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52.
Shigeru Yamaguchi Shunsuke Terasaka Hiroyuki Kobayashi Katsuyuki Asaoka Hiroaki Motegi Hiroshi Nishihara Hiromi Kanno Rikiya Onimaru Yoichi M. Ito Hiroki Shirato Kiyohiro Houkin 《PloS one》2014,9(5)
Background
Radiotherapy for high-grade meningioma (HGM) is one of the essential treatment options for disease control. However, appropriate irradiation timing remains under debate. The object of this study is to discern which prognostic factors impact recurrence in HGM patients and to propose a risk-stratification system for the application of postoperative radiotherapy.Methods
We retrospectively reviewed 55 adult patients who were diagnosed with Grade II and III intracranial meningioma. Cox regression models were applied to the analysis for impact on early recurrence in HGM patients without postoperative radiotherapy.Results
Grade III malignancy (P = 0.0073) and transformed histology (P = 0.047) proved to be significantly poor prognostic factors of early recurrence by multivariate analysis. The other candidates for recurrence factors were Simpson Grade 3–5 resection, preoperative Karnofsky Performance status < = 70%, and MIB-1 labeling index > = 15%. According to these prognostic factors, postoperative HGM patients could be stratified into three recurrence-risk groups. The prognoses were significantly different between each group, as the 3-year actual recurrence-free rates were 90% in low-risk group, 31% in intermediate-risk group, and 15% in high-risk group.Conclusion
We propose recurrence-risk stratification for postoperative HGM patients using clinically available factors. Our results suggest that the prognosis for patients with high-risk HGMs is dismal, whereas HGM patients belonging to the low-risk group could have favorable prognoses. This stratification provides us with the criteria necessary to determine whether to apply adjuvant radiotherapy to postoperative HGM patients, and to also help identify potentially curable HGMs without adjuvant radiotherapy. 相似文献53.
Tomohiro Yamauchi Yasumasa Kuroda Takahiro Morita Hideo Shichinohe Kiyohiro Houkin Mari Dezawa Satoshi Kuroda 《PloS one》2015,10(3)
Objective
Bone marrow stromal cells (BMSCs) are heterogeneous and their therapeutic effect is pleiotropic. Multilineage-differentiating stress enduring (Muse) cells are recently identified to comprise several percentages of BMSCs, being able to differentiate into triploblastic lineages including neuronal cells and act as tissue repair cells. This study was aimed to clarify how Muse and non-Muse cells in BMSCs contribute to functional recovery after ischemic stroke.Methods
Human BMSCs were separated into stage specific embryonic antigen-3-positive Muse cells and -negative non-Muse cells. Immunodeficient mice were subjected to permanent middle cerebral artery occlusion and received transplantation of vehicle, Muse, non-Muse or BMSCs (2.5×104 cells) into the ipsilateral striatum 7 days later.Results
Motor function recovery in BMSC and non-Muse groups became apparent at 21 days after transplantation, but reached the plateau thereafter. In Muse group, functional recovery was not observed for up to 28 days post-transplantation, but became apparent at 35 days post-transplantation. On immunohistochemistry, only Muse cells were integrated into peri-infarct cortex and differentiate into Tuj-1- and NeuN-expressing cells, while negligible number of BMSCs and non-Muse cells remained in the peri-infarct area at 42 days post-transplantation.Conclusions
These findings strongly suggest that Muse cells and non-Muse cells may contribute differently to tissue regeneration and functional recovery. Muse cells may be more responsible for replacement of the lost neurons through their integration into the peri-infarct cortex and spontaneous differentiation into neuronal marker-positive cells. Non-Muse cells do not remain in the host brain and may exhibit trophic effects rather than cell replacement. 相似文献54.
Shigenori Nagatomo Yukifumi Nagai Yayoi Aki Hiroshi Sakurai Kiyohiro Imai Naoki Mizusawa Takashi Ogura Teizo Kitagawa Masako Nagai 《PloS one》2015,10(8)
Human hemoglobin (Hb), which is an α2β2 tetramer and binds four O2 molecules, changes its O2-affinity from low to high as an increase of bound O2, that is characterized by ‘cooperativity’. This property is indispensable for its function of O2 transfer from a lung to tissues and is accounted for in terms of T/R quaternary structure change, assuming the presence of a strain on the Fe-histidine (His) bond in the T state caused by the formation of hydrogen bonds at the subunit interfaces. However, the difference between the α and β subunits has been neglected. To investigate the different roles of the Fe-His(F8) bonds in the α and β subunits, we investigated cavity mutant Hbs in which the Fe-His(F8) in either α or β subunits was replaced by Fe-imidazole and F8-glycine. Thus, in cavity mutant Hbs, the movement of Fe upon O2-binding is detached from the movement of the F-helix, which is supposed to play a role of communication. Recombinant Hb (rHb)(αH87G), in which only the Fe-His in the α subunits is replaced by Fe-imidazole, showed a biphasic O2-binding with no cooperativity, indicating the coexistence of two independent hemes with different O2-affinities. In contrast, rHb(βH92G), in which only the Fe-His in the β subunits is replaced by Fe-imidazole, gave a simple high-affinity O2-binding curve with no cooperativity. Resonance Raman, 1H NMR, and near-UV circular dichroism measurements revealed that the quaternary structure change did not occur upon O2-binding to rHb(αH87G), but it did partially occur with O2-binding to rHb(βH92G). The quaternary structure of rHb(αH87G) appears to be frozen in T while its tertiary structure is changeable. Thus, the absence of the Fe-His bond in the α subunit inhibits the T to R quaternary structure change upon O2-binding, but its absence in the β subunit simply enhances the O2-affinity of α subunit. 相似文献
55.
Kiyama R Fukudome K Hiyoshi T Umemoto A Yoshimoto Y Maeda T 《Journal of applied biomechanics》2011,27(2):122-129
The aim of this study was to examine the dexterity of both lower extremities in patients with stroke. Twenty patients with stroke and 20 age-matched control subjects participated in this study. To determine the dexterity of the lower extremities, we examined the ability to control muscle force during submaximal contractions in the knee extensor muscles using a force tracking task. The root mean square errors were calculated from the difference between the target and response force. The root mean square error was significantly greater in the affected limb of patients with stroke compared with those of the unaffected limb and the control subjects, and in the unaffected limb compared with that of the control subjects. Furthermore, the root mean square error of the affected limb was related significantly to motor function as determined by Fugl-Myer assessment. These results demonstrate impairment of the dexterity of both the affected and the unaffected lower extremities in patients with stroke. 相似文献
56.
Masataka Horiuchi Kosei Takeuchi Nobuo Noda Nobuyuki Muroya Toru Suzuki Takahisa Nakamura Junko Kawamura-Tsuzuku Kiyohiro Takahasi Tadashi Yamamoto Fuyuhiko Inagaki 《The Journal of biological chemistry》2009,284(19):13244-13255
The Tob/BTG family is a group of antiproliferative proteins containing two
highly homologous regions, Box A and Box B. These proteins all associate with
CCR4-associated factor 1 (Caf1), which belongs to the ribonuclease D (RNase D)
family of deadenylases and is a component of the CCR4-Not deadenylase complex.
Here we determined the crystal structure of the complex of the N-terminal
region of Tob and human Caf1 (hCaf1). Tob exhibited a novel fold, whereas
hCaf1 most closely resembled the catalytic domain of yeast Pop2 and human
poly(A)-specific ribonuclease. Interestingly, the association of hCaf1 was
mediated by both Box A and Box B of Tob. Cell growth assays using both
wild-type and mutant proteins revealed that deadenylase activity of Caf1 is
not critical but complex formation is crucial to cell growth inhibition. Caf1
tethers Tob to the CCR4-Not deadenylase complex, and thereby Tob gathers
several factors at its C-terminal region, such as poly(A)-binding proteins, to
exert antiproliferative activity.The Tob/BTG family (also called the APRO family) is a group of
antiproliferative proteins (1,
2) consisting of Tob
(3), Tob2
(4), BTG1
(5), BTG2/Tis21/PC3
(6-8),
PC3B (9), and ANA/BTG3
(10,
11) in mammalian cells,
in Drosophila, and FOG-3 in Caenorhabditis elegans
( AF17746412). A recent genome project
reported that the BTG/Tob family protein had already existed in
Choanoflagellida Monosiga brevicollis MX1. The N-terminal region of
the Tob/BTG family proteins is conserved and includes two highly homologous
regions, Box A and Box B. The Tob/BTG family proteins are involved in cell
cycle regulation in a variety of cells such as T lymphocytes, fibroblasts,
epithelial cells, and germ cells. In Tob-deficient mice, the incidence of
liver tumors is higher than in wild-type mice. Furthermore, because the levels
of tob expression are often repressed in human lung cancers,
suppression of its expression is thought to contribute to tumor progression
(13).The antiproliferative activities of the Tob/BTG family proteins are due to
their association with target proteins in cells. For example, Tob associates
with SMAD family proteins and acts as a negative regulator of SMAD signaling.
In osteoblasts, this negative regulation occurs via association with SMAD 1,
5, 6, and 8 (14,
15), and via association with
SMAD 2 and 4 in anergic quiescent T cells
(16). Tob/BTG family proteins
also bind to protein arginine methyltransferase, which regulates chromatin
assembly by histone methylation
(17). Much evidence has been
accumulated to suggest that CCR4-associated factor 1
(Caf1),2 also known as
Cnot7 and involved in the CCR4-Not deadenylase complex, is a common binding
partner of the Tob/BTG family proteins
(4,
18-21).
To reveal the functions of Caf1 in vivo, caf1-/- mice have
been generated in two groups. Male caf1-deficient mice are infertile
because of a malfunction of the testicular somatic cells that leads to a
defect in spermatogenesis (22,
23). Genetic analysis of the
nematode C. elegans also suggests that FOG3 (Tob orthologue)
interacts with CCF1, the C. elegans homologue of Caf1, and that this
interaction is essential for germ cells to initiate spermatogenesis
(24).Mouse and human Caf1 (mCaf1 and hCaf1) were found as homologues of yeast
Pop2, a component of the CCR4-Not complex
(18,
25). Yeast Pop2 displays weak
RNase activity but enhances the deadenylation of the poly(A) tail of mRNA by
the CCR4-Not deadenylase complex
(26-29).
The primary structure of mammalian Caf1 is related to that of the ribonuclease
D (RNase D) family, and all of the active site residues are well conserved
(30). Indeed, both mCaf1 and
hCaf1 have deadenylase activity
(31-33).Although the relationship between cell cycle repression and poly(A)
deadenylation is not well understood, mRNA degradation and synthesis are major
events in maintaining the cell cycle
(34). The mRNAs in a
eukaryotic cell have a wide range of half-lives. Degradation of mRNA is
initiated by shortening of the poly(A) tail. Thereafter, the 5′-cap
structure is removed and the remaining portion of the mRNA is rapidly
degraded. The degradation of eukaryotic mRNAs is regulated precisely at each
stage of the cell cycle. Tob was reported to associate with inducible
poly(A)-binding protein (iPABP) and to abrogate the translation of
interleukin-2 mRNA in vitro
(35). Recent reports also
showed that Tob and BTG2 interact with the CCR4-Not deadenylase complex using
the Tob/BTG2 domain and the cytoplasmic poly(A)-binding protein (PABPC1) using
the C-terminal tail and enhanced mRNA degradation
(36-38).To help elucidate the relationship between the antiproliferative activity
of Tob and the degradation of the poly(A) tail, we determined the crystal
structure of the Tob-hCaf1 complex. We found that hCaf1 has a structure
similar to yeast Pop2 and human PARN of deadenylases, exonuclease I, and the
Klenow fragment of DNA polymerase I from Escherichia coli. In
contrast, Tob has a novel structure. Specifically, Box A and Box B mediate the
interaction between Tob and hCaf1. Cell growth assays using the wild and
mutant proteins, together with the structural studies, revealed that the
complex formation is crucial to cell growth inhibition. 相似文献
57.
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59.
The Monod-Wyman-Changeux allosteric model parameters evaluated from accurate oxygen equilibrium curves (OECs) of hemoglobin that were measured in an extremely wide range of structural constraints, imposed by allosteric effectors, yielded a closed circle when log K(T) and log K(R) were plotted against log L(0) and log L(4), respectively, showing novel phenomena that L(0) and L(4) have a maximal value and a minimal value, respectively, and K(T) and K(R) vary by more than three orders of magnitude. These phenomena were successfully described by a global allostery model, which mathematically keeps the frame work of the MWC model, but allows that K(T) under a set of solution conditions becomes larger than K(R) under another set of solution conditions and postulates that a representative allosteric effector binds to both the T and R states with a lower affinity but with a larger stoichiometry for the R state than for the T state. Thus, this global model can describe any given OEC measured under universal solution conditions with the single adjustable parameter, the concentration of the representative effector. 相似文献
60.
Tsushima S Kai M Yamada K Imai S Houkin K Kanoh H Sakane F 《The Journal of biological chemistry》2004,279(27):28603-28613
Nine diacylglycerol kinase (DGK) isozymes have been identified. However, our knowledge of their individual functions is still limited. Here, we demonstrate the role of DGKgamma in regulating Rac1-governed cell morphology. We found that the expression of kinase-dead DGKgamma, which acts as a dominant-negative mutant, and inhibition of endogenous DGKgamma activity with R59949 induced lamellipodium and membrane ruffle formation in NIH3T3 fibroblasts in the absence of growth factor stimulation. Reciprocally, lamellipodium formation induced by platelet-derived growth factor was significantly inhibited upon expression of constitutively active DGKgamma. Moreover, the constitutively active DGKgamma mutant suppressed integrin-mediated cell spreading. These effects are isoform-specific because, in the same experiments, none of the corresponding mutants of DGKalpha and DGKbeta, closely related isoforms, affected cell morphology. These results suggest that DGKgamma specifically participates in the Rac1-mediated signaling pathway leading to cytoskeletal reorganization. In support of this, DGKgamma co-localized with dominant-active Rac1 especially in lamellipodia. Moreover, we found that endogenous DGKgamma was physically associated with cellular Rac1. Dominant-negative Rac1 expression blocked the lamellipodium formation induced by kinase-dead DGKgamma, indicating that DGKgamma acts upstream of Rac1. This model is supported by studies demonstrating that kinase-dead DGKgamma selectively activated Rac1, but not Cdc42. Taken together, these results strongly suggest that DGKgamma functions through its catalytic action as an upstream suppressor of Rac1 and, consequently, lamellipodium/ruffle formation. 相似文献