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Biomedical subjects

Kaoru Tanaka

Publications and source records attributed to Kaoru Tanaka.

16 recordsLinked to original sources
PubMed2024

Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade.

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.

Humans↗
PubMed2006

Volumetric intravascular ultrasound assessment of neointimal hyperplasia and nonuniform stent strut distribution in sirolimus-eluting stent restenosis.

The neointimal hyperplasia (IH) distribution pattern of in-stent restenotic lesions after sirolimus-eluting stent (SES) implantation has not been well described. We identified 48 in-stent restenotic lesions (41 patients) after SES implantation and performed volumetric intravascular ultrasound analyses. Lumen area, stent area, and IH area at the minimal lumen area site were 2.7 +/- 1.0, 5.4 +/- 1.9, and 2.7 +/- 1.4 mm(2), respectively. IH area at the minimal lumen site was larger in the group with a stent area > or =5.0 mm(2) than the group with a stent area <5.0 mm(2) (3.7 +/- 1.3 vs 1.9 +/- 0.8 mm(2), p <0.001). There were fewer visualized stent struts in lesions with a minimum stent area > or =5.0 mm(2) at the minimum lumen site compared with those with a stent area <5.0 mm(2) (0.69 +/- 0.25 vs 0.83 +/- 0.16, p = 0.04). When we compared lesions in patients with diabetes mellitus with patients without diabetes, minimum lumen areas, percent IH at minimal lumen area, percent IH, and neointima-free stent length were identical. In conclusion, (1) lesions without SES underexpansion at the minimum lumen site had more IH and greater nonuniform stent strut distribution compared with restenotic SESs that were underexpanded, and (2) the IH response did not appear to be more aggressive in patients with diabetes mellitus than in those without diabetes mellitus.

Aged↗
PubMed2006

Impact of pretilachlor herbicide and pyridaphenthion insecticide on aquatic organisms in model streams.

To detect the impact of pesticides on aquatic organisms, model streams (3m wide, 20 m long) were established in paddy field in Japan. More than 100 species of aquatic organisms were generated in the model streams. Field tests with pretilachlor herbicide and pyridaphenthion insecticide were carried out in the streams for 3 yr (2001-2003). Exposure of pretilachlor (max. 0.382 mg/L) showed little density changes in algae with a Bray-Curtis percent similarity in the range 81.6-93.3% for algae. Exposure to high concentrations (>0.1mg/L) of pyridaphenthion produced visible density reductions in Cladocera zooplankton species. Reduction of individual aquatic insects in the model streams by pyridaphenthion caused an increase of chlorophyll a greater than that of the control streams. The pesticides used showed no substantial differences in the ecosystems of model streams exposed to maximum environmental concentrations (e.g., 0.01 mg/L) detected in real rivers.

Acetanilides↗
PubMed2006

Outcome after acute incomplete sirolimus-eluting stent apposition as assessed by serial intravascular ultrasound.

We investigated the fate of postprocedural incomplete stent apposition (ISA) after sirolimus-eluting stent (SES) implantation by evaluating long-term intravascular ultrasound findings in 168 consecutive patients (182 de novo lesions). Postprocedural ISA was defined as > or = 1 stent strut that was clearly separated from the vessel wall with evidence of blood speckle behind the strut without overlapping a side branch. After SES implantation, there were 61 ISA sites in 46 stents in 31 patients (23 at the proximal edge, 7 at the distal edge, and 31 within the stent body). There were no clinical, procedural, or intravascular ultrasound measurement differences between patients and lesions with versus without ISA. At follow-up, 15 acute ISA sites (25%) in 11 patients completely resolved and 40 sites (75%) in 20 patients persisted, although 32 of 46 persisting ISA sites (70%) decreased. There was a greater decrease in effective lumen area and a greater increase in peristent plaque area in the complete-resolution group than in the persistent-ISA group. No lesion developed stent thrombosis or in-stent restenosis (angiographic diameter stenosis > 50%). Six acute ISA sites were also associated with new, late acquired ISA, only 1 of which resulted in aneurysm formation. Although most ISAs after SES implantation do not resolve completely, the incidence of restenosis or thrombosis is not affected.

Acute Disease↗
PubMed2006

Intravascular ultrasound profile analysis of ruptured coronary plaques.

Angiographic studies have shown that lesions preceding nonfatal acute events are usually not hemodynamically significant. This has led to the concept that plaque ruptures occur at minimal disease sites. We used intravascular ultrasound to create a prerupture "profile" of unstable (vulnerable) plaques. We analyzed 112 ruptured plaques detected by intravascular ultrasound. Reference and lesion external elastic membrane (EEM) and lumen areas were measured to calculate prerupture estimates of plaque area, plaque burden (plaque/EEM area), eccentricity, area stenosis, and remodeling. The narrowest coefficients of variance were for lesion EEM area, maximum plaque thickness, and plaque burden, reference lumen area, and remodeling index (coefficients of variance 0.29, 0.25, 0.12, 0.29, and 0.18, respectively); conversely, there was great variability in measurements of calcification and lumen compromise (minimum lumen area and area stenosis). When using the 5 variables with the narrowest coefficient of variance, we found that 67% of ruptured plaques fit all of following 10th or 90th percentile parameters (> 14.3 mm2 lesion EEM area, > 8.1 mm2 reference lumen area, > 1.6 mm maximum lesion plaque thickness, > 0.63 lesion plaque burden, and > 0.87 remodeling index). Further, 89% of ruptured plaques fit 4 of 5 parameters and 96% fit 3 of 5 parameters. In conclusion, plaque ruptures do not occur at minimal disease sites. Rather, vulnerable (rupture-prone) plaques predictably have significant plaque accumulation and remodeling and occur in larger arteries. It is only the degree of lumen compromise that is variable and often insignificant.

Coronary Artery Disease↗
PubMed2006

IVUS makes important strides in 2005.

Researchers utilized intravascular ultrasound in unique ways in 2005, from assessing transplant vasculopathy to evaluating long-term drug-eluting stent outcomes to identifying predictors of stent thrombosis. These and other applications signify key developments in the field of intravascular imaging.

Blood Vessel Prosthesis Implantation↗
PubMed2006

Frequency and determinants of black holes in sirolimus-eluting stent restenosis.

BACKGROUND: In-stent neointimal hyperplasia typically has a homogenous echoreflective appearance during intravascular ultrasound (IVUS) imaging. However, the neointimal hyperplasia of some brachytherapy failure lesions contains a very echolucent, dark zone that has been termed black hole. We sought to investigate the frequency and determinants of black holes (BH) after sirolimus-eluting stent (SES) implantation. METHODS: A prospective, consecutive series of 33 intrastent SES restenosis (> 50% neointimal hyperplasia with a minimal lumen area < 4.0 mm2) was studied with IVUS. Patients were divided into 2 groups: 8 patients with BH versus 25 patients without BH. RESULTS: Fifty percent of the BH cases occurred in saphenous vein graft lesions. BH tissue was noticed in 8% of all patients with in-stent restenosis. Three patients in each group had previous vascular brachytherapy failure (p = 0.1). Compared to non-BH cases, a greater proportion of BH cases occurred after SES treatment of bare-metal stent restenosis (75% vs. 32%; p = 0.035). BH cases presented earlier (89.9 +/- 34.3 vs. 161.3 +/- 78.8 days; p = 0.001) with more severe in-stent restenosis, as indicated by greater absolute and relative amounts of neointimal hyperplasia (41.3 +/- 10.0 vs. 26.9 +/- 19.5 mm3; p = 0.012, and 19.6 +/- 6.8 vs. 10.4 +/- 7.9%; p = 0.0001, respectively). CONCLUSIONS: Echolucent restenotic tissue (black hole) is more often observed in SES restenosis after treatment of saphenous vein graft lesions or treatment of bare-metal stent restenosis. It occurs earlier and is more severe than typical SES failures.

Aged↗
PubMed2005

Pre-operative atrial fibrillation as the key determinant of outcome of mitral valve repair for degenerative mitral regurgitation.

AIMS: To examine the impact of pre-operative atrial fibrillation (AF) on the outcome of mitral valve repair (MVR) for degenerative mitral regurgitation (MR). METHODS AND RESULTS: Among 392 patients with moderate to severe MR who underwent MVR between 1991 and 2002, 283 patients with isolated degenerative MR were followed for 4.7+/-3.3 years. Of 27 deaths, nine were due to cardioembolic events and four were due to left ventricular (LV) dysfunction. When compared with patients with pre-operative AF, those with sinus rhythm (SR) had better survival (96+/-2.1 vs. 87+/-3.2% at 5 years, P=0.002) and higher cardiac event-free rates (96+/-2.0 vs. 75+/-4.4% at 5 years, P<0.001). In patients with pre-operative SR, observed and expected survival were similar (P=0.811). Cox multivariable regression analysis confirmed AF [P=0.027, adjusted hazard ratio (AHR) 2.9] and age as independently predictive of survival, and AF (P=0.002, AHR 3.1), New York Heart Association Class, and LV fractional shortening as independently predictive of cardiac event. CONCLUSION: Death due to LV dysfunction was not frequent and cardioembolic events due to AF were the leading cause for cardiac death. Pre-operative AF became a strong independent predictor of survival and morbidity. Patients with pre-operative SR had excellent prognosis. The benefits of preventing cardioembolic events due to AF validate the indication of MVR for patients with high risk for AF.

Adult↗
PubMed2005

DNA-dependent protein kinase enhances DNA damage-induced apoptosis in association with Friend gp70.

Friend leukemia virus (FLV) infection strongly enhances gamma-irradiation-induced apoptosis of hematopoietic cells of C3H hosts leading to a lethal anemia. Experiments using p53 knockout mice with the C3H background have clarified that the apoptosis is p53-dependent and would not be associated with changes of cell populations caused by the infection with FLV. In bone marrow cells of FLV + total body irradiation (TBI)-treated C3H mice, the p53 protein was prominently activated to overexpress p21 and bax suggesting that apoptosis-enhancing mechanisms lay upstream of p53 protein in the signaling pathway. Neither of DNA-dependent protein kinase (DNA-PK)-deficient SCID mice nor ataxia telangiectasia mutated (ATM) gene knockout mice with the C3H background exhibited a remarkable enhancement of apoptosis or p53 activation on FLV + TBI-treatment indicating that DNA-PK and ATM were both essential. ATM appeared necessary for introducing DNA damage-induced apoptosis, while DNA-PK enhanced p53-dependent apoptosis under FLV-infection. Surprisingly, viral envelope protein, gp70, was co-precipitated with DNA-PK but not with ATM in FLV + TBI-treated C3H mice. These results indicated that FLV-infection enhances DNA damage-induced apoptosis via p53 activation and that DNA-PK, in association with gp70, might play critical roles in modulating the signaling pathway.

Animals↗
PubMed2005

Effects of prenatal irradiation with an accelerated heavy-ion beam on postnatal development in rats: I. Neurophysiological alterations.

Effects on postnatal neurophysiological development in offspring were studied after exposure of pregnant Wistar rats to accelerated carbon-ion beams with an LET of about 13 keV/ mum at doses ranging from 0.1 Gy to 2.5 Gy on the 15th day of gestation. The age at which four physiological markers appeared and five reflexes were acquired was examined prior to weaning. Gain in body weight was monitored until the offspring were 3 months old. Male offspring were evaluated as young adults using two behavioral tests. The effects of X rays estimated for the same biological end points were studied for comparison. For most of the end points at early age, no significant alterations were observed in offspring that received prenatal irradiation with 0.1 Gy of either accelerated carbon ions or X rays compared to the offspring of sham-irradiated dams. However, all offspring whose dams received 2.5 Gy died prior to weaning. Offspring from dams irradiated with accelerated carbon ions generally showed higher incidences of prenatal death and preweaning mortality, markedly delayed accomplishment in their physiological markers and reflexes, and gain in body weight compared to those exposed to X rays at doses of 0.5 to 2 Gy. Significantly reduced ratios of main organ weight to body weight at the postnatal ages of 30, 60 and 90 days were also observed within this dose range. The results indicate that irradiation with 0.5 to 2 Gy on day 15 of gestation caused permanent alterations in offspring that were dependent on dose. The alterations include permanent growth retardation, morphological malformations in main organs, including microcephaly, diminished reflex attainment, delayed appearance of physiological markers, and changes in adult behavior. Exposure to 1 to 2 Gy of radiation resulted in growth retardation and behavioral alterations that persisted throughout life. Accelerated carbon ions generally induced more detrimental effects than X rays.

Abnormalities, Radiation-Induced↗
PubMed2004

Adaptive response in embryogenesis: IV. Protective and detrimental bystander effects induced by X radiation in cultured limb bud cells of fetal mice.

The radioadaptive response and the bystander effect represent important phenomena in radiobiology that have an impact on novel biological response mechanisms and risk estimates. Micromass cultures of limb bud cells provide an in vitro cellular maturation system in which the progression of cell proliferation and differentiation parallels that in vivo. This paper presents for the first time evidence for the correlation and interaction in a micromass culture system between the radioadaptive response and the bystander effect. A radioadaptive response was induced in limb bud cells of embryonic day 11 ICR mice. Conditioning irradiation of the embryonic day 11 cells with 0.3 Gy resulted in a significant protective effect against the occurrence of apoptosis, inhibition of cell proliferation, and differentiation induced by a challenging dose of 5 Gy given the next day. Both protective and detrimental bystander effects were observed; namely, irradiating 50% of the embryonic day 11 cells with 0.3 Gy led to a successful induction of the protective effect, and irradiating 70% of the embryonic day 12 cells with 5 Gy produced a detrimental effect comparable to that seen when all the cells were irradiated. Further, the bystander effect was markedly decreased by pretreatment of the cells with an inhibitor to block the gap junction-mediated intercellular communication. These results indicate that the bystander effect plays an important role in both the induction of a protective effect by the conditioning dose and the detrimental effect of the challenge irradiation. Gap junction-mediated intercellular communication was suggested to be involved in the induction of the bystander effect.

Adaptation, Physiological↗
PubMed2004

Adaptive response in embryogenesis: V. Existence of two efficient dose-rate ranges for 0.3 Gy of priming irradiation to adapt mouse fetuses.

The adaptive response is an important phenomenon in radiobiology. A study of the conditions essential for the induction of an adaptive response is of critical importance to understanding the novel biological defense mechanisms against the hazardous effects of radiation. In our previous studies, the specific dose and timing of radiation for induction of an adaptive response were studied in ICR mouse fetuses. We found that exposure of the fetuses on embryonic day 11 to a priming dose of 0.3 Gy significantly suppressed prenatal death and malformation induced by a challenging dose of radiation on embryonic day 12. Since a significant dose-rate effect has been observed in a variety of radiobiological phenomena, the effect of dose rate on the effectiveness of induction of an adaptive response by a priming dose of 0.3 Gy administered to fetuses on embryonic day 11 was investigated over the range from 0.06 to 5.0 Gy/min. The occurrence of apoptosis in limb buds, incidences of prenatal death and digital defects, and postnatal mortality induced by a challenging dose of 3.5 Gy given at 1.8 Gy/min to the fetuses on embryonic day 12 were the biological end points examined. Unexpectedly, effective induction of an adaptive response was observed within two dose-rate ranges for the same dose of priming radiation, from 0.18 to 0.98 Gy/ min and from 3.5 to 4.6 Gy/min, for reduction of the detrimental effect induced by a challenging dose of 3.5 Gy. In contrast, when the priming irradiation was delivered at a dose rate outside these two ranges, no protective effect was observed, and at some dose rates elevation of detrimental effects was observed. In general, neither a normal nor a reverse dose- rate effect was found in the dose-rate range tested. These results clearly indicated that the dose rate at which the priming irradiation was delivered played a crucial role in the induction of an adaptive response. This paper provides the first evidence for the existence of two dose-rate ranges for the same dose of priming radiation to successfully induce an adaptive response in mouse fetuses.

Adaptation, Physiological↗
PubMed2003

Impact of a preoperative mitral regurgitation scoring system on outcome of surgical repair for mitral valve prolapse.

The optimal timing of surgical correction of severe mitral regurgitation (MR) is important for improved morbidity and mortality. We utilized a scoring system to decide the timing of procedures. Based on clinical features and echocardiographic data, we hypothesized that preoperative semi-quantitation of MR using this scoring system may be useful for predicting prognosis after repair. The MR score was composed of 6 parameters associated with disease severity (i.e., history of heart failure, atrial fibrillation, pulmonary hypertension, left ventricular end-systolic dimension, fractional shortening, and left atrial dimension). The maximum score was 6. Of 267 patients who underwent mitral valve repair in the last 10 years, 191 patients with mitral valve prolapse were studied. Patients were categorized into 2 groups according to MR score (group low [L] : 0 to 2.5 and group high [H]: >/=3.0) irrespective of New York Heart Association functional class. A significant difference in postoperative event-free survival was observed between both groups (p = 0.0014); the adjusted risk ratio was 3.4 (95% confidence interval 1.6 to 7.2). Postoperative echocardiography showed larger left ventricular systolic dimensions (p <0.0001), lower fractional shortening (p = 0.0016), and larger left atrial dimensions (p <0.0001) in group H than group L. Thus, an MR score is a simple way to predict the prognosis of severe MR independently of subjective symptoms in patients undergoing mitral valve repair.

Chi-Square Distribution↗
PubMed2003

Echocardiographic prediction of left ventricular dysfunction after mitral valve repair for mitral regurgitation as an indicator to decide the optimal timing of repair.

OBJECTIVES: This study sought to determine whether echocardiography before mitral valve repair (MVR) for mitral regurgitation (MR) was predictive of postoperative left ventricular (LV) dysfunction and useful for deciding the optimal timing of repair. BACKGROUND: Some reports have shown that the preoperative echocardiographic data of left ventricular ejection fraction (LVEF) and left ventricular end-systolic diameter (LVDs) were good predictors of postoperative LV dysfunction. However, few reports were based on long-term follow-up data of large numbers of patients who underwent MVR in the last decade. METHODS: A total of 274 patients with moderate or severe MR underwent MVR between October 1, 1991, and September 30, 2000. Among them, 171 patients who had both an operation for isolated MR due to degenerative pathology and a postoperative echocardiogram were studied. Postoperative echocardiograms were performed 3.9 +/- 2.4 years after the operation. The LVEF decreased from 66 +/- 10% before surgery to 63 +/- 11% after surgery (p < 0.0001). On univariate analysis, preoperative LVEF and LVDs correlated with postoperative LVEF (r = 0.41 and r = -0.39, respectively). Overall, postoperative LV dysfunction (defined as LVEF <50%) was not frequent (12%). However, the incidence of postoperative LV dysfunction was high in patients with preoperative LVEF <55% (38%) or LVDs > or =40 mm (23%). CONCLUSIONS: In patients with MR, the echocardiographic data of LVEF and LVDs were good predictors of postoperative LV dysfunction. When a decrease in LVEF or an increase in LVDs is detected, MVR should be considered to preserve postoperative LV function.

Adult↗
PubMed2002

Friend leukemia virus infection enhances DNA damage-induced apoptosis of hematopoietic cells, causing lethal anemia in C3H hosts.

Exposure of hematopoietic progenitors to gamma irradiation induces p53-dependent apoptosis. However, host responses to DNA damage are not uniform and can be modified by various factors. Here, we report that a split low-dose total-body irradiation (TBI) (1.5 Gy twice) to the host causes prominent apoptosis in bone marrow cells of Friend leukemia virus (FLV)-infected C3H mice but not in those of FLV-infected DBA mice. In C3H mice, the apoptosis occurs rapidly and progressively in erythroid cells, leading to lethal host anemia, although treatment with FLV alone or TBI alone induced minimal apoptosis in bone marrow cells. A marked accumulation of P53 protein was demonstrated in bone marrow cells from FLV-infected C3H mice 12 h after treatment with TBI. Although a similar accumulation of P53 was also observed in bone marrow cells from FLV-infected DBA mice treated with TBI, the amount appeared to be parallel to that of mice treated with TBI alone and was much lower than that of FLV- plus TBI-treated C3H mice. To determine the association of p53 with the prominent enhancement of apoptosis in FLV- plus TBI-treated C3H mice, p53 knockout mice of the C3H background (C3H p53(-/-)) were infected with FLV and treated with TBI. As expected, p53 knockout mice exhibited a very low frequency of apoptosis in the bone marrow after treatment with FLV plus TBI. Further, C3H p53(-/-) --> C3H p53(+/+) bone marrow chimeric mice treated with FLV plus TBI survived even longer than the chimeras treated with FLV alone. These findings indicate that infection with FLV strongly enhances radiation-induced apoptotic cell death of hematopoietic cells in host animals and that the apoptosis occurs through a p53-associated signaling pathway, although the response was not uniform in different host strains.

Anemia↗