Natural killer (NK) cells are normal white blood cells capable of killing malignant cells without prior sensitization. Allogeneic NK cell infusions are attractive for cancer therapy because of ...non-cross-resistant mechanisms of action and minimal overlapping toxicities with standard cancer treatments. Although NK therapy is promising, many obstacles will need to be overcome, including insufficient cell numbers, failure of homing to tumor sites, effector dysfunction, exhaustion, and tumor cell evasion. Capitalizing on the wealth of knowledge generated by recent NK cell biology studies and the advancements in biotechnology, substantial progress has been made recently in improving therapeutic efficiency and reducing side effects. A multipronged strategy is essential, including immunogenetic-based donor selection, refined NK cell bioprocessing, and novel augmentation techniques, to improve NK function and to reduce tumor resistance. Although data from clinical trials are currently limited primarily to hematologic malignancies, broader applications to a wide spectrum of adult and pediatric cancers are under way. The unique properties of human NK cells open up a new arena of novel cell-based immunotherapy against cancers that are resistant to contemporary therapies.
Summary
Analogous to T cells, Natural Killer (NK) cells may facilitate engraftment, combat infection, and control cancer in bone marrow or haematopoietic stem cell transplantation (HSCT); however, NK ...cells do not cause graft‐versus‐host disease. Killer immunoglobulin‐like receptors (KIRs) regulate NK cell function, and recent data suggest that KIR is as important as its ligand (human leucocyte antigen; HLA) in HSCT for both malignant and non‐malignant conditions. Because there is substantial variability in KIR gene content, allelic polymorphism, and cell‐surface expression among people, careful selection of donors based on HLA and KIR is essential to optimize HSCT outcomes. Furthermore, NK cells may be used for adoptive immunotherapy after HSCT in place of conventional donor lymphocyte infusion, as part of pre‐transplant cytoreductive therapy, or as an independent therapeutic agent in high‐risk leukaemia in place of sibling donor HSCT.
Summary
In patients with acute leukaemia, the relative risk of relapse influences the choice between chemotherapy and haematopoietic stem cell transplantation (HSCT). The demonstration that minimal ...residual disease (MRD) is the strongest overall prognostic indicator and can identify patients who are unlikely to be cured by standard chemotherapy has added a powerful new factor to consider when making this decision. There is substantial data indicating that the likelihood of relapse after transplant is directly correlated with levels of MRD before transplant. This knowledge can be used to adjust the timing of HSCT, and guide the selection of donor, conditioning regimen, and post‐HSCT strategies to maximize the graft‐versus‐leukaemia effect. Because MRD emerging post‐transplant carries a dire prognosis, its detection can trigger withdrawal of immunosuppression, additional cellular and molecular therapies, or preparations for a second HSCT. Although it is not yet clear whether any of these actions will significantly improve outcome, it is likely that they will be most effective for patients with a relatively low tumour burden, who can be identified only through MRD testing. In this article, we review the clinical significance of MRD in the context of autologous and allogeneic HSCT.
To enhance environmental sustainability, many countries will electrify their transportation systems in their future smart city plans, so the number of electric vehicles (EVs) running in a city will ...grow significantly. There are many ways to recharge EVs' batteries and charging stations will be considered as the main source of energy. The locations of charging stations are critical; they should not only be pervasive enough such that an EV anywhere can easily access a charging station within its driving range, but also widely spread so that EVs can cruise around the whole city upon being recharged. Based on these new perspectives, we formulate the EV charging station placement problem (EVCSPP) in this paper. We prove that the problem is nondeterministic polynomial-time hard. We also propose four solution methods to tackle EVCSPP, and evaluate their performance on various artificial and practical cases. As verified by the simulation results, the methods have their own characteristics and they are suitable for different situations depending on the requirements for solution quality, algorithmic efficiency, problem size, nature of the algorithm, and existence of system prerequisite.
The development of site‐specific, target‐selective and biocompatible small molecule ligands as a fluorescent tool for real‐time study of cellular functions of RNA G‐quadruplexes (G4s), which are ...associated with human cancers, is of significance in cancer biology. We report a fluorescent ligand that is a cytoplasm‐specific and RNA G4‐selective fluorescent biosensor in live HeLa cells. The in vitro results show that the ligand is highly selective targeting RNA G4s including VEGF, NRAS, BCL2 and TERRA. These G4s are recognized as human cancer hallmarks. Moreover, intracellular competition studies with BRACO19 and PDS, and the colocalization study with G4‐specific antibody (BG4) in HeLa cells may support that the ligand selectively binds to G4s in cellulo. Furthermore, the ligand was demonstrated for the first time in the visualization and monitoring of dynamic resolving process of RNA G4s by the overexpressed RFP‐tagged DHX36 helicase in live HeLa cells.
A fluorescent ligand is designed as a cytoplasm‐specific probe targeting RNA G4s including VEGF, NRAS and BCL2 in live cancer cells. The ligand is demonstrated for the first time in real‐time visualization of RNA G4‐resolving process with the overexpressed RFP‐tagged DHX36 helicase in live HeLa cells and could be a nontoxic and highly selective fluorescent tool for the study of RNA G4s of cancer hallmarks at low concentration for their cancer biology in live human cells.
Italy was one of the first European countries affected by the Covid-19 pandemic after the beginning of the outbreak in China in January 2020. Applying critical discourse analysis and theories of the ...mediation of suffering, this article explores the discursive strategies used by the Italian media to represent China and Chinese people in relation to the outbreak in the early stage of the pandemic. Employing the theoretical frameworks of Mary Douglas, Michel Foucault, and other thinkers on biopolitics, racism, and emergency, the results bring to light the persistent ideologies behind the media representations of an imagined Other, which reflect existing discourses toward the Chinese community in Italy. In this study, the contentious discourses around China and the Chinese amidst the pandemic reveal the role of the Italian media in presenting risks, mediating suffering as a distant event and, later, as a national concern.
This article looks at the predominance of freelancing in the film and television industries as a lens to examine the persistence of gender inequalities within these fields. Previous research has ...indicated that women fare better in larger organizations with more stable patterns of employment, and in this article we explore why that might be the case, by focusing on the experiences of female freelancers at a moment when project-based, precarious work and informal recruitment practices are increasing in the UK film and television sector. We highlight in particular the ways in which gender inequality is mediated by age and parental status, and the impact of intersectional identities on women's ability to sustain a career in film and television.
To investigate the association of attention-deficit/hyperactivity disorder (ADHD) with the 48-base pair (bp) variable number of tandem repeats (VNTR) in exon 3 of the dopamine receptor D4 (DRD4) ...gene, we genotyped 240 ADHD patients and their parents from Hong Kong. The 4R allele was most common, followed by 2R. We examined association between the 2R allele (relative to 4R) and ADHD by Transmission Disequilibrium Test (TDT). The odds ratio (OR) (95% confidence interval) was 0.90 (0.64-1.3). The p-value was 0.6. Examining subgroups revealed nominally significant association of 2R with inattentive ADHD: OR = 0.33 (0.12-0.92) and p = 0.03. Because our study used TDT analysis, we meta-analyzed the association of 2R with ADHD in Asians (1329 patient alleles), revealing results similar to ours: OR = 0.97 (0.80-1.2) and p = 0.8. To examine the association of 2R with inattentive ADHD, we meta-analyzed all studies (regardless of analysis type or ethnicity, in order to increase statistical power): 702 patient alleles, 1420 control alleles, OR = 0.81 (0.57-1.1) and p = 0.2. Overall, there is no evidence of association between ADHD and the 2R allele, but the suggestive association with the inattentive type warrants further investigation.
The formation of G-quadruplex structures (G4s)
from guanine (G)-rich nucleic acid sequences of DNA and RNA stabilized with monovalent cations, typically K
and Na
, under physiological conditions, has ...been verified experimentally and some of them have high-resolution NMR or
-ray crystal structures; however, the biofunction of these special noncanonical secondary structures of nucleic acids has not been fully understood and their existence
is still controversial at present. It is generally believed that the folding and unfolding of G4s
is a transient process. Accumulating evidence has shown that G4s may play a role in the regulation of certain important cellular functions including telomere maintenance, replication, transcription and translation. Therefore, both DNA and RNA G4s of human cancer hallmark genes are recognized as the potential anticancer drug target for the investigation in cancer biology, chemical biology and drug discovery. The relationship between the sequence, structure and stability of G4s, the interaction of G4s with small molecules, and insights into the rational design of G4-selective binding ligands have been intensively studied over the decade. At present, some G4-ligands have achieved a new milestone and successfully entered the human clinical trials for anticancer therapy. Over the past few decades, numerous efforts have been devoted to anticancer therapy; however, G4s for molecular recognition and live cell imaging and for application as antibacterial agents and antibiofilms against antibiotic resistance have been obviously underexplored. The recent advances in G4-ligands in these areas are thus selected and discussed concentratedly in this article in order to shed light on the emerging role of G4s in chemical biology and therapeutic prospects against bacterial infections. In addition, the recently published molecular scaffolds for designing small ligands selectively targeting G4s in live cell imaging, bacterial biofilm imaging, and antibacterial studies are discussed. Furthermore, a number of underexplored G4-targets from the cytoplasmic membrane-associated DNA, the conserved promoter region of
genomes, the RNA G4-sites in the transcriptome of
and
, and the mRNA G4-sites in the sequence for coding the vital bacterial FtsZ protein are highlighted to further explore in G4-drug development against human diseases.
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