Verification of the Usefulness of an Assessment and Risk Control Sheet that Promotes Management of Cancer Drug Therapy.

Background: Proper management of adverse events is crucial for the safe and effective implementation of anticancer drug treatment. Showa University Hospital uses our interview sheet (assessment and risk control [ARC] sheet) for the accurate evaluation of adverse events. On the day of anticancer drug treatment, a nurse conducts a face-to-face interview. As a feature of the ARC sheet, by separately describing the symptoms the day before treatment and the day of treatment and sharing the information on the medical record, it is possible to clearly determine the status of adverse events. In this study, we hypothesized that the usefulness and points for improvement of the ARC sheet would be clarified by using and evaluating a patient questionnaire. Methods: This study included 174 patients (144 at Showa University Hospital (Hatanodai Hospital) and 30 at Showa University Koto Toyosu Hospital (Toyosu Hospital) who underwent pre-examination interviews by nurses and received cancer chemotherapy at the outpatient center of Hatanodai and Toyosu Hospital. In the questionnaire survey, the ARC sheet's content and quality, respondents' satisfaction, structural strengths, and points for improvement were evaluated on a five-point scale. Results: The patient questionnaire received responses from 160 participants, including the ARC sheet use group (132 people) and the non-use group (28 people). Unlike the ARC sheet non-use group, the ARC sheet use group recognized that the sheet was useful to understand the adverse events of aphthous ulcers (p = 0.017) and dysgeusia (p = 0.006). In the satisfaction survey questionnaire, there was a high sense of security in the pre-examination interviews by nurses using the ARC sheet. Conclusions: The ARC sheet is considered an effective tool for comprehensively evaluating adverse events. Pre-examination interviews by nurses using ARC sheets accurately determined the adverse events experienced by patients with anxiety and tension due to confrontation with physicians.

Shape relatedness between geographic populations of Culex tritaeniorhynchus, the primary vector of Japanese encephalitis virus: A landmark study.

BACKGROUND: Japanese encephalitis is a severe disease of acute encephalitis, with children and the elderly primarily affected, and with mortality rates reaching over 25%. The virus is transmitted mainly by species of the Culex (Culex) vishnui subgroup, primarily the widely spread Cx. tritaeniorhynchus Giles. The latter is known as a highly migratory mosquito which moves with airflow over large distances. We explored the geometric variation of the wing venation among distant areas of its geographic distribution. Our working hypothesis was that shape variation across geography could reveal known past and present migratory routes. MATERIALS METHODS: We compared the wing venation geometry of 236 female Culex tritaeniorhynchus from different locations in the Madagascan (La Reunion), Oriental (Thailand, Vietnam) and Paleartic (Japan) regions. To ascertain the taxonomic signal of the wing venation we also used two species as relative outgroups, Cx. whitmorei and Cx. brevipalpis. RESULTS: In spite of an increasing morphometric variation as expected with larger geographic dispersion, our Cx. tritaeniorhynchus samples were clustered as a single species when considered relative to other Culex species. The relationships between geographic sites of Cx. tritaeniorhynchus globally conformed with an isolation by distance model. The shape homogeneity of our Palearctic samples (Japan) contrasted with some heterogeneity observed in the Oriental region (Thailand, Vietnam), and could be related to the different regimes of wind trajectories in these regions. CONCLUSION: The average shape variation of Culex tritaeniorhynchus disclosed a separation between Madagascan, Oriental and Palearctic regions in accordance with geography. The wing venation not only could reflect geography, it also contained a clear taxonomic signal separating three Culex species. Within Cx. tritaeniorhynchus, a contrasting pattern of shape variation between the Palearctic and the Oriental regions is tentatively explained by the influence of wind trajectories.

Genome-wide association study identifies pharmacogenomic loci linked with specific antihypertensive drug treatment and new-onset diabetes.

We conducted a discovery genome-wide association study with expression quantitative trait loci (eQTL) annotation of new-onset diabetes (NOD) among European Americans, who were exposed to a calcium channel blocker-based strategy (CCB strategy) or a ß-blocker-based strategy (ß-blocker strategy) in the INternational VErapamil SR Trandolapril STudy. Replication of the top signal from the SNP*treatment interaction analysis was attempted in Hispanic and African Americans, and a joint meta-analysis was performed (total 334 NOD cases and 806 matched controls). PLEKHH2 rs11124945 at 2p21 interacted with antihypertensive exposure for NOD (meta-analysis P=5.3 × 10-8). rs11124945 G allele carriers had lower odds for NOD when exposed to the ß-blocker strategy compared with the CCB strategy (Odds ratio OR=0.38(0.24-0.60), P=4.0 × 10-5), whereas A/A homozygotes exposed to the ß-blocker strategy had increased odds for NOD compared with the CCB strategy (OR=2.02(1.39-2.92), P=2.0 × 10-4). eQTL annotation of the 2p21 locus provides functional support for regulating gene expression.

Phase I and biomarker study of OPB-51602, a novel signal transducer and activator of transcription (STAT) 3 inhibitor, in patients with refractory solid malignancies.

BACKGROUND: The aim of this study was to determine the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of OPB-51602, an oral, direct signal transduction activator of transcription 3 (STAT3) inhibitor, in patients with refractory solid tumors. PATIENTS AND METHODS: Three cohorts were studied: cohort A, a sequential dose escalation of OPB-51602 administered intermittently (days 1-14 every 21 days); cohort B, an expansion cohort evaluating the dose lower than the MTD; cohort C, evaluating continuous daily dosing. RESULTS: Fifty-one patients were studied at 2, 4, and 5 mg per day dosing. The MTD was 5 mg; first-cycle dose-limiting toxicities (DLTs) were grade 3 hyponatremia in one patient, and grade 3 dehydration in another. Intermittent dosing of both 2 and 4 mg doses were tolerable, and the recommended phase II dose was 4 mg. Cohort B investigated 4 mg intermittently, whereas cohort C investigated 4 mg continuously. Common toxicities included fatigue, nausea/vomiting, diarrhea, anorexia, and early-onset peripheral neuropathy. Drug-induced pneumonitis occurred in two patients in cohort C. Continuous dosing was associated with a higher incidence of peripheral neuropathy and a lower mean relative dose intensity, compared with intermittent dosing. Steady-state pharmacokinetics was characterized by high oral clearance, mean elimination half-life ranging from 44 to 61 h, and a large terminal-phase volume of distribution. An active metabolite, OPB-51822, accumulated to a greater extent than OPB-51602. Flow cytometry of peripheral blood mononuclear cells demonstrated pSTAT3 (Tyr(705)) inhibition following exposure. Two patients achieved partial responses at 5 mg intermittently and 4 mg continuously; both had epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor exposure. CONCLUSION: OPB-51602 demonstrates promising antitumor activity, particularly in NSCLC. Its long half-life and poorer tolerability of continuous dosing, compared with intermittent dosing, suggest that less frequent dosing should be explored. CLINICALTRIALSGOV IDENTIFIER: NCT01184807.

Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders.

We developed a next-generation sequencing (NGS) based mutation screening strategy for neurodevelopmental diseases. Using this system, we screened 284 genes in 40 patients. Several novel mutations were discovered. Patient 1 had a novel mutation in ACTB. Her dysmorphic feature was mild for Baraitser-Winter syndrome. Patient 2 had a truncating mutation of DYRK1A. She lacked microcephaly, which was previously assumed to be a constant feature of DYRK1A loss of function. Patient 3 had a novel mutation in GABRD gene. She showed Rett syndrome like features. Patient 4 was diagnosed with Noonan syndrome with PTPN11 mutation. He showed complete agenesis of corpus callosum. We have discussed these novel findings.

Risk factors for bacteraemia attributable to Pseudomonas aeruginosa resistant to imipenem, levofloxacin, or gentamicin.

We studied the risk factors associated with resistance to imipenem, levofloxacin and gentamicin in Pseudomonas aeruginosa isolated from blood cultures of 175 patients in a hospital in Japan. Imipenem resistance was associated with transfer from another hospital, and receiving antifungal medication. Gentamicin resistance was associated with previous administration of a penicillin. No specific risk factors were associated with levofloxacin resistance.

Common variant in 6q26-q27 is associated with distal colon cancer in an Asian population.

BACKGROUND AND AIM: Colorectal cancer (CRC) is a multifactorial disease with both environmental and genetic factors contributing to its development. The incidence of CRC is increasing year by year in Japan. Patients with CRC in advanced stages have a poor prognosis, but detection of CRC at earlier stages can improve clinical outcome. Therefore, identification of epidemiologial factors that influence development of CRC would facilitate the prevention or early detection of disease. METHODS: To identify loci associated with CRC risk, we performed a genome-wide association study (GWAS) for CRC and sub-analyses by tumour location using 1583 Japanese CRC cases and 1898 controls. Subsequently, we conducted replication analyses using a total of 4809 CRC cases and 2973 controls including 225 Korean subjects with distal colon cancer and 377 controls. RESULTS: We identified a novel locus on 6q26-q27 region (rs7758229 in SLC22A3, p = 7.92 × 10⁻9, OR of 1.28) that was significantly associated with distal colon cancer. We also replicated the association between CRC and SNPs on 8q24 (rs6983267 and rs7837328, p = 1.51 × 10⁻8 and 7.44 × 10⁻8, ORs of 1.18 and 1.17, respectively). Moreover, we found cumulative effects of three genetic factors (rs7758229, rs6983267, and rs4939827 in SMAD7) and one environmental factor (alcohol drinking) which appear to increase CRC risk approximately twofold. CONCLUSIONS: We found a novel susceptible locus in SLC22A3 that contributes to the risk of distal colon cancer in an Asian population. These findings would further extend our understanding of the role of common genetic variants in the aetiology of CRC.

Laparoscopy-assisted spleen-preserving pancreatic resection for epidermoid cyst in an intrapancreatic accessory spleen.

A rare case of an epidermoid cyst originating in an intrapancreatic accessory spleen in a 50-year-old Japanese female is reported. A hypoechoic cystic tumor was detected incidentally by abdominal ultrasonography. It appeared to be a single cyst in the pancreatic tail with a contrasted mass lesion beside it. Laparoscopy-assisted spleen-preserving pancreatic tail resection was performed. Microscopic examination revealed that the cyst was surrounded by fibrous tissue and a thin layer of splenic tissue, adjacent to normal pancreatic parenchyma. The inner surface of the cyst was lined with non-keratinizing squamous epithelium. The diagnosis of an epidermoid cyst occurring in an intrapancreatic accessory spleen was confirmed. Laparoscopy-assisted spleen-preserving pancreatic resection is a safe and effective procedure for benign or low-grade malignant cystic diseases in the pancreas.

Identification of HLA-A2-restricted CTL epitopes of a novel tumour-associated antigen, KIF20A, overexpressed in pancreatic cancer.

BACKGROUND: Identification of tumour-associated antigens (TAAs) that induce cytotoxic T lymphocytes (CTLs) specific to cancer cells is critical for the development of anticancer immunotherapy. In this study, we aimed at identifying a novel TAA of pancreatic cancer for immunotherapy. METHODS: On the basis of the genome-wide cDNA microarray analysis, we focused on KIF20A (also known as RAB6KIFL/MKlp2) as a candidate TAA in pancreatic cancer cells. The HLA-A2 (A*02:01)-restricted CTL epitopes of KIF20A were identified using HLA-A2 transgenic mice (Tgm) and the peptides were examined to check whether they could generate human CTLs exhibiting cytotoxic responses against KIF20A(+), HLA-A2(+) tumour cells in vitro. RESULTS: KIF20A was overexpressed in pancreatic cancer and in some other malignancies, but not in their non-cancerous counterparts and many normal adult tissues. We found that KIF20A-2 (p12-20, LLSDDDVVV), KIF20A-8 (p809-817, CIAEQYHTV), and KIF20A-28 (p284-293, AQPDTAPLPV) peptides could induce HLA-A2-restricted CTLs in HLA-A2 Tgm without causing autoimmunity. Peptide-reactive human CTLs were generated from peripheral blood mononuclear cells of HLA-A2(+) healthy donors by in vitro stimulation with the three peptides, and those CTLs successfully exhibited cytotoxic responses to cancer cells expressing both KIF20A and HLA-A2. CONCLUSION: KIF20A is a novel promising candidate for anticancer immunotherapeutic target for pancreatic cancers.

c-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis.

The development of cancer is due to the growth and proliferation of transformed normal cells. Recent evidence suggests that the nature of oncogenic stress and the state of the cell of origin critically affect both tumorigenic activity and tumor histological type. However, this mechanistic relationship in mesenchymal tumors is currently largely unexplored. To clarify these issues, we established a mouse osteosarcoma (OS) model through overexpression of c-MYC in bone marrow stromal cells (BMSCs) derived from Ink4a/Arf (-/-) mice. Single-cell cloning revealed that c-MYC-expressing BMSCs are composed of two distinctly different clones: highly tumorigenic cells, similar to bipotent-committed osteochondral progenitor cells, and low-tumorigenic tripotent cells, similar to mesenchymal stem cells (MSCs). It is noteworthy that both bipotent and tripotent cells were capable of generating histologically similar, lethal OS, suggesting that both committed progenitor cells and MSCs can become OS cells of origin. Shifting mesenchymal differentiation by depleting PPARγ in tripotent MSC-like cells and overexpressing PPARγ in bipotent cells affected cell proliferation and tumorigenic activity. Our findings indicate that differentiation potential has a key role in OS tumorigenic activity, and that the suppression of adipogenic ability is a critical factor for the development of OS.

Risk factors for depression after kidney transplantation.

OBJECTIVE: Kidney transplantation is recognized as the only potentially curative treatment for end-stage renal failure. But many psychiatric problems are associated with the procedure. The purpose of this study was to identify predictors of a risk for depression after kidney transplantation. MATERIALS AND METHODS: This retrospective cohort study recruited 116 first kidney-only Japanese recipients whose mean age was 50.2 +/- 11.87 years include a male/female ratio of 63/53. They underwent transplantation between 1990 and 2008. At enrollment, we used the Zung Self-rating Depression Scale score as well as characterized demographic and clinical features of recipients and donors. Comparisons between depressed and non-depressed patients concerning sociodemographic and clinical characteristics were used chi(2) tests for categorical variables and Student's t-tests for continuous variables. Risk factors with significant correlation coefficients (P < .05) were entered into a stepwise logistic regression model to identify the best single risk factor for depression after kidney transplantation. RESULT: The prevalence of depression in this study was 41.4%. Depressed patients were significantly more likely to not have regular incomes, nor to have desired kidney transplantation, to have experienced a rejection episode, and to live alone (P < .05). The single best predictor of future depression was living alone; subjects living alone were 2.51 times more likely to be depressed as those living with others (adjusted odds ratio [OR], 2.51; 95% confidence interval [CI], 1.31-5.22; P < .05). CONCLUSION: Although depression after kidney transplantation is driven by multiple, complex, and often overlapping risk factors, we observed characteristic features of recipients including their social environment and follow-up treatment.

Activation of the non-canonical Dvl-Rac1-JNK pathway by Frizzled homologue 10 in human synovial sarcoma.

We previously reported that Frizzled homologue 10 (FZD10), a member of the Wnt signal receptor family, was highly and specifically upregulated in synovial sarcoma and played critical roles in its cell survival and growth. We here report a possible molecular mechanism of the FZD10 signaling in synovial sarcoma cells. We found a significant enhancement of phosphorylation of the Dishevelled (Dvl)2/Dvl3 complex as well as activation of the Rac1-JNK cascade in synovial sarcoma cells in which FZD10 was overexpressed. Activation of the FZD10-Dvls-Rac1 pathway induced lamellipodia formation and enhanced anchorage-independent cell growth cells. FZD10 overexpression also caused the destruction of the actin cytoskeleton structure, probably through the downregulation of the RhoA activity. Our results have strongly implied that FZD10 transactivation causes the activation of the non-canonical Dvl-Rac1-JNK pathway and plays critical roles in the development/progression of synovial sarcomas.

Influence of aggregation and relative humidity on longevity of unfed bush tick, Haemaphysalis longicornis Neumann (Acari: Ixodidae).

The survival of all stages of Haemaphysalis longicornis was investigated at different densities and at 3 levels of relative humidity. Larvae survived longer when the density was higher, or the size of a cluster was larger, or both. However, in nymphs and adults, there was no significant relationship between the density and the survival period. Moreover, in nymphs and adults, there was no positive relationship between the size of the aggregation and tick longevity, except for 2 nymphs/vial in high humidity. These results suggest that the advantage gained from a higher density, or from taking part in a cluster, or both, differed between stages. Furthermore, the fact that the survival period of larvae and nymphs was influenced by cohort suggests that a maternal effect, as well as aggregation, influences the survival of immature ticks.

Efficacy of carotid artery stenting.

SUMMARY: Carotid Artery Stenting(CAS) was performed for 51 lesions in 46 patients for almost clinically symptomatic stenotic (> 70%)lesions of cervical carotid arteries. The lesions involved the contralateral occlusion cases in eight cases, the bilateral stenotic cases in six cases and the ipsilateral internal carotid artery stenotic cases in two cases. In all cases, endovascular technique was performed from a transfemoral approach under local anesthesia primarily. Under systemic heparinization, CAS was performed using a selfexpanding stent system. For the pre-stenting and post-stenting dilatation, percutaneous transluminal angioplasty (PTA) balloon catheters were used. The balloon was inflated up to the pressure of six to ten atoms for 20 to 30 seconds.After CAS, stenotic lesion dilated successfully in all cases (0-20% residual stenosis; mean, 5.5%) even if in the case of the contra-lateral occlusion cases, more than 90% severe stenotic cases, and the tortuous artery cases. The cerebral protection system was always used, mainly distal blocking balloon type. Only one symptomatic complication occurred after CAS. Follow-up ultrasonic carotid echogram was performed in 30 cases.No cases showed restenosis (more than 50% restenosis). Clinical follow up was performed in all cases for one to 41 months (mean, 15.2 months) and no clinical deterioration such as TIA or stroke occurred. CAS is technically feasible and can be performed with relatively low morbidity even if complicated stenotic cases. It may be useful, but the increase the number of patients and the long-term follow-up are necessary to evaluate the safety and usefulness of this method.

Risk factors for de novo acute cardiac events in patients initiating hemodialysis with no previous cardiac symptom.

An initial major adverse cardiac event (MACE) is an important predictor of future cardiovascular events in patients with chronic kidney disease (CKD). We sought to identify factors influencing occurrence of initial MACE in new maintenance hemodialysis patients without previous cardiac symptoms during the predialysis phase of CKD. Among 112 participating patients with no predialysis cardiac history, 57 underwent coronary angiography, whereas the other 55 underwent stress thallium-201 single-photon emission computed tomography within 1 month of beginning hemodialysis to detect asymptomatic coronary artery disease (CAD). In subsequent follow-up for a median of 24 months, subjects experiencing an initial MACE were compared with those who did not have such an event based on several clinical parameters at the end of predialysis phase. Asymptomatic CAD was present in 47 patients (42%), who had a higher cumulative MACE rate, than subjects without CAD (49 vs 3%, P<0.001). Multivariate Cox's regression analysis showed that three variables independently predicted initial MACE: asymptomatic CAD (hazard ratio or HR, 611.31; 95% confidence interval or CI, 14.07-26549.23; P<0.001), diabetes (HR, 20.41; 95% CI, 2.07-200.00; P=0.010), and each 1 mg/l increment in C-reactive protein (CRP) (HR, 1.94; 95% CI, 1.27-2.94; P=0.002). In conclusion, detection of asymptomatic CAD, presence of diabetes, or elevated CRP at the end of the predialysis phase were significantly associated with occurrence of an initial MACE in CKD patients starting hemodialysis who had no CAD symptoms.

The expression of platelet-derived growth factor and connective tissue growth factor in different types of abdominal aortic aneurysms.

AIM: An atherosclerotic abdominal aortic aneurysms (AAAA) differ from inflammatory abdominal aortic aneurysms (IAAA), which are characterized by a non specific inflammatory reaction leading to considerable aneurysmal wall thickness from the media to adventitia and retroperitoneal fibrosis in the surrounding tissue. Platelet-derived growth factor (PDGF) and its receptor have been localized to specific cell types within atherosclerotic plaques. Human connective tissue growth factor (CTGF) is a cysteine rich polypeptide that has similar structures to PDGF and has been implicated in connective tissue formation. PDGF and CTGF may play a role in the development of aneurysmal walls in both AAAA and IAAA. METHODS: Using in situ hybridization technique with DIG-labeled RNA probes and immunostaining, we investigated CTGF gene expression, and expression of PDGF and its receptor protein, in human aneurysmal walls. RESULTS: Expression of CTGF mRNA was found on vascular smooth muscle cells (VSMC) in specimens from AAAA and IAAA. Strong CTGF expression was localized in VSMC around calcification in AAAA. In IAAA, strong expression of CTGF was observed around inflammatory cells. In the aneurysmal walls of AAAA, PDGF A and B chains were strongly stained on small vessels, and the PDGF beta receptor was also strongly stained on VSMC around calcification. In the aneurysmal wall of IAAA, weak expressions of PDGF A and B chains were observed in endothelial cells of vessel walls around the inflammatory cells, but the intensity of expression was much weaker than that on the vessel walls in AAAA. CONCLUSIONS: Such differences in fibrogenic cytokine expression may be involved in characteristic aneurysmal formation.

Single nucleotide polymorphisms in the gene encoding Krüppel-like factor 7 are associated with type 2 diabetes.

AIMS/HYPOTHESIS: Although genetic susceptibility plays an important role in the pathogenesis of type 2 diabetes, most of the genes that influence susceptibility to type 2 diabetes have yet to be identified. Krüppel-like transcription factors are known to play important roles in development and cell differentiation, and have recently been implicated in the pathogenesis of type 2 diabetes. The present study aimed to examine the associations of single nucleotide polymorphisms (SNPs) in genes encoding members of the Krüppel-like-factor (KLF) family with type 2 diabetes in a large cohort of Japanese subjects. METHODS: We genotyped 33 SNP loci found in 12 KLF genes in subjects with type 2 diabetes and in subjects from the general population using the PCR-Invader assay. We also examined the effects of the overexpression of KLF7 on adipogenesis in 3T3-L1 cells. RESULTS: We identified a significant association between an SNP in KLF7 and type 2 diabetes (A vs C: p=0.004 after Bonferroni's correction, odds ratio=1.59, 95% CI 1.27-2.00). The expression of Klf7 decreased in response to the differentiation of 3T3-L1 adipocytes, and the overexpression of KLF7 resulted in significant inhibition of adipogenesis in 3T3-L1 cells. CONCLUSIONS/INTERPRETATION: These results indicate that the gene encoding KLF7 is a novel candidate for conferring genetic susceptibility to type 2 diabetes.

CUL1, a component of E3 ubiquitin ligase, alters lymphocyte signal transduction with possible effect on rheumatoid arthritis.

Ubiquitination affects various immune processes and E3 ubiquitin ligases (E3) play an important role in determining substrate specificity. We identified 11 human E3 ligase genes of potential importance in pathogenesis of autoimmune diseases by search of public databases and screened them for candidacy of biological investigation with case-control linkage disequilibrium tests on multiple SNPs in the genes using rheumatoid arthritis (RA) as a model of autoimmune diseases. Significant association with RA was observed in an SNP in intron 3 of Cullin 1 (CUL1) that affected transcriptional efficiency of the promoter activity in lymphocytic cell lines. Quantitative expression analysis revealed that CUL1 mRNA was highly detected in lymphoid tissues including spleen and tonsil, and was specifically expressed in T and B lymphocytes in fractionated peripheral leukocytes. Histological evaluation of tonsils indicated that CUL1 protein expression was relatively specific for maturing germinal centers. Suppression of CUL1 expression had influence on the phenotype of T-cell line, that is, it inhibited IL-8 induction, which is known to play an important role in the migration of inflammatory cells into the affected area seen in RA. Our data suggest that the regulation of CUL1 expression in immunological tissues may affect the susceptibility of RA via altering lymphocyte signal transduction.