AIM To describe the development and implementation of a person-centered endoscopy safety checklist and to evaluate the effects of a "checklist intervention".METHODS The checklist,based on previously publishe...AIM To describe the development and implementation of a person-centered endoscopy safety checklist and to evaluate the effects of a "checklist intervention".METHODS The checklist,based on previously published safety checklists,was developed and locally adapted,taking patient safety aspects into consideration and using a person-centered approach. This novel checklist was introduced to the staff of an endoscopy unit at a Stockholm University Hospital during half-day seminars and team training sessions. Structured observations of the endoscopy team's performance were conducted before and after the introduction of the checklist. In addition,questionnaires focusing on patient participation,collaboration climate,and patient safety issues were collected from patients and staff. RESULTS A person-centered safety checklist was developed and introduced by a multi-professional group in the endoscopy unit. A statistically significant increase in accurate patient identity verification by the physicians was noted(from 0% at baseline to 87% after 10 mo,P < 0.001),and remained high among nurses(93% at baseline vs 96% after 10 mo,P = nonsignificant). Observations indicated that the professional staff made frequent attempts to use the checklist,but compliance was suboptimal: All items in the observed nurse-led "summaries" were included in 56% of these interactions,and physicians participated by directly facing the patient in 50% of the interactions. On the questionnaires administered to the staff,items regarding collaboration and the importance of patient participation were rated more highly after the introduction of the checklist,but this did not result in statistical significance(P = 0.07/P = 0.08). The patients rated almost all items as very high both before and after the introduction of the checklist;hence,no statistical difference was noted.CONCLUSION The intervention led to increased patient identity verification by physicians-a patient safety improvement. Clear evidence of enhanced person-centeredness or team work was not found.展开更多
Objective:Vascular endothelial growth factor(VEGF),apart from its predominant roles in angiogenesis,can enhance cancer cell proliferation,but its mechanisms remain elusive.The purpose of the present study was therefor...Objective:Vascular endothelial growth factor(VEGF),apart from its predominant roles in angiogenesis,can enhance cancer cell proliferation,but its mechanisms remain elusive.The purpose of the present study was therefore to identify how VEGF regulates cancer cell proliferation.Methods:VEGF effects on cancer cell proliferation were investigated with the VEGF receptor 2 inhibitor,Ki8751,and the breast cancer cell lines,MCF-7 and MDA-MB-231,using flow cytometry,mass spectrometry,immunoblotting,and confocal microscopy.Data were analyzed using one-way analysis of variance followed by Tukey’s multiple comparison test.Results:VEGF blockade by Ki8751 significantly reduced cancer cell proliferation,and enhanced breast cancer cell apoptosis.Mass spectrometric analyses revealed that Ki8751 treatment significantly upregulated the expression of mitochondrial proteins,suggesting the involvement of mitochondrial biogenesis.Confocal microscopy and flow cytometric analyses showed that Ki8751 treatment robustly increased the mitochondrial masses of both cancer cells,induced endomitosis,and arrested cancer cells in the high aneuploid phase.VEGFR2 knockdown by sh RNAs showed similar effects to those of Ki8751,confirming the specificity of Ki8751 treatment.Enhanced mitochondrial biogenesis increased mitochondrial oxidative phosphorylation and stimulated reactive oxygen species(ROS)production,which induced cancer cell apoptosis.Furthermore,Ki8751 treatment downregulated the phosphorylation of Akt and PGC1α,and translocated PGC1αinto the nucleus.The PGC1αalterations increased mitochondrial transcription factor A(TFAM)expression and subsequently increased mitochondrial biogenesis.Conclusions:VEGF enhances cancer cell proliferation by decreasing Akt-PGC1α-TFAM signaling-mediated mitochondrial biogenesis,ROS production,and cell apoptosis.These findings suggested the anticancer potential of Ki8751 via increased mitochondrial biogenesis and ROS production.展开更多
Dear Editor,The activating receptor DNAX accessory molecule-1(DNAM-1)plays an important role in T and natural killer(NK)cell-mediated cytotoxicity via the interaction with its ligands poliovirus receptor(PVR,CD155)and...Dear Editor,The activating receptor DNAX accessory molecule-1(DNAM-1)plays an important role in T and natural killer(NK)cell-mediated cytotoxicity via the interaction with its ligands poliovirus receptor(PVR,CD155)and Nectin-2(CD112).Compared with peripheral blood NK cells,tumor-infiltrating NK cells show reduced expression of DNAM-1 across several solid tumors,including ovarian and breast cancer resulting in impaired NK cell function.Early studies reported an inverse correlation between DNAM-1 expression and its ligands in leukemic blasts and ovarian cancer[1].展开更多
The TP53 tumor suppressor gene encodes a DNA-binding transcription factor that regulates multiple cellular processes including cell growth and cell death. The ability of p53 to bind to DNA and activate transcription i...The TP53 tumor suppressor gene encodes a DNA-binding transcription factor that regulates multiple cellular processes including cell growth and cell death. The ability of p53 to bind to DNA and activate transcription is tightly regulated by post-translational modifications and is dependent on a reducing cellular environment. Some p53 transcriptional target genes are involved in regulation of the cellular redox homeostasis, e.g. TIGAR and GLS2. A large fraction of human tumors carry TP53 mutations, most commonly missense mutations that lead to single amino acid substitutions in the core domain. Mutant p53 proteins can acquire so called gain-of-function activities and influence the cellular redox balance in various ways, for instance by binding of the Nrf2 transcription factor, a major regulator of cellular redox state. The DNA-binding core domain of p53 has 10 cysteine residues, three of which participate in holding a zinc atom that is critical for p53 structure and function. Several novel compounds that refold and reactivate missense mutant p53 bind to specific p53 cysteine residues. These compounds can also react with other thiols and target components of the cellular redox system, such as glutathione. Dual targeting of mutant p53 and redox homeostasis may allow more efficient treatment of cancer.展开更多
Lin28a is a pluripotent factor that promotes somatic cell reprogramming. Unlike other pluripotent factors, Lin28a expression is transient and accumulated in primed embryonic stem (ES) cells, but its exact function and...Lin28a is a pluripotent factor that promotes somatic cell reprogramming. Unlike other pluripotent factors, Lin28a expression is transient and accumulated in primed embryonic stem (ES) cells, but its exact function and mechanism in the conversion of ES cells from naive to primed state remain unclear. Here, we present evidence for Dppa3, a protein originally known for its role in germ cell development, as a downstream target of Lin28a in naive–primed conversion. Using rescue experiment, we demonstrate that Dppa3 functions predominantly downstream of Lin28a during naive–primed state conversion. Higher level of Lin28a prevents let-7 maturation and results in Dnmt3a/b (target of let-7) upregulation, which in turn induces hypermethylation of the Dppa3 promoter. Dppa3 demarcates naive versus primed pluripotency states. These results emphasize that Lin28a plays an important role during the naive–primed state conversion of ES cells, which is partially mediated by a Lin28a–let-7–Dnmt3a/b–Dppa3 axis.展开更多
Ischemic stroke represents a major,worldwide health burden with increasing incidence.Patients affected by ischemic strokes currently have few clinically approved treatment options available.Most currently approved tre...Ischemic stroke represents a major,worldwide health burden with increasing incidence.Patients affected by ischemic strokes currently have few clinically approved treatment options available.Most currently approved treatments for ischemic stroke have narrow therapeutic windows,severely limiting the number of patients able to be treated.Mesenchymal stem cells represent a promising novel treatment for ischemic stroke.Numerous studies have demonstrated that mesenchymal stem cells functionally improve outcomes in rodent models of ischemic stroke.Recent studies have also shown that exosomes secreted by mesenchymal stem cells mediate much of this effect.In the present review,we summarize the current literature on the use of mesenchymal stem cells to treat ischemic stroke.Further studies investigating the mechanisms underlying mesenchymal stem cells tissue healing effects are warranted and would be of benefit to the field.展开更多
Well-differentiated thyroid carcinoma(WDTC,including papillary thyroid carcinoma and follicular thyroid carcinoma)are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery...Well-differentiated thyroid carcinoma(WDTC,including papillary thyroid carcinoma and follicular thyroid carcinoma)are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery and postoperative radioiodine therapy.Subsets of WDTCs may dedifferentiate into poorly differentiated thyroid carcinoma(PDTC)and anaplastic thyroid carcinoma(ATC),of which especially the latter has an exceptionally poor patient outcome.The underlying genetics responsible for this tumor progression is only partly understood,and is complicated by the fact that subgroups of ATCs are thought to arise de novo without a demonstrable,pre-existing WDTC.Even so,recent advances using next generation sequencing(NGS)techniques have identified a genetic link between WDTCs and ATCs,suggesting a step-wise accumulation of mutations driving the loss of differentiation for most cases.In this Commentary,recent findings from an NGS study on synchronous FTC,PDTC,and ATC tumor components from the same patient are highlighted.By using whole-genome data,clonality analyses identified a chief ancestral clone carrying mutations in TP53-associated signaling networks regulating genes involved in DNA repair,with sub-clones in each tumor component that were identified also in the less differentiated,neighboring tumor.Moreover,mutational signatures suggested a general mismatch repair(MMR)deficiency along with microsatellite instability.These findings support the chained progression model of dedifferentiation in thyroid cancer,and pinpoint a central role for defective DNA repair.Since effective treatment modalities for ATCs are urgently needed,studies regarding therapeutic agents specifically targeting defective MMR in dedifferentiated thyroid carcinoma could be pursued.展开更多
Dear Editor Mitochondria are multifunctional organelles of eukaryotic cells. Biogenesis and functionality of mitochondria require the import of more than 90% of its resident proteins after synthesis by cytosolic ribos...Dear Editor Mitochondria are multifunctional organelles of eukaryotic cells. Biogenesis and functionality of mitochondria require the import of more than 90% of its resident proteins after synthesis by cytosolic ribosomes.展开更多
文摘AIM To describe the development and implementation of a person-centered endoscopy safety checklist and to evaluate the effects of a "checklist intervention".METHODS The checklist,based on previously published safety checklists,was developed and locally adapted,taking patient safety aspects into consideration and using a person-centered approach. This novel checklist was introduced to the staff of an endoscopy unit at a Stockholm University Hospital during half-day seminars and team training sessions. Structured observations of the endoscopy team's performance were conducted before and after the introduction of the checklist. In addition,questionnaires focusing on patient participation,collaboration climate,and patient safety issues were collected from patients and staff. RESULTS A person-centered safety checklist was developed and introduced by a multi-professional group in the endoscopy unit. A statistically significant increase in accurate patient identity verification by the physicians was noted(from 0% at baseline to 87% after 10 mo,P < 0.001),and remained high among nurses(93% at baseline vs 96% after 10 mo,P = nonsignificant). Observations indicated that the professional staff made frequent attempts to use the checklist,but compliance was suboptimal: All items in the observed nurse-led "summaries" were included in 56% of these interactions,and physicians participated by directly facing the patient in 50% of the interactions. On the questionnaires administered to the staff,items regarding collaboration and the importance of patient participation were rated more highly after the introduction of the checklist,but this did not result in statistical significance(P = 0.07/P = 0.08). The patients rated almost all items as very high both before and after the introduction of the checklist;hence,no statistical difference was noted.CONCLUSION The intervention led to increased patient identity verification by physicians-a patient safety improvement. Clear evidence of enhanced person-centeredness or team work was not found.
基金supported by grants from the Swedish HeartLung Foundation(Grant No.20160419)the Swedish Research Council+5 种基金the Swedish Foundation for International Cooperation in Research and Higher Educationthe National Natural Science Foundation of China(Grant Nos.81700110 and 8171101454)the China Scholarship CouncilKarolinska InstitutetShandong University-Karolinska Institutet Cooperative Research Fundthe Stockholm County Council。
文摘Objective:Vascular endothelial growth factor(VEGF),apart from its predominant roles in angiogenesis,can enhance cancer cell proliferation,but its mechanisms remain elusive.The purpose of the present study was therefore to identify how VEGF regulates cancer cell proliferation.Methods:VEGF effects on cancer cell proliferation were investigated with the VEGF receptor 2 inhibitor,Ki8751,and the breast cancer cell lines,MCF-7 and MDA-MB-231,using flow cytometry,mass spectrometry,immunoblotting,and confocal microscopy.Data were analyzed using one-way analysis of variance followed by Tukey’s multiple comparison test.Results:VEGF blockade by Ki8751 significantly reduced cancer cell proliferation,and enhanced breast cancer cell apoptosis.Mass spectrometric analyses revealed that Ki8751 treatment significantly upregulated the expression of mitochondrial proteins,suggesting the involvement of mitochondrial biogenesis.Confocal microscopy and flow cytometric analyses showed that Ki8751 treatment robustly increased the mitochondrial masses of both cancer cells,induced endomitosis,and arrested cancer cells in the high aneuploid phase.VEGFR2 knockdown by sh RNAs showed similar effects to those of Ki8751,confirming the specificity of Ki8751 treatment.Enhanced mitochondrial biogenesis increased mitochondrial oxidative phosphorylation and stimulated reactive oxygen species(ROS)production,which induced cancer cell apoptosis.Furthermore,Ki8751 treatment downregulated the phosphorylation of Akt and PGC1α,and translocated PGC1αinto the nucleus.The PGC1αalterations increased mitochondrial transcription factor A(TFAM)expression and subsequently increased mitochondrial biogenesis.Conclusions:VEGF enhances cancer cell proliferation by decreasing Akt-PGC1α-TFAM signaling-mediated mitochondrial biogenesis,ROS production,and cell apoptosis.These findings suggested the anticancer potential of Ki8751 via increased mitochondrial biogenesis and ROS production.
基金supported by grants from The Swedish Cancer Society(#CAN 2018/451 and#211524 Pj)The Cancer Research Funds of Radiumhemmet(#161192,#181183,and#211253)+1 种基金The Swedish Society for Medical Research(P17-0134)The Swedish Society of Medicine(SLS-960960).
文摘Dear Editor,The activating receptor DNAX accessory molecule-1(DNAM-1)plays an important role in T and natural killer(NK)cell-mediated cytotoxicity via the interaction with its ligands poliovirus receptor(PVR,CD155)and Nectin-2(CD112).Compared with peripheral blood NK cells,tumor-infiltrating NK cells show reduced expression of DNAM-1 across several solid tumors,including ovarian and breast cancer resulting in impaired NK cell function.Early studies reported an inverse correlation between DNAM-1 expression and its ligands in leukemic blasts and ovarian cancer[1].
文摘The TP53 tumor suppressor gene encodes a DNA-binding transcription factor that regulates multiple cellular processes including cell growth and cell death. The ability of p53 to bind to DNA and activate transcription is tightly regulated by post-translational modifications and is dependent on a reducing cellular environment. Some p53 transcriptional target genes are involved in regulation of the cellular redox homeostasis, e.g. TIGAR and GLS2. A large fraction of human tumors carry TP53 mutations, most commonly missense mutations that lead to single amino acid substitutions in the core domain. Mutant p53 proteins can acquire so called gain-of-function activities and influence the cellular redox balance in various ways, for instance by binding of the Nrf2 transcription factor, a major regulator of cellular redox state. The DNA-binding core domain of p53 has 10 cysteine residues, three of which participate in holding a zinc atom that is critical for p53 structure and function. Several novel compounds that refold and reactivate missense mutant p53 bind to specific p53 cysteine residues. These compounds can also react with other thiols and target components of the cellular redox system, such as glutathione. Dual targeting of mutant p53 and redox homeostasis may allow more efficient treatment of cancer.
基金the National Natural Science Foundation of China (31771636, 81671734, and 81501528)National Key R&D Plan (2017YFA0103201 and 2011DAV00088)+2 种基金Tianjin Natural Science Foundation (18JCYBJC24400)CAMS Initiative for Innovative Medicine (CAMS-12M 2016-12M-1-017)Program for Changjiang Scholars and Innovative Research Team in University (IRT13023).
文摘Lin28a is a pluripotent factor that promotes somatic cell reprogramming. Unlike other pluripotent factors, Lin28a expression is transient and accumulated in primed embryonic stem (ES) cells, but its exact function and mechanism in the conversion of ES cells from naive to primed state remain unclear. Here, we present evidence for Dppa3, a protein originally known for its role in germ cell development, as a downstream target of Lin28a in naive–primed conversion. Using rescue experiment, we demonstrate that Dppa3 functions predominantly downstream of Lin28a during naive–primed state conversion. Higher level of Lin28a prevents let-7 maturation and results in Dnmt3a/b (target of let-7) upregulation, which in turn induces hypermethylation of the Dppa3 promoter. Dppa3 demarcates naive versus primed pluripotency states. These results emphasize that Lin28a plays an important role during the naive–primed state conversion of ES cells, which is partially mediated by a Lin28a–let-7–Dnmt3a/b–Dppa3 axis.
文摘Ischemic stroke represents a major,worldwide health burden with increasing incidence.Patients affected by ischemic strokes currently have few clinically approved treatment options available.Most currently approved treatments for ischemic stroke have narrow therapeutic windows,severely limiting the number of patients able to be treated.Mesenchymal stem cells represent a promising novel treatment for ischemic stroke.Numerous studies have demonstrated that mesenchymal stem cells functionally improve outcomes in rodent models of ischemic stroke.Recent studies have also shown that exosomes secreted by mesenchymal stem cells mediate much of this effect.In the present review,we summarize the current literature on the use of mesenchymal stem cells to treat ischemic stroke.Further studies investigating the mechanisms underlying mesenchymal stem cells tissue healing effects are warranted and would be of benefit to the field.
基金This work was supported by the Swedish Cancer Society(Junior Clinical Investigator Award).
文摘Well-differentiated thyroid carcinoma(WDTC,including papillary thyroid carcinoma and follicular thyroid carcinoma)are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery and postoperative radioiodine therapy.Subsets of WDTCs may dedifferentiate into poorly differentiated thyroid carcinoma(PDTC)and anaplastic thyroid carcinoma(ATC),of which especially the latter has an exceptionally poor patient outcome.The underlying genetics responsible for this tumor progression is only partly understood,and is complicated by the fact that subgroups of ATCs are thought to arise de novo without a demonstrable,pre-existing WDTC.Even so,recent advances using next generation sequencing(NGS)techniques have identified a genetic link between WDTCs and ATCs,suggesting a step-wise accumulation of mutations driving the loss of differentiation for most cases.In this Commentary,recent findings from an NGS study on synchronous FTC,PDTC,and ATC tumor components from the same patient are highlighted.By using whole-genome data,clonality analyses identified a chief ancestral clone carrying mutations in TP53-associated signaling networks regulating genes involved in DNA repair,with sub-clones in each tumor component that were identified also in the less differentiated,neighboring tumor.Moreover,mutational signatures suggested a general mismatch repair(MMR)deficiency along with microsatellite instability.These findings support the chained progression model of dedifferentiation in thyroid cancer,and pinpoint a central role for defective DNA repair.Since effective treatment modalities for ATCs are urgently needed,studies regarding therapeutic agents specifically targeting defective MMR in dedifferentiated thyroid carcinoma could be pursued.
文摘Dear Editor Mitochondria are multifunctional organelles of eukaryotic cells. Biogenesis and functionality of mitochondria require the import of more than 90% of its resident proteins after synthesis by cytosolic ribosomes.
