Biomedical subjects

Kenji Ono

Publications and source records attributed to Kenji Ono.

18 recordsLinked to original sources

PubMed2006

Neuroprotective effect of exogenous microglia in global brain ischemia.

Exogenous microglia pass through the blood-brain barrier and migrate to ischemic hippocampal lesions when injected into the circulation. We investigated the effect of exogenous microglia on ischemic CA1 pyramidal neurons. Microglia were isolated from neonatal mixed brain cultures, labeled with the fluorescent dye PKH26, and injected into the subclavian artery of Mongolian gerbils subjected to ischemia reperfusion neuronal injury. PKH26-labeled microglia migrated to the ischemic hippocampal lesion, resulting in increased numbers of surviving neurons compared with control animals, even when injected 24 h after ischemia. Interferon-gamma stimulation of isolated microglia enhanced the neuroprotective effect. Administration of exogenous microglia resulted in normal performance in a passive avoidance-learning task. Additionally, administration of exogenous microglia increased the expression of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in the ischemic hippocampus, and thus might have induced neurotrophin-dependent protective activity in damaged neurons. Peripherally injected microglia exhibited a specific affinity for ischemic brain lesions, and protected against ischemic neuronal injury in vivo. It is possible that administration of exogenous microglia can be developed as a potential candidate therapy for central nervous system repair after transitory global ischemia.

Animals↗

PubMed2005

Epidermal growth factor receptor mutations are associated with gefitinib sensitivity in non-small cell lung cancer in Japanese.

The protein-kinase family is the most frequently mutated gene family found in human cancer. Gefitinib, an ATP-competitive inhibitor of epidermal growth factor receptor (EGFR), also appears to be particularly effective in adenocarcinoma of the lung and in patients without smoking history. To determine whether lung tumors sensitive to gefitinib contained mutations within the tyrosine kinase (TK) domain of EGFR, we screened exons 18-23 of EGFR of tumors in 20 patients with non-small cell lung cancer (NSCLC) who had been treated with gefitinib. Nine (45%) tumors had TK domain mutations. All mutations were observed in adenocarcinoma. Seven (77.8%) of 9 cases with mutated types showed sensitivity to gefitinib, while no cases of 11 with wild type showed gefitinib sensitivity. Such mutations were more frequently observed in patients who had never smoked (5/8 or 62.5%) than in smokers (4/12 or 33.3%). The patients with mutations of EGFR to have a more favorable prognosis than those with wild type (p=0.033). These data show that adenocarcinomas from patients who had never smoked comprise a specific subset of patients with NSCLC sensitive to gefitinib treatment.

Adult↗

PubMed2005

Expression of aldehyde dehydrogenase 2 in the normal esophageal epithelium and alcohol consumption in patients with esophageal cancer.

Alcohol consumption is a risk factor for esophageal cancer. Acetaldehyde, a highly toxic intermediate produced from ethanol, is converted to acetic acid mainly by aldehyde dehydrogenase 2 (ALDH2) in the metabolic pathway of ethanol. Fifty percent of Japanese have inactive ALDH2 due to genetic polymorphism, which is considered to be a risk factor associated with esophageal cancer. In our previous study, we have demonstrated that ALDH2 is expressed in the esophagus with a considerable variation among individuals. In this study, we further investigated the expression of ALDH2 in esophagus and its relationship with risk factors of esophageal cancer. Tissue specimens resected from 51 patients with esophageal cancer were analyzed by immunohistochemistry using ALDH2-antibody. The immuno-staining of ALDH2 in the esophageal epithelium was compared with both the drinking habit and the occurrence of flushing that is closely associated with the ALDH2 deficiency. ALDH2 was not detectable in 8 (16%) among 51 specimens. All of the 8 patients were non- or light-drinkers but not heavy-drinkers. Among 18 patients showing the high level ALDH2 expression in the esophagus, 15 patients (83%) were heavy-drinkers. Although the relationship between the ALDH2 deficiency and drinking habit is not clear, the patients with ALDH2 deficiency tend to be non- or light drinkers while heavy-drinkers tend to have the active form of ALDH2. These results suggest that both inactive and active forms of ALDH2 are induced in the esophagus by heavy drinking and also support a hypothesis that ALDH2 deficiency might be a high-risk factor of esophageal cancer for the individuals having a heavy-drinking habit. To our knowledge, this is the first study demonstrating the induction of ALDH2 in the esophagus by ethanol consumption.

Alcohol Drinking↗

PubMed2005

Immunohistochemical evaluation of cytochrome P450 (CYP) and p53 in breast cancer.

In breast cancer, cytochrome P450 (CYP) metabolizes both endogenous substrates (i.e. estradiol) and exogenous substrates (i.e. anticancer drugs), which is associated not only with tumor development and progression but also with efficacy of cancer treatment. Therefore, we examined the expression of CYPs (CYP2A6, CYP1B1 and CYP3A) and p53 in specimens from 34 Japanese patients with breast cancer by immunohistochemistry. The expression of CYP3A was not detected in the 34 cases. CYP2A6 was detected only in one specimen (2.9%). Twenty-eight specimens (82.4%) showed positive signals for CYP1B1 expression. Eight of 34 (23.5%) were positive for p53 expression. Positive rate of CYP1B1 in stage I disease (100%) was statistically higher than that in stage II - IV disease (70.0%). Positive rate of p53 was 21.4% (6/28) in CYP1B1-positive cases and 33.3% (2/6) in CYP1B1-negative cases. There was no significant relationship between CYP1B1 expression and p53 expression. In conclusion, the expression of CYP3A in breast cancer may be less frequent in Japanese population although the expression of CYP3A has been reported in 20% of breast cancer in Caucasian, suggesting that the CYP3A expression in breast cancer may be dependent on ethnic groups. Since CYP3A is involved in the conversion of tamoxifen to its metabolites, the variation of the CYP3A expression in breast cancer tissues among ethnic groups might cause differences in the efficacy of tamoxifen.

Adult↗

PubMed2005

Tracheobronchopathia osteochondroplastica occurring in a subsegmental bronchus and causing obstructive pneumonia.

A 59-year-old man was referred to the University of Occupational and Environmental Health hospital because a chest roentgenogram obtained at an annual medical examination showed an abnormal shadow. We treated the patient for tracheobronchopathia osteochondroplastica, which caused segmental obstructive pneumonia that proved to be difficult to accurately diagnose before surgery.

Humans↗

PubMed2005

Expression of endoplasmic reticulum molecular chaperone Grp78 in human lung cancer and its clinical significance.

All eukaryotic cells respond to the accumulation of unfolded proteins in the endoplasmic reticulum (ER) by signaling an adaptive pathway termed the unfolded protein response (UPR). Glucose-regulated protein (Grp) 78 is a molecular chaperone involved in the UPR. The aim of this study was to detect Grp78 expression in lung cancer using immunohistochemical (IHC) staining, and also to evaluate the relationship between the Grp78 expression level and the prognosis of patients with lung cancer. We used immunohistochemistry to analyze the protein expression of Grp78 in paraffin-embedded tumor samples from 132 well-characterized lung cancer patients and compared the expression level of Grp78, clinical variables and survival outcome. A positive expression of Grp78 was detected in the cytoplasm of tumor cells in 88 of the 132 patients (66.7%) with lung cancer. No significant difference was observed between the Grp78 expression and the gender, age at operation, histological type, pathologic stage, pathologic T status, and pathologic N status. Lung cancer patients with a positive Grp78 expression tended to show a better prognosis than those with a negative Grp78 expression. In addition, a multivariate analysis of the clinicopathologic characteristics of lung cancer indicated a positive expression of Grp78 to be a significant factor for predicting a favorable prognosis (p < 0.001, risk ratio = 2.35). A positive expression of Grp78 may thus be a useful marker for predicting a favorable prognosis in patients undergoing a resection of lung cancer. The ER stress pathway mediated by Grp78 may therefore be responsible for controlling the growth of lung cancer cells.

Adult↗

PubMed2005

A lack of prognostic significance regarding DeltaNp63 immunoreactivity in lung cancer.

DeltaNp63 is an isoform of the p53 homologue p63, which lacks an amino-terminal transactivation domain and antagonizes the induction of the gene expression by Deltap63. The aim of this study was to detect the DeltaNp63 expression in lung cancer using immunohistochemical (IHC) staining, and to evaluate the relationship between theDeltaNp63 expression level and the prognosis based on resected lung cancer tissues specimens from the of patients. We used immunohistochemistry to analyze the protein expression of DeltaNp63 in paraffin-embedded tumor samples from 161 well-characterized squamous cell carcinoma patients and compared the expression level of DeltaNp63, clinical variables and the survival outcome. Seventy-seven patients (47.8%) showed positive staining for DeltaNp63 in the nuclei of tumor cells. No significant difference was observed between the DeltaNp63 expression and the gender, age at operation, pathologic stage, pathologic T status, and pathologic N status. Based on the actuarial survival method, Kaplan-Meier method, and the log-rank test, the DeltaNp63 expression was not associated with survival for lung cancer. Differences in survival remained insignificant even after lung cancer patients were stratified according to stage or differentiation. The prognostic effects of DeltaNp63 expression do not appear to act as an important prognostic indicator in lung cancer. Our findings do not support that immunocytochemical markers demonstrate a relevant prognostic role in lung cancer.

Aged↗

PubMed2004

Cytokine production of activated microglia and decrease in neurotrophic factors of neurons in the hippocampus of Lewy body disease brains.

Dementia is a frequent complication of Parkinson's disease (PD) and usually occurs late in the protracted course of the illness. We have already reported numerous MHC class II-positive microglia in the hippocampus in PD patients, and that this phenomenon may be responsible for functional changes in the neurons and the cognitive decline in PD patients. In this study, we have investigated the distribution of activated microglia and the immunohistochemical and the mRNA expression of several cytokines and neurotrophic factors of the hippocampus in PD and dementia with Lewy bodies (DLB). The brains from five cases of PD and five cases of DLB that were clinically and neuropathologically diagnosed, and those from four normal controls (NC) were evaluated by immunohistochemistry using anti-HLA-DP, -DQ, -DR (CR3/43), anti-alpha-synuclein, anti-brain-derived neurotrophic factor (BDNF), and anti-glial fibrillary acidic protein antibodies. In addition, the mRNA expressions of cytokines (IL-1alpha, IL-1beta, TNF-alpha, IL-6, TGF-beta) and neurotrophic factors (BDNF, GDNF, NGF, NT-3) of these brains were evaluated by the reverse transcription-PCR method. MHC class II-positive microglia were distributed diffusely in the hippocampus of PD and DLB brains. Although the cytoplasm of pyramidal and granular cells of the hippocampus in NC brains was strongly stained by anti-BDNF antibodies, it was only weakly stained in PD and DLB brains. The mRNA expression of IL-6 was significantly increased in the hippocampus of PD and DLB brains, and that of BDNF was significantly decreased in the hippocampus of DLB brains. The increased number of activated microglia and the production of neurotrophic cytokines such as IL-6, together with the decreased expression of the neurotrophic factors of neurons in the hippocampus of PD and DLB brains, may be related to functional cellular changes associated with dementia.

Aged↗

PubMed2004

Expression of deltaNp73 predicts poor prognosis in lung cancer.

PURPOSE: DeltaNp73 is an isoform of the p53 homologue p73, which lacks an NH(2)-terminal transactivation domain and antagonizes the induction of gene expression by p53/p73. The aim of this study was to detect DeltaNp73 expression in lung cancer and to evaluate the relationship between the DeltaNp73 expression level and the prognosis of patients with resected lung cancer. EXPERIMENTAL DESIGN: We used immunohistochemistry to analyze the protein expression of DeltaNp73 in paraffin-embedded tumor samples from 132 well-characterized lung cancer patients and compared the expression level of DeltaNp73, clinical variables, and survival outcome. RESULTS: Positive expression of DeltaNp73 was detected mainly in the cytoplasm of tumor cells in 77 of 132 patients (58.3%) with lung cancer. The incidence of positive expression of DeltaNp73 was 52.2, 50.0, and 70.2% in patients with stage I, II, and III, respectively (P = 0.04). Positive expression of DeltaNp73 was associated with gender but not associated with age, histologic type, pathological stage, pathological T status, and pathological N status. Lung cancer patients with positive DeltaNp73 expression had a poorer prognosis than those with negative DeltaNp73 expression. In addition, multivariate analysis of the clinicopathological characteristics of lung cancer indicated that positive expression of DeltaNp73 was a significant independent factor for predicting poor prognosis (P < 0.0001, risk ratio = 3.39). CONCLUSIONS: Expression of DeltaNp73 may be a useful marker for predicting poor prognosis of patients who underwent resection of lung cancer.

Adult↗

PubMed2003

Preservation of hematopoietic properties in transplanted bone marrow cells in the brain.

Recent studies have described the possible transdifferentiation of bone marrow cells (BMC) into neurons and glia when they migrate to the brain. However, we have reported that some immature BMC migrating into the brain parenchyma after bone marrow transplantation express early hematopoietic markers but not neural or glial markers. The present study further characterizes transplanted BMC that migrate to the brain. Double immunolabeling confirmed that BMC migrating to the brain expressed hematopoietic but not neural markers, such as nestin, microtubule-associated protein-2 and glial fibrillary acidic protein, even 4 and 18 weeks after bone marrow transplantation. BMC that expressed green fluorescent protein also expressed hematopoietic but not neural markers when cultured with mixed brain cells according to double immunolabeling and single-cell dissection using a laser. Analysis of the DNA content indicated that most of the migrated BMC were arrested at the G0/G1 phase, and aneuploidy or tetraploidy was undetectable. Thus, BMC that migrate to the brain probably have preserved hematopoietic properties under physiological conditions.

Animals↗

PubMed2003

Usefulness of magnetic motor evoked potentials in the surgical treatment of hemiplegic patients with intractable epilepsy.

Five hemiplegic patients with intractable epilepsy were studied with transcranial magnetic stimulation (TMS) before and after various surgical treatments. These patients had unilateral widespread cerebral lesions acquired at various times, including congenital, infantile and childhood injury. Motor evoked potentials (MEPs) of the abductor pollicis brevis (APB) muscles were simultaneously recorded on both sides following TMS of the motor cortex in the respective hemisphere using a figure-8 or circular coil. In all patients with congenital disease, the abolition of motor function in the affected hemisphere was estimated by magnetic MEPs, and the hemiplegia did not deteriorate after functional hemispherectomy (HS) was performed in two of them. In two patients with acquired disease, HS was not performed because it was shown by magnetic maps that the motor function in the affected hemisphere remained. Furthermore, it was shown by electric MEPs using subdural electrodes that a patient who had had encephalitis in early childhood had a reorganised motor area in the parietal cortex of the affected hemisphere. The present findings indicate that magnetic MEPs are a very useful non-invasive method of assessing whether the motor area in the affected hemisphere can be resected in hemiplegic patients with intractable epilepsy.

Adolescent↗

PubMed2003

Callosal role in generation of epileptiform discharges: quantitative analysis of EEGs recorded in patients undergoing corpus callosotomy.

OBJECTIVE: Corpus callosotomy tends to decrease seizure frequency and severity rather than transforming the seizure pattern from a generalized form into a lateralized or a partial one. The finding implies that bisection of the corpus callosum (CC) disrupts the epileptogenicity itself. In order to gain further insight into the possible role played by the CC in intractable generalized epilepsy, quantitative analyses of long-term EEGs were performed. METHODS: Analyses were made of epileptiform discharges contained in the pre- and postoperative long-term EEGs in 7 patients who had an anterior callosotomy for intractable epilepsy. The duration, number, and amplitude of all epileptiform burst activities were measured and statistically analyzed. RESULTS: After callosotomy, the total number of epileptiform burst activities, mean duration, and the total number of spike discharges decreased significantly. The two hemispheres could be divided into dominant and non-dominant ones as to the quantity of the residual epileptiform discharges. CONCLUSIONS: Corpus callosotomy unevenly reduced preoperative epileptiform discharges in both hemispheres, suggesting a facilitatory role played by the callosal neurons that enables the asymmetrical epileptogenic susceptible state of the two hemispheres to develop bisynchronous and bisymmetrical epileptiform discharges. SIGNIFICANCE: Corpus callosotomy decreased the quantity of the epileptiform discharges, suggesting the transhemispheric facilitation of seizure mechanisms.

Cerebral Cortex↗

PubMed2002

Existence of functional beta1- and beta2-adrenergic receptors on microglia.

We examined the expression and function of beta-adrenergic receptor (beta-AR) subtypes in both isolated primary rat microglia and a rat microglial cell line. RT-PCR analyses revealed that microglia expressed beta(1)- and beta(2)-ARs but not beta(3)-ARs, whereas rat primary peritoneal macrophages expressed only beta(2)-ARs. Stimulation of beta-ARs on microglia by norepinephrine (NE) resulted in an increase in the level of intracellular cAMP and the subsequent expression of interleukin-1beta mRNA. These effects were prevented by propranolol. Similar results were obtained with other selective beta(1)-AR agonists and antagonists. beta(2)-ARs on microglia were also functional. It is possible that noradrenergic innervations participate in the control of microglial functions via beta(1)-ARs on microglia in the brain, because NE has high affinity for beta(1)- and beta(3)-ARs but little or no affinity for beta(2)-ARs. It seems physiologically significant that microglia can be controlled by NE, which predominates over epinephrine in the brain, whereas macrophages in peripheral tissues can be controlled by epinephrine, which is at higher levels in peripheral tissues.

Adrenergic beta-1 Receptor Agonists↗

PubMed2002

Suppressive effect of callosotomy on epileptic seizures is due to the blockade of enhancement of cortical reactivity by transcallosal volleys.

The present work demonstrates that the cortical reactivity of the rat, monitored by thalamocortical responses, can be enhanced by repetitive transcallosal volleys (5-20 Hz). This effect can be completely inhibited by callosotomy. We believe that the interhemispheric epileptogenesis and the suppressive effect of callosotomy for intractable epilepsy can be explained by this facilitatory effect of the corpus callosum on the cerebral cortex.

Animals↗

PubMed2002

Is a cortical spike discharge "transferred" to the contralateral cortex via the corpus callosum?: An intraoperative observation of electrocorticogram and callosal compound action potentials.

PURPOSE: By means of the intraoperative electrophysiologic observation, we reevaluated the "transfer" theory that a transcallosal volley invoked by a cortical spike discharge in one hemisphere directly causes its contralateral counterpart via the corpus callosum (CC). METHODS: Twenty-six patients who underwent corpus callosotomy were the subjects of this study. Intraoperatively, electrocorticograms from both hemispheres were simultaneously monitored with callosal compound action potentials (CCAPs) from the CC. Analysis was conducted on (a) the interhemispheric delay of bilaterally synchronous spike-and-wave discharges (BSSWs), and (b) the chronological relation between BSSWs and CCAPs. RESULTS: The side of prior spike discharges was never fixed but was occasionally reversed. Interhemispheric delays between the BSSWs were not constant, regardless of direction, and fluctuated in all patients. Most of the interhemispheric delays were distributed within 20 ms with a mode of 0 ms. The waveform of the CCAP was characterized by slow-rising negative potential change that attained its peak after a cortical spike discharge. These findings were identical in all the patients regardless of whether the BSSWs were changed or unchanged after callosotomy. CONCLUSIONS: If the "transfer" role of the CC is true, interhemispheric delays between BSSWs must be longer than interhemispheric axonal conduction time (about 20 ms), and a preceding cortical spike discharge must produce a CCAP and then a contralateral one in order of time. However, this hypothesis was not confirmed in the present study. We propose the interhemispheric recruitment of the epileptogenic state as a different role of the CC on epileptogenesis.

Adolescent↗

PubMedDate not supplied

Expression of deltaNp63 in squamous cell carcinoma of the esophagus.

BACKGROUND: The p63 gene is present as two isoforms, namely TAp63 and deltaNp63. The biological role of deltaNp63 in the progression of esophageal cancer is still controversial. PATIENTS AND METHODS: The expression of deltaNp63, as well as that of p63, was immunohistochemically examined in 61 resected specimens of squamous cell carcinoma of the esophagus. RESULTS: The incidences of a positive deltaNp63 expression were 32 and 64% in carcinomas with and without adventitial invasion, respectively, and 37 and 65% in those with and without lymph node metastasis, respectively (p<0.05). The prognosis was significantly better in the positive deltaNp63 group than in the negative group (p<0.01). However, a multivariate analysis revealed deltaNp63 not to be an independent prognostic factor. Regarding p63, diminished expression was more frequently observed in advanced carcinomas, however, there were no statistically significant differences. CONCLUSION: The impaired deltaNp63 reflects the progression of squamous cell carcinoma of the esophagus.

Adult↗

PubMedDate not supplied

Expression of FHIT in esophageal epithelium and carcinoma: reference to drinking, smoking and multicentric carcinogenesis.

BACKGROUND: Both alcohol consumption and cigarette smoking are risk factors for esophageal cancer. The purpose of this study was to clarify whether the fragile histidine triad (FHIT) is their target gene in esophageal carcinogenesis as well as in multicentric carcinogenesis. PATIENTS AND METHODS: The expression of FHIT was immunohistochemically examined in the squamous cell carcinoma as well as in the normal esophageal epithelium of 55 cases with esophageal cancer. RESULTS: The median drinking indices (DIs) were 546 and 1092 (p<0.01) in cases with positive FHIT expression and those with a diminished expression in the esophageal epithelium, respectively. Furthermore, the incidences of intra-esophageal multiple cancer were 44% and 13%, respectively (p<0.05). Regarding the expression in cancer lesions, the median DIs were 280 and 721 in positive and diminished cases, respectively (p=0.081). CONCLUSION: A loss of FHIT expression is associated not only with alcohol-induced esophageal carcinogenesis, but also with multicentric carcinogenesis.

Acid Anhydride Hydrolases↗

PubMedDate not supplied

Expression of the p53 family in lung cancer.

BACKGROUND: p53 is mutated in about 50% of various malignant diseases including lung cancer. The p53 family consists of p53, p73 and p63. Although transactivating protein isoforms display p53-like functions, the deltaNp73 or deltaNp63 isoforms act toward p53 in a dominantly negative way. The aim of this study was to detect p53, deltaNp73 and deltaNp63 expressions in lung cancer and to evaluate the relationship between the expression levels of the proteins and the prognosis of patients with resectable lung cancer. MATERIALS AND METHODS: Immunohistochemistry was employed to analyze the protein expression of p53, deltaNp73 and deltaNp63 in paraffin-embedded tumor samples from 132 well-characterized lung cancer patients. The correlation among the expression levels of p53, deltaNp73 and deltaNp63, clinical variables and survival outcome was analyzed. RESULTS: Positive expressions of p53, deltaNp73 and deltaNp63 were detected in the tumor cells in 52, 77 and 44 of the 132 patients, respectively (39.4%, 58.3% and 33.3%) with lung cancer. The incidence of p53 positive expression was 54.5% and 27.6% in patients with squamous cell carcinoma and adenocarcinoma, respectively (p = 0.03). The incidence of a positive expression of deltaNp73 was 64.5% and 43.6% in male and female patients, respectively (p = 0.03). The incidence of deltaNp63 positive expression was 68.2% and 15.8% in the patients with squamous cell carcinoma and adenocarcinoma, respectively (p < 0.0001). The expressions of p53 and deltaNp63 were not found to significantly affect survival. However, lung cancer patients with a positive deltaNp73 expression had a poorer prognosis than those with a negative deltaNp73 expression. In addition, multivariate analysis indicated that a positive expression of deltaNp73 was a significantly independent factor for predicting a poor prognosis (p < 0.0001, risk ratio = 3.38). CONCLUSION: Clinical evidence that the p53 family is frequently overexpressed in lung cancer specimens, especially deltaNp63 in squamous cell carcinoma, was provided. The expression of deltaNp73 may be a useful marker for predicting a poor prognosis in resectable lung cancer. Understanding how groups of lung cancer cell genes are coordinately expressed in response to physiological, immunological and micro-environmental stimuli remains an important goal. A better understanding of the gene expression profiles of tumors may help to identify molecular targets, such as deltaNp73, for effective therapy.

Adult↗