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  • Author or Editor: Jeffery D. Kocsis x
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Shunya Ohtaki, Masahiko Wanibuchi, Yuko Kataoka-Sasaki, Masanori Sasaki, Shinichi Oka, Shouhei Noshiro, Yukinori Akiyama, Takeshi Mikami, Nobuhiro Mikuni, Jeffery D. Kocsis and Osamu Honmou

OBJECTIVE

Glioma is a major class of brain tumors, and glioblastoma (GBM) is the most aggressive and malignant type. The nature of tumor invasion makes surgical removal difficult, which results in remote recurrence. The present study focused on glioma invasion and investigated the expression of actin, alpha cardiac muscle 1 (ACTC1), which is 1 of 6 actin families implicated in cell motility.

METHODS

mRNA expression of ACTC1 expression was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR) in 47 formalin-fixed, paraffin-embedded glioma tissues that were graded according to WHO criteria: Grade I (n = 4); Grade II (n = 12); Grade III (n = 6); and Grade IV (n = 25). Survival was analyzed using the Kaplan-Meier method. The relationships between ACTC1 expression and clinical features such as radiological findings at the time of diagnosis and recurrence, patient age, Karnofsky Performance Scale status (KPS), and the MIB-1 index were evaluated.

RESULTS

The incidence of ACTC1 expression as a qualitative assessment gradually increased according to WHO grade. The hazard ratio for the median overall survival (mOS) of the patients with ACTC1-positive high-grade gliomas as compared with the ACTC1-negative group was 2.96 (95% CI, 1.03–8.56). The mOS was 6.28 years in the ACTC1-negative group and 1.26 years in the positive group (p = 0.037). In GBM patients, the hazard ratio for mOS in the ACTC1-positive GBMs as compared with the ACTC1-negative group was 2.86 (95% CI 0.97–8.45). mOS was 3.20 years for patients with ACTC1-negative GBMs and 1.08 years for patients with ACTC1-positive GBMs (p = 0.048). By the radiological findings, 42.9% of ACTC1-positive GBM patients demonstrated invasion toward the contralateral cerebral hemisphere at the time of diagnosis, although no invasion was observed in ACTC1-negative GBM patients (p = 0.013). The recurrence rate of GBM was 87.5% in the ACTC1-positive group; in contrast, none of the ACTC1-negative patients demonstrated distant recurrence (0.007). No remarkable relationship was demonstrated among ACTC1 expression and patient age, KPS, and the MIB-1 index.

CONCLUSIONS

ACTC1 may serve as a novel independent prognostic and invasion marker in GBM.

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Takuro Sakai, Masanori Sasaki, Yuko Kataoka-Sasaki, Shinichi Oka, Masahito Nakazaki, Shinobu Fukumura, Masaki Kobayashi, Hiroyuki Tsutsumi, Jeffery D. Kocsis and Osamu Honmou

The authors intravenously infused mesenchymal stem cells (MSCs) into a rat model of neonatal hypoxia-ischemia and found improvements in functional outcome, increased brain volume, and enhanced synaptogenesis. The results of this animal study suggest that the intravenous administration of MSCs should be further explored as a potential treatment for patients suffering from cerebral palsy after hypoxic-ischemic encephalopathy.

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Ai Namioka, Takahiro Namioka, Masanori Sasaki, Yuko Kataoka-Sasaki, Shinichi Oka, Masahito Nakazaki, Rie Onodera, Junpei Suzuki, Yuichi Sasaki, Hiroshi Nagahama, Jeffery D. Kocsis and Osamu Honmou

OBJECTIVE

Morbidity and mortality in patients with posterior circulation stroke remains an issue despite advances in acute stroke therapies. The intravenous infusion of mesenchymal stem cells (MSCs) elicits therapeutic efficacy in experimental supratentorial stroke models. However, since there are few reliable animal models of ischemia in the posterior circulation, the therapeutic approach with intravenous MSC infusion has not been tested. The objective of this study was to test the hypothesis that intravenously infused MSCs provide functional recovery in a newly developed model of brainstem infarction in rats.

METHODS

Basilar artery (BA) occlusion (BAO) was established in rats by selectively ligating 4 points of the proximal BA with 10-0 nylon monofilament suture. The intravenous infusion of MSCs was performed 1 day after BAO induction. MRI and histological examinations were performed to assess ischemic lesion volume, while multiple behavioral tests were performed to evaluate functional recovery.

RESULTS

The MSC-treated group exhibited a greater reduction in ischemic lesion volume, while behavioral testing indicated that the MSC-infused group had greater improvement than the vehicle group 28 days after the MSC infusion. Accumulated infused MSCs were observed in the ischemic brainstem lesion.

CONCLUSIONS

Infused MSCs may provide neuroprotection to facilitate functional outcomes and reduce ischemic lesion volume as evaluated in a newly developed rat model of persistent BAO.

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Takahiro Namioka, Ai Namioka, Masanori Sasaki, Yuko Kataoka-Sasaki, Shinichi Oka, Masahito Nakazaki, Rie Onodera, Junpei Suzuki, Yuichi Sasaki, Hiroshi Nagahama, Jeffery D. Kocsis and Osamu Honmou

OBJECTIVE

Intravenous infusion of mesenchymal stem cells (MSCs) derived from adult bone marrow improves behavioral function in rat models of cerebral infarction. Although clinical studies are ongoing, most studies have focused on the acute or subacute phase of stroke. In the present study, MSCs derived from bone marrow of rats were intravenously infused 8 weeks after the induction of a middle cerebral artery occlusion (MCAO) to investigate whether delayed systemic injection of MSCs improves functional outcome in the chronic phase of stroke in rats.

METHODS

Eight weeks after induction of the MCAO, the rats were randomized and intravenously infused with either MSCs or vehicle. Ischemic volume and behavioral performance were examined. Blood-brain barrier (BBB) integrity was assessed by quantifying the leakage of Evans blue into the brain parenchyma after intravenous infusion. Immunohistochemical analysis was also performed to evaluate the stability of the BBB.

RESULTS

Motor recovery was better in the MSC-treated group than in the vehicle-treated group, with rapid improvement (evident at 1 week post-infusion). In MSC-treated rats, reduced BBB leakage and increased microvasculature/repair and neovascularization were observed.

CONCLUSIONS

These results indicate that the systemic infusion of MSCs results in functional improvement, which is associated with structural changes in the chronic phase of cerebral infarction, including in the stabilization of the BBB.

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Masahito Nakazaki, Masanori Sasaki, Yuko Kataoka-Sasaki, Shinichi Oka, Takahiro Namioka, Ai Namioka, Rie Onodera, Junpei Suzuki, Yuichi Sasaki, Hiroshi Nagahama, Takeshi Mikami, Masahiko Wanibuchi, Jeffery D. Kocsis and Osamu Honmou

OBJECTIVE

Reperfusion therapy with intravenous recombinant tissue plasminogen activator (rtPA) is the standard of care for acute ischemic stroke. However, hemorrhagic complications can result. Intravenous infusion of mesenchymal stem cells (MSCs) reduces stroke volume and improves behavioral function in experimental stroke models. One suggested therapeutic mechanism is inhibition of vascular endothelial dysfunction. The objective of this study was to determine whether MSCs suppress hemorrhagic events after rtPA therapy in the acute phase of transient middle cerebral artery occlusion (tMCAO) in rats.

METHODS

After induction of tMCAO, 4 groups were studied: 1) normal saline [NS]+vehicle, 2) rtPA+vehicle, 3) NS+MSCs, and 4) rtPA+MSCs. The incidence rate of intracerebral hemorrhage, both hemorrhagic and ischemic volume, and behavioral performance were examined. Matrix metalloproteinase–9 (MMP-9) levels in the brain were assessed with zymography. Quantitative analysis of regional cerebral blood flow (rCBF) was performed to assess hemodynamic change in the ischemic lesion.

RESULTS

The MSC-treated groups (Groups 3 and 4) experienced a greater reduction in the incidence rate of intracerebral hemorrhage and hemorrhagic volume 1 day after tMCAO even if rtPA was received. The application of rtPA enhanced activation of MMP-9, but MSCs inhibited MMP-9 activation. Behavioral testing indicated that both MSC-infused groups had greater improvement than non-MSC groups had, but rtPA+MSCs provided greater improvement than MSCs alone. The rCBF ratio of rtPA groups (Groups 2 and 4) was similar at 2 hours after reperfusion of tMCAO, but both were greater than that in non-rtPA groups.

CONCLUSIONS

Infused MSCs may inhibit endothelial dysfunction to suppress hemorrhagic events and facilitate functional outcome. Combined therapy of infused MSCs after rtPA therapy facilitated early behavioral recovery.