Publications by authors named "Shinichi Kobayashi"

130 Publications

A case report on severe nivolumab-induced adverse events similar to primary sclerosing cholangitis refractory to immunosuppressive therapy.

Medicine (Baltimore) 2021 Jun;100(23):e25774

Division of Medical Oncology, Department of Medicine, Showa University School of Medicine.

Introduction: Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibody, have dramatically changed cancer treatment; however, fatal immune-related adverse events (irAEs) can develop. Here, we describe a severe case of sclerosing cholangitis-like irAE. We report the use of 3 immunosuppressive agents that resulted in the death of the patient due to treatment inefficacy. According to a postmarketing study of nivolumab, the frequency of ICI-related sclerosing cholangitis is 0.27% and that of ICI-related cholangitis is 0.20%. There have been 4 case reports of sclerosing cholangitis-like irAE, with imaging findings, including typical intrahepatic bile duct beaded constriction in primary sclerosing cholangitis. Treatment starts with prednisolone and is combined with an immunosuppressant in refractory cases. There are no reports of severe cases that ultimately led to death.

Patients Concerns: The patient is a 64-year-old male with Stage IV squamous cell lung carcinoma; he was hospitalized with abdominal pain and elevation of aspartate transaminase and alanine transaminase, approximately 4 months after ICI administration was suspended. This occurred because the patient treated with nivolumab as the second-line chemotherapy and developed type 1 diabetes mellitus after 11 courses.

Diagnosis: A grade 3 increase in bilirubin was observed and he was diagnosed with sclerosing cholangitis, based on magnetic resonance cholangiopancreatography imaging and pathological findings of the liver and bile duct.

Interventions: Prednisolone, mycophenolate mofetil, and tacrolimus combination therapy was administered.

Outcomes: The treatment was difficult and failed. He died from liver failure 8 months after diagnosis. In this case, hepatitis and cholangitis, mainly alanine transaminase-dominant liver disorder, developed in the early stages of irAEs. Although he showed some improvement after prednisolone administration, bilirubin levels began rising again, and sclerosing cholangitis did not improve even with the use of 3 immunosuppressive agents recommended by the ESMO Clinical Practice Guidelines for immune-related hepatotoxicity management. Although the antitumor effect showed a complete response, liver failure led to death.

Conclusion: This is the first case report on the ineffectiveness of triple immunosuppressant combination therapy recommended by the guidelines for immune-related hepatotoxicity. It is necessary to develop more appropriate treatment for severe sclerosing cholangitis-like irAE based on the robust evidence.
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http://dx.doi.org/10.1097/MD.0000000000025774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202549PMC
June 2021

Rare Nivolumab-associated Super Hyper Progressive Disease in Patients With Advanced Gastric Cancer.

In Vivo 2021 May-Jun;35(3):1865-1875

Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

Background/aim: Rapid tumor growth after administration of immune checkpoint inhibitors is designated hyper progressive disease (HPD). In this study, besides the conventional HPD category, we proposed the "super HPD" category where the disease is naturally rapidly growing.

Patients And Methods: Patients treated for advanced gastric cancer with irinotecan or nivolumab as a third-line treatment were retrospectively compared.

Results: Eighteen and 26 patients were treated with irinotecan or nivolumab, respectively. There were 3 HPD cases (16.7%) in the irinotecan group, 6 cases (23.1%) in the nivolumab group, and the frequency of HPD was not significantly different. Two cases satisfied the super HPD definition only in the nivolumab group. When one of them was analyzed immunologically, the number of regulatory T cells was found to be increased, resulting in a low neutrophil-to-lymphocyte ratio.

Conclusion: Our proposed super HPD was likely to represent a true HPD, with a frequency of 7.7%.
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http://dx.doi.org/10.21873/invivo.12449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193338PMC
June 2021

Analysis of ADAM12-Mediated Ephrin-A1 Cleavage and Its Biological Functions.

Int J Mol Sci 2021 Mar 1;22(5). Epub 2021 Mar 1.

Department of Pharmacology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo 162-8666, Japan.

Accumulating evidence indicates that an elevated ephrin-A1 expression is positively correlated with a worse prognosis in some cancers such as colon and liver cancer. The detailed mechanism of an elevated ephrin-A1 expression in a worse prognosis still remains to be fully elucidated. We previously reported that ADAM12-cleaved ephrin-A1 enhanced lung vascular permeability and thereby induced lung metastasis. However, it is still unclear whether or not cleaved forms of ephrin-A1 are derived from primary tumors and have biological activities. We identified the ADAM12-mediated cleavage site of ephrin-A1 by a Matrix-assisted laser desorption ionization mass spectrometry and checked levels of ephrin-A1 in the serum and the urine derived from the primary tumors by using a mouse model. We found elevated levels of tumor-derived ephrin-A1 in the serum and the urine in the tumor-bearing mice. Moreover, inhibition of ADAM-mediated cleavage of ephrin-A1 or antagonization of the EphA receptors resulted in a significant reduction of lung metastasis. The results suggest that tumor-derived ephrin-A1 is not only a potential biomarker to predict lung metastasis from the primary tumor highly expressing ephrin-A1 but also a therapeutic target of lung metastasis.
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http://dx.doi.org/10.3390/ijms22052480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957476PMC
March 2021

The Prognostic Impact of Eosinophils and the Eosinophil-to-Lymphocyte Ratio on Survival Outcomes in Stage II Resectable Pancreatic Cancer.

Pancreas 2021 02;50(2):167-175

Division of Medical Oncology, Department of Medicine, School of Medicine.

Objectives: The relationship between eosinophils and cancer prognosis is unknown. Therefore, we analyzed the relationship between circulating eosinophils and the survival of stage IIA and IIB pancreatic cancer patients who underwent surgical resection.

Methods: This study included a retrospective cohort of 67 consecutive patients. Patients were categorized into two different groups based on the optimal cutoff for pretreatment levels of each biomarker, according to the receiver operating characteristic curves.

Results: The Kaplan-Meier method showed that low eosinophil (P = 0.0403), high neutrophil (P = 0.0066), and high monocyte (P = 0.0003) counts were associated with short overall survival (OS). Low lymphocyte-to-monocyte ratio (P = 0.0194) and eosinophil-to-lymphocyte ratio (ELR) (P = 0.0413) were associated with reduced OS. In multivariate analysis, histological differentiation (P = 0.0014), high neutrophils (P = 0.047), high monocytes (P = 0.029), and low eosinophils (P < 0.0001) were correlated with poorer OS. Histological differentiation (P = 0.033), low lymphocyte-to-monocyte ratio (P = 0.029), and low ELR (P = 0.005) were correlated with poor OS and were significant independent prognostic factors of poor outcomes.

Conclusions: Low eosinophils and low ELR were significant independent prognostic factors of poor outcomes.
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http://dx.doi.org/10.1097/MPA.0000000000001731DOI Listing
February 2021

[Spontaneous resolution of refractory ascites in the late phase after cord blood transplantation in acute myeloid leukemia].

Rinsho Ketsueki 2021 ;62(1):20-24

Division of Hematology, Department of Internal Medicine, National Defense Medical College.

Patients with refractory ascites that develops >3 months after allogenic stem cell transplantation typically have a poor prognosis. We present the case of a 61-year-old man who developed refractory massive ascites approximately 3 months after cord blood transplantation (CBT) and showed complete and spontaneous remission from ascites after 18 months. The patient complained of severe bloating and needed weekly paracentesis to manage the fluid levels. Laboratory tests indicated that the ascites was caused by liver fibrosis. After the patient underwent Keisuke-Matsusaki cell-free and concentrated ascites reinfusion therapy (KM-CART), we were able to decrease the frequency of paracentesis treatments. We planned a transjugular liver biopsy, but the patient contracted pneumocystis pneumonia before the procedure could be performed. Although the pneumonia improved, the ascites worsened again. However, weekly paracentesis spontaneously stopped the progression of ascites and eventually resolved it completely, resulting in the patient's survival.
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http://dx.doi.org/10.11406/rinketsu.62.20DOI Listing
February 2021

High levels of human epididymis protein 4 mRNA and protein expression are associated with chemoresistance and a poor prognosis in pancreatic cancer.

Int J Oncol 2021 01 12;58(1):57-69. Epub 2020 Nov 12.

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo 157‑8577, Japan.

Pancreatic cancer is associated with an exceedingly poor prognosis, warranting the development of novel therapeutic strategies and discovery of prognostic predictors. Given that chemoresistance‑related molecules are reportedly associated with the poor prognosis of pancreatic cancer, the present study aimed to identify molecules that could be efficacious therapeutic targets for pancreatic cancer. First, 10 patient‑derived xenografts (PDXs) were established from patients with pancreatic cancer. Subsequently, after treating tumor tissue generated from the PDXs with standard drugs, next‑generation sequencing (NGS) was performed using these tissues. The results of NGS analysis and immunohistochemical analysis on 80 pancreatic cancer tissues revealed that human epididymis protein 4 (HE4) expression in the anticancer drug‑treated PDX group was higher than that in the untreated PDXs. In addition, chemoresistance ability was observed in tumor cell lines overexpressing HE4. Furthermore, Kaplan‑Meier analysis of tumor tissues from 80 patients with pancreatic cancer was performed and it was found that patients with a high HE4 expression level had a poor survival rate compared with those who had a low HE4 expression level. Multivariate analysis also indicated the high expression level of HE4 was an independent poor prognostic biomarker. Thus, it was concluded that high gene and protein expression levels of HE4 mediate chemoresistance and are independent prognostic factors for pancreatic cancer.
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http://dx.doi.org/10.3892/ijo.2020.5147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721086PMC
January 2021

CEP131 Abrogates CHK1 Inhibitor-Induced Replication Defects and Is Associated with Unfavorable Outcome in Neuroblastoma.

J Oncol 2020 15;2020:2752417. Epub 2020 Sep 15.

Department of Clinical Diagnostic Oncology, Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, 6-11-11 Kita-Karasuyama, Setagaya-ku, Tokyo 157-8577, Japan.

Checkpoint kinase 1 (CHK1) plays a key role in genome surveillance and integrity throughout the cell cycle. Selective inhibitors of CHK1 (CHK1i) are undergoing clinical evaluation for various human malignancies, including neuroblastoma. Recently, we reported that CHK1i, PF-477736, induced a p53-mediated DNA damage response. As a result, the cancer cells were able to repair DNA damage and became less sensitive to CHK1i. In this study, we discovered that PF-477736 increased expression of MDM2 oncogene along with CHK1i-induced replication defects in neuroblastoma NB-39-nu cells. A mass spectrometry analysis of protein binding to MDM2 in the presence of CHK1i identified the centrosome-associated family protein 131 (CEP131), which was correlated with unfavorable prognosis of neuroblastoma patients. We revealed that MDM2 was associated with CEP131 protein degradation, whereas overexpression of CEP131 accelerated neuroblastoma cell growth and exhibited resistance to CHK1i-induced replication defects. Thus, these findings may provide a future therapeutic strategy against centrosome-associated oncogenes involving CEP131 as a target in neuroblastoma.
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http://dx.doi.org/10.1155/2020/2752417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7512061PMC
September 2020

A high number of PD-L1 CD14 monocytes in peripheral blood is correlated with shorter survival in patients receiving immune checkpoint inhibitors.

Cancer Immunol Immunother 2021 Feb 5;70(2):337-348. Epub 2020 Aug 5.

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-Karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan.

Purpose: Targeting of anti-programmed cell death protein-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) is a standard therapeutic strategy for various cancers. The aim of the present study was to investigate the prognostic effect of pretreatment PD-L1 expression levels in peripheral blood mononuclear cell (PBMC) subsets for patients with several cancer types receiving anti-PD-1 blockade therapies.

Patients And Methods: Thirty-two patients undergoing anti-PD-L1 blockade therapy, including 15 with non-small cell lung cancer, 14 with gastric cancer, 1 with melanoma, 1 with parotid cancer, and 1 with bladder cancer, were recruited for the present study. PD-L1 expression levels in CD3, CD4, CD8, CD45RA and CCR7 T cells; CD20 B cells; CD14 and CD16 monocytes were measured via flow cytometry before treatment. The percentages of PD-L1 cells in respective PBMC subsets were compared with respect to different clinicopathological conditions and the association with overall survival (OS) was assessed.

Results: The percentages of PD-L1 with CD3, CD4 and CD8 T cells including naïve and memory T cell subsets, or CD20 B cells during pretreatment were not markedly correlated with the OS of patients (p > 0.05); however, the percentage of the PD-L1 CD14 monocyte subset was significantly correlated with OS (p = 0.0426).

Conclusion: Increase in pretreatment expression levels of PD-L1 on CD14 monocytes is associated with the OS of patients treated with immune checkpoint inhibitors. Further evaluation of large sample size and each specific cancer type might clarify the predictive role of PBMC in patients.
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http://dx.doi.org/10.1007/s00262-020-02686-6DOI Listing
February 2021

High expression levels of polymeric immunoglobulin receptor are correlated with chemoresistance and poor prognosis in pancreatic cancer.

Oncol Rep 2020 Jul 11;44(1):252-262. Epub 2020 May 11.

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo 157‑8577, Japan.

Pancreatic cancer has extremely poor prognosis, warranting the discovery of novel therapeutic and prognostic markers. The expression of polymeric immunoglobulin receptor (pIgR), a key component of the mucosal immune system, is increased in several cancers. However, its clinical relevance in pancreatic cancer remains unclear. In the present study, the prognostic value of pIgR in pancreatic cancer patients after surgical resection was assessed and it was determined that the expression of pIgR was correlated with poor prognosis. Ten pancreatic cancer patient‑derived xenograft (PDX) lines were established, followed by next‑generation sequencing of tumor tissues from these lines after standard chemotherapy. Immunohistochemical analysis of chemoresistance‑related molecules using 77 pancreatic cancer tissues was also performed. The expression of pIgR mRNA in the PDX group treated with anticancer drugs was higher than in the untreated group. High pIgR expression in tissue specimens from 77 pancreatic cancer patients was significantly associated with poor prognosis and was revealed to be an independent prognostic factor, predicting poor outcomes. High pIgR mRNA and protein levels were independent prognostic factors, indicating that pIgR could be a novel predictor for poor prognosis of pancreatic cancer patients.
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http://dx.doi.org/10.3892/or.2020.7610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251687PMC
July 2020

[Bendamustine and rituximab combination therapy for recurrent indolent B-cell lymphomas: a retrospective single-institution study].

Rinsho Ketsueki 2020 ;61(6):598-604

Division of Hematology, National Defense Medical College Hospital.

This retrospective study evaluated the outcomes of patients treated with combination of bendamustine and rituximab (BR) for recurrent indolent B-cell lymphoma from January 2011 to February 2018 in our department. The cohort included 36 males and 27 females, and majority of the patients (59%) were between 51 and 70 years of age. The disease types were follicular lymphoma (FL) and mantle-cell lymphoma in 42 (67%) and 15 (24%) patients, respectively. Median progression-free survival (PFS) was not reached in patients with FL who completed BR therapy. The analysis of patients who received BR therapy revealed that the number of CD4-positive lymphocytes remained around 200/µl even five years after the end of treatment. BR therapy was a useful treatment option for recurrent indolent B-cell lymphoma, especially in patients with FL, and completion of BR therapy appeared to be important for improved PFS. Furthermore, attention should be paid for potential infections for at least five years after BR therapy because cell-mediated immunodeficiency may become apparent after treatment.
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http://dx.doi.org/10.11406/rinketsu.61.598DOI Listing
July 2020

High expression of olfactomedin-4 is correlated with chemoresistance and poor prognosis in pancreatic cancer.

PLoS One 2020 10;15(1):e0226707. Epub 2020 Jan 10.

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology & Therapeutics, Showa University, Tokyo, Japan.

Pancreatic cancer has an extremely poor prognosis, and identification of novel predictors of therapeutic efficacy and prognosis is urgently needed. Chemoresistance-related molecules are correlated with poor prognosis and may be effective targets for cancer treatment. Here, we aimed to identify novel molecules correlated with chemoresistance and poor prognosis in pancreatic cancer. We established 10 patient-derived xenograft (PDX) lines from patients with pancreatic cancer and performed next-generation sequencing (NGS) of tumor tissues from PDXs after treatment with standard drugs. We established a gene-transferred tumor cell line to express chemoresistance-related molecules and analyzed the chemoresistance of the established cell line against standard drugs. Finally, we performed immunohistochemical (IHC) analysis of chemoresistance-related molecules using 80 pancreatic cancer tissues. From NGS analysis, we identified olfactomedin-4 (OLFM4) as having high expression in the PDX group treated with anticancer drugs. In IHC analysis, OLFM4 expression was also high in PDXs administered anticancer drugs compared with that in untreated PDXs. Chemoresistance was observed by in vitro analysis of tumor cell lines with forced expression of OLFM4. In an assessment of tissue specimens from 80 patients with pancreatic cancer, Kaplan-Meier analysis showed that patients in the low OLFM4 expression group had a better survival rate than patients in the high OLFM4 expression group. Additionally, multivariate analysis showed that high expression of OLFM4 was an independent prognostic factor predicting poor outcomes. Overall, our study revealed that high expression of OLFM4 was involved in chemoresistance and was an independent prognostic factor in pancreatic cancer. OLFM4 may be a candidate therapeutic target in pancreatic cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226707PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953839PMC
April 2020

[VEGF secretion from Epstein-Barr virus-infected cells as a cause of severe anasarca in a patient with angioimmunoblastic T-cell lymphoma].

Rinsho Ketsueki 2019 ;60(12):1647-1651

Division of Hematology, National Defense Medical College Hospital.

A 69-year-old woman presented to National Defense Medical College hospital for suspected nephrotic syndrome due to weight gain of 30 kg in 3 weeks and bilateral lower leg edema. However, her urinalysis showed microproteinuria, which excluded nephrotic syndrome. Computed tomography revealed severe systemic edema, pleural effusion, ascites, and enlarged cervical and axillary lymph nodes. Histological examination of axillary lymph node specimen showed a typical architecture of angioimmunoblastic T-cell lymphoma. One course of CHOP chemotherapy regimen was administered which improved the lymph nodes and systemic edema. The patient achieved complete remission after 6 courses of CHOP. Because serum vascular endothelial growth factor (VEGF) level was elevated before the treatment and normalized after the treatment, increased vascular permeability mediated by VEGF was hypothesized to have caused the systemic edema. In addition, VEGF secretion from Epstein-Barr virus (EBV)-infected cells was likely associated with the patient's clinical condition because B lymphocytes stained with CD20 were positive for Epstein-Barr virus-encoded small RNAs (EBERs) and VEGF.
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http://dx.doi.org/10.11406/rinketsu.60.1647DOI Listing
January 2020

Improvement of early mortality in single-unit cord blood transplantation for Japanese adults from 1998 to 2017.

Am J Hematol 2020 04 2;95(4):343-353. Epub 2020 Jan 2.

Division of Hematology, National Defense Medical College, Tokorozawa, Japan.

The major limitation of cord blood transplantation (CBT) for adults remains the delayed hematopoietic recovery and higher incidence of graft failure, which result in a higher risk of early mortality in CBT. We evaluated early overall survival (OS), non-relapse mortality (NRM), neutrophil engraftment, acute graft-vs-host disease, and cause of early death among 9678 adult patients who received single-unit CBT in Japan between 1998 and 2017. The probability of OS at 100 days was 64.4%, 71.7%, and 78.9% for the periods 1998 to 2007, 2008 to 2012, and 2013 to 2017, respectively (P < .001). The cumulative incidences of NRM at 100 days during the same period were 28.3%, 20.8%, and 14.6%, respectively (P < .001). The cumulative incidences of neutrophil engraftment were also improved during the same period (P < .001). The most common cause of death within 100 days after CBT was bacterial infection in 1998 to 2007 and primary disease in the latter two time periods. Across the three time periods, the proportions of deaths from bacterial and fungal infection, graft failure, hemorrhage, sinusoidal obstructive syndrome, and organ failure decreased in a stepwise fashion. Landmark analysis of OS and NRM after 100 days showed that OS did not change over time in the multivariate analysis. Our registry-based data demonstrated a significant improvement of early OS after CBT for adults over the past 20 years. The landmark analysis suggested that improvement of early mortality could lead to an improvement of long-term OS after CBT.
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http://dx.doi.org/10.1002/ajh.25705DOI Listing
April 2020

Plasma Levels of Soluble PD-L1 Correlate With Tumor Regression in Patients With Lung and Gastric Cancer Treated With Immune Checkpoint Inhibitors.

Anticancer Res 2019 Sep;39(9):5195-5201

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo, Japan

Background/aim: Cancer immune therapy by immune checkpoint inhibitors (ICIs) is a promising therapeutic strategy for various cancer types. Among ICIs, anti-programmed cell death protein-1 (PD1) and anti-programmed death-ligand 1 (PD-L1) antibodies have shown a remarkable clinical benefit. The present study aimed to address the functional and clinical significance of serum levels of soluble PD-L1 (sPD-L1) in patients.

Materials And Methods: A total of 21 patients, 11 with NSCLC, nine with gastric cancer and one with bladder cancer, who underwent anti-PD-1 therapy were evaluated for sPD-L1 concentration by ELISA analyses at diagnosis and after treatment.

Results: Pretreatment levels of sPD-L1 in patients who received ICIs were not remarkably correlated with the overall survival of these patients (r=0.3394, p=0.1323). Reduction of plasma sPD-L1 level was significantly correlated with tumor regression in patients administered four cycles of treatment (p<0.05).

Conclusion: sPD-L1 might be derived and secreted from tumors and might be useful to identify primary responders to ICIs at a relatively early treatment timepoint.
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http://dx.doi.org/10.21873/anticanres.13716DOI Listing
September 2019

Coffee Abundant in Chlorogenic Acids Reduces Abdominal Fat in Overweight Adults: A Randomized, Double-Blind, Controlled Trial.

Nutrients 2019 Jul 16;11(7). Epub 2019 Jul 16.

Health Care Food Research Laboratories, Kao Corporation, 2-1-3 Bunka, Sumida, Tokyo 131-8501, Japan.

The components of roasted or green coffee beans that promote abdominal fat reduction are not clear. We investigated the effects of daily consumption of coffee enriched in chlorogenic acids (CGA) on abdominal fat area in a randomized, double-blind, parallel controlled trial. Healthy, overweight men and women ( = 150, body mass index (BMI) ≥25 to <30 kg/m) were randomly allocated to high-CGA (369 mg CGA/serving) or control (35 mg CGA/serving) coffee groups. Instant coffee was consumed once daily for 12 weeks, with four-week pre- and post-observation periods. Abdominal fat area and anthropometric measurements were analyzed at baseline and at four, eight, and 12 weeks, and 142 subjects completed the trial. Visceral fat area (VFA), total abdominal fat area (TFA), body weight, and waist circumference significantly decreased in the CGA group compared with the control group, with a group × time interaction ( < 0.001, = 0.001, = 0.025, and = 0.001, respectively). Changes in VFA and TFA from baseline to 12 weeks were significantly greater in the CGA group than in the control group (-9.0 ± 13.9 cm vs. -1.0 ± 14.3 cm, < 0.001; -13.8 ± 22.9 cm vs. -2.0 ± 16.2 cm, < 0.001). No severe adverse events occurred. Consumption of high-CGA coffee for 12 weeks by overweight adults might lower VFA, TFA, BMI, and waist circumference.
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http://dx.doi.org/10.3390/nu11071617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683100PMC
July 2019

Increased SLAMF7 monocytes in myelofibrosis patients harboring V617F provide a therapeutic target of elotuzumab.

Blood 2019 09 3;134(10):814-825. Epub 2019 Jul 3.

Division of Hematology, Department of Internal Medicine, National Defense Medical College, Saitama, Japan.

Monocyte-derived fibrocytes recently garnered attention because the novel pathogenesis of myelofibrosis (MF), and suppression of fibrocyte differentiation by serum amyloid P remarkably improved MF. We previously revealed that human fibrocytes highly expressed signaling lymphocytic activation molecule F7 (SLAMF7) compared with macrophages and that SLAMF7 monocytes in the peripheral blood (PB) of MF patients were significantly elevated relative to those in healthy controls (HCs). In this study, we evaluated SLAMF7 monocyte percentage in the PB of HCs, myeloproliferative neoplasm (MPN) patients with MF, and MPN patients without MF by using a cross-sectional approach. We found that MPN patients with MF who harbored V617F had a significantly elevated SLAMF7 monocyte percentage, which correlated positively with the V617F allele burden. In addition, the serum concentration of interleukin-1ra (IL-1ra) was significantly correlated with the SLAMF7 monocyte percentage and V617F allele burden. These findings suggest that both SLAMF7 monocytes and IL-1ra could be useful noninvasive markers of MF onset. Furthermore, the V617F allele burden of SLAMF7 monocytes was significantly higher than that of SLAMF7 monocytes and could be a potential target of elotuzumab (Elo), an anti-SLAMF7 antibody used for treating multiple myeloma. Elo independently inhibited differentiation of fibrocytes derived not only from HCs but also from MF patients in vitro. Elo also ameliorated MF and splenomegaly induced by romiplostim administration in humanized NOG mice. In conclusion, an increase of SLAMF7 monocytes with higher V617F allele burden was associated with the onset of MF in MPN patients harboring V617F, and Elo could be a therapeutic agent for MPN patients with MF who harbor V617F.
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http://dx.doi.org/10.1182/blood.2019000051DOI Listing
September 2019

Computed tomography-measured pulmonary artery to aorta ratio and EUTOS score for detecting dasatinib-induced pulmonary arterial hypertension.

Int J Cardiovasc Imaging 2019 Aug 4;35(8):1435-1442. Epub 2019 Feb 4.

Division of Cardiology, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513, Japan.

Background: Periodic echo-based screening to detect early stages of a rare complication of dasatinib, pulmonary arterial hypertension (PAH), is inefficient and weakens the potential benefit of dasatinib as a potent drug for chronic myelogenous leukemia (CML). This study aimed to identify the predisposing factors of DASA-PAH to stratify high-risk patients for dasatinib-induced PAH (DASA-PAH).

Methods: Sixty consecutive adult patients who received dasatinib were enrolled in this case-control study. We defined DASA-PAH when at least one of the following four criteria was met: (1) recent electrocardiographic changes indicating right ventricular pressure overload, (2) estimated systolic pulmonary arterial pressure > 40 mmHg measured by Doppler echocardiography; (3) computed tomography (CT)-measured pulmonary artery to aorta diameter (PaD/AoD) ratio > 1; and (4) mean pulmonary arterial pressure > 25 mmHg and pulmonary artery wedge pressure < 15 mmHg measured by right heart catheterization.

Results: We identified 13 patients with DASA-PAH among 59 patients analyzed. Baseline PaD/AoD ratios of patients who developed DASA-PAH (PH group) were significantly larger than those who did not (NPH group). A dramatic rise in PaD/AoD ratio after dasatinib treatment was observed. Interestingly, the EUTOS score and spleen size were significantly smaller in the PH than in the NPH group.

Conclusion: High baseline PaD/AoD ratio and low EUTOS score were associated with DASA-PAH development. The spleen might play a protective role against DASA-PAH.
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http://dx.doi.org/10.1007/s10554-019-01548-2DOI Listing
August 2019

Low mucosal-associated invariant T-cell number in peripheral blood of patients with immune thrombocytopenia and their response to prednisolone.

PLoS One 2018 8;13(11):e0207149. Epub 2018 Nov 8.

Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.

Mucosal-associated invariant T (MAIT) cells help protect against certain infections and are related to some autoimmune diseases. Immune thrombocytopenia (ITP) is a relatively rare hematological autoimmune disease associated with low platelet count. We designed a cross-sectional study wherein we examined peripheral blood samples of patients with ITP for the number of MAIT cells (CD3+TCR-Vα7.2+CD161+IL-18Rα+ lymphocytes) and their CD4/8 subsets (by flow cytometry) and levels of cytokines (by multiplex assays). The study cohort included 18 patients with ITP and 20 healthy controls (HCs). We first compared the number of MAIT cells between HCs and patients with ITP and then performed subgroup analysis in patients with ITP. The number of total MAIT cells in patients with ITP was significantly lower than that in HCs (p < 0.0001), and the CD4-CD8+ subset of MAIT cells showed the same trend. Moreover, patients with ITP refractory to prednisolone exhibited a significantly lower number of total MAIT and CD4-CD8+ MAIT cells than patients sensitive to prednisolone. The number of total MAIT and CD4-CD8+ MAIT cells was not correlated with the response to thrombopoietin receptor agonist treatment or with Helicobacter pylori infection. We found no relation between cytokine levels and response to prednisolone treatment, although the levels of IP-10 and RANTES showed a correlation with the number of total MAIT and CD4-CD8+ MAIT cells. In conclusion, total MAIT and CD4-CD8+ MAIT cells in peripheral blood were decreased in patients with ITP, correlating with their response to prednisolone.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207149PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224073PMC
April 2019

Emergence of New Recombinant Noroviruses GII.P16-GII.2 and GII.P16-GII.4 in Aichi, Japan, during the 2016/17 Season.

Jpn J Infect Dis 2018 Jul 27;71(4):319-322. Epub 2018 Apr 27.

Laboratory of Virology, Department of Microbiology and Medical Zoology, Aichi Prefectural Institute of Public Health.

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http://dx.doi.org/10.7883/yoken.JJID.2017.520DOI Listing
July 2018

Effects of Chlorogenic Acid-Enriched and Hydroxyhydroquinone-Reduced Coffee on Postprandial Fat Oxidation and Antioxidative Capacity in Healthy Men: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial.

Nutrients 2018 Apr 23;10(4). Epub 2018 Apr 23.

Health Care Food Research Laboratories, Kao Corporation, 2-1-3 Bunka, Sumida, Tokyo 131-8501, Japan.

Chlorogenic acids (CGAs) reduce blood pressure and body fat, and enhance fat metabolism. In roasted coffee, CGAs exist together with the oxidant component hydroxyhydroquinone (HHQ). HHQ counteracts the antihypertensive effects of CGA, but its effects on CGA-induced fat oxidation (FOX) are unknown. Here we assessed the effects of CGA-enriched and HHQ-reduced coffee on FOX. Fifteen healthy male volunteers (age: 38 ± 8 years (mean ± SD); BMI: 22.4 ± 1.5 kg/m²) participated in this crossover study. Subjects consumed the test beverage (coffee) containing the same amount of CGA with HHQ (CGA-HHQ(+)) or without HHQ (CGA-HHQ(−)) for four weeks. Postprandial FOX and the ratio of the biological antioxidant potential (BAP) to the derivatives of reactive oxygen metabolites (d-ROMs) as an indicator of oxidative stress were assessed. After the four-week intervention, postprandial FOX and the postprandial BAP/d-ROMs ratio were significantly higher in the CGA-HHQ(−) group compared with the CGA-HHQ(+) group (4 ± 23 mg/min, group effect: = 0.040; 0.27 ± 0.74, group effect: = 0.007, respectively). In conclusion, reducing the amount of HHQ facilitated the postprandial FOX effects of CGA in coffee. Our findings also suggest that the mechanism underlying the inhibition of FOX by HHQ is related to postprandial oxidative stress.
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http://dx.doi.org/10.3390/nu10040525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946310PMC
April 2018

CBL mutation and MEFV single-nucleotide variant are important genetic predictors of tumor reduction in glucocorticoid-treated patients with chronic myelomonocytic leukemia.

Int J Hematol 2018 Jul 29;108(1):47-57. Epub 2018 Mar 29.

Division of Hematology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.

Glucocorticoid (GC) therapy occasionally relieves tumor-related fever and promotes tumor reduction in patients with chronic myelomonocytic leukemia (CMML). A mutation analysis of 24 patients with CMML revealed the relationship of GC effectiveness, defined as a monocyte reduction of > 50% within 3 days of methylprednisolone administration, with the MEFV single-nucleotide variant (SNV) and CBL mutation. Lipopolysaccharide-stimulated monocytes harboring MEFV E148Q produced greater amounts of IL-1β and TNF-α than did wild-type monocytes; this was effectively suppressed by GC. Primary CMML cells harboring the MEFV SNV and CBL mutation, and the myelomonocytic leukemia cell line GDM-1, harboring the CBL mutation, were both more significantly suppressed than non-mutated cells following GC treatment in the presence of GM-CSF. A loss-of-function CBL mutation prolonged STAT5 phosphorylation after GM-CSF stimulation, which was rapidly terminated in both patient samples and GDM-1 cells. In conclusion, GC therapy effectively treats CMML cells harboring the MEFV SNV and CBL mutation by reducing inflammatory cytokine production and terminating prolonged STAT5 phosphorylation in the GM-CSF signaling pathway.
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http://dx.doi.org/10.1007/s12185-018-2436-0DOI Listing
July 2018

Prognostic analysis according to the 2017 ELN risk stratification by genetics in adult acute myeloid leukemia patients treated in the Japan Adult Leukemia Study Group (JALSG) AML201 study.

Leuk Res 2018 03 17;66:20-27. Epub 2018 Jan 17.

Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Many genetic alterations that are associated with the prognosis of acute myeloid leukemia (AML) have been identified, and several risk stratification systems based on the genetic status have been recommended. The European LeukemiaNet (ELN) first proposed the risk stratification system for AML in 2010 (ELN-2010), and recently published the revised system (ELN-2017). We validated the long-term prognosis and clinical characteristics of each ELN-2017 risk category in Japanese adult AML patients who were treated in the Japan Adult Leukemia Study Group (JALSG) AML-201 study. We demonstrated that the 3-risk category system of the ELN-2017 successfully discriminated the overall survival and complete remission rates in our cohort in comparison with the 4-risk category of the ELN-2010. However, there were still genetic categories in which stratification of patients into favorable or intermediate risk categories was controversial; the low allelic ratio of FLT3-ITD was not necessarily associated with a better prognosis in patients with FLT3-ITD, and cytogenetic abnormalities may affect the prognosis in patients with favorable genetic lesions such as NPM1 and CEBPA mutations. As many molecular targeting agents, such as FLT3 inhibitors, have been developed, we must continue to modify the genetic risk stratification system to match the progression of therapeutic strategies.
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http://dx.doi.org/10.1016/j.leukres.2018.01.008DOI Listing
March 2018

Sudden blast phase in chronic myeloid leukemia developed during nilotinib therapy after major molecular response was achieved.

Int J Hematol 2018 Apr 14;107(4):495-497. Epub 2017 Oct 14.

Division of Hematology, Department of Internal Medicine, National Defense Medical College Hospital, 3-2 Namiki, Tokorozawa, Saitama, 359-0042, Japan.

Sudden blast phase (SBP) is a rare event in which patients with chronic myeloid leukemia (CML) in complete cytogenetic response (CCyR) rapidly progress to the blast phase. Few patients on second-generation tyrosine kinase inhibitors (2nd TKIs) have been reported to develop SBP. Here, we report a 45-year-old man diagnosed with CML in the chronic phase in April 2008 and immediately started on imatinib therapy. He achieved CCyR 12 months after starting imatinib therapy. Imatinib was followed by treatment with the 2nd TKIs nilotinib and dasatinib from January 2011 to yield a better response. He achieved major molecular response (MMR) during dasatinib therapy in February 2012, but did not tolerate dasatinib well; hence, he was switched to nilotinib in July 2012. In December 2015, he presented at our hospital with fever and lumbago. A complete blood count revealed a white blood cell count of 30,500/µL with 60% blasts, leading to diagnosis of SBP. After dasatinib therapy and conventional chemotherapy, he again achieved MMR. This case demonstrates that SBP may occur after achieving MMR on treatment with 2nd TKIs. Continuous careful monitoring is required for the early detection of SBP, even in patients who have achieved MMR.
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http://dx.doi.org/10.1007/s12185-017-2354-6DOI Listing
April 2018

TAK1 inhibition ameliorates survival from graft-versus-host disease in an allogeneic murine marrow transplantation model.

Int J Hematol 2018 Feb 12;107(2):222-229. Epub 2017 Oct 12.

Division of Hematology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.

Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation (allo-HCT). Majority of the current immunosuppressive strategies targeting donor T cells to prevent or treat acute GVHD are only partially effective, and often require escalated immunosuppressive therapy. Recent studies have revealed that activation of antigen-presenting cells in the proinflammatory milieu is important for the priming and promotion of GVHD. This activation is mediated by innate immune signaling pathways, which therefore potentially represent new targets in addressing GVHD. Using gene expression analysis of peripheral monocytes from patients' post-allo-HCT, we detected an upregulation of TGF-β-activated kinase 1 (TAK1), a key regulator of the toll-like receptor signaling pathway. 5Z-7-oxozeaenol, a selective inhibitor of TAK1, reduced proinflammatory cytokine production by activated monocytes under lipopolysaccharide stimulation and T cell proliferation in allogeneic-mixed leukocyte reactions with monocyte-derived dendritic cells. In an experimental mouse model of GVHD, 5Z-7-oxozeaenol administration after allo-HCT ameliorated GVHD severity and mortality, with significant reduction in serum TNFα, IL-1β, and IL-12 levels. Our findings suggest that altering the activation status of innate immune cells by TAK1 inhibition may be a novel therapeutic approach for acute GVHD.
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http://dx.doi.org/10.1007/s12185-017-2345-7DOI Listing
February 2018

Prognostic value of genetic mutations in adolescent and young adults with acute myeloid leukemia.

Int J Hematol 2018 Feb 12;107(2):201-210. Epub 2017 Oct 12.

Division of Hematology, Department of Internal Medicine, National Defense Medical College, Saitama, Japan.

Clinical outcomes and the genetic background of acute myeloid leukemia (AML) in adolescent and young adults (AYAs) are known to differ in younger children and older adults. To clarify the impact of genetic mutations on clinical outcomes of AYAs with AML, we analyzed data from the JPLSG AML-05 and JALSG AML201 studies. AYAs aged 15-39 years (n = 103) were included. FLT3-ITD, KIT, CEBPA, NRAS, KRAS, WT1, MLL-PTD, and NPM1 mutations were analyzed. Overall survival (OS) of the AYAs was 61% and event-free survival was 38% at 3 years. FLT3-ITD (HR 2.10; 95% CI 1.07-4.12; p = 0.031) and NPM1 (HR 0.24; 95% CI 0.06-1.00; p = 0.050) mutations were associated with risk of overall mortality in multivariate analysis. OS was significantly different according to FLT3-ITD and NPM1 mutation status (p = 0.03). Survival was 100% with NPM1 mutations in the absence of FLT3-ITD and 35% (95% CI 14-57%) with FLT3-ITD in the absence of NPM1 mutations. The OS of AYAs, children (n = 413) and older adults (n = 124) of the AML-05 and AML201 participants were significantly different (p < 0.0001). This is the first report to combine clinical and genetic data of AYA AML from the major Japanese pediatric and adult study groups.
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http://dx.doi.org/10.1007/s12185-017-2340-zDOI Listing
February 2018

Deeper molecular response is a predictive factor for treatment-free remission after imatinib discontinuation in patients with chronic phase chronic myeloid leukemia: the JALSG-STIM213 study.

Int J Hematol 2018 Feb 19;107(2):185-193. Epub 2017 Sep 19.

Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

The objective of this prospective clinical trial (JALSG-STIM213, UMIN000011971) was to evaluate treatment-free remission (TFR) rates after discontinuation of imatinib in chronic myeloid leukemia (CML). CML patients who received imatinib treatment for at least 3 years and sustained deep molecular response for at least 2 years were eligible. Molecular recurrence was defined as loss of major molecular response (MMR). Of the 68 eligible patients, 38.2% were women, the median age was 55.0 years, and the median duration of imatinib treatment was 97.5 months. The 12-month TFR rate was 67.6%. Patients who lost MMR were immediately treated with imatinib again; all re-achieved MMR. Three-year treatment-free survival (TFS) was estimated as 64.6% using the Kaplan-Meier method. Undetectable molecular residual disease (UMRD) was defined as no BCR-ABL1 in > 100,000 ABL1 control genes using international scale polymerase chain reaction. UMRD at the study baseline was found to be predictive of continuation of TFR. Our findings suggest that CML patients who meet all the eligibility criteria that have commonly been used in the TFR trials are able to discontinue imatinib use safely. TFR may thus be valuable as a new goal for CML treatment in Japan.
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http://dx.doi.org/10.1007/s12185-017-2334-xDOI Listing
February 2018

Evaluation of CYP2D6 Protein Expression and Activity in the Small Intestine to Determine Its Metabolic Capability in the Japanese Population.

Biol Pharm Bull 2017 Sep 14;40(9):1344-1351. Epub 2017 Jun 14.

Department of Pharmacology, St. Marianna University School of Medicine.

CYP2D6 plays an important role in the metabolism of many drugs such as opioids and antidepressants. Polymorphisms of the CYP2D6 gene are widely observed in the Japanese population, and can affect the first-pass metabolism of orally administered drugs. Several CYP enzymes have been identified in the small intestine of Caucasians, but intestinal CYP enzymes have not been reported in the Japanese population, except for CYP3A4 and CYP2C19. In this study, we evaluated the CYP2D6 metabolic capacity by measurement of CYP2D6 mRNA and protein levels and activity in the small intestine of Japanese individuals. Normal jejunal tissues were obtained from 31 patients who had undergone pancreaticoduodenectomy, and the CYP2D6*10 variant was identified in these tissues. CYP2D6 mRNA and CYP2D6 protein levels were analyzed using real-time RT-PCR and Western blotting, respectively. Bufuralol 1'-hydroxylation, a marker of CYP2D6 activity, was analyzed using HPLC. Frequencies of the CYP2D6*1/*1, *1/*10, and *10/*10 genotypes in the jejunal tissue were 29.0% (n=9), 35.5% (n=11), and 35.5% (n=11), respectively. CYP2D6 protein and activity levels did not differ significantly between the genotypes. A positive correlation was found between CYP2D6 protein and activity levels. Furthermore, CYP2D6 protein levels and activity in the small intestine were significantly lower than those in the liver. These findings suggest that the metabolic capacity of CYP2D6 in the small intestine of the Japanese population has a relatively small effect on drug metabolism.
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http://dx.doi.org/10.1248/bpb.b16-00370DOI Listing
September 2017

Second-generation total synthesis of aplyronine A featuring Ni/Cr-mediated coupling reactions.

Org Biomol Chem 2016 Dec;15(1):124-131

Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, Japan.

Second-generation total synthesis of aplyronine A, a potent antitumor marine macrolide, was achieved using Ni/Cr-mediated coupling reactions as key steps. The overall yield of the second-generation synthetic pathway of aplyronine A was 1.4%, obtained in 38 steps based on the longest linear sequence. Compared to our first-generation synthetic pathway of aplyronine A, the second-generation synthesis greatly improved both the yield and number of steps. In particular, we improved the stereoselectivity in the construction of the C13 stereogenic center and the C14-C15 (E)-trisubstituted double bond using the asymmetric Ni/Cr-mediated coupling reaction. Furthermore, we established efficient reaction conditions for the asymmetric Ni/Cr-mediated coupling reaction between the C21-C28 segment and C29-C34 segment. Thus, this coupling reaction proceeded with an equimolar ratio of each segment.
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http://dx.doi.org/10.1039/c6ob02241cDOI Listing
December 2016

Community Attitudes and Practices of Urban Residents Regarding Predation by Pet Cats on Wildlife: An International Comparison.

PLoS One 2016 6;11(4):e0151962. Epub 2016 Apr 6.

School of Veterinary and Life Sciences, Murdoch University, Murdoch, Western Australia, Australia.

International differences in practices and attitudes regarding pet cats' interactions with wildlife were assessed by surveying citizens from at least two cities in Australia, New Zealand, the UK, the USA, China and Japan. Predictions tested were: (i) cat owners would agree less than non-cat owners that cats might threaten wildlife, (ii) cat owners value wildlife less than non-cat owners, (iii) cat owners are less accepting of cat legislation/restrictions than non-owners, and (iv) respondents from regions with high endemic biodiversity (Australia, New Zealand, China and the USA state of Hawaii) would be most concerned about pet cats threatening wildlife. Everywhere non-owners were more likely than owners to agree that pet cats killing wildlife were a problem in cities, towns and rural areas. Agreement amongst non-owners was highest in Australia (95%) and New Zealand (78%) and lowest in the UK (38%). Irrespective of ownership, over 85% of respondents from all countries except China (65%) valued wildlife in cities, towns and rural areas. Non-owners advocated cat legislation more strongly than owners except in Japan. Australian non-owners were the most supportive (88%), followed by Chinese non-owners (80%) and Japanese owners (79.5%). The UK was least supportive (non-owners 43%, owners 25%). Many Australian (62%), New Zealand (51%) and Chinese owners (42%) agreed that pet cats killing wildlife in cities, towns and rural areas was a problem, while Hawaiian owners were similar to the mainland USA (20%). Thus high endemic biodiversity might contribute to attitudes in some, but not all, countries. Husbandry practices varied internationally, with predation highest where fewer cats were confined. Although the risk of wildlife population declines caused by pet cats justifies precautionary action, campaigns based on wildlife protection are unlikely to succeed outside Australia or New Zealand. Restrictions on roaming protect wildlife and benefit cat welfare, so welfare is a better rationale.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151962PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822884PMC
August 2016

Dataset of calcified plaque condition in the stenotic coronary artery lesion obtained using multidetector computed tomography to indicate the addition of rotational atherectomy during percutaneous coronary intervention.

Data Brief 2016 Jun 27;7:376-80. Epub 2016 Feb 27.

Division of Cardiology, Department of Medicine, Showa University School of Medicine, Japan.

Our data shows the regional coronary artery calcium scores (lesion CAC) on multidetector computed tomography (MDCT) and the cross-section imaging on MDCT angiography (CTA) in the target lesion of the patients with stable angina pectoris who were scheduled for percutaneous coronary intervention (PCI). CAC and CTA data were measured using a 128-slice scanner (Somatom Definition AS+; Siemens Medical Solutions, Forchheim, Germany) before PCI. CAC was measured in a non-contrast-enhanced scan and was quantified using the Calcium Score module of SYNAPSE VINCENT software (Fujifilm Co. Tokyo, Japan) and expressed in Agatston units. CTA were then continued with a contrast-enhanced ECG gating to measure the severity of the calcified plaque condition. We present that both CAC and CTA data are used as a benchmark to consider the addition of rotational atherectomy during PCI to severely calcified plaque lesions.
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http://dx.doi.org/10.1016/j.dib.2016.02.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4781927PMC
June 2016
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