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MRI can help to categorize tissues as malignant or non-malignant both anatomically and functionally, with a high level of spatial and temporal resolution. This non-invasive imaging modality has been integrated with radiotherapy in devices that can differentially target the most aggressive and resistant regions of tumours. The past decade has seen the clinical deployment of treatment devices that combine imaging with targeted irradiation, making the aspiration of integrated MRI-guided radiotherapy (MRIgRT) a reality. The two main clinical drivers for the adoption of MRIgRT are the ability to image anatomical changes that occur before and during treatment in order to adapt the treatment approach, and to image and target the biological features of each tumour. Using motion management and biological targeting, the radiation dose delivered to the tumour can be adjusted during treatment to improve the probability of tumour control, while simultaneously reducing the radiation delivered to non-malignant tissues, thereby reducing the risk of treatment-related toxicities. The benefits of this approach are expected to increase survival and quality of life. In this Review, we describe the current state of MRIgRT, and the opportunities and challenges of this new radiotherapy approach.In the past decade, treatment devices that combine imaging with targeted irradiation have been developed to deliver MRI-guided radiotherapy (MRIgRT). This treatment modality uses motion management and biological targeting to improve local control rates whilst reducing the radiation delivered to non-malignant tissues. The authors of this Review describe the current state of MRIgRT, and the opportunities and challenges of this radiotherapy approach.

PurposeThis paper explores how platforms reconfigure versatile digital resources to achieve marketing agility in international markets.Design/methodology/approachWe draw on a case study of a Chinese digital platform to explore the processes and mechanisms of reconfiguring during marketing agility development. Data from different sources are collected, including interviews, informal dialogue and archival data.FindingsVersatile digital resources create productive applications for previously less amendable marketing and nonmarketing resources to be malleable, editable and reconfigurable in marketing agility development. This study identifies and clarifies three versatile digital resource-enabled reconfiguration activities in marketing agility building: recombining digital artifacts, repurposing human capital and cross-pollinating markets.Research limitations/implicationsSince our study adopts a case study method, future research can extend our insights by using quantitative methods to test and verify our theoretical framework.Practical implicationsFirst, we provide insights into how organizations can reconfigure versatile digital resources to achieve the benefits of marketing agility in international markets. Second, while recruiting new employees during internationalization is vital, we suggest that assisted by digital artifacts, firms can repurpose the existing workforce, such as via multitasking, swift task-switching and flexible job redirecting to satisfy dynamic international business requirements with lower adjustment costs. Third, we offer two localization approaches in which firms can use digital artifacts as the enabler to remix sociocultural elements with local adaptations to develop glocal content and decentralize content production to generate inclusive local content.Originality/valueWe provide a process model that specifies how platforms reconfigure versatile digital resources to achieve marketing agility in international markets. Furthermore, we provide novel insights into the literature on marketing agility in international markets and localization.

PurposeBrand information is ubiquitous online and offline; consumers exhibit brand avoidance tendencies towards brand stimuli when there is a discrepancy between a brand image/personality and one’s self-concept. Given the multifaceted culturally constituted self-domains and self-importance, this research investigates how cultural variation affects reactions to self-brand discrepancy, considering two types of narcissist orientations.Design/methodology/approachUsing national culture as proxy for cultural orientation, sample data were collected through surveys administered to 410 participants (210 in China and 200 in the USA). A multi-group structural equation model was adopted to examine the conceptual model and proposed hypotheses. The follow-up qualitative study was conducted to allow further discussion of the quantitative results.FindingsThe results show that self-brand discrepancy can only be converted into brand avoidance tendency through the activation of cognitive dissonance for both Americans and Chinese. Specifically, for Chinese consumers only (ideal) social identity self-brand discrepancies can activate avoidance behaviour. In addition, grandiose and vulnerable narcissism orientations co-exist for both Chinese and Americans, these negatively moderate the relationship between social self-brand discrepancies and cognitive dissonance. For US consumers, idealised identity discrepancies mitigate dissonance; only those with a vulnerable narcissistic orientation would act on avoidance when experiencing dissonance.Originality/valueBy incorporating cultural variations in the investigations of self-brand discrepancy, this paper advances existing knowledge on dissonance and coping mechanisms. In addition, by bringing narcissistic orientations to the fore, it allows for a deeper understanding of how these cultural variations operate. In addition, our research provides important guidelines for brand practitioners to better leverage their marketing campaigns in offline and online contexts and to reduce brand avoidance tendencies across the international marketplace.

Where the Mekong River discharges into the East Sea (also known as the South China Sea), it has formed the world’s third largest delta plain with an area of ~50,000 km². Numerous cores recovered from the subaerial delta reveal that it has prograded ~220 km southeastward within the past 7,500 years. Recent extensive seismic and geochemical surveys of the adjacent subaqueous delta indicate that the Mekong River forms a classic sigmoidal, cross-shelf clinoform immediately off its distributaries that is up to 15 m thick, with topset, foreset, and bottomset facies. These deposits are constrained within water depths of 20 m. Mekong-derived sediment packages extend ~300 km along shelf in the southwestward direction to the tip of the Ca Mau Peninsula, where they form a distal mud depocenter up to 22 m thick. These sediment packages can also be traced into the Gulf of Thailand to water depths of 25 m. The proximal and distal deposits cover ~11,000 km² of the shelf. Historically, the Mekong Delta has prograded seaward at a mean rate of >30 m yr−1, or 7 km² yr−1; however, study of the past 43 years of Landsat images indicates that the mode of sedimentation in the delta shifted starting in 2005. From 1973 to 2005, the Mekong Delta’s seaward shoreline growth decreased gradually from a mean of 7.8 m yr−1to 2.8 m yr−1, and after 2005 it became negative, with a retreat rate of −1.4 m yr−1. The net deltaic land area gain has also been slowing, with the mean rate decreasing from 4.3 km² yr−1(1973–1979) to 1.0 km² yr−1(1995–2005), and then to −0.05 km² yr−1(2005–2015). Thus, in about 2005, the subaerial Mekong Delta transitioned from a constructive mode to an erosional (or destructive) mode. Furthermore, not only is the subaerial Mekong Delta land area gradually diminishing, but high-resolution CHIRP sonar profiling surveys off the east-central Ca Mau Peninsula reveal that this portion of the subaqueous delta is also eroding. With the construction of more dams, sand mining, delta subsidence, increasing storms, and sea level rise, the Mekong Delta will likely face more destructive changes, with erosion both of coastlines and underwater deposits.

Ultrasound (US) imaging is clinically used to guide needle insertions because it is safe, real-time, and low cost. The localization of the needle in the ultrasound image, however, remains a challenging problem due to specular reflection off the smooth surface of the needle, speckle noise, and similar line-like anatomical features. This study presents a novel robust needle localization and enhancement algorithm based on deep learning and beam steering methods with three key innovations. First, we employ beam steering to maximize the reflection intensity of the needle, which can help us to detect and locate the needle precisely. Second, we modify the U-Net which is an end-to-end network commonly used in biomedical segmentation by using two branches instead of one in the last up-sampling layer and adding three layers after the last down-sample layer. Thus, the modified U-Net can real-time segment the needle shaft region, detect the needle tip landmark location and determine whether an image frame contains the needle by one shot. Third, we develop a needle fusion framework that employs the outputs of the multi-task deep learning (MTL) framework to precisely locate the needle tip and enhance needle shaft visualization. Thus, the proposed algorithm can not only greatly reduce the processing time, but also significantly increase the needle localization accuracy and enhance the needle visualization for real-time clinical intervention applications.

Starting with the launch of the Human Genome Project three decades ago, and continuing after its completion in 2003, genomics has progressively come to have a central and catalytic role in basic and translational research. In addition, studies increasingly demonstrate how genomic information can be effectively used in clinical care. In the future, the anticipated advances in technology development, biological insights, and clinical applications (among others) will lead to more widespread integration of genomics into almost all areas of biomedical research, the adoption of genomics into mainstream medical and public-health practices, and an increasing relevance of genomics for everyday life. On behalf of the research community, the National Human Genome Research Institute recently completed a multi-year process of strategic engagement to identify future research priorities and opportunities in human genomics, with an emphasis on health applications. Here we describe the highest-priority elements envisioned for the cutting-edge of human genomics going forward—that is, at ‘The Forefront of Genomics’. In this Perspective, authors from the National Human Genome Research Institute (NHGRI) present a vision for human genomics research for the coming decade.

Runt-related transcription factor 1 (RUNX1) is generally considered to function as a tumor suppressor in the development of leukemia, but a growing body of evidence suggests that it has pro-oncogenic properties in acute myeloid leukemia (AML). Here we have demonstrated that the antileukemic effect mediated by RUNX1 depletion is highly dependent on a functional p53-mediated cell death pathway. Increased expression of other RUNX family members, including RUNX2 and RUNX3, compensated for the antitumor effect elicited by RUNX1 silencing, and simultaneous attenuation of all RUNX family members as a cluster led to a much stronger antitumor effect relative to suppression of individual RUNX members. Switching off the RUNX cluster using alkylating agent-conjugated pyrrole-imidazole (PI) polyamides, which were designed to specifically bind to consensus RUNX-binding sequences, was highly effective against AML cells and against several poor-prognosis solid tumors in a xenograft mouse model of AML without notable adverse events. Taken together, these results identify a crucial role for the RUNX cluster in the maintenance and progression of cancer cells and suggest that modulation of the RUNX cluster using the PI polyamide gene-switch technology is a potential strategy to control malignancies.

The leukemia fusion gene CBFB-MYH11 requires RUNX1 for leukemogenesis, but the underlying mechanism is unclear. By in vitro studies, we found that CBFβ-SMMHC, the chimeric protein encoded by CBFB-MYH11, could enhance the binding affinity between RUNX1 and its target DNA. Increased RUNX1-DNA binding was also observed in myeloid progenitor cells from mice expressing CBFβ-SMMHC. Moreover, only CBFβ-SMMHC variants able to enhance the DNA binding affinity by RUNX1 could induce leukemia in mouse models. Marked transcriptomic changes, affecting genes associated with inflammatory response and target genes of CBFA2T3, were observed in mice expressing leukemogenic CBFβ-SMMHC variants. Finally, we show that CBFβ-SMMHC could not induce leukemia in mice with a Runx1-R188Q mutation, which reduces RUNX1 DNA binding but does not affect its interaction with CBFβ-SMMHC or its sequestration to cytoplasm by CBFβ-SMMHC. Our data suggest that, in addition to binding RUNX1 to regulate gene expression, enhancing RUNX1 binding affinity to its target DNA is an important mechanism by which CBFβ-SMMHC contributes to leukemogenesis, highlighting RUNX1-DNA interaction as a potential therapeutic target in inv(16) acute myeloid leukemia.

MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro , and substantially inhibits leukaemia development and maintenance in vivo . Mechanistically, miR-22 targets multiple oncogenes, including CRTC1 , FLT3 and MYCBP , and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo . Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy. Mir-22 has been shown to be an oncogenic microRNA in breast cancer and myelodysplastic syndrome. Here, the authors show that mir-22 functions as a tumour suppressor in de novo acute myeloid leukaemia by inhibiting the expression of several oncogenes and that restoring mir-22 expression suppresses AML progression.