Comparison of the five different definitions of equol producers: The relationship between blood and urine equol concentrations and blood parameters in 466 healthy men and women.

BACKGROUND AND AIMS: No studies have compared various definitions of "equol producers" until now. Therefore, we aimed to explore the accuracy of five different definitions of equol producers (EQP) and their associations with health benefits. METHODS: This is a cross-sectional study of 466 healthy Japanese men and women aged between 22 and 88 years. Equol producer proportions were calculated from their serum and urine isoflavone concentrations using five commonly used definitions. We then examined their accuracy, and associations with the blood parameters. RESULTS: Proportions of equol ranged from 29 % in the most stringent definition to 47.6 % in the most sensitive definition. EQP identified under all definitions had significantly low serum PSA1 levels compared to nonequol producers (NEQP). The most stringent definition, which is defined as the urinary equol level of 1.0 µM and above, corresponded to the highest median serum equol level and was associated with better health outcomes. Male EQP identified by this definition seemed to have reduced risk of LDL2-hypercholesterolemia by 50 %, and female EQP identified by this definition seemed to have lower risk of high hs-CRP,3 compared to NEQP. Both the first and second stringent definition, which is defined as the serum equol level of 1.0 ng/mL and above, was associated with lower thyroid stimulating hormone level. CONCLUSIONS: More stringent definitions were associated with better parameters in general. Combined with the dietary inquires, a reliable definition for equol producer is crucial to evaluate the health benefits of equol.

Delivery of a BET protein degrader via a CEACAM6-targeted antibody-drug conjugate inhibits tumour growth in pancreatic cancer models.

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all cancers. To improve PDAC therapy, we establish screening systems based on organoid and co-culture technologies and find a payload of antibody-drug conjugate (ADC), a bromodomain and extra-terminal (BET) protein degrader named EBET. We select CEACAM6/CD66c as an ADC target and developed an antibody, #84.7, with minimal reactivity to CEACAM6-expressing normal cells. EBET-conjugated #84.7 (84-EBET) has lethal effects on various PDAC organoids and bystander efficacy on CEACAM6-negative PDAC cells and cancer-associated fibroblasts. In mouse studies, a single injection of 84-EBET induces marked tumor regression in various PDAC-patient-derived xenografts, with a decrease in the inflammatory phenotype of stromal cells and without significant body weight loss. Combination with standard chemotherapy or PD-1 antibody induces more profound and sustained regression without toxicity enhancement. Our preclinical evidence demonstrates potential efficacy by delivering BET protein degrader to PDAC and its microenvironment via CEACAM6-targeted ADC.

Comparison of blood and urine concentrations of equol by LC‒MS/MS method and factors associated with equol production in 466 Japanese men and women.

Equol is produced from daidzein by the action of gut bacteria on soy isoflavones. However, not all people can produce equol, and metabolism differs even among the producers. We aimed to examine the equol producer status in both men and women, and investigate the relationships among the serum and urinary isoflavones as well as to other biomedical parameters. In this study, we measured the equol and daidzein concentrations from the blood and urine of 292 men and 174 women aged between 22 and 88 years by liquid chromatography-tandem mass spectrometry (LC‒MS/MS). We then analysed the cut-off value for equol producers in both sexes, the relationship of serum and urinary equol concentrations, and other parameters, such as sex, age, endocrine function, glucose metabolism, lipid metabolism, and renal function with regards to equol-producing ability, among the different age groups. Equol producers were defined as those whose log ratio of urinary equol and daidzein concentration or log (equol/daidzein) was -1.42 or higher. Among 466 participants, 195 were equol producers (42%). The proportion of equol producers was larger in women. The cut-off value for equol producers was consistent in both sexes. Positive relationships were noted between serum and urinary equol levels in equol producers of both sexes; however, such a relationship was not detected in nonproducers. Lipid and uric acid abnormalities were more common with non equol producers in both men and women. Prostate specific antigen (PSA) levels in men were significantly lower in equol producers, especially in those in their 40 s. This study suggests a relationship between equol-producing ability and reduced risk of prostate disease as well as positive effects of equol on blood lipids and uric acid levels. However, lack of dietary information and disperse age groups were major drawbacks in generalizing the results of this study.

Divergent progression pathways in male androgenetic alopecia and female pattern hair loss: Trichoscopic perspectives.

BACKGROUND: Despite similarities in progressive miniaturization of hair follicles and transition of terminal hairs to vellus hairs, insufficient trichoscopic comparisons between male androgenetic alopecia (MAGA) and female pattern hair loss (FPHL) hinder our ability to select effective treatments. AIM: Our study aimed to explore gender-specific trichoscopic characteristics of MAGA and FPHL, while formulating hypotheses regarding the progression of these conditions across clinical stages. METHODS: We classified 126 male MAGA subjects using Hamilton-Norwood Classification and 57 FPHL subjects using adopted Sinclair Scale. Subsequently, we analyzed nine trichoscopic factors divided into three categories: hair-diameter related, hair-number per follicular unit related, and hair density related factors. RESULTS: Of the nine quantitative trichoscopic factors, hair-diameter and hair-number per follicular unit showed strong correlations with clinical stages in both genders. Hair density, a common trichoscopic factor for hair loss evaluation, weakly correlated with clinical stages in FPHL, but not at all in MAGA. In addition, MAGA was characterized by a progressive reduction in hair-diameter, followed by a reduction in hair-number per follicular unit. FPHL, on the contrary, showed the opposite progression. CONCLUSIONS: Trichoscopic factors vary with disease severity in a gender-specific manner. Our research highlights that MAGA and FPHL involve two distinct streams: hair-diameter decreasing by hair follicle miniaturization (Stream 1), and hair-number per follicular unit decreasing by hair follicle tri-lineage niche dysfunction (Stream 2). MAGA typically starts from Stream 1 to Stream 2, while FPHL starts from Stream 2. These diverse progression pathways underscore the importance of personalized treatment approaches.

Gold(I)-Catalyzed Cascade Cyclization of Alkynyl Indoles for the Stereoselective Construction of the Quaternary Carbon Center of Akuammiline Alkaloids.

A gold-catalyzed cyclization reaction of alkynyl-indoles has been developed for the stereoselective construction of the quaternary carbon center of fused indolines. This reaction efficiently produces fused indolines via diastereoselective 6-endo-dig cyclization controlled by a bulky TIPS group, followed by nucleophilic attack of the carboxy group on the resulting imine. The lactone moiety of the fused indoline can be reductively cleaved to produce a tricyclic indoline, which could be useful for the synthesis of akuammiline alkaloids.

Trichoscopic evaluation of dental pulp stem cell conditioned media for androgenic alopecia.

BACKGROUND: Conditioned media (CM) derived from mesenchymal stem cells (MSC) is known to induce hair regrowth in androgenic alopecia. OBJECTIVES: The objectives of the study were to assess the efficacy and safety of one type of MSC-CM, the CM derived from dental pulp stem cells obtained from human exfoliated deciduous teeth (SHED-CM) and to compare the efficacy of SHED-CM with and without dihydrotestosterone synthesis inhibitor (DHT-inhibitor). METHODS: Eighty-eight male androgenic alopecia subjects with Hamilton-Norwood Classification (H-N C) I-VII were evaluated by trichoscopy to explore which trichoscopic factors statistically correlated with H-N C. After being screened, 33 subjects received six SHED-CM treatments at 1-month intervals. Clinical severity was assessed through global and trichoscopic images from baseline to 9th month. RESULTS: SHED-CM was effective for 75% of subjects regardless of disease severity, concomitant DHT-inhibitor use, and age. Adverse effects including pain and small hemorrhages were transient and mild. We also found that clinical hair status evaluated by absolute values of three quantitative trichoscopic factors (maximum hair diameter, vellus hair rate, and multi-hair follicular unit rate) showed a good correlation with H-N C stages, and what is more-a scoring system of these three factors can be a possible predictor of SHED-CM efficacy. CONCLUSIONS: We have shown that SHED-CM provides global and trichoscopic image improvement for androgenic alopecia, regardless of concomitant DHT-inhibitor use.

Identification of circulating tumour DNA (ctDNA) from the liquid biopsy results: Findings from an observational cohort study.

Liquid biopsies can be a rapid, cost-effective and non-invasive alternative to tumour biopsies for detecting genetic mutations in somatic tumours. Genetic profiling of liquid biopsies can also be used to identify novel antigens for targeted therapy, provide updated information on disease prognosis and evaluate treatment efficacy. In this study, we aimed to examine mutations that could be identified in liquid biopsy and their distribution in a small study cohort. We studied the genomic profiles of 99 blood samples from 85 patients with 21 different types of cancer using two commercially available liquid biopsy tests. The mean circulating free DNA (cfDNA) concentration was 162.7 ± 352.3 nanograms per 20 millilitres. Amongst cfDNA, the circulating tumour DNA (ctDNA) percentage ranged from 0.006% to 90.6%. With the exception of samples with gene amplification and high microsatellite instability, the number of mutations in each sample varied from zero to 21, with an average of 5.6 mutations in each patient. Amongst these mutations, nonsynonymous mutations were the most frequently observed type of mutation (90% of the sample, with an average frequency of 3.6 mutations per patient). Mutations were observed in 76 different genes. TP53 mutations constituted more than 16% of the detectable mutations, especially in non-small cell lung cancer. All the tumour types, except the ovary, kidney and apocrine gland tumours, harboured at least one type of TP53 mutation. KRAS (mainly in pancreatic cancer) and PIK3CA (mostly in breast cancer) mutations, were responsible for an additional 10% of the mutations in the studied samples. The tumour mutations were specific to each patient, as approximately 94.7% of the mutations were so unique that there was almost no duplication amongst the patients. These findings indicate that liquid biopsy can detect specific molecular changes of tumour, which is useful for precision oncology and personalized cancer treatment.

Brain atrophy in middle age using magnetic resonance imaging scans from Japan's health screening programme.

Although health screening plays a key role in the management of chronic diseases associated with lifestyle choices, brain health is not generally monitored, remaining a black box prior to the manifestation of clinical symptoms. Japan is unique in this regard, as brain MRI scans have been widely performed for more than two decades as part of Brain Dock, a comprehensive health screening programme. A vast number of stored images (well over a million) of longitudinal scans and extensive health data are available, offering a valuable resource for investigating the prevalence of various types of brain-related health conditions occurring throughout adulthood. In this paper, we report on the findings of our preliminary quantitative analysis of T1-weighted MRIs of the brain obtained from 13 980 subjects from three participating sites during the period 2015-19. We applied automated segmentation analysis and observed age-dependent volume loss of various brain structures. We subsequently investigated the effects of scan protocols and the feasibility of calibration for pooling the data. Last, the degree of brain atrophy was correlated with four known risk factors of dementia; blood glucose level, hypertension, obesity, and alcohol consumption. In this initial analysis, we identified brain ventricular volume as an effective marker of age-dependent brain atrophy, being highly sensitive to ageing and evidencing strong robustness against protocol variability. We established the normal range of ventricular volumes at each age, which is an essential first step for establishing criteria used to interpret data obtained for individual participants. We identified a subgroup of individuals at midlife with ventricles that substantially exceeded the average size. The correlation studies revealed that all four risk factors were associated with greater ventricular volumes at midlife, some of which reached highly significant sizes. This study demonstrates the feasibility of conducting a large-scale quantitative analysis of existing Brain Dock data in Japan. It will importantly guide future efforts to investigate the prevalence of large ventricles at midlife and the potential reduction of this prevalence, and hence of dementia risk, through lifestyle changes.

Prediction model of Graves' disease in general clinical practice based on complete blood count and biochemistry profile.

Although untreated Graves' disease (GD) is associated with a higher risk of cardiac complications and mortality, there is no well-established way to predict the onset of thyrotoxicosis in clinical practice. The aim of this study was to identify important variables that will make it possible to predict GD and thyrotoxicosis (GD + painless thyroiditis (PT)) by using a machine-learning-based model based on complete blood count and standard biochemistry profile data. We identified 19,335 newly diagnosed GD patients, 3,267 PT patients, and 4,159 subjects without any thyroid disease. We built a GD prediction model based on information obtained from subjects regarding sex, age, a complete blood count, and a standard biochemistry profile. We built the model in the training set and evaluated the performance of the model in the test set by using the artificial intelligence software Prediction One. Our machine learning-based model showed high discriminative ability to predict GD in the test set (area under the curve [AUC] 0.99). The main contributing factors to predict GD included age and serum creatinine, total cholesterol, alkaline phosphatase, and total protein levels. We still found high discriminative ability even when we restricted the variables to these five most contributory factors in our prediction model (AUC 0.97) built by using artificial intelligence software showed high GD prediction ability based on information regarding only five factors.

Impact of mature dendritic cells pulsed with a novel WT1 helper peptide on the induction of HLA­A2­restricted WT1­reactive CD8+ T cells.

The proliferation and activation of CD4+ T helper 1 (Th1) cells and CD8+ cytotoxic T lymphocytes (CTLs) that produce interferon­Î³ (IFN­Î³) is an essential action of effective cancer vaccines. Recently, a novel Wilms' tumor 1 (WT1) helper peptide (WT1 HP34­51; amino acid sequence, WAPVLDFAPPGASAYGSL) applicable for various human leukocyte antigen (HLA) subtypes (HLA­DR, HLA­DP and HLA­DQ) was reported to increase peptide immunogenicity; however, the function of WT1 HP34­51 remains unclear. In the present study, mature dendritic cells (mDCs) pulsed with WT1 HP34­51 (mDC/WT1 HP34­51) activated not only WT1­specific CD4+ T cells but also CD8+ T cells that produced IFN­Î³ following stimulation with immature dendritic cells (imDCs) pulsed with WT1 killer peptide (imDC/WT1 KP37­45) in an HLA­A*02:01­ or HLA­A*02:06­restricted manner. Furthermore, the activated WT1­reactive CD4+ Th1 cells were predominantly effector memory (EM) T cells. In 5 of 12 (41.7%) patients with cancer carrying the HLA­A*02:01 or HLA­A*02:06 allele, WT1­reactive CD8+ T cells stimulated with mDC/WT1 HP34­51 enhanced their levels of WT1 KP37­45­specific IFN­Î³ production, with an increase >10%. Simultaneous activation of CD4+ and CD8+ T cells occurred more often when stimulation with mDC/WT1 HP34­51 was combined with imDC/WT1 KP37­45 restimulation. These results indicated that the novel mDC/WT1 HP34­51 combination induced responses by WT1­specific EM CD4+ Th1 cells and HLA­A*02:01­ or HLA­A*02:06­restricted CD8+ CTLs, suggesting its potential as a WT1­targeting cancer vaccine.

Factors affecting the accuracy of respiratory tracking of the image-guided robotic radiosurgery system.

PURPOSE: To analyze the factors affecting the tracking accuracy of the CyberKnife Synchrony Respiratory Tracking System (SRTS). MATERIALS AND METHODS: A dynamic motion phantom (motion phantom) reproduced the respiratory motions of each patient treated with the SRTS using a ball as the target. CyberKnife tracked the ball using the SRTS, and this process was recorded by a video camera mounted on the linear accelerator head. The tracking error was evaluated from the images captured by the video camera. Multiple regression analysis was used to identify factors affecting tracking accuracy from 91 cases. RESULTS: The median tracking error was 1.9 mm (range 0.9-5.3 mm). Four factors affected the tracking accuracy: the average absolute amplitude of the tumor motion in the cranio-caudal (CC) direction (p = 0.007), average position gap due to the phase shift between the internal tumor and external marker positions in the CC direction (p < 0.001), and average velocity of the tumor in the CC (p < 0.001) and anterior-posterior directions (p = 0.033). CONCLUSION: We identified factors that affected tracking accuracy. This information may assist the identification of suitable margins that should be added to each patient's clinical target volume.

Pilot study of WT1 peptide-pulsed dendritic cell vaccination with docetaxel in esophageal cancer.

In the present study, the immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell (DC) vaccination combined with docetaxel (DCDOC) in advanced esophageal cancer patients who had already received first-line chemotherapy was investigated. Ten HLA-A*2402 patients were treated with docetaxel (50 mg/m2) on day 1 and WT1 peptide-pulsed DC vaccination (1×107 cells) on days 15 and 22 (repeated every 4 weeks for 3 cycles). The delayed-type hypersensitivity skin test, HLA tetramer assay and interferon-γ enzyme-linked immunospot (ELISPOT) assay were used to evaluate the induction of a WT1-specific immune response. Median overall survival was 5 months (range, 1.1-11.6). The clinical effect of DCDOC therapy was not observed and only 1 patient could complete the protocol therapy. Disease progression was observed in 9 patients and 1 patient succumbed to fatality during the second cycle of therapy. As a pilot study, it was not possible to evaluate the safety of WT1 peptide-pulsed DCDOC therapy for esophageal squamous cell cancer. However, a WT1-specific response in 6 patients, as indicated by the ELISPOT or HLA/WT1-tetramer assay, was demonstrated. The results suggested that the positive immune response had significant relevance on the low percentage of CD11b+ and CD66b+ granulocytic myeloid-derived suppressor cells in CD15+ cells. Furthermore, DCDOC elicited a WT1-specific immune response regardless of the myelosuppression associated with docetaxel. The present findings support future studies and further work to assess DCDOC as an adjuvant therapy for esophageal cancer will be performed. The present clinical trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry on November 11th, 2011, no. UMIN000006704.

Detection rates and sites of unruptured intracranial aneurysms according to sex and age: an analysis of MR angiography-based brain examinations of 4070 healthy Japanese adults.

OBJECTIVIE: The purpose of this study was to evaluate the detection rate and occurrence site according to patient sex and age of unruptured intracranial aneurysms detected through MRI and MR angiography (MRA). METHODS: A total of 4070 healthy adults 22 years or older (mean age [± SD] 50.6 ± 11.0 years; 41.9% women) who underwent a brain examination known as "Brain Dock" in the central Tokyo area between April 2014 and March 2015 were checked for unruptured saccular aneurysm using 3-T MRI/MRA. The following types of cases were excluded: 1) protrusions with a maximum diameter < 2 mm at locations other than arterial bifurcations, 2) conical protrusions at arterial bifurcations with a diameter < 3 mm, and 3) cases of suspected aneurysms with unclear imaging of the involved artery. When an aneurysm was definitively diagnosed, the case was included in the aneurysm group. The authors also investigated the relationship between aneurysm occurrence and risk factors (age, sex, smoking history, hypertension, diabetes, and hyperlipidemia). RESULTS: One hundred eighty-eight aneurysms were identified in 176 individuals (detection rate 4.32%), with the detection rate for women being significantly higher (6.2% vs 3.0%, p < 0.001). The average age in the aneurysm group was significantly higher than in the patients in whom aneurysms were not detected (53.0 ± 11.1 vs 50.5 ± 11.0 years). The detection rate tended to increase with age. The detection rates were 3.6% for people in their 30s, 3.5% for those in their 40s, 4.1% for those in their 50s, 6.9% for those in their 60s, and 6.8% for those in their 70s. Excluding persons in their 20s and 80s­age groups in which no aneurysms were discovered­the detection rate in women was higher in all age ranges. Of the individuals with aneurysms, 12 (6.81%) had multiple cerebral aneurysms; no sex difference was observed with respect to the prevalence of multiple aneurysms. Regarding aneurysm size, 2.0­2.9 mm was the most common size range, with 87 occurrences (46.3%), followed by 3.0­3.9 mm (67 [35.6%]) and 4.0­4.9 mm (20 [10.6%]). The largest aneurysm was 13 mm. Regarding location, the internal carotid artery (ICA) was the most common aneurysm site, with 148 (78.7%) occurrences. Within the ICA, C1 was the site of 46 aneurysms (24.5%); C2, 57 (30.3%); and C3, 29 (15.4%). The aneurysm detection rates for C2, C3, and C4 were 2.23%, 1.23%, and 0.64%, respectively, for women and 0.68%, 0.34%, and 0.21%, respectively, for men; ICA aneurysms were significantly more common in women than in men (5.27% vs 2.20%, p < 0.001). Multivariate logistic regression analysis revealed that age (p < 0.001, OR 1.03, 95% CI 1.01­1.04), female sex (p < 0.001, OR 2.28, 95% CI 1.64­3.16), and smoking history (p = 0.011, OR 1.52, 95% CI 1.10­2.11) were significant risk factors for aneurysm occurrence. CONCLUSIONS: In this study, both female sex and older age were independently associated with an increased aneurysm detection rate. Aneurysms were most common in the ICA, and the frequency of aneurysms in ICA sites was markedly higher in women.

Peptide-pulsed dendritic cell vaccine in combination with carboplatin and paclitaxel chemotherapy for stage IV melanoma.

In this study, we aimed to evaluate the feasibility and efficacy of peptide-pulsed dendritic cell (DC) vaccine in combination with carboplatin and paclitaxel chemotherapy (DCCP) for patients with stage IV melanoma previously treated with dacarbazine-containing regimen. Six HLA-A24 and 3 HLA-A02 patients were treated with carboplatin (area under the curve 5) and paclitaxel (175 mg/m) on day 1 and DCs (2×10 cells) pulsed with Wilms tumor gene 1 (WT1), gp100, tyrosinase, and either MAGE-A3 (for HLA-A24) or MAGE-A2 (for HLA-A02) peptides on days 8 and 22 in 28-day cycle for up to three cycles. DCCP was well tolerated, and median progression-free survival and median overall survival were 2.3 and 12.0 months, respectively. In four of nine patients, a WT1-specific immune response (WT1-IR) was detected using the interferon-γ enzyme-linked ImmunoSpot assay and WT1/HLA tetramer assay. DCCP was more likely to elicit a WT1-IR in patients who received DCs pulsed with the HLA-A24-restricted peptide (75%) compared with patients who received DCs pulsed with the HLA-A02-restricted peptide (0%, P=0.058). Furthermore, three (75%) of four patients with a WT1-IR survived longer than 12 months, whereas only one (20%) of five patients without a WT1-IR who received the BRAF inhibitor after DCCP survived longer than 12 months. These results suggest that DCCP may be beneficial for HLA-A24 melanoma patients with a WT1-IR.

Development of system using beam's eye view images to measure respiratory motion tracking errors in image-guided robotic radiosurgery system.

The accuracy of the CyberKnife Synchrony Respiratory Tracking System (SRTS) is considered to be patient-dependent because the SRTS relies on an individual correlation between the internal tumor position (ITP) and the external marker position (EMP), as well as a prediction method to compensate for the delay incurred to adjust the position of the linear accelerator (linac). We aimed to develop a system for obtaining pretreatment statistical measurements of the SRTS tracking error by using beam's eye view (BEV) images, to enable the prediction of the patient-specific accuracy. The respiratory motion data for the ITP and the EMP were derived from cine MR images obtained from 23 patients. The dynamic motion phantom was used to reproduce both the ITP and EMP motions. The CyberKnife was subsequently operated with the SRTS, with a CCD camera mounted on the head of the linac. BEV images from the CCD camera were recorded during the tracking of a ball target by the linac. The tracking error was measured at 15 Hz using in-house software. To assess the precision of the position detection using an MR image, the positions of test tubes (determined from MR images) were compared with their actual positions. To assess the precision of the position detection of the ball, ball positions measured from BEV images were compared with values measured using a Vernier caliper. The SRTS accuracy was evaluated by determining the tracking error that could be identified with a probability of more than 95% (Ep95). The detection precision of the tumor position (determined from cine MR images) was < 0.2 mm. The detection precision of the tracking error when using the BEV images was < 0.2mm. These two detection precisions were derived from our measurement system and were not obtained from the SRTS. The median of Ep95 was found to be 1.5 (range, 1.0-3.5) mm. The difference between the minimum and maximum Ep95 was 2.5mm, indicating that this provides a better means of evaluating patient-specific SRTS accuracy. A suitable margin, based on the predicted patient-specific SRTS accuracy, can be added to the clinical target volume.

Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer.

This study aimed to evaluate the feasibility of and immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell vaccination combined with gemcitabine (DCGEM) as a first-line therapy among patients with advanced pancreatic cancer. Ten HLA-A*2402 patients were treated with WT1 peptide-pulsed DC vaccination (1 × 10(7) cells) on days 8 and 22 and gemcitabine (1000 mg/m(2) ) on days 1, 8 and 15. Induction of a WT1-specific immune response was evaluated using the delayed-type hypersensitivity (DTH) skin test, interferon-γ enzyme-linked immunospot and HLA tetramer assays, along with assays for various immunological factors. DCGEM was well-tolerated, and the relative dose intensity of gemcitabine was 87%. Disease control associated with a low neutrophil/lymphocyte ratio was observed in all three patients with DTH positivity; it was also correlated with a low percentage of granulocytic myeloid derived suppressor cells in the pretreatment peripheral blood (P = 0.017). Patients with liver metastases and high levels of inflammatory markers such as C-reactive protein and interleukin-8 (IL-8) showed poor survival even though a WT1-specific immune response was induced in them. WT1 peptide-pulsed DCGEM is feasible and effective for inducing anti-tumor T-cell responses. Our results support future investigations for pancreatic cancer patients with non-liver metastases and favorable immunological conditions. This trial was registered with the University hospital Medical Information Network (UMIN) Clinical Trials Registry (http://www.umin.ac.jp/ctr/ number: UMIN-000004855).

Effect of residual patient motion on dose distribution during image-guided robotic radiosurgery for skull tracking based on log file analysis.

PURPOSE: The present study aimed to assess the effect of residual patient motion on dose distribution during intracranial image-guided robotic radiosurgery by analyzing the system log files. MATERIALS AND METHODS: The dosimetric effect was analyzed according to the difference between the original and estimated dose distributions, including targeting error, caused by residual patient motion between two successive image acquisitions. One hundred twenty-eight treatments were analyzed. Forty-two patients were treated using the isocentric plan, and 86 patients were treated using the conformal (non-isocentric) plan. RESULTS: The median distance from the imaging center to the target was 55 mm, and the median interval between the acquisitions of sequential images was 79 s. The median translational residual patient motion was 0.1 mm for each axis, and the rotational residual patient motion was 0.1° for Δpitch and Δroll and 0.2° for Δyaw. The dose error for D 95 was within 1 % in more than 95 % of cases. The maximum dose error for D 10 to D 90 was within 2 %. None of the studied parameters, including the interval between the acquisitions of sequential images, was significantly related to the dosimetric effect. CONCLUSION: The effect of residual patient motion on dose distribution was minimal.

Manganese superoxide dismutase polymorphism affects the oxidized low-density lipoprotein-induced apoptosis of macrophages and coronary artery disease.

AIMS: Oxidative damage promotes atherosclerosis. Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme localized in mitochondria. We investigated the associations of the MnSOD polymorphism (valine-to-alanine in the mitochondrial-targeting domain) with its activity in leukocytes, with macrophage apoptosis by oxidized low-density lipoprotein (oxLDL), and with coronary artery disease (CAD). METHODS AND RESULTS: Blood samples were taken from 50 healthy subjects. The mitochondrial MnSOD activities in leukocytes were 542.4 +/- 71.6 U/mg protein (alanine/alanine, n = 2), 302.0 +/- 94.9 U/mg protein (alanine/valine, n = 12), and 134.0 +/- 67.1 U/mg protein (valine/valine, n = 36; P < 0.0001 for non-valine/valine vs. valine/valine). Macrophages were treated with oxLDL. After incubation, the percentages of apoptotic macrophages were 48.6 +/- 3.6% (alanine/alanine), 78.6 +/- 9.8% (alanine/valine), and 87.5 +/- 7.0% (valine/valine) (P < 0.0001, non-valine/valine vs. valine/valine). The association of the MnSOD polymorphism with CAD was investigated using blood samples collected from 498 CAD patients and 627 healthy subjects; the alanine allele was found to reduce the risk of CAD and acute myocardial infarction (AMI). CONCLUSION: Our data indicate that the alanine variant of signal peptide increases the mitochondrial MnSOD activity, protects macrophages against the oxLDL-induced apoptosis, and reduces the risk of CAD and AMI.