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1.
Cancer Med ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714026

RESUMO

Multiple myeloma (MM) continues to be considered incurable, necessitating new drug discovery. The mitotic kinase T-LAK cell-originated protein kinase/PDZ-binding kinase (TOPK/PBK) is associated with proliferation of tumor cells, maintenance of cancer stem cells, and poor patient prognosis in many cancers. In this report, we demonstrate potent anti-myeloma effects of the TOPK inhibitor OTS514 for the first time. OTS514 induces cell cycle arrest and apoptosis at nanomolar concentrations in a series of human myeloma cell lines (HMCL) and prevents outgrowth of a putative CD138+ stem cell population from MM patient-derived peripheral blood mononuclear cells. In bone marrow cells from MM patients, OTS514 treatment exhibited preferential killing of the malignant CD138+ plasma cells compared with the CD138- compartment. In an aggressive mouse xenograft model, OTS964 given orally at 100 mg/kg 5 days per week was well tolerated and reduced tumor size by 48%-81% compared to control depending on the initial graft size. FOXO3 and its transcriptional targets CDKN1A (p21) and CDKN1B (p27) were elevated and apoptosis was induced with OTS514 treatment of HMCLs. TOPK inhibition also induced loss of FOXM1 and disrupted AKT, p38 MAPK, and NF-κB signaling. The effects of OTS514 were independent of p53 mutation or deletion status. Combination treatment of HMCLs with OTS514 and lenalidomide produced synergistic effects, providing a rationale for the evaluation of TOPK inhibition in existing myeloma treatment regimens.

2.
Sci Rep ; 9(1): 17332, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31757997

RESUMO

Genome-wide association studies (GWAS) have successfully identified about 70 genomic loci associated with breast cancer. Owing to the complexity of linkage disequilibrium and environmental exposures in different populations, it is essential to perform regional GWAS for better risk prediction. This study aimed to investigate the genetic architecture and to assess common genetic risk model of breast cancer with 6,669 breast cancer patients and 21,930 female controls in the Japanese population. This GWAS identified 11 genomic loci that surpass genome-wide significance threshold of P < 5.0 × 10-8 with nine previously reported loci and two novel loci that include rs9862599 on 3q13.11 (ALCAM) and rs75286142 on 21q22.12 (CLIC6-RUNX1). Validation study was carried out with 981 breast cancer cases and 1,394 controls from the Aichi Cancer Center. Pathway analyses of GWAS signals identified association of dopamine receptor medicated signaling and protein amino acid deacetylation with breast cancer. Weighted genetic risk score showed that individuals who were categorized in the highest risk group are approximately 3.7 times more likely to develop breast cancer compared to individuals in the lowest risk group. This well-powered GWAS is a representative study to identify SNPs that are associated with breast cancer in the Japanese population.

3.
J Hum Genet ; 64(12): 1187-1194, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31588121

RESUMO

Lynch syndrome (LS) is an autosomal dominantly inherited disease predisposed to not only colorectal cancer but also other LS-related tumors. Although the clinical and genetic characteristics of LS in Western countries have been well characterized, the information of Japanese LS is limited. As a collaborative study of Japanese Society for Cancer of the Colon and Rectum (JSCCR), we registered colorectal cancer (CRC) patients who fulfilled the modified Amsterdam II criteria including gastric cancer as an LS-related tumor. Among 4030 CRC patients initially registered in this project, 85 patients (2.1%) fulfilled the modified criteria. An additional 26 patients who met the same criteria were enrolled in the analysis. We analyzed three major responsible genes, MLH1, MSH2, and MSH6 by direct sequencing, and further performed multiplex ligation-dependent probe amplification for MLH1 and MSH2. Consequently, we identified pathogenic variants in 64 of the 111 patients comprising of 34 patients in MLH1, 28 in MSH2, and 2 in MSH6. It is of note that large structural alterations were found in 17 patients. Among the 64 patients, 11 patients would not have been enrolled in the analysis if gastric cancer were not included in the modified criteria. In addition, 10 of the 64 variant carriers (15.6%) had medical history of gastric cancer. Furthermore, the standardized incidence ratio of gastric cancer in the LS patients to the Japanese population is estimated to be as high as 20.2. These data underscore the importance of gastric cancer in the diagnosis and healthcare of Japanese LS patients.

4.
Oral Oncol ; 96: 77-88, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31422218

RESUMO

OBJECTIVES: In this study we describe the tumor microenvironment, the signaling pathways and genetic alterations associated with the presence or absence of CD8+ T-cell infiltration in primary squamous cell carcinoma of the head and neck (SCCHN) tumors. MATERIALS AND METHODS: Two SCCHN multi-analyte cohorts were utilized, the Cancer Genome Atlas (TCGA) and the Chicago Head and Neck Genomics (CHGC) cohort. A well-established chemokine signature classified SCCHN tumors into high and low CD8+ T-cell inflamed phenotypes (TCIP-H, TCIP-L respectively). Gene set enrichment and iPANDA analyses were conducted to dissect differences in signaling pathways, somatic mutations and copy number aberrations for TCIP-H versus TCIP-L tumors, stratified by HPV status. RESULTS: TCIP-H SCCHN tumors were enriched in multiple immune checkpoints irrespective of HPV-status. HPV-positive tumors were enriched in markers of T-regulatory cells (Tregs) and HPV-negative tumors in protumorigenic M2 macrophages. TCIP-L SCCHN tumors were enriched for the ß-catenin/WNT and Hedgehog signaling pathways, had frequent mutations in NSD1, amplifications in EGFR and YAP1, as well as CDKN2A deletions. TCIP-H SCCHN tumors were associated with the MAPK/ERK, JAK/STAT and mTOR/AKT signaling pathways, and were enriched in CASP8, EP300, EPHA2, HRAS mutations, CD274, PDCD1LG2, JAK2 amplifications. CONCLUSIONS: Our findings support that combinatorial immune checkpoint blockade and depletion strategies targeting Tregs in HPV-positive and M2 macrophages in HPV-negative tumors may lead to improved antitumor immune responses in patients with TCIP-H SCCHN. We highlight novel pathways and genetic events that may serve as candidate biomarkers and novel targeted therapies to enhance the efficacy of immunotherapy in SCCHN patients.

5.
Neurol Ther ; 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31401796

RESUMO

INTRODUCTION: The Japanese government's current policy is to encourage hospitals to discharge hospital patients with schizophrenia earlier and provide them with community care. This study aims to analyze clinical and economic outcomes of different discharge strategies in psychiatric hospitals in Japan. METHODS: A simulation was conducted to compare patient relapse and hospital revenues for different discharge plans. We constructed a decision tree where each tree consists of a different Markov chain that models hospital revenue for four different discharge plans: discharge of the patient after 1, 2, or 3 months, or 4 months or more. The simulation also included variations in the medical treatment regimen in an outpatient setting as part of the discharge strategy. In particular, we looked at the choice between risperidone long-acting injectable (RLAI) and generic risperidone (RIS GE). RESULTS: The use of RLAI in an outpatient setting reduced the number of rehospitalizations compared to generic risperidone use under all discharge plans. Different discharge plans were associated with differences in economic outcomes as well. One of the key revenue drivers for the hospital was the continuation of treatment in the outpatient setting after discharge. CONCLUSION: The use of RLAI in an outpatient setting could help to prevent rehospitalization, thereby contributing to better community care. FUNDING: The Rapid Service Fee was funded by Janssen KK.

7.
Adv Exp Med Biol ; 2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31228130

RESUMO

Clinical application of induced pluripotent stem cells (iPSCs), which can be differentiated into a wide variety of functional cells, is underway and some clinical trials have already been performed or are ongoing. On the other hand, the risk of carcinogenesis is an issue and the mechanism of cellular reprograming remains unknown. When iPSCs and differentiated cells are used for medical applications, quality control is also important. Here we discuss the possibility of performing quality control of iPSCs by evaluation of phospholipids, which are not just structural components of lipid bilayer membranes, but also have multiple physiological functions. Recently, methods for analysis of lipids have become more widely available and easier to perform. This article reviews the role of iPSCs in regenerative medicine and examines the possibility of using phospholipids for quality control of iPSCs and differentiated cells.

8.
Jpn J Clin Oncol ; 49(7): 596-603, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31135897

RESUMO

The advancement of cancer genomics research due to the development of next generation sequencing technologies is going to bring the promise of cancer precision medicine, in turn revolutionizing cancer detection and treatment. In this review, we will discuss the possible road map for implementation of cancer precision medicine into the clinical practice by mainly focusing on the role of liquid biopsy, particularly circulating tumor DNA, as a potential tool for cancer screening, selection of an appropriate drug(s), surveillance of minimal residual diseases, and early detection of recurrence. We will also review the current status of genome-driven oncology and emerging field of immunotherapies that could be provided to patients to improve their clinical outcome and quality of life. Lastly, we will discuss the usefulness of artificial intelligence that facilitate complex data integration in our health care/medical care system.


Assuntos
Detecção Precoce de Câncer , Imunoterapia , Invenções , Neoplasias/terapia , Medicina de Precisão , Inteligência Artificial , Humanos
9.
Pathol Int ; 69(4): 211-218, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30990957

RESUMO

We aimed to propose a biosafety algorithm for the protection of pathology staff during intraoperative examinations of pulmonary lesions when working with cytological imprints and/or frozen sections for the intraoperative diagnosis of pulmonary lesions. We examined 148 pulmonary surgical tissues obtained intraoperatively for imprint cytology (IC) and for frozen sectioning and compared the diagnoses against the final pathological diagnoses. We analyzed concordance and non-concordance rates and then used the data to produce a biosafety algorithm. The diagnostic sensitivity, specificity, positive predictive value, negative predictive value and accuracy of scratch-IC were 91%, 100%, 100%, 50% and 92%, respectively, and those of frozen sectioning were 99%, 100%, 100%, 96% and 99%, respectively. Our data indicate that frozen sectioning is unnecessary if scratch-IC yields a 'malignant' diagnosis but recommended with a 'benign' diagnosis. When a scratch-IC preparation deemed inadequate for a diagnosis or an abscess, the pathologist must consult the surgeon concerning the possibility of granuloma with caseous necrosis and should ask the surgeon to be prepared for a frozen section. If granuloma with caseous necrosis is found in the frozen section, the pathologist must immediately communicate the information to entire staff and perform a PCR test before making a permanent section.


Assuntos
Algoritmos , Granuloma/diagnóstico , Abscesso Pulmonar/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Contenção de Riscos Biológicos , Citodiagnóstico , Feminino , Secções Congeladas , Granuloma/patologia , Granuloma/cirurgia , Humanos , Cuidados Intraoperatórios , Abscesso Pulmonar/patologia , Abscesso Pulmonar/cirurgia , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Manejo de Espécimes
10.
Org Lett ; 21(8): 2663-2667, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30958676

RESUMO

Umpolung reactions of N-trimethylsilyl α-iminoester with organometallics gave directly N-alkylaminoesters in high yields without the need for removing a protecting group at the nitrogen atom. Efficient syntheses of pyrrolidines, piperidines, and iminodiacetate derivatives were also developed via tandem N,N- or N, C-dialkylation reactions utilizing characteristics of the silyl substituent. Furthermore, under the influence of silica gel, the addition of an enolate to the imino nitrogen proceeded to give an iminodiacetate derivative.

11.
Oncol Rep ; 41(4): 2540-2548, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30720113

RESUMO

Maternal embryonic leucine zipper kinase (MELK) has been reported to serve critical roles in the maintenance of stemness of cancer cells, although its mechanism remains unclear. Since SRY­box 2 (SOX2) was demonstrated to be involved in self­renewal and tumorigenicity of head and neck squamous cell carcinoma (HNSCC) and is aberrantly expressed in HNSCC tumors, the association between MELK and SOX2 was examined. Firstly, MELK inhibition was performed by small interfering RNA or MELK inhibitor OTS167, and it was determined that MELK inhibition by these approaches could decrease the SOX2 expression in HNSCC cells and OTS167 could suppress the SOX2 expression in a dose­dependent manner. The present results indicated that MELK inhibition may target cancer stem cells (CSCs) through downregulation of the SOX2 gene. To further confirm the transcriptional regulation of SOX2, the transcription factors (TFs) were screened for SOX2 using a promoter­binding TF assay followed by reverse transcription­quantitative polymerase chain reaction and a decrease of the majority of the SOX2 TFs following MELK knockdown was observed. The present results provide evidence that MELK serves a key role in CSCs through the regulation of SOX2 and further indicates that MELK inhibition may also be promising for clinical applications in the treatment of HNSCC.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Células-Tronco Neoplásicas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição SOXB1/genética , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo , Técnicas de Silenciamento de Genes , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Naftiridinas/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição SOXB1/metabolismo
12.
Mol Cancer Ther ; 18(3): 507-516, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30674566

RESUMO

Maternal embryonic leucine zipper kinase (MELK) activates pathways that mediate aggressive tumor growth and therapy resistance in many types of adult cancers. Pharmacologic and genomic inhibition of MELK impairs tumor growth and increases sensitivity to radiation and chemotherapy. On the basis of these promising preclinical studies, early-phase adult clinical trials testing the MELK inhibitor OTS167 are ongoing. To investigate whether MELK is also a therapeutic target in neuroblastoma, we analyzed MELK expression in primary tumors and cell lines, and examined the effects of OTS167 on neuroblastoma growth. In primary tumors, high levels of MELK were associated with advanced stage disease and inferior survival. Higher levels of MELK were also detected in tumorigenic versus nontumorigenic neuroblastoma cell lines, and cells with higher levels of MELK expression were more sensitive to OTS167 than low-MELK expressing cells. OTS167 suppressed the growth of neuroblastoma xenografts, and in a preclinical model of minimal residual disease, survival was prolonged with MELK inhibition. OTS167 treatment downregulated MELK and its target enhancer of zeste homolog 2 (EZH2), a component of the polycomb repressive complex 2 (PRC2) that is known to modulate the DNA damage response. We also show that OTS167 reduced the formation of collapsed replication forks induced by camptothecin or radiation. Taken together, our results indicate that MELK indirectly mediates efficient processing of replication-associated DNA lesions in neuroblastoma, and that OTS167 sensitizes cells to DNA-damaging agents by abrogating this process. Further studies evaluating the activity of combination treatment regimens with OTS167 in neuroblastoma are warranted.

13.
Clin Exp Allergy ; 49(5): 582-590, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30667100

RESUMO

BACKGROUND: Fractional exhaled nitric oxide concentration (FeNO) is widely used to support diagnosis and monitoring of bronchial asthma (BA). Tsoukias and George proposed a two-compartment model (2CM) for assessing the alveolar concentration of NO, referred to as CANO(2CM), while Condorelli et al proposed a model based on the trumpet shape of the airway tree and axial diffusion (TMAD), referred to as CANO(TMAD). In addition, Högman et al proposed non-linear model, referred to as CANO(non-linear). OBJECTIVE: We examined associations between the expression of inducible nitric oxide synthase (iNOS) mRNA in airway cells (ACs) by bronchoscopy and NO-parameters calculated by the three methods and identified which of them accurately reflected expression of iNOS mRNA from different airway portions. METHODS: We retrospectively analysed data of 18 patients with stable, mild-moderate asthma, including 10 steroid-naïve BA (snBA) patients. Samples were obtained from airway brushings and bronchoalveolar lavage (BAL). Expressions of iNOS protein in tissue samples were evaluated by immunostaining. The iNOS mRNA in ACs was measured by qPCR. NO-parameters calculated by the three methods above and evaluated whether they were associated with iNOS mRNA in ACs derived from proximal (2nd carina), distal (10-15th) airways and alveolar regions. RESULTS: Immunostaining revealed expression of iNOS proteins mainly in epithelial cells in the airways, while it was mainly expressed in macrophages in the alveolar region in the snBA group. The iNOS mRNA expression was increased in both proximal and distal ACs in the snBA group compared with steroid-treated BA group (stBA). CANO(2CM) negatively associated with FEV1 (%predicted) and also associated with iNOS mRNA in distal ACs significantly. However, CANO(TMAD) and CANO(non-linear) showed no correlation with lung function nor iNOS mRNA expression in any portions of ACs. CONCLUSIONS: These results suggested that CANO(2CM) reflected distal airway inflammation in steroid-naïve asthma.

14.
Cancer Sci ; 110(3): 867-874, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30582659

RESUMO

Recent clinical trials of non-small cell lung cancer with immune checkpoint inhibitors revealed that patients with epidermal growth factor receptor (EGFR) mutations had more unfavorable outcomes compared with those with wild-type EGFR. However, the underlying mechanism for the link between EGFR mutations and immune resistance remains unclear. We performed T cell receptor (TCR) repertoire analysis of resected lung adenocarcinoma tissues with and without EGFR mutations to investigate the characteristics of TCR repertoires. We collected a total of 39 paired (normal and tumor) lung tissue samples (20 had EGFR mutations) and conducted TCR repertoire analysis as well as whole-exome sequencing (WES) and transcriptome analysis. The TCR diversity index in EGFR-mutant tumors was significantly higher than that in EGFR-wild-type tumors (median [range] 552 [162-1,135] vs 230 [30-764]; P < .01), suggesting higher T cell clonal expansion in EGFR-wild-type tumors than in EGFR-mutant tumors. In WES, EGFR-mutant tumors showed lower numbers of non-synonymous mutations and predicted neoantigens than EGFR-wild-type tumors (P < .01, P = .03, respectively). The number of non-synonymous mutations revealed a positive correlation with the sum of frequencies of the TCRß clonotypes of 1% or higher in tumors (r = .52, P = .04). The present study demonstrates significant differences in TCR repertoires and the number of predicted neoantigens between EGFR-mutant and wild-type lung tumors. Our findings provide important information for understanding the molecular mechanism behind EGFR-mutant patients showing unfavorable responses to immune checkpoint inhibitors.


Assuntos
Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Mutação/genética , Receptores de Antígenos de Linfócitos T/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Clin Pharmacol Ther ; 2018 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-30506689

RESUMO

The CYP4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at individual patients' level to capture the possible effect of ethnicity, gene-gene interaction or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95%CI 7-10%), with a higher effect in females, in patients taking acenocoumarol and in Whites. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived. This article is protected by copyright. All rights reserved.

16.
Cytopathology ; 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30417954

RESUMO

OBJECTIVE: This study aimed to determine the reliability of imprint cytology (IC) for intraoperative diagnosis of pulmonary lesions. METHODS: We reviewed 113 cases of pulmonary lesion resection for which a scratch imprint was made intraoperatively. We divided the specimens into two groups (benign and malignant) and compared the scratch IC-based diagnoses against the final histopathological diagnoses in each group for concordance. We also analysed those cases in which the scratch IC preparation was classified as inadequate. RESULTS: The sensitivity, specificity, positive and negative predictive values, and accuracy of IC diagnoses among the patient cohort were 87.7% (72/82), 100% (7/7), 100% (72/72), 41.2% (7/17) and 88.8% (79/89), respectively. IC yielded some false-negative results in terms of malignancy, although most of these imprints were of early cancer or cancer with mild cytological atypia. Five (41.6%) of 12 lesions for which the imprint was deemed inadequate were diagnosed histologically as granulomas with caseous necrosis. CONCLUSION: IC-based diagnoses of pulmonary lesions as malignant corresponded well with the final histopathological diagnoses, but IC-based diagnoses of negative (ie, without malignant cells) were not as reliable. Thus, pathologists should recognise the limitations of IC, especially for identifying malignant lesions. Also, the possibility of latent bacterial infection in a granuloma with caseous necrosis indicates that an IC preparation deemed inadequate for diagnosis should not be ignored.

17.
Oncol Lett ; 16(5): 5775-5784, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30333861

RESUMO

The present study established systems to predict the chemo-sensitivity of muscle invasive bladder cancer (MIBC) for neoadjuvant chemotherapy (NAC) with methotrexate, vinblastine, doxorubicin plus cisplatin (M-VAC) and carboplatin plus gemcitabine (CaG) by analyzing microarray data. The primary aim of the study was to investigate whether the clinical response would increase by combining these prediction systems. Treatment of each MIBC case was allocated into M-VAC NAC, CaG NAC, surgery, or radiation therapy groups by their prediction score (PS), which was calculated using the designed chemo-sensitivity prediction system. The therapeutic effect of the present study was compared with the results of historical controls (n=76 patients) whose treatments were not allocated using the chemo-sensitivity prediction system. In addition, the overall survival between the predicted to be responder (positive PS) group and predicted to be non-responder (negative PS) group was investigated in the present study. Of the 33 patients with MIBC, 25 cases were positive PS and 8 were negative PS. Among the 25 positive PS cases, 7 were allocated to receive M-VAC NAC and 18 were allocated to receive CaG NAC according to the results of the prediction systems. Of the 8 negative PS cases, 3 received CaG NAC, 1 received surgery without NAC and 4 received radiation therapy. The total clinical response to NAC was 88.0% (22/25), which was significantly increased compared with the historical controls [56.6% (43/76) P=0.0041]. Overall survival of the positive PS group in the study was significantly increased compared with the negative PS group (P=0.027). In conclusion, the combination of the two prediction systems may increase the treatment efficacy for patients with MIBC by proposing the optimal NAC regimen. In addition, the positive PS group would have a better prognosis compared with the negative PS group. These results suggest that the two prediction systems may lead to the achievement of 'precision medicine'.

18.
Cancer Sci ; 109(12): 4015-4024, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30281874

RESUMO

Gastric cancer is the third leading cause of cancer mortality in Japan and worldwide. Although previous studies identify various genetic variations associated with gastric cancer, host genetic factors are largely unidentified. To identify novel gastric cancer loci in the Japanese population, herein, we carried out a large-scale genome-wide association study using 6171 cases and 27 178 controls followed by three replication analyses. Analysis using a total of 11 507 cases and 38 904 controls identified two novel loci on 12q24.11-12 (rs6490061, P = 3.20 × 10-8 with an odds ratio [OR] of 0.905) and 20q11.21 (rs2376549, P = 8.11 × 10-10 with an OR of 1.109). rs6490061 is located at intron 19 of the CUX2 gene, and its expression was suppressed by Helicobacter pylori infection. rs2376549 is included within the gene cluster of DEFB families that encode antibacterial peptides. We also found a significant association of rs7849280 in the ABO gene locus on 9q34.2 (P = 2.64 × 10-13 with an OR of 1.148). CUX2 and ABO expression in gastric mucosal tissues was significantly associated with rs6490061 and rs7849280 (P = 0.0153 and 8.00 × 10-11 ), respectively. Our findings show the crucial roles of genetic variations in the pathogenesis of gastric cancer.

19.
Health Policy ; 2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-30297300

RESUMO

In the continuously aging society, private sectors are expected to play a role in older adult care. Implementing an agreement between municipalities and private sectors is one of the key mechanisms for encouraging private sectors to participate in supporting older adults. The study's aim was to evaluate whether the support agreement has promoted support activities by convenience store staff for older adults. A retrospective observational study was conducted between 2013 and 2016 using data from a nationwide survey of convenience stores. The municipality-level matching produced 168 municipality pairs, with 2242 convenience stores that entered into a support agreement with municipalities from 2014 to 2015, and 2141 stores without such an agreement. Convenience store-level logistic regression analysis evaluated the impact of the agreement on staff activities. The analysis showed that some staff activities increased significantly with the support agreement, such as corresponding or collaborating with community support centers (AOR = 3.40; 95% CI: 2.22 to 5.26), participating in role-playing programs for older adult care (AOR = 2.05; 95% CI: 1.01 to 4.26), and attending dementia support lectures (AOR = 18.21; 95% CI: 8.27 to 45.34). Emergency protection for older adults did not increase with the support agreement. The results suggest that the support agreement positively influenced some convenience store staff's support activities for older adults.

20.
Neoplasia ; 20(10): 1038-1044, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30208353

RESUMO

Alteration of protein O-glycosylation in various human cancers including breast cancer is well known, but molecular roles of their aberrant glycosylations on cancer have not been fully understood. We previously reported critical roles of polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6 or GalNAc-T6) that was upregulated in a great majority of breast cancer tissues. Here we further report O-glycosylation of estrogen receptor alpha (ER-α) by GALNT6 and the significant role of its nuclear localization in breast cancer cells. Knockdown of GALNT6 expression in two breast cancer cell lines, T47D and MCF7, in which both ER-α and GALNT6 were highly expressed, by small interfering RNA could significantly attenuate expression of ER-α. Immunocytochemical analysis clearly demonstrated the drastic decrease of ER-α protein in the nucleus of these cancer cells. Accordingly, the downstream genes of the ER-α pathway such as MYC, CCND1, and CTSD were significantly downregulated. We confirmed GALNT6-dependent ER-α O-glycosylation and identified O-glycosylation of S573 in an F domain of ER-α by GALNT6 through LC-MS/MS analysis. We also obtained evidences showing that the glycosylation of ER-α at S573 by GALNT6 is essential for protein stability and nuclear localization of ER-α in breast cancer cells. Furthermore, we designed cell membrane-permeable peptides including the O-glycosylation site and found a significant decrease of the cell viability of breast cancer cells by treatment of these peptides in a GALNT6 expression-dependent manner. Our study suggests that targeting the GALNT6 enzymatic activity as well as the GALNT6/ER-α interaction could be a promising therapeutic approach to ER-α-positive breast cancer patients.

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