithelium. Topo II alpha LI alone did not correlate with any of clinicopathological parameters examined but among carcinoma cases, cases with lymph nodes metastasis or higher histological stages had significantly higher T/K ratio than those without lymph node metastasis or lower histological stages. In addition, carcinoma cases with T/K ratio of greater than 0.8 demonstrated significantly worse prognosis than those with T/K ratio of smaller than 0.8., Conclusions: The relative overexpression of topo II alpha as compared with Ki67, i.e., increased T/K ratio was detected in esophageal squamous cell carcinoma and is considered to represent a dysregulation or qualitative alteration in topo II alpha, possibly associated with malignances, as reported in other human cancers. In addition, topo II alpha overexpression may also be correlated with the aggressive biological behavior of the patients with esophageal squamous cell carcinoma.

The morphologic characteristics of the mitotic figures present in intestinal metaplasia (IM) of the gastric mucosa were investigated in 70 consecutive gastrectomy specimens from Japanese nationals. The specimens contained, in addition, early gastric cancer of intestinal type (n = 44) or of diffuse type (n = 22). The remaining 4 were recorded as mixed. One hundred or more consecutive mitoses/specimens were studied by high-power microscopy in hematoxylin and eosin-stained preparations (at x1000). A total of 7259 mitoses were recorded (mean 103.7 mitoses/case). Of these, 1089 mitoses (i.e. 19.1%) were considered as atypical according to a previous classification. The percentage of atypical mitoses was found to be unrelated to the gender, to the increasing age of the patients, to the histologic type of the adenocarcinoma contained in the specimens, or to the anatomic site (e.g. corpus or antrum or tumor proximity). Comparative studies were done with gastrectomy specimens from Swedish nationals (a population with a 4-times-lower incidence of gastric carcinoma than the Japanese). The results showed a much lower frequency of mitotic figures/specimen and only occasional atypical mitosis. Since atypical mitosis has so far been reported only for neoplastic lesions in the gastrointestinal tract, it is suggested that IM with atypical mitosis may be a genuine precancerous lesion in the gastric mucosa in Japanese subjects.