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"Ku, S"
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YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage
Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non-small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated
with in vitro
and
in vivo
cisplatin sensitivity. YAP overexpression protected while YAP knockdown sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC.
Journal Article
Reconstruction and interpretation of ionization asymmetry in magnetic confinement via synthetic diagnostics
Strong poloidal refueling asymmetry in the DIII-D tokamak is inferred from line radiation measurements. Synthetic diagnostics in neutral transport modeling coupled to gyrokinetic simulations illuminate implications for the plasma flow profile in the scrape-off layer of single-null beam-driven discharges. Recycling occurs primarily either on the inner or outer divertor legs, depending on the toroidal magnetic field direction. By reversing the toroidal magnetic field, the observed line radiation asymmetry is nearly eliminated or reversed. It is determined that, while relatively simple physics can describe the observed ionization asymmetry, predicting the overall brightness of the hydrogenic Lyman-α signal requires detailed simulation of the plasma and resulting turbulence. To this end, kinetic plasma simulations fully coupled to comprehensive neutral transport calculations—a novel capability—provide first-principles reproduction of Lyman-α observations on DIII-D.
Journal Article
Digital marketing innovation and industrial marketing: evidence from restaurants' service robots
PurposeThis study aims to explore how perceived anthropomorphism, perceived warmth, and customer–artificial intelligence (AI) assisted exchange (CAIX) of service robots affect customers’ satisfaction via digital marketing innovation.Design/methodology/approachA customer satisfaction model was formulated based on the perspective of parasocial relationships and hybrid intelligence; 236 completed questionnaires were returned by partial least squares structural equation modeling analysis.FindingsThis study demonstrates that perceived anthropomorphism, perceived warmth and CAIX's impact on digital marketing innovation were supported, and customer satisfaction impacted the continued intention to use service robots.Originality/valueRestaurants that leverage service robots differentiate themselves from competitors by offering innovative and technologically advanced dining experiences. Integrating AI capabilities sets these restaurants apart and attracts tech-savvy customers who value convenience and efficiency.
Journal Article
Role of inter-organizational systems in driving tourism businesses forward in the post-COVID-19 new normal
Purpose
This study aims to explore how inter-organizational systems (IOSs) drive tourism businesses to a new normal based on the resource-based view through the supply chain of tourism and information and computer technology used in IOSs.
Design/methodology/approach
Data were collected from the management of tourism businesses, and stratified sampling was used in the study. The authors selected 1,000 travel agencies as the study sample, mailed the research questionnaire to their managers and received 252 completed questionnaires. The authors analyzed the data using the partial least squares approach.
Findings
IOS is seen as a transformational service mechanism that provides a dynamic support weapon for members of the tourism supply chain. Tourism businesses should look for suppliers providing comprehensive services through IOS, excellent quality tourism products and customized tourism products to enhance the competitiveness of tourism businesses in the new normal.
Originality/value
This study provides an industrial marketing research perspective on tourism businesses facing the challenges of the new normal. For tourism businesses, technological innovation allows for changes in the strategies and procedures for their transformation and improves the business model of tourism businesses in the new normal.
Journal Article
The TGF-β/SMAD pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia
Natural killer (NK) cells are key components of the innate immune system, providing potent antitumor immunity. Here, we show that the tumor growth factor-β (TGF-β)/SMAD signaling pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia (ALL). We characterized NK cells in 50 consecutive children with B-ALL at diagnosis, end induction and during maintenance therapy compared with age-matched controls. ALL-NK cells at diagnosis had an inhibitory phenotype associated with impaired function, most notably interferon-γ production and cytotoxicity. By maintenance therapy, these phenotypic and functional abnormalities partially normalized; however, cytotoxicity against autologous blasts remained impaired. We identified ALL-derived TGF-β1 to be an important mediator of leukemia-induced NK cell dysfunction. The TGF-β/SMAD signaling pathway was constitutively activated in ALL-NK cells at diagnosis and end induction when compared with healthy controls and patients during maintenance therapy. Culture of ALL blasts with healthy NK cells induced NK dysfunction and an inhibitory phenotype, mediated by activation of the TGF-β/SMAD signaling pathway, and abrogated by blocking TGF-β. These data indicate that by regulating the TGF-β/SMAD pathway, ALL blasts induce changes in NK cells to evade innate immune surveillance, thus highlighting the importance of developing novel therapies to target this inhibitory pathway and restore antileukemic cytotoxicity.
Journal Article
A new paradigm emerges from the study of de novo mutations in the context of neurodevelopmental disease
The study of
de novo
point mutations (new germline mutations arising from the gametes of the parents) remained largely static until the arrival of next-generation sequencing technologies, which made both whole-exome sequencing (WES) and whole-genome sequencing (WGS) feasible in practical terms. Single nucleotide polymorphism genotyping arrays have been used to identify
de novo
copy-number variants in a number of common neurodevelopmental conditions such as schizophrenia and autism. By contrast, as point mutations and microlesions occurring
de novo
are refractory to analysis by these microarray-based methods, little was known about either their frequency or impact upon neurodevelopmental disease, until the advent of WES.
De novo
point mutations have recently been implicated in schizophrenia, autism and mental retardation through the WES of case-parent trios. Taken together, these findings strengthen the hypothesis that the occurrence of
de novo
mutations could account for the high prevalence of such diseases that are associated with a marked reduction in fecundity.
De novo
point mutations are also known to be responsible for many sporadic cases of rare dominant Mendelian disorders such as Kabuki syndrome, Schinzel–Giedion syndrome and Bohring–Opitz syndrome. These disorders share a common feature in that they are all characterized by intellectual disability. In summary, recent WES studies of neurodevelopmental and neuropsychiatric disease have provided new insights into the role of
de novo
mutations in these disorders. Our knowledge of
de novo
mutations is likely to be further accelerated by WGS. However, the collection of case-parent trios will be a prerequisite for such studies. This review aims to discuss recent developments in the study of
de novo
mutations made possible by technological advances in DNA sequencing.
Journal Article