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Current evidence indicates that immune checkpoint inhibitors (ICIs) have a limited efficacy in patients with lung cancer harboring epidermal growth factor receptor (EGFR) mutations. However, there is a lack of data on the efficacy of ICIs after osimertinib treatment, and the predictors of ICI efficacy are unclear.We retrospectively assessed consecutive patients with EGFR-mutant NSCLC who received ICI-based therapy after osimertinib treatment at 10 institutions in Japan, between March 2016 and March 2021. Immunohistochemical staining was used to evaluate the expression of p53 and AXL. The deletions of exon 19 and the exon 21 L858R point mutation in EGFR were defined as common mutations; other mutations were defined as uncommon mutations.A total of 36 patients with advanced or recurrent EGFR-mutant NSCLC were analyzed. In multivariate analysis, p53 expression in tumors was an independent predictor of PFS after ICI-based therapy (p = 0.002). In patients with common EGFR mutations, high AXL expression was a predictor of shorter PFS and overall survival after ICI-based therapy (log-rank test; p = 0.04 and p = 0.02, respectively).The levels of p53 in pretreatment tumors may be a predictor of ICI-based therapy outcomes in patients with EGFR-mutant NSCLC after osimertinib treatment. High levels of AXL in tumors may also be a predictor of ICI-based therapy outcomes, specifically for patients with common EGFR mutations. Further prospective large-scale investigations on the predictors of ICI efficacy following osimertinib treatment are warranted.

Growth morphology of carbon clusters deposited on different substrates were investigated by theoretical and experimental approach. For theoretical approach, molecular dynamics was employed to evaluate an adsorptive stability of different size of carbon clusters placed on different substrates. The adsorptive stability was estimated by the difference of total energy of supercell designed as carbon cluster placed on a certain crystal plane of substrate. Among the simulations of this study, carbon cluster flatly settled down on the surface of SrTiO$$_{3}$$ 3 (001). The result was experimentally verified with layer by layer growth of graphene by pulsed laser deposition in carbon dioxide atmosphere. The absorptive stability can be useful reference for screening substrate for any target material other than graphene.

[Purpose] To describe our newly developed Sedentary Behavior and Light-Intensity Physical Activity Questionnaire and examine its reliability and validity. [Participants and Methods] We identified and selected self-reported items through a literature review and interviews with 11 inactive individuals. Thirty-one individuals with lower limb prostheses and an expert panel assessed the content validity of the integrated items and identified 17 items. Patients who had undergone lower limb surgeries were regarded as inactive individuals, and 112 patients completed the questionnaire twice for test-retest reliability and wore an accelerometer for criterion validity. The ethics committee of Kyushu University approved this study (2019-126 and 2019-273). [Results] Item analysis was revised to the Sedentary Behavior and Light-Intensity Physical Activity Questionnaire-10 (six light-intensity physical activity and four sedentary behavior items) because of the floor effect. The test-retest correlation coefficient showed high reliability. Moderate to weak correlation coefficient was observed between the questionnaire and accelerometer (light-intensity physical activity: 0.43 and sedentary behavior: 0.20), and the Bland-Altman plots indicated no bias. [Conclusion] The Sedentary Behavior and Light-Intensity Physical Activity Questionnaire-10 had acceptable validity and reliability among inactive individuals and it could be used for studying light-intensity physical activity.

Background Over 40% Japanese patients with lung cancer are above 75 years of age. A specific strategy to treat such older patients is necessary because most trials exclude older patients with poor physical health. Herein, we aimed to identify predictive factors associated with overall survival (OS) in older patients by evaluating patient backgrounds and laboratory data before the start of treatment. Methods This multicenter retrospective medical chart review study was conducted at three Japanese institutions and involved patients aged 75 years and above with epidermal growth factor receptor (EGFR) mutation-negative advanced non-small cell lung cancer (NSCLC). Of the patients, 75 had received best supportive care (BSC) and 49 mono-chemotherapy or platinum-doublet chemotherapy, including immune checkpoint inhibitors (ICIs). OS after diagnosis was analyzed using the Kaplan-Meier survival analysis. Cox proportional hazard models, which included age, Eastern Cooperative Oncology Group performance status (ECOG PS), staging, serum albumin levels, and receipt of chemotherapy were analyzed. Results Age at diagnosis was not shown to be related to OS in patients receiving BSC. In patients aged 81 years and above, the chemotherapy group tended to have longer survival than did the BSC group, but there was no statistically significant difference in the median OS between the two groups due to the very small number of subjects (n: 30 vs. 12, median: 52 vs. 30 weeks, hazard ratio: 0.512, 95% confidence interval: 0.232-1.130, P=0.088). The patients' performance status and albumin levels at lung cancer diagnosis had the highest impact on OS in the BSC group. Conclusions Careful consideration should be given to the indications of chemotherapy for patients aged 81 years and above with wild-type EGFR advanced non-small lung cancer.

The Hospital for Special Surgery Hip Replacement Expectations Survey (HSS-THRES) is used in many countries to determine patient expectations before surgery. This study aimed to assess the reliability and validity of the Japanese version of HSS-THRES.A total of 134 patients scheduled for total hip arthroplasty (THA) underwent a self-administered preoperative survey questionnaire. Patient's expectation and quality of life (QOL) were measured using the Japanese version of HSS-THRES, overall expectations for THA, Oxford hip score (OHS), and EuroQol-5D (EQ-5D). Some patients completed the Japanese version of HSS-THRES and the overall expectations for THA after a ten-day interval. Cross-cultural adaptation was validated by an expert committee comprising health professionals, a methodologist, language experts, and orthopedic specialists. The internal consistency was evaluated by the Cronbach α coefficient. The test-retest reliability was examined using the intraclass coefficient correlation (ICC) and the Bland and Altman analysis. To test the construct validity, nine priori hypotheses were tested by correlation analysis between the Japanese version of HSS-THRES and two QOL scales, and by examining the association with demographic variables.A total of 116 patients completed four scales. Patients were predominantly female (75.9%), with an average age of 62.2 ± 11.7. In the cross-cultural adaptation, all patients responded to the questionnaire without problems. The Japanese version of HSS-THRES showed good internal consistency (Cronbach α: 0.9). ICC was 0.94 and Bland-Altman analysis indicated no bias. The correlation between Japanese HSS-THRES and overall expectations for THA was high (r = 0.67). Similarly, the correlation with the OHS was higher than that with EQ-5D. A total of 77.8% of the hypotheses were confirmed.The Japanese version of HSS-THRES showed good cultural acceptability, high reliability, and validity to evaluate preoperative expectations for THA patients.

Background / Regular physical activity (PA) is important for maintaining mental and physical health after liver transplantation (LT); however, the fluctuations in routine PA during COVID-19 and its putative impacts are currently unknown. This study examined the changes in PA during the COVID-19 pandemic and explored its association with fear and depression during the pandemic. / Material/Methods / This longitudinal study included 83 LT patients whose PA was measured using the short form of the International Physical Activity Questionnaire before and during COVID-19. Fear of COVID-19 was estimated based on previous studies, and depression was assessed using the Patient Health Questionnaire-9. Participants were also asked about important sources of information on COVID-19. PA was classified as inactive or active depending on the changes in PA, and logistic regression analyses with PA as a dependent variable were conducted to explore the associations among PA, depression, and fear of COVID-19. / Results / Moderate and high PA exhibited decreasing trends before and during the COVID-19 pandemic, especially in males. Fear of being infected with SARS-CoV-2, the virus that causes COVID-19, while shopping was significantly higher in females and was significantly independent of inactivity during the COVID-19 pandemic. Only 1 patient reported that their transplant center was their main source of information about COVID-19. Only 4.9% of the LT participants were depressed. / Conclusions / Our study results indicate the need to support the provision of accurate information about COVID-19 by health care professionals in transplant centers, especially for patients with low PA, to prevent PA decline in LT patients.

Purpose The primary objective of this study was to identify the potential predictors to assess impact of maintenance therapy after induction immunochemotherapy in the real-world setting of patients with advanced non-small cell lung cancer (NSCLC). Methods We retrospectively identified 152 patients with advanced NSCLC who received immunochemotherapy at eight hospitals in Japan between January 2019 to December 2019. Patients who received at least four cycles of induction immunochemotherapy and one cycle of maintenance therapy with immune-checkpoint inhibitors were included. We investigated the biomarkers for progression-free survival (PFS) for maintenance therapy after induction immunochemotherapy. Results Out of the 92 patients with advanced NSCLC included in the study, 42 received maintenance therapy with cytotoxic agents whereas 50 received maintenance therapy without cytotoxic agents. Among those who received maintenance therapy without cytotoxic agents, responders to prior immunochemotherapy had significantly longer PFS than non-responders (p = 0.004), except those with maintenance therapy with cytotoxic agents. In non-responders to prior immunochemotherapy, patients with maintenance therapy with cytotoxic agents had significantly longer PFS than those with maintenance therapy without cytotoxic agents (log-rank p = 0.007), whereas among responders to prior immunochemotherapy, there was no significant difference in PFS for different maintenance regimens (log-rank p = 0.31). Conclusions This retrospective study showed that response to prior immunochemotherapy was associated with clinical outcomes among patients with advanced NSCLC who received maintenance therapy.

The conventional skin color separation method suffers from the severe limitation that the input skin image must have no shading component and must have substantial variation in the pigment density distribution, simultaneously. We therefore propose an improved method, which uses two input skin images instead of one. In this improved method, one input image has no shading component and the other has substantial variation in pigment density distribution. To verify the effect of our method, we took images of four subjects and separated them into pigment components. We then compared the independence evaluation value of the separated signals extracted using our method and that of the conventional method. The results show that we obtain separated signals that have a better independence evaluation value by our method than by the conventional method.

Aim: This study aimed to evaluate the effect of diet on serum lipids and to assess the effectiveness of long-term dietary therapy for hypertriglyceridemia. Methods: Seventy-nine patients (34 males and 45 females) with hypertriglyceridemia were enrolled and underwent dietary counseling for 12 months based on the following three recommendations: (1) reduce carbohydrate intake, (2) increase n-3 polyunsaturated fatty acid (PUFA) intake, and (3) limit alcohol drinking. We examined the effect of dietary therapy for 6 months on serum triglyceride (TG) levels and also compared the effectiveness of dietary and combined drug therapies on preventing arteriosclerotic disease from 7 to 12 months. Results: We observed that serum TG levels of the patients receiving dietary counseling were decreased compared with baseline at 6 months. Body weight and serum TG levels were decreased, and serum high-density lipoprotein levels were increased in the dietary therapy alone group, whereas BW, body mass index, and abdominal circumference were decreased in the combined drug treatment group compared with baselines at 6 and 12 months. Furthermore, the dietary therapy alone group demonstrated reductions in intake of total energy, carbohydrate, and saturated fatty acids, as well as n-6/n-3 PUFA ratio compared with baselines, but only n-6/n-3 PUFA ratio was decreased in the combined drug treatment group. Conclusion: This study demonstrated a decrease in serum TG level after 12 months of dietary therapy similar to drug therapy, which suggests that it is an effective treatment for hypertriglyceridemia, and heightened awareness should be made to encourage its use. The clinical trial registration number: UMIN000028860.

Currently, antimicrobial-resistant staphylococci, particularly methicillin-resistant Staphylococcus pseudintermedius (MRSP), are frequently isolated from canine superficial pyoderma in Japan. However, little is known regarding the nasal prevalence of MRSP in pet dogs. Here, we determined the prevalence of antimicrobial-resistant staphylococci in nares and affected sites of pet dogs with superficial pyoderma. Of the 125 nares and 108 affected sites of pet dogs with superficial pyoderma, 107 (13 species) and 110 (eight species) staphylococci strains, respectively, were isolated. The isolation rate of S. pseudintermedius from pyoderma sites (82/110 strains, 74.5%) was significantly higher than that from nares (57/107 strains, 53.3%) (P

Cancer immunotherapy, including atezolizumab monotherapy, is a promising alternative strategy for patients with advanced non-small-cell lung cancer (NSCLC). Several inflammatory indices have been reported as potential biomarkers regarding the effectiveness of various treatments. This study aimed to analyze the efficacy of atezolizumab monotherapy using baseline inflammatory markers in NSCLC patients. We retrospectively enrolled 81 NSCLC patients who received atezolizumab monotherapy at six different medical institutions in Japan. The Cox proportional hazards model was used to assess the impact of the clinical variables, including inflammatory indexes, on clinical outcomes. Median progression-free survival (PFS) and overall survival (OS) were 60 days and 252 days, respectively. The objective response rate was 7.4%, and the disease control rate was 54.3%. Patients with high neutrophil to lymphocyte ratio (NLR), low lymphocyte to monocyte ratio (LMR), and/or high platelet to lymphocyte ratio (PLR), at baseline, demonstrated substantially shorter PFS and OS compared to those with a low NLR, high LMR, and/or low PLR. The multivariate analysis demonstrated that a high baseline NLR was substantially associated with short PFS and short OS. Our retrospective observations suggest that inflammatory indices may be a potential negative prognostic factor of atezolizumab monotherapy outcomes in NSCLC patients.

AIM The aims of this study were to: (a) describe the physical activity (PA) and quality of life (QOL) in living donor liver transplant (LDLT) recipients pre-operatively and at 3 months and 6 months post-operatively; (b) compare PA and QOL at 6 months post-operatively with a healthy control group; and (c) explore pre-operative factors that predict PA changes. METHODS Patients over 20 years of age who were undergoing LDLT were recruited. PA was measured based on the number of steps/day and time spent performing moderate-to-vigorous PA (MVPA) during 1 week using an accelerometer. QOL was assessed based on a physical (PCS) and mental (MCS) component summary of the eight-item Short-Form Health Survey. The LDLT and healthy control groups were matched for age (±3 years) and gender. Pre-operative factors predicting a change in PA were calculated using a generalized linear mixed model. RESULTS Twenty-four patients completed the study. By 6 months post-LDLT, the MCS and PCS were comparable to those in the control group. The number of steps (3,887 steps/day) and MVPA (29.3 min/week) showed significant improvement by 6 months post-operatively, but remained much lower compared with those in the control group. The multivariate analysis showed that younger age (p

Mycobacterium shigaense has recently been recognized as an emerging human pathogen, and is well known as a skin pathogen in immunocompromised individuals. In this report we describe the first case of chronic pulmonary infectious disease caused by M. shigaense in an immunocompetent individual. Keywords: Chest computed tomography (CT) images, emerging infectious diseases, immunocompetent, Mycobacterium shigaense, Mycobacterium simiae complex, Pulmonary disease, skin disease

Fusion images of diffusion-weighted whole-body imaging with background body signal suppression and T2-weighted image (DWIBS/T2) demonstrate a strong signal for malignancies, with a high contrast against the surrounding tissues, and enable anatomical analysis. In the present study, DWIBS/T2 was compared with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for diagnosing cancer in the abdomen. Patient records, including imaging results of examination conducted between November 2012 and May 2014, were analyzed retrospectively. In total, 10 men (age, 73.6±9.6 years) and 8 women (age, 68.9±7.1 years) were enrolled into the current study. Of the enrolled patients, 2 were diagnosed with hepatocellular carcinoma, 1 with cholangiocellular carcinoma, 1 with liver metastasis, 2 with pancreatic ductal adenocarcinoma, 1 with renal cell carcinoma and 1 with malignant lymphoma. Benign lesions were also analyzed, including adenomyomatosis of the gallbladder (5 patients), intraductal papillary mucinous neoplasm (4 patients) and right adrenal adenoma (1 case). All the patients with cancer showed positive results on DWIBS/T2 images. However, only 7 out of 8 patients were positive with PET/CT. One patient with right renal cellular carcinoma was positive with DWIBS/T2, but negative with PET/CT. All the patients with benign lesions were negative with DWIBS/T2 and PET/CT. In conclusion, DWIBS/T2 was more sensitive in diagnosing cancer of organs in the abdominal cavity compared with PET/CT. Furthermore, negative results with DWIBS/T2 and PET/CT were useful for the diagnosis of benign lesions, such as adenomyomatosis of the gallbladder and intraductal papillary mucinous neoplasm.

Isoprene units derived from dimethylallyl diphosphate (DMAPP) are an important motif in many natural products including terpenoids, carotenoids, steroids, and natural rubber. Understanding the chemical characteristics of DMAPP is an important topic in natural products chemistry, organic chemistry, and biochemistry. We have developed a direct bioinspired indole prenylation reaction using DMAPP or its equivalents as the electrophile in homogeneous aqueous acidic media in the absence of enzyme to provide prenylated indole products. After establishing the bioinspired indole prenylation reaction, this was then used to achieve the synthesis of a series of natural products, namely, N-prenylcyclo-l-tryptophyl-l-proline, tryprostatins, rhinocladins, and terezine D.

Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) images show significant contrast for cancer tissues against non-cancerous tissues. Fusion of a DWIBS and a T2-weighted image (DWIBS/T2) can be used to obtain functional, as well as anatomic, information. In the present study, the performance of DWIBS/T2 in the diagnosis of abdominal solid cancer was evaluated. The records of 14 patients were retrospectively analyzed [5 patients with hepatocellular carcinoma (HCC), 4 with metastatic liver cancer, 3 with pancreatic cancer, 1 with renal cellular carcinoma and 1 with malignant lymphoma of the para-aortic lymph node]. T1WI and T2WI scans did not detect pancreatic cancer in certain cases, whereas DWIs and DWIBS/T2 clearly demonstrated pancreatic cancer in all cases. In addition, metastatic liver cancer and HCC were successfully detected with abdominal US and CECT; however, US did not detect pancreatic cancer in 1 case, while CECT and DWIBS/T2 detected pancreatic cancer in all cases. In conclusion, the diagnostic performance of DWIBS/T2 was the same as that of abdominal US and CECT in detecting primary and metastatic liver cancer. DWIBS/T2 enabled the diagnosis of pancreatic cancer in cases where it was not detected with US, T1WI or T2WI.

Since the discovery of graphene by sticking and peeling scotch tape off graphite, it has also been prepared by other methods, such as thermal decomposition of SiC and chemical vapor deposition (CVD) with catalytic layer. Both the exfoliation and CVD methods impose to transfer the graphene layers on other insulating substrates for device applications. We reported that diamond grows in oxygen atmosphere (Yoshimoto, M.; Nature 1999, 399, 340−342) in which oxidative etching and depositing carbon compete under equivalent conditions. However, oxygen atmosphere is too intense for graphite growth. Although carbon dioxide (CO2) is produced after hydrocarbon combustion, it can be a gentle and tender oxidant in certain situations. Here, we show the direct growth of graphene on insulating substrates in 100% CO2 environment and observe its layer-by-layer growth on the stepped edge of an insulating substrate. The direct growth can have a significant advantage of excluding the necessary process of transferring the graph...

Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) yields positive results for cancer against the surrounding tissues. The combination of DWIBS and T2-weighted images (DWIBS/T2) in the diagnosis of gastrointestinal tract cancers was retrospectively analyzed in the present study. Patients were subjected to magnetic resonance imaging after cancer was diagnosed through specimens obtained via biopsy or endoscopic mucosal resection. Sixteen patients were assessed between July, 2012 and June, 2013 and the correlation between detection with DWIBS/T2 and T staging was analyzed. Regarding patients who underwent surgery, the correlation between detection with DWIBS/T2 and the diameter or depth of invasion was analyzed. All cancers that had advanced to >T2 stage were detectable by DWIBS/T2, whereas all cancers staged as T2) or invading beyond the muscularis propria.

In a clinical setting, it is important to diagnose complications of acute cholecystitis accurately. Diffusion-weighted whole body imaging with background body signal suppression/T2-weighted image fusion (DWIBS/T2) provides high signal intensity with a strong contrast against surrounding tissues in anatomical settings. In the present study, patients who were being treated for acute cholecystitis and underwent DWIBS/T2 in the National Hospital Organization Shimoshizu Hospital between December 2012 and August 2015 were enrolled. A total of 10 men and 4 women underwent DWIBS/T2. Records, including DWIBS/T2 and computed tomography (CT) imaging, were retrospectively analyzed for patients with acute cholecystitis. CT images revealed thickened gallbladder walls in patients with acute cholecystitis, and high signal intensity was observed in DWIBS/T2 images for the thickened gallbladder wall. Inflammation of the pericholecystic space and the liver resulted in high intensity signals with DWIBS/T2 imaging, whereas CT imaging revealed a low-density area in the cholecystic space. Plain CT scanning identified a low-density area in the liver, which became more obvious with contrast-enhanced CT. DWIBS/T2 imaging showed the inflammation of the liver and pericholesyctic space as an area of high signal intensity. Detectability of inflammation of the pericholecystic space and the liver was the same for DWIBS/T2 and CT, which suggests that DWIBS/T2 has the same sensitivity as CT scanning for the diagnosis of complicated acute cholecystitis. However, the strong contrast shown by DWIBS/T2 allows for easier evaluation of acute cholecystitis than CT scanning.

Previous studies have indicated that extended exposure to a high level of sound might increase the risk of hearing loss among professional symphony orchestra musicians. One of the major problems associated with musicians’ hearing loss is difficulty in estimating its risk simply on the basis of the physical amount of exposure, i.e. the exposure level and duration. The aim of this study was to examine whether the measurement of the medial olivocochlear reflex (MOCR), which is assumed to protect the cochlear from acoustic damage, could enable us to assess the risk of hearing loss among musicians. To test this, we compared the MOCR strength and the hearing deterioration caused by one-hour instrument practice. The participants in the study were music university students who are majoring in the violin, whose left ear is exposed to intense violin sounds (broadband sounds containing a significant number of high-frequency components) during their regular instrument practice. Audiogram and click-evoked otoacoustic emissions (CEOAEs) were measured before and after a one-hour violin practice. There was a larger exposure to the left ear than to the right ear, and we observed a left-ear specific temporary threshold shift (TTS) after the violin practice. Left-ear CEOAEs decreased proportionally to the TTS. The exposure level, however, could not entirely explain the inter-individual variation in the TTS and the decrease in CEOAE. On the other hand, the MOCR strength could predict the size of the TTS and CEOAE decrease. Our findings imply that, among other factors, the MOCR is a promising measure for assessing the risk of hearing loss among musicians.

Antimutagenesis against N-nitroso compounds contribute to prevention of human cancer. We have found that Glycyrrhiza aspera ethanolic extract exhibits antimutagenic activity against N-methyl-N-nitrosourea (MNU) using the Ames assay with Salmonella typhimurium TA1535. In the present study, eight purified components from Glycyrrhiza, namely glabridin, glycyrrhetinic acid, glycyrrhizin, licochalcone A, licoricesaponin H2, licoricesaponin G2, liquiritigenin and liquiritin were evaluated for their antimutagenicity against MNU in the Ames assay with S. typhimurium TA1535. Glycyrrhetinic acid, glycyrrhizin, licoricesaponin G2, licoricesaponin H2 and liquiritin did not show the antimutagenicity against MNU in S. typhimurium TA1535. Glabridin, licochalcone A and liquiritigenin reduced revertant colonies derived from MNU in S. typhimurium TA1535 without showing cytotoxic effects, indicating that these compounds possess antimutagenic activity against MNU. The inhibitory activity of glabridin and licochalcone A was more effective than that of liquiritigenin. Thus, Glycyrrhiza contains antimutagenic components against DNA alkylating, direct-acting carcinogens.

Polycomb group gene Bmi1 functions as a tumor suppressor in myelofibrosis., Polycomb-group (PcG) proteins form the multiprotein polycomb repressive complexes (PRC) 1 and 2, and function as transcriptional repressors through histone modifications. They maintain the proliferative capacity of hematopoietic stem and progenitor cells by repressing the transcription of tumor suppressor genes, namely Ink4a and Arf, and thus have been characterized as oncogenes. However, the identification of inactivating mutations in the PcG gene, EZH2, unveiled a tumor suppressor function in myeloid malignancies, including primary myelofibrosis (PMF). Here, we show that loss of another PcG gene, Bmi1, causes pathological hematopoiesis similar to PMF. In a mouse model, loss of Bmi1 in Ink4a-Arf−/− hematopoietic cells induced abnormal megakaryocytopoiesis accompanied by marked extramedullary hematopoiesis, which eventually resulted in lethal myelofibrosis. Absence of Bmi1 caused derepression of a cohort of genes, including Hmga2, which is an oncogene overexpressed in PMF. Chromatin immunoprecipitation assays revealed that Bmi1 directly represses the transcription of Hmga2. Overexpression of Hmga2 in hematopoietic stem cells induced a myeloproliferative state with enhanced megakaryocytopoiesis in mice, implicating Hmga2 in the development of pathological hematopoiesis in the absence of Bmi1. Our findings provide the first genetic evidence of a tumor suppressor function of Bmi1 and uncover the role of PcG proteins in restricting growth by silencing oncogenes.

Myeloproliferative neoplasms (MPN), a group of haematopoietic stem cell (HSC) disorders, are often accompanied by myelofibrosis. We previously identified the fusion of the ETV6 gene to the LYN gene (ETV6-LYN) in idiopathic myelofibrosis with ins(12;8)(p13;q11q21). The introduction of ETV6-LYN into HSCs resulted in fatal MPN with massive myelofibrosis in mice, implicating the rearranged LYN kinase in the pathogenesis of MPN with myelofibrosis. However, the signalling molecules directly downstream from and activated by ETV6-LYN remain unknown. In this study, we demonstrated that the direct activation of STAT5 by ETV6-LYN is crucial for the development of MPN. ETV6-LYN was constitutively active as a kinase through autophosphorylation. ETV6-LYN, but not its kinase-dead mutant, supported cytokine-free proliferation of haematopoietic cells. STAT5 was activated in a JAK2-independent manner in ETV6-LYN-expressing cells. ETV6-LYN interacted with STAT5 and directly activated STAT5 both in vitro and in vivo. Of note, ETV6-LYN did not support the formation of colonies by Stat5-deficient HSCs under cytokine-free conditions and the capacity of ETV6-LYN to induce MPN with myelofibrosis was profoundly attenuated in a Stat5-null background. These findings define STAT5 as a direct target of ETV6-LYN and unveil the LYN-STAT5 axis as a novel pathway to augment proliferative signals in MPN and leukaemia.

高分子鎖をポリスチレンおよびポリメチルメタクリレートとする 2 種類のアミジノ尿素樹脂(AU 樹脂)を用い，高分子鎖の金属イオン捕獲能に及ぼす影響について検討した．メタクリレートを主鎖とするアミジノ尿素樹脂(MCAU 樹脂)は，シアノグアニジンと塩化メタクリロイルとの反応によりメタクリロイルシアノグアニジンを合成後，ラジカル重合ついで水和反応により得た．Cu2+, Zn2+, Ni2+, Co2+, Cd2+ を対象とした捕獲試験において，両樹脂は Cu2+ に高い選択的捕獲能を示したが，MCAU 樹脂の捕獲率は対応するポリスチレン系 AU 樹脂の 60～70%にとどまった．一方，MCAU 樹脂は塩基水溶液に浸漬処理をすることにより，捕獲能が大幅に上昇する挙動を示した．この原因がポリメチルメタクリレート鎖の電子吸引効果による金属イオン捕獲部位の塩基性度の上昇にあることを MCAU 樹脂のモノマーモデルの UV スペクトルおよび X 線回折により明らかにした．

The occurrence of a sound event in a sound stream can be perceived without difficulty even when it is difficult to define the acoustic boundary. This study was designed to investigate which acoustical feature functions as an effective cue to “mark” the occurrence of a new event. When two steady sounds are connected by a short frequency glide, at which point do we perceive the occurrence of the second sound: the starting point of the frequency glide or its ending point? To answer this question, experimental stimuli were designed to establish an isochronous structure that was conveyed exclusively by the starting or by the ending point of the glide. The frequency glide was made by modulating the carrier frequency of a sinusoid or the resonant frequency of a complex tone. In two experiments, the deviation from the isochronous structure was detected more easily under the starting-point condition than under the ending-point condition. The results suggest that the starting point functions as a more effective cue for marking a new event than does the ending point.

Background: Behavioral and psychological symptoms of dementia (BPSD) are frequently observed in patients with dementia and often cause serious problems. However, the cause of BPSD has not yet been elucidated. Moreover, the precise evaluation of BPSD in mild dementia has not been studied in any great detail. In the present study, we investigated the relationship between psychiatric symptoms and regional cerebral blood flow (rCBF) in patients with mild Alzheimer's disease (AD). Methods: The present study included 47 patients (20 men and 27 women) who were diagnosed with mild AD. Mean patient age was 72.8 ± 8.2 years. Single photon emission computed tomography (SPECT) with 99mTc-ethyl cysteinate dimer (99mTc-ECD) was performed in all patients. The SPECT data were analyzed using a three-dimensional stereotactic region of interest template, which evaluated CBF in 24 segments. Psychiatric symptoms were evaluated in patients using the Brief Psychiatric Rating Scale. Each psychiatric symptom was designated as ‘symptom present’ in cases in which the BPRS item score was more than 3. We compared 10 segments of rCBF in symptom-present patients with those in symptom-absent patients. Results: Motor retardation was the most common psychiatric symptom (36.2%), followed by depression (19.1%), anxiety (17.0%), emotional withdrawal (17.0%), and somatic concern (14.9%). Alzheimer's disease patients with motor retardation exhibited a tendency towards lower rCBF in seven segments (left callosomarginal, bilateral parietal, bilateral angular, and bilateral temporal). However, no specific tendency was observed in depression, anxiety, and somatic concern. Conclusions: In the present study, we observed a tendency for decreased brain perfusion in patients with motor retardation. Further studies are necessary to confirm that this trend contributes to the appearance of psychiatric symptoms in patients with mild AD.

アミジノ尿素樹脂における捕獲部位周辺置換基の，金属イオン捕獲能に及ぼす影響について検討した．捕獲部位に隣接して存在する 3 個の置換基は立体因子効果あるいは親水・疎水効果により捕獲能に影響を及ぼすと考えられる．この点を明らかにするために，炭素鎖長の異なる鎖式および環式の 8 種類の異なる置換基をもつ置換アミジノ尿素樹脂を合成し，金属イオン捕獲能および水に対する溶解性から検討した結果，親水・疎水効果の寄与がより大きいことがわかった．無置換アミジノ尿素樹脂も含めた検討から，アミジノ尿素樹脂における金属イオン捕獲の最適構造は，捕獲部位に隣接して 3 個のメチル基が導入された形であると結論した．

Prompt and accurate diagnosis is critical in the treatment of acute cholecystitis. Diffusion-weighted whole-body magnetic resonance imaging with background body signal suppression/T2 image fusion (DWIBS/T2) identifies areas with high signal intensity, corresponding to inflammation. In the present study, the records and images of patients with acute cholecystitis who underwent DWIBS/T2 between January 2013 and March 2014 were retrospectively analyzed. A total of 11 patients with acute cholecystitis were enrolled. In one patient, DWIBS/T2 identified a thickened wall and high signal intensity, with high signal intensity in the pericholecystic space that suggested localized peritonitis. Positive DWIBS/T2 results indicating acute cholecystitis were obtained in 10/11 patients, with a sensitivity of 90.9%. In addition, wall thickening and high signal intensity were absent in DWIBS/T2 images when wall thickening was not detected by computed tomography. Wall thickening and high signal intensity was attenuated when patients with acute cholecystitis were clinically treated. These data suggest that a thickened gallbladder wall and high signal intensity are indicative of acute cholecystitis and that DWIBS/T2 may be a useful technique in evaluating the severity of acute cholecystitis.

Purpose: Canada’s perinatal, infant and maternal mortality rates were examined and compared with other Organization for Economic Cooperation and Development (OECD) countries. The type and the quality of the available data and best practices in several OECD countries were evaluated. Source: A literature search was performed in PubMed and the Cochrane Library. Vital statistics data were obtained from the OECD Health Database and Statistics Canada and subjected to secondary analysis. Principal findings: Overall, Canadian pregnancy mortality rates have fallen dramatically since the early 1960’s. Perinatal and infant mortality rates remain low and stable, but the maternal mortality rate has increased slightly and both mortality rates have declined in their relative OECD rankings over the last 20 years. Data quality and coverage across Canada and internationally, especially for Indigenous peoples, is inconsistent and registration practices differ greatly, making comparisons difficult. Available data do show that Indigenous people’s perinatal and infant mortality rates are nearly twice those of the general population. Best practices in other OECD countries include Australia’s National Maternity Services plan to improve Aboriginal perinatal health, the Netherlands’ midwifery services and National Perinatal Registry and Japan’s national pregnancy registration and Maternal Handbook. Conclusion: To diminish Canadian disparities in perinatal health rates and improve health outcomes we recommend a) uniform registration practices across Canada, b) better data quality and coverage especially among Indigenous communities, c) adoption of a national pregnancy registration and a maternal handbook along with d) improved midwifery and primary practice services to rural and remote communities. At a time when Canada is focusing upon improving pregnancy health in developing nations, it also needs to address its own challenges in improving pregnancy outcomes.

Leukemia differs substantially with respect to stromal milieu from tumors that progress locally as solid masses, and the physiological importance of immunosurveillance in leukemia remains unclear. However, currently available mouse leukemia models have critical limitations in the context of analyzing immunological regulation of leukemia development. In this study, we transferred mouse MLL/AF9 leukemia-initiating cells into immunocompetent recipient mice without any pre-conditioning such as irradiation, and then analyzed the spontaneous T cell response to an immunogenic antigen expressed in leukemia cells. When the minimum numbers of leukemia-initiating cells for engraftment were transferred, leukemia cells were eradicated by the adaptive immune response in most, if not all, wild-type mice, but not in Rag2 -/- recipient mice, which lack adaptive immunity. By contrast, mice transplanted with larger numbers of leukemia cells always developed leukemia. In mice with advanced leukemia, antigen-specific CTLs were also expanded, but were unresponsive to antigen stimulation and expressed high levels of PD-1 and LAG-3. These results provide the first clear demonstration that the spontaneous CTL response to a tumor-cell antigen has the potential to eradicate leukemia, whereas antigen-specific CTLs are exhausted in animals with advanced leukemia. This immunocompetent mouse leukemia model provides a useful platform for developing effective immunotherapies against leukemia.