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Articles by T Morita
Total Records ( 5 ) for T Morita
  M Tada , A Kakita , Y Toyoshima , O Onodera , T Ozawa , T Morita , M Nishizawa and H. Takahashi
 

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by prominent autonomic failure with ataxia and/or parkinsonism. The leading cause of death in MSA is sudden death. We have shown that the early development of autonomic failure is an independent risk factor for sudden death. The depletion of sympathetic preganglionic neurons in the spinal intermediolateral cell column (IML) and its afferent medullary catecholaminergic and serotonergic neurons has been proposed to be partly responsible for autonomic failure in MSA. In this study, we investigated whether the depletion of neurons in any of these autonomic neuron groups contributes to sudden death in MSA. Out of 52 autopsy-proven patients with MSA, we selected 12 individuals who had died within 3.5 years after disease onset to define the accurate levels of slices and identify early neuropathological changes of autonomic nuclei in MSA. Four patients succumbed to sudden death and eight patients died through established causes. Serial 10 µm sections were obtained from the 8th segment of the thoracic cord and the rostral medulla oblongata. Sections from the medulla oblongata were immunostained for thyrosine hydroxylase and tryptophan hydroxylase. The total cell number in the five sections was computed for comparison. Compared with the control, the MSA group showed a marked depletion of neurons in the IML (38.0 ± 7.1 versus 75.2 ± 7.6 cells, P < 0.001), thyrosine hydroxylase-immunoreactive neurons in the ventrolateral medulla (VLM) (17.4 ± 5.1 versus 72.8 ± 13.6 cells, P < 0.01) and tryptophan hydroxylase-immunoreactive neurons in the VLM (15.6 ± 9.2 versus 60.8 ± 17.0 cells, P < 0.01), nucleus raphe obscurus (19.3 ± 4.4 versus 75.3 ± 8.6 cells, P < 0.001), nucleus raphe pallidus (2.1 ± 2.7 versus 9.0 ± 3.4 cells, P < 0.03), and arcuate nucleus (0.4 ± 0.8 versus 2.3 ± 1.5 cells, P < 0.05). Moreover, in patients who succumbed to sudden death, when compared with patients who had established causes of death, we found a marked depletion of tryptophan hydroxylase-immunoreactive neurons in the VLM (7.3 ± 3.5 versus 21.8 ± 6.5 cells, P < 0.02) and nucleus raphe obscurus (15.0 ± 2.0 versus 22.5 ± 2.1 cells, P < 0.01). The results indicate that the spinal IML and medullary catecholaminergic and serotonergic systems are involved even in the early stages of MSA, and the dysfunction of the medullary serotonergic system regulating cardiovascular and respiratory systems could be responsible for sudden death in patients with MSA.

  T Yoshio , T Morita , M Tsujii , N Hayashi and K. Sobue
 

Two members of the myocardin protein family, myocardin-related transcription factor (MRTF)-A and MRTF-B are co-activators of serum response factor (SRF). We recently reported that MRTF-A/B activates the transcription of several actin cytoskeletal/focal adhesion genes SRF dependently, thereby enhancing the formation of stress fibers and focal adhesions. Here, we showed that the levels of caldesmon and tropomyosin, both SRF/MRTF-regulated actin cytoskeletal proteins, were reduced in rat intestinal epithelial (RIE) cell lines that had been transformed with oncogenic ras (RIE-ras) or src (RIE-src) compared with their parental cell line. These cells exhibited morphological abnormalities associated with a disorganized actin cytoskeleton. The serum-stimulated nuclear translocation of MRTF-A/B was suppressed in the RIE-ras and RIE-src cells. However, the transient expression of constitutively active (CA) MRTF-A or MRTF-B reversed the reduced expression levels of caldesmon and tropomyosin and the associated morphological phenotypes. We isolated stable CA-MRTF-A-expressing cell lines from transfected RIE-ras and RIE-src cells and found that their levels of caldesmon and tropomyosin were close to those of untransformed RIE cells. Their morphologies were also normal, with a flattened cell shape and well-developed stress fibers. The CA-MRTF-A-expressing RIE-ras and RIE-src lines also showed lower invasiveness and anchorage-independent growth than their transformed parental cells, in vitro. In vivo, CA-MRTF-A expression suppressed tumor formation and reduced liver metastases. Therefore, we concluded that MRTF-A/B are potent repressors of cancer progression and metastasis and may be good targets for cancer therapy.

  I Hyodo , T Morita , I Adachi , Y Shima , A Yoshizawa and K. Hiraga
  Objective

To develop a predicting tool for survival of terminally ill cancer patients.

Methods

This prospective, multicenter study was composed of two cohorts of samples: development and test. In the development sample of terminally ill cancer patients, 32 candidate predictors were studied to develop a new tool, Japan Palliative Oncology Study-Prognostic Index using the Cox proportional hazard model. Then the test sample was studied to validate Japan Palliative Oncology Study-Prognostic Index and compared it with the conventional predicting tools, such as palliative prognostic score and simplified palliative prognostic index.

Results

Five significant predictors, physician's clinical prediction of survival, consciousness, pleural effusion, white blood cell count and lymphocyte % were derived from the analysis of 201 patients, and Japan Palliative Oncology Study-Prognostic Index was developed using these predictors. It could divide patients into three risk groups: low (A), intermediate (B) and high (C). Median survival times for Groups A, B and C were 51, 35 and 16 days, respectively. Survival probability for more than 30 days for Groups A, B and C in the development sample was 78%, 61% and 16%, respectively. Japan Palliative Oncology Study-Prognostic Index was studied in subsequent 208 patients for the test sample, and constant results (median survival times for Groups A, B and C; 67, 31 and 10 days, and survival probability for more than 30 days for Groups A, B and C; 81, 48 and 11%) were obtained. Palliative prognostic score can also predict three risk groups well, but simplified palliative prognostic index could not discriminate low risk from intermediate risk group.

Conclusion

Japan Palliative Oncology Study-Prognostic Index, a tool to predict survival, has been developed. Its reliability should be confirmed further in the future study, comparing with palliative prognostic score.

  T Hisanaga , T Shinjo , T Morita , N Nakajima , M Ikenaga , M Tanimizu , Y Kizawa , T Maeno , Y Shima and I. Hyodo
  Objective

The aim of this study was to evaluate the efficacy and safety of octreotide for malignant bowel obstruction in a multicenter study.

Methods

Terminally ill patients diagnosed with inoperable malignant bowel obstruction were treated with octreotide 300 µg/day. The primary endpoint was the overall improvement rate of subjective abdominal symptoms. The degrees of nausea, vomiting, abdominal pain, distension, anorexia, fatigue, thirst and overall quality of life were evaluated by the self-rating scores selected from the MD Anderson Symptoms Inventory and Kurihara's Face Scale.

Results

Forty-nine patients were enrolled in the study, and 46 patients received study treatment, including 17 gastric, 13 colorectal, 7 ovarian and other cancers. The median survival time was 25 days. The number of vomiting episodes significantly correlated with the MD Anderson Symptoms Inventory nausea and vomiting scores (P< 0.001) before octreotide treatment. Of 43 patients evaluable for efficacy, the scores of all the MD Anderson Symptoms Inventory items except abdominal pain and the number of vomiting episodes improved during the first 4 days of octreotide treatment (P< 0.0062). The MD Anderson Symptoms Inventory scores were decreased in 59–72% of patients, and overall quality-of-life scores improved in 56% of patients. No serious adverse events were observed.

Conclusions

The high improvement rate in abdominal symptoms suggested the efficacy of octreotide in terminally ill patients with malignant bowel obstruction.

  A Oguri , T Tanaka , H Iida , K Meguro , H Takano , H Oonuma , S Nishimura , T Morita , T Yamasoba , R Nagai and T. Nakajima
 

Voltage-gated Ca2+ channels (CaV) are ubiquitously expressed in various cell types and play vital roles in regulation of cellular functions including proliferation. However, the molecular identities and function of CaV remained unexplored in preadipocytes. Therefore, whole cell voltage-clamp technique, conventional/quantitative real-time RT-PCR, Western blot, small interfering RNA (siRNA) experiments, and immunohistochemical analysis were applied in mouse primary cultured preadipocytes as well as mouse 3T3-L1 preadipocytes. The effects of CaV blockers on cell proliferation and cell cycle were also investigated. Whole cell recordings of 3T3-L1 preadipocytes showed low-threshold CaV, which could be inhibited by mibefradil, Ni2+ (IC50 of 200 µM), and NNC55-0396. Dominant expression of 1G mRNA was detected among CaV transcripts (1A1I), supported by expression of CaV3.1 protein encoded by 1G gene, with immunohistochemical studies and Western blot analysis. siRNA targeted for 1G markedly inhibited CaV. Dominant expression of 1G mRNA and expression of CaV3.1 protein were also observed in mouse primary cultured preadipocytes. Expression level of 1G mRNA and CaV3.1 protein significantly decreased in differentiated adipocytes. Mibefradil, NNC55-0396, a selective T-type CaV blocker, but not diltiazem, inhibited cell proliferation in response to serum. NNC55-0396 and siRNA targeted for 1G also prevented cell cycle entry/progression. The present study demonstrates that the CaV3.1 T-type Ca2+ channel encoded by 1G subtype is the dominant CaV in mouse preadipocytes and may play a role in regulating preadipocyte proliferation, a key step in adipose tissue development.

 
 
 
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