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Cardiofaciocutaneous syndrome (CFC) is a rare genetic disorder that presents with cardiac, craniofacial, and cutaneous symptoms, and is often accompanied by neurological abnormalities, including neurodevelopmental disorders and epilepsy. Regarding epilepsy in CFC, the onset of seizures commonly occurs in childhood. Since research data has mainly been collected from young patients with relatively short observation period, there is insufficient information regarding adult-onset epilepsy in CFC. Here, we report the long-term clinical course of epilepsy and other complications in a 45-year-old female with genetically confirmed CFC carrying a pathogenic de novo heterozygous variant of MAP2K1, c.389 A>G (p.Tyr130Cys). The patient presented psychomotor delay from infancy and had severe intellectual disability with autistic features. At the age of 30, she first developed combined generalized and focal epilepsy that was resistant to anti-seizure medication. Her refractory epilepsy was fairly controlled with a combination of three anti-seizure medications, especially lacosamide, which effectively suppressed both generalized and focal seizures. The present case provides detailed information regarding the clinical course and treatment of adult-onset epilepsy, which may be useful for optimal treatment and prognostic prediction of CFC.

For autonomous mobile robots to work safely in human-coexistent environments, human-velocity estimation is essential. However, the human body periodically fluctuates to the front, rear, right, and left while walking. Also, a significant estimation error occurs due to the vibration of sensors installed in the robot. Quick trajectory adjustment requires high-accuracy and low-latency estimation, but these are in a trade-off relationship. We thus propose a human velocity estimation system (VES) using the Kalman filter (KF) and least squares (LS) with adjustable window size (AWS) to control the accuracy and latency. The VES adjusts two window sizes to calculate a system noise distribution for KF and a velocity vector for LS using a newly proposed cost function, including accuracy (direction and magnitude) and latency (time delay) costs. To select window sizes suitable for walking trajectories and individual gaits, we collected human walking data, calculated the three costs, and selected the window sizes with the minimum cost. The results of experiments using a laser range finder installed on a mobile robot indicate that the cost function could reveal window sizes to increase accuracy or reduce latency depending on walking trajectories and individual gaits, and the VES with AWS could enhance the performance of estimating human walking velocity for mobile robots.

Abstract Background On the basis of international clinical trials, capecitabine plus cisplatin (XP) as a first-line treatment of advanced gastric cancer is considered a global standard regimen. However, the usefulness of XP as compared with S-1 plus cisplatin (SP), which is considered standard therapy in Japan, has not yet been assessed. Methods/design This is a multicenter randomized phase II trial to elucidate the efficacy of XP as compared with SP for first-line treatment of advanced gastric cancer. Patients with unresectable metastatic or recurrent gastric cancer, 20–74 years of age and human epidermal growth factor 2 (HER2)-negative status, will be assigned in a 1:1 ratio to receive either S-1 40 mg/m2 bid for 21 days plus cisplatin 60 mg/m2 (day 8) every 5-week cycle or capecitabine 1000 mg/m2 bid for 14 days plus cisplatin 80 mg/m2 (day 1) every 3-week cycle. Patients will be also asked to the analysis of tumor tissues for translational investigations. The Primary endpoint is progression-free survival and secondary endpoints are overall survival, time to treatment failure, tumor response rate and safety. These comparisons will also be evaluated in terms of biomarkers. Planned sample size is 100 (50 in each arm), which is appropriate for this trial. Discussion Fluoropyrimidine plus cisplatin combination is the standard regimen of the first line treatment for advanced gastric cancer. Both S-1 and capecitabine are the prodrug of 5-FU but differ from their process of metabolism. Result of this trial and translational research will provide the important clues to prepare the individualized therapy for advanced gastric cancer in the near future. Trial registration ClinicalTrials.gov Identifier NCT01406249

Abstract Aim Mutation spectrum of TP53 in gastric cancer (GC) has been investigated world-widely, but a comparison of mutation spectrum among GCs from various regions in the world are still sparsely documented. In order to identify the difference of TP53 mutation spectrum in GCs in Eastern Europe and in East Asia, we sequenced TP53 in GCs from Eastern Europe, Lujiang (China), and Yokohama, Kanagawa (Japan) and identified the feature of TP53 mutations of GC in these regions. Subjects and method In total, 689 tissue samples of GC were analyzed: 288 samples from East European populations (25 from Hungary, 71 from Poland and 192 from Romania), 268 from Yokohama, Kanagawa, Japan and 133 from Lujiang, Anhui province, China. DNA was extracted from FFPE tissue of Chinese, East European cases; and from frozen tissue of Japanese GCs. PCR products were direct-sequenced by Sanger method, and in ambiguous cases, PCR product was cloned and up to 8 clones were sequenced. We used No. NC_000017.11(hg38) as the reference sequence of TP53. Mutation patterns were categorized into nine groups: six base substitutions, insertion, deletion and deletion-insertion. Within G:C > A:T mutations the mutations in CpG and non-CpG sites were divided. The Cancer Genome Atlas data (TCGA, ver.R20, July, 2019) having somatic mutation list of GCs from Whites, Asians, and other ethnicities were used as a reference for our data. Results The most frequent base substitutions were G:C > A:T transition in all the areas investigated. The G:C > A:T transition in non-CpG sites were prominent in East European GCs, compared with Asian ones. Mutation pattern from TCGA data revealed the same trend between GCs from White (TCGA category) vs Asian countries. Chinese and Japanese GCs showed higher ratio of G:C > A:T transition in CpG sites and A:T > G:C mutation was more prevalent in Asian countries. Conclusion The divergence in mutation spectrum of GC in different areas in the world may reflect various pathogeneses and etiologies of GC, region to region. Diversified mutation spectrum in GC in Eastern Europe may suggest GC in Europe has different carcinogenic pathway of those from Asia.

Abstract Background The cerebellum plays an important role in motor control, however, its involvement in epilepsy has not been fully understood. Arterial spin labelling perfusion magnetic resonance image (ASL) is a noninvasive method to evaluate cerebral and cerebellar blood flow. We investigated cerebellar perfusion in patients with epileptic seizures using ASL. Methods Adult patients with epileptic seizures who underwent ASL in three post labeling delay (PLD) conditions (1525, 1800, and 2500 msec) and conventional electroencephalography (EEG) on the same day were investigated. Clinical and EEG characteristics of them were retrospectively analyzed. Results Six patients (6 women, age; 36.2 ± 17.9 years (mean ± SD)) showed hyperperfusion in selective areas in the cerebellar paravermis of lobule VIIb. One patient with generalized epilepsy (tentative diagnosis of juvenile myoclonic epilepsy or epilepsy with myoclonic absences) showed unilateral hypoperfusion in PLD 1525 msec and hyperperfusion in PLD 1800 and 2500 msec at the area while EEG showed generalized spike-wave complexes. After successful treatment, these perfusion abnormalities disappeared. In two patients with focal epilepsy manifesting with asymmetrical motor symptoms, cerebellar hyperperfusion was found on the opposite side to the seizure focus estimated by seizure semiology. Besides hyperperfusion of the VIIb lobule, hypoperfusion at the same area was detected in shorter PLD condition in four patients and in longer PLD condition in one patient. Conclusion The cerebellar paravermis of lobule VIIb can be a component of motor circuit and participate in epileptic network in humans. Cerebellar perfusion abnormalities can be associated with neurovascular coupling via capillary bed.

Abstract Biomarkers for selecting gastric cancer (GC) patients likely to benefit from sequential paclitaxel treatment followed by fluorinated-pyrimidine-based adjuvant chemotherapy (sequential paclitaxel) were investigated using tissue samples of patients recruited into SAMIT, a phase III randomized controlled trial. Total RNA was extracted from 556 GC resection samples. The expression of 105 genes was quantified using real-time PCR. Genes predicting the benefit of sequential paclitaxel on overall survival, disease-free survival, and cumulative incidence of relapse were identified based on the ranking of p-values associated with the interaction between the biomarker and sequential paclitaxel or monotherapy groups. Low VSNL1 and CD44 expression predicted the benefit of sequential paclitaxel treatment for all three endpoints. Patients with combined low expression of both genes benefitted most from sequential paclitaxel therapy (hazard ratio = 0.48 [95% confidence interval, 0.30–0.78]; p

Endogenous neural stem/progenitor cells (NPCs) can migrate toward sites of injury, but the migration activity of NPCs is insufficient to regenerate damaged brain tissue. In this study, we showed that p38 MAP kinase (p38) is expressed in doublecortin-positive adult NPCs. Experiments using the p38 inhibitor SB203580 revealed that endogenous p38 participates in NPC migration. To enhance NPC migration, we generated a cell-permeable wild-type p38 protein (PTD-p38WT) in which the HIV protein transduction domain (PTD) was fused to the N-terminus of p38. Treatment with PTD-p38WT significantly promoted the random migration of adult NPCs without affecting cell survival or differentiation; this effect depended on the cell permeability and kinase activity of the fusion protein. These findings indicate that PTD-p38WT is a novel and useful tool for unraveling the roles of p38, and that this protein provides a reasonable approach for regenerating the injured brain by enhancing NPC migration.

Abstract Aim Gastric cancer is the second leading cause of cancer death worldwide. Surgery is the mainstay treatment for gastric cancer. There are no prediction models that examine the severity of postoperative morbidity. Herein, we constructed prediction models that analyze the risk for postoperative morbidity based on severity. Methods Perioperative data were retrieved from the National Clinical Database in patients who underwent elective gastric cancer resection between 2011 and 2012 in Japan. Severity of postoperative complications was determined by Clavien‐Dindo classification. Patients were randomly divided into two groups, the development set and the validation set. Logistic regression analysis was used to build prediction models. Calibration powers of the models were assessed by a calibration plot in which linearity between the observed and predicted event rates in 10 risk bands was assessed by the Pearson R2 statistic. Results We obtained 154 278 patients for the analysis. Prediction models were constructed for grade ≥2, grade ≥3, grade ≥4, and grade 5 in the development set (n = 77 423). Calibration plots of these models showed significant linearity in the validation set (n = 76 855): R2 = 0.995 for grade ≥2, R2 = 0.997 for grade ≥3, R2 = 0.998 for grade ≥4, and R2 = 0.997 for grade 5 (all: P

BACKGROUND Stable coronary artery disease is caused by a variable combination of organic coronary stenosis and functional coronary abnormalities, such as coronary artery spasm. Thus, we examined the clinical importance of comorbid significant coronary stenosis and coronary spasm. METHODS AND RESULTS We enrolled 236 consecutive patients with suspected angina who underwent acetylcholine provocation testing for coronary spasm and fractional flow reserve (FFR) measurement. Among them, 175 patients were diagnosed as having vasospastic angina (VSA), whereas the remaining 61 had no VSA (non‐VSA group). The patients with VSA were further divided into the following 3 groups based on angiography and FFR: no organic stenosis (≤50% luminal stenosis; VSA‐alone group, n=110), insignificant stenosis of FFR>0.80 (high‐FFR group, n=36), and significant stenosis of FFR≤0.80 (low‐FFR group, n=29). The incidence of major adverse cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, urgent percutaneous coronary intervention, and hospitalization attributed to unstable angina was evaluated. All patients with VSA received calcium channel blockers, and 28 patients (95%) in the low‐FFR group underwent a planned percutaneous coronary intervention. During a median follow‐up period of 656 days, although the incidence of major adverse cardiovascular events was low and comparable among non‐VSA, VSA‐alone, and high‐FFR groups, the low‐FFR group had an extremely poor prognosis (non‐VSA group, 1.6%; VSA‐alone group, 3.6%; high‐FFR group, 5.6%; low‐FFR group, 27.6%) (P

It is very important to design electrical machineries with high efficiency from the point of view of saving energy. Therefore, topology optimization (TO) is occasionally used as a design method for improving the performance of electrical machinery under the reasonable constraints. Because TO can achieve a design with much higher degree of freedom in terms of structure, there is a possibility for deriving the novel structure which would be quite different from the conventional structure. In this paper, topology optimization using sequential linear programming using move limit based on adaptive relaxation is applied to two models. The magnetic shielding, in which there are many local minima, is firstly employed as firstly benchmarking for the performance evaluation among several mathematical programming methods. Secondly, induction heating model is defined in 2-D axisymmetric field. In this model, the magnetic energy stored in the magnetic body is maximized under the constraint on the volume of magnetic body. Furthermore, the influence of the location of the design domain on the solutions is investigated.