An emerging strategy for cancer treatment targeting aberrant glycogen synthase kinase 3β

金沢大学がん研究所分子標的がん医療研究開発センターImprovement in the outcome of cancer patients who are refractory to currently available treatments relies on the development of target-directed therapies. One group of molecular targets with potential clinical relevance is a set of protein tyrosine kinases encoded mostly by proto-oncogenes and that are frequently deregulated in cancer. Glycogen synthase kinase 3β (GSK3β), a serine/threonine protein kinase, has emerged as a therapeutic target for common chronic diseases including type 2 diabetes mellitus, neurodegenerative disorders, inflammation and osteoporosis. This is based on its currently known functions and primary pathologic causalities. GSK3β has well characterized roles in the regulation of gene transcription and in oncogenic signaling. We have shown that deregulated GSK3β promotes gastrointestinal, pancreatic and liver cancers and glioblastomas. Furthermore, we have demonstrated that inhibition of GSK3β attenuates cancer cells survival and proliferation, induces cell senescence and apoptosis and sensitizes tumor cells to chemotherapeutic agents and ionizing radiation. This has led us to propose GSK3β as a potential therapeutic target in cancer. The anti-tumor effects of GSK3β inhibition are mediated by changes in the expression and phosphorylation of molecules critical to the regulation of cell cycling, proliferation and apoptosis and underlie the pathological role for GSK3β in cancer. Investigation of the mechanisms responsible for deregulation of GSK3β and the consequent downstream pathologic effects in cancer cells has shed light on the molecular pathways leading to tumorigenesis. This will allow exploration of novel therapeutic strategies for cancer that target aberrant GSK3β. © 2009 Bentham Science Publishers Ltd

Glycogen synthase kinase-3β is a pivotal mediator of cancer invasion and resistance to therapy

Tumor cell invasion and resistance to therapy are the most intractable biological characteristics of cancer and, therefore, the most challenging for current cancer research and treatment paradigms. Refractory cancers, including pancreatic cancer and glioblastoma, show an inextricable association between the highly invasive behavior of tumor cells and their resistance to chemotherapy, radiotherapy and targeted therapies. These aggressive properties of cancer share distinct cellular pathways that are connected to each other by several molecular hubs. There is increasing evidence to show that glycogen synthase kinase (GSK)-3β is aberrantly activated in various cancer types and this has emerged as a potential therapeutic target. In many but not all cancer types, aberrant GSK3β sustains the survival, immortalization, proliferation and invasion of tumor cells, while also rendering them insensitive or resistant to chemotherapeutic agents and radiation. Here we review studies that describe associations between therapeutic stimuli/resistance and the induction of pro-invasive phenotypes in various cancer types. Such cancers are largely responsive to treatment that targets GSK3β. This review focuses on the role of GSK3β as a molecular hub that connects pathways responsible for tumor invasion and resistance to therapy, thus highlighting its potential as a major cancer therapeutic target. We also discuss the putative involvement of GSK3β in determining tumor cell stemness that underpins both tumor invasion and therapy resistance, leading to intractable and refractory cancer with dismal patient outcomes. © 2016 Japanese Cancer Association.(Please refer to a different file for the Supporting information of this article.

Deregulated GSK3β sustains gastrointestinal cancer cells survival by modulating human telomerase reverse transcriptase and telomerase

金沢大学がん研究所分子標的がん医療研究開発センターPurpose: Glycogen synthase kinase-3β (GSK3β) regulates multiple cell signaling pathways and has been implicated in glucose intolerance, neurodegenerative disorders, and inflammation. We investigated the expression, activity, and putative pathologic role of GSK3β in gastrointestinal, pancreatic, and liver cancers. Experimental Design: Colon, stomach, pancreatic, and liver cancer cell lines; nonneoplastic HEK293 cells; and matched pairs of normal and tumor tissues of stomach and colon cancer patients were examined for GSK3β expression and its phosphorylation at serine 9 (inactive form) and tyrosine 216 (active form) by Western immunoblotting and for GSK3β activity by in vitro kinase assay. The effects of small-molecule GSK3β inhibitors and of RNA interference on cell survival, proliferation, and apoptosis were examined in vitro and on human colon cancer cell xenografts in athymic mice. The effects of GSK3β inhibition on human telomerase reverse transcriptase (hTERT) expression and telomerase activity were compared between colon cancer and HEK293 cells. Results: Cancer cell lines and most cancer tissues showed increased GSK3β expression and increased tyrosine 216 phosphorylation and activity but decreased serine 9 phosphorylation compared with HEK293 cells and nonneoplastic tissues. Inhibition of GSK3β resulted in attenuated cell survival and proliferation and increased apoptosis in most cancer cell lines and in HT-29 xenografts in rodents but not in HEK293 cells. GSK3β inhibition in colon cancer cells was associated with decreased hTERT expression and telomerase activity. Conclusion: The results indicate that deregulated GSK3β sustains gastrointestinal cancer cells survival through modulation of hTERT and telomerase. © 2009 American Association for Cancer Research

Cross-cultural conceptualization of a good end of life with dementia: A qualitative study

BACKGROUND: Research on the nature of a "good death" has mostly focused on dying with cancer and other life-limiting diseases, but less so on dementia. Conceptualizing common cross-cultural themes regarding a good end of life in dementia will enable developing international care models. METHODS: We combined published qualitative studies about end of life with dementia, focus group and individual interviews with the researchers, and video-conferencing and continuous email discussions. The interviews were audio-recorded and transcribed verbatim. The data were analyzed thematically, and the researchers developed common themes referring to their original studies. RESULTS: Fourteen qualitative researchers representing 14 cross-cultural studies covering qualitative data of 121 people with dementia and 292 family caregivers. The researchers and data were from eight countries UK, The Netherlands, Japan, Portugal, Germany, Canada, Brazil, and Ireland. Three focus groups, five individual interviews, and video-conferencing were conducted and feedback on multiple iterations was gained by 190 emails between May 2019 and April 2020 until consensus was achieved. Nine cross-culturally common themes emerged from the discussions and shared interpretation of the data of persons with dementia and family caregivers. Three represent basic needs: "Pain and Symptoms Controlled," "Being Provided Basic Care," and "A Place like Home." Other themes were "Having Preferences Met," "Receiving Respect as a Person," "Care for Caregivers," "Identity Being Preserved," "Being Connected," and "Satisfaction with Life and Spiritual Well-being." "Care for Caregivers" showed the greatest difference in emphasis across cultures. Good relationships were essential in all themes. CONCLUSIONS: The common cross-cultural themes comprise a framework underpinned by value placed on personhood and dignity, emphasizing that interdependency through relationships is essential to promote a good end of life with dementia. These themes and valuing the importance of relationships as central to connecting the themes could support care planning and further development of a dementia palliative care model. TRIAL REGISTRATION: The Graduate School and Faculty of Medicine Kyoto University (R1924-1)

Cross-cultural conceptualization of a good end of life with dementia:A qualitative study

Background: Research on the nature of a “good death” has mostly focused on dying with cancer and other life-limiting diseases, but less so on dementia. Conceptualizing common cross-cultural themes regarding a good end of life in dementia will enable developing international care models. Methods: We combined published qualitative studies about end of life with dementia, focus group and individual interviews with the researchers, and video-conferencing and continuous email discussions. The interviews were audio-recorded and transcribed verbatim. The data were analyzed thematically, and the researchers developed common themes referring to their original studies. Results: Fourteen qualitative researchers representing 14 cross-cultural studies covering qualitative data of 121 people with dementia and 292 family caregivers. The researchers and data were from eight countries UK, The Netherlands, Japan, Portugal, Germany, Canada, Brazil, and Ireland. Three focus groups, five individual interviews, and video-conferencing were conducted and feedback on multiple iterations was gained by 190 emails between May 2019 and April 2020 until consensus was achieved. Nine cross-culturally common themes emerged from the discussions and shared interpretation of the data of persons with dementia and family caregivers. Three represent basic needs: “Pain and Symptoms Controlled,” “Being Provided Basic Care,” and “A Place like Home.” Other themes were “Having Preferences Met,” “Receiving Respect as a Person,” “Care for Caregivers,” “Identity Being Preserved,” “Being Connected,” and “Satisfaction with Life and Spiritual Well-being.” “Care for Caregivers” showed the greatest difference in emphasis across cultures. Good relationships were essential in all themes. Conclusions: The common cross-cultural themes comprise a framework underpinned by value placed on personhood and dignity, emphasizing that interdependency through relationships is essential to promote a good end of life with dementia. These themes and valuing the importance of relationships as central to connecting the themes could support care planning and further development of a dementia palliative care model.info:eu-repo/semantics/publishedVersio

Baastrup's Disease Is Associated with Recurrent of Sciatica after Posterior Lumbar Spinal Decompressions Utilizing Floating Spinous Process Procedures

Study DesignRetrospective case-control study.PurposeTo determine whether kissing spine is a risk factor for recurrence of sciatica after lumbar posterior decompression using a spinous process floating approach.Overview of LiteratureKissing spine is defined by apposition and sclerotic change of the facing spinous processes as shown in X-ray images, and is often accompanied by marked disc degeneration and decrement of disc height. If kissing spine significantly contributes to weight bearing and the stability of the lumbar spine, trauma to the spinous process might induce a breakdown of lumbar spine stability after posterior decompression surgery in cases of kissing spine.MethodsThe present study included 161 patients who had undergone posterior decompression surgery for lumbar canal stenosis using a spinous process floating approaches. We defined recurrence of sciatica as that resolved after initial surgery and then recurred. Kissing spine was defined as sclerotic change and the apposition of the spinous process in a plain radiogram. Preoperative foraminal stenosis was determined by the decrease of perineural fat intensity detected by parasagittal T1-weighted magnetic resonance imaging. Preoperative percentage slip, segmental range of motion, and segmental scoliosis were analyzed in preoperative radiographs. Univariate analysis followed by stepwise logistic regression analysis determined factors independently associated with recurrence of sciatica.ResultsStepwise logistic regression revealed kissing spine (p=0.024; odds ratio, 3.80) and foraminal stenosis (p<0.01; odds ratio, 17.89) as independent risk factors for the recurrence of sciatica after posterior lumbar spinal decompression with spinous process floating procedures for lumbar spinal canal stenosis.ConclusionsWhen a patient shows kissing spine and concomitant subclinical foraminal stenosis at the affected level, we should sufficiently discuss the selection of an appropriate surgical procedure

Baastrup\u27s Disease Is Associated with Recurrent of Sciatica after Posterior Lumbar Spinal Decompressions Utilizing Floating Spinous Process Procedures

Study DesignRetrospective case-control study.PurposeTo determine whether kissing spine is a risk factor for recurrence of sciatica after lumbar posterior decompression using a spinous process floating approach.Overview of LiteratureKissing spine is defined by apposition and sclerotic change of the facing spinous processes as shown in X-ray images, and is often accompanied by marked disc degeneration and decrement of disc height. If kissing spine significantly contributes to weight bearing and the stability of the lumbar spine, trauma to the spinous process might induce a breakdown of lumbar spine stability after posterior decompression surgery in cases of kissing spine.MethodsThe present study included 161 patients who had undergone posterior decompression surgery for lumbar canal stenosis using a spinous process floating approaches. We defined recurrence of sciatica as that resolved after initial surgery and then recurred. Kissing spine was defined as sclerotic change and the apposition of the spinous process in a plain radiogram. Preoperative foraminal stenosis was determined by the decrease of perineural fat intensity detected by parasagittal T1-weighted magnetic resonance imaging. Preoperative percentage slip, segmental range of motion, and segmental scoliosis were analyzed in preoperative radiographs. Univariate analysis followed by stepwise logistic regression analysis determined factors independently associated with recurrence of sciatica.ResultsStepwise logistic regression revealed kissing spine (p=0.024; odds ratio, 3.80) and foraminal stenosis (p<0.01; odds ratio, 17.89) as independent risk factors for the recurrence of sciatica after posterior lumbar spinal decompression with spinous process floating procedures for lumbar spinal canal stenosis.ConclusionsWhen a patient shows kissing spine and concomitant subclinical foraminal stenosis at the affected level, we should sufficiently discuss the selection of an appropriate surgical procedure

CNVs in Three Psychiatric Disorders

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD

SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values ,261025 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P=7.3361027 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P=1.7761029) and rs3781834 (P=1.0461028). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P=1.7161025) and rs744373 near BIN1 (P = 1.3961024). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations

Topologically nontrivial phase-change compound GeSb2Te4

Chalcogenide phase-change materials show strikingly contrasting optical and electrical properties, which has led to their extensive implementation in various memory devices. By performing spin-, time-, and angle-resolved photoemission spectroscopy combined with the first-principles calculation, we report the experimental results that the crystalline phase of GeSb2Te4 is topologically nontrivial in the vicinity of the Dirac semimetal phase. The resulting linearly dispersive bulk Dirac-like bands that cross the Fermi level and are thus responsible for conductivity in the stable crystalline phase of GeSb2Te4 can be viewed as a 3D analogue of graphene. Our finding provides us with the possibility of realizing inertia-free Dirac currents in phase-change materials.The ARPES experiments were performed with the approval of the Proposal Assessing Committee of HSRC (Proposal No. 18BG039). The TARPES measurements were jointly carried out by the Laser and Synchrotron Research Center of the Institute for Solid State Physics at the University of Tokyo. This work was financially supported by KAKENHI (Grant No. 17H06138, No. 17H06152, No. 18H03683, No. 18H01148). This work was also supported by the ‘‘Tomsk State University competitiveness improvement programme’’ (Project No. 8.1.01.2018), by Saint Petersburg State University (Project ID 51126254), and by Russian Science Foundation No. 17-12-01047 (in the crystal growth part). T.V.M. and I.P.R. acknowledge support from Ministry of Education and Science of the Russian Federation (State Task No. 0721-2020-0033) (study of intermixed crystalline phase of GST-124). Calculations were performed at the SKIF-Cyberia supercomputer of Tomsk State University (Russian Federation). K.A.K. acknowledges RFBR Grant 17-08-00955 and a state contract of IGM SB RAS.Peer reviewe