Acute Promyelocytic Leukemia, Retinoic Acid, and Arsenic: A Tale of Dualities.

Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)/retinoic acid receptor α (RARA) fusion oncoprotein. Over the years, it has emerged as a model system to understand how this simple (and sometimes sole) genetic alteration can transform hematopoietic progenitors through the acquisition of dominant-negative properties toward both transcriptional control by nuclear receptors and PML-mediated senescence. The fortuitous identification of two drugs, arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA), that respectively bind PML and RARA to initiate PML/RARA degradation, has allowed an unprecedented dissection of the cellular and molecular mechanisms involved in patients' cure by the ATO/ATRA combination. This analysis has unraveled the dual and complementary roles of RARA and PML in both APL initiation and cure by the ATRA/ATO combination. We discuss how some of the features unraveled by APL studies may be more broadly applicable to some other forms of leukemia. In particular, the functional synergy between drugs that promote differentiation and those that initiate apoptosis/senescence to impede self-renewal could pave the way to novel curative combinations.

Assessing the sustainability of smart healthcare applications using a multi-perspective fuzzy comprehensive evaluation approach.

A smart healthcare application can be judged as sustainable if it was already widely used before and will also be prevalent in the future. In contrast, if a smart healthcare application developed during the COVID-19 pandemic is not used after it, then it is not sustainable. Assessing the sustainability of smart healthcare applications is a critical task for their users and suppliers. However, it is also a challenging task due to the availability of data, users' subjective beliefs, and different perspectives. In response to this problem, this study proposes a multi-perspective fuzzy comprehensive evaluation approach to evaluate the sustainability of a smart healthcare application from qualitative, multi-criteria decision-making and time-series perspectives. The proposed methodology has been used to evaluate the sustainability of eight smart healthcare applications. The experimental results showed that the sustainability of a smart healthcare application evaluated from different perspectives may be different. Nevertheless, another technique can be used to confirm the evaluation result generated using one technique. In other words, these views compensate for each other.

Optical Imaging Deformation Inspection and Quality Level Determination of Multifocal Glasses.

Multifocal glasses are a new type of lens that can fit both nearsighted and farsighted vision on the same lens. This property allows the glass to have various curvatures in distinct regions within the glass during the grinding process. However, when the curvature varies irregularly, the glass is prone to optical deformation during imaging. Most of the previous studies on imaging deformation focus on the deformation correction of optical lenses. Consequently, this research uses an automatic deformation defect detection system for multifocal glasses to replace professional assessors. To quantify the grade of deformation of curved multifocal glasses, we first digitally imaged a pattern of concentric circles through a test glass to generate an imaged image of the glass. Second, we preprocess the image to enhance the clarity of the concentric circles' appearance. A centroid-radius model is used to represent the form variation properties of every circle in the processed image. Third, the deviation of the centroid radius for detecting deformation defects is found by a slight deviation control scheme, and we gain a difference image indicating the detected deformed regions after comparing it with the norm pattern. Fourth, based on the deformation measure and occurrence location of multifocal glasses, we build fuzzy membership functions and inference regulations to quantify the deformation's severity. Finally, a mixed model incorporating a network-based fuzzy inference and a genetic algorithm is applied to determine a quality grade for the deformation severity of detected defects. Testing outcomes show that the proposed methods attain a 94% accuracy rate of the quality levels for deformation severity, an 81% recall rate of deformation defects, and an 11% false positive rate for multifocal glass detection. This research contributes solutions to the problems of imaging deformation inspection and provides computer-aided systems for determining quality levels that meet the demands of inspection and quality control.

Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia.

By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures. Multiple metabolic pathways were impacted upon xCT inhibition, resulting in depletion of glutathione pools in leukemic cells and oxidative stress-dependent cell death, only in part through ferroptosis. Higher expression of cysteine metabolism genes and greater cystine dependency was noted in NPM1-mutated AMLs. Among eight anti-leukemic drugs, the anthracycline daunorubicin was identified as the top synergistic agent in combination with sulfasalazine in vitro. Addition of sulfasalazine at a clinically relevant concentration significantly augmented the anti-leukemic activity of a daunorubicin-cytarabine combination in a panel of 45 primary samples enriched in NPM1-mutated AML. These results were confirmed in vivo in a patient-derived xenograft model. Collectively, our results nominate cystine import as a druggable target in AML and raise the possibility to repurpose sulfasalazine for the treatment of AML, notably in combination with chemotherapy.

A fuzzy analytic hierarchy process-enhanced fuzzy geometric mean-fuzzy technique for order preference by similarity to ideal solution approach for suitable hotel recommendation amid the COVID-19 pandemic.

Cities around the world have reopened from the lockdown caused by the COVID-19 pandemic, and more and more people are planning regional travel. Therefore, it is a practical problem to recommend suitable hotels to travelers amid the COVID-19 pandemic. However, it is also a challenging task since the critical factors that affect hotel selection amid the COVID-19 pandemic may be different from those usually considered. From this perspective, the fuzzy analytic hierarchy process-enhanced fuzzy geometric mean-fuzzy technique for order preference by similarity to ideal solution approach is proposed in this study for hotel recommendation. The proposed methodology not only considers the critical factors affecting hotel selection amid the COVID-19 pandemic, but also establishes a systematic mechanism, that is, enhanced fuzzy geometric mean, to simultaneously improve the accuracy and efficiency of the recommendation process. The fuzzy analytic hierarchy process-enhanced fuzzy geometric mean-fuzzy technique for order preference by similarity to ideal solution approach has been successfully applied to recommend suitable hotels to 10 travelers for regional trips amid the COVID-19 pandemic.

Effects of compression garment on muscular efficacy, proprioception, and recovery after exercise-induced muscle fatigue onset for people who exercise regularly.

Fatigue is a major cause of exercise-induced muscle damage (EIMD). Compression garments (CGs) can aid post-exercise recovery, therefore, this study explored the effects of CGs on muscular efficacy, proprioception, and recovery after exercise-induced muscle fatigue in people who exercise regularly. Twelve healthy participants who exercised regularly were enrolled in this study. Each participant completed an exercise-induced muscle fatigue test while wearing a randomly assigned lower-body CG or sports pants (SP); after at least 7 days, the participant repeated the test while wearing the other garment. The dependent variables were muscle efficacy, proprioception (displacements of center of pressure/COP, and absolute error), and fatigue recovery (muscle oxygen saturation/SmO2, deoxygenation and reoxygenation rate, and subjective muscle soreness). A two-way repeated measure analysis of variance was conducted to determine the effect of garment type. The results indicated that relative to SP use, CG use can promote muscle efficacy, proprioception in ML displacement of COP, and fatigue recovery. Higher deoxygenation and reoxygenation rates were observed with CG use than with SP use. For CG use, SmO2 quickly returned to baseline value after 10 min of rest and was maintained at a high level until after 1 h of rest, whereas for SP use, SmO2 increased with time after fatigue onset. ML displacement of COP quickly returned to baseline value after 10 min of rest and subsequently decreased until after 1 hour of rest. Relative to SP use, CG use was associated with a significantly lower ML displacement after 20 min of rest. In conclusion, proprioception and SmO2 recovery was achieved after 10 min of rest; however, at least 24 h may be required for recovery pertaining to muscle efficacy and soreness regardless of CG or SP use.

Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML).

BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including NPM1c AML cells. Nevertheless, the biological consequences of BETi in NPM1c AML were not fully investigated. Even if of better prognosis AML patients with NPM1c may relapse and treatment remains difficult. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) demonstrated activity in NPM1c AML. We found that BETi, similar to ATO + ATRA, induced differentiation and apoptosis which was TP53 independent in the NPM1c cell line OCI-AML3 and primary cells. Furthermore, BETi induced proteasome-dependent degradation of NPM1c. BETi degraded NPM1c in the cytosol while BRD4 is degraded in the nucleus which suggests that restoration of the NPM1/BRD4 equilibrium in the nucleus of NPM1c cells is essential for the efficacy of BETi. While ATO + ATRA had significant biological activity in NPM1c IMS-M2 cell line, those cells were resistant to BETi. Gene profiling revealed that IMS-M2 cells probably resist to BETi by upregulation of LSC pathways independently of the downregulation of a core BET-responsive transcriptional program. ATO + ATRA downregulated a NPM1c specific HOX gene signature while anti-leukemic effects of BETi appear HOX gene independent. Our preclinical results encourage clinical testing of BETi in NPM1c AML patients.

Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy.

Acute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and overall association with favorable therapeutic responses remain incompletely understood. Here we demonstrate that an oncogenic mutant form of NPM1 (NPM1c) impairs mitochondrial function. NPM1c also hampers formation of promyelocytic leukemia (PML) nuclear bodies (NB), which are regulators of mitochondrial fitness and key senescence effectors. Actinomycin D (ActD), an antibiotic with unambiguous clinical efficacy in relapsed/refractory NPM1c-AMLs, targets these primed mitochondria, releasing mitochondrial DNA, activating cyclic GMP-AMP synthase signaling, and boosting reactive oxygen species (ROS) production. The latter restore PML NB formation to drive TP53 activation and senescence of NPM1c-AML cells. In several models, dual targeting of mitochondria by venetoclax and ActD synergized to clear AML and prolong survival through targeting of PML. Our studies reveal an unexpected role for mitochondria downstream of NPM1c and implicate a mitochondrial/ROS/PML/TP53 senescence pathway as an effector of ActD-based therapies. SIGNIFICANCE: ActD induces complete remissions in NPM1-mutant AMLs. We found that NPM1c affects mitochondrial biogenesis and PML NBs. ActD targets mitochondria, yielding ROS which enforce PML NB biogenesis and restore senescence. Dual targeting of mitochondria with ActD and venetoclax sharply potentiates their anti-AML activities in vivo. This article is highlighted in the In This Issue feature, p. 2945.

PML/RARA destabilization by hyperthermia: a new model for oncogenic fusion protein degradation?

In this issue, Maimaitiyiming and colleagues demonstrate thermic stress-induced PML/RARA oncogenic fusion protein destabilization driven by corepressor aggregation. Hyperthermia synergizes with PML/RARA degradation by ATO and may circumvent ATO-resistance in historical APL patients. This novel approach could be extended to other corepressor-associated oncogenic fusion proteins.

A novel leukemic route of mutant NPM1 through nuclear import of the overexpressed long noncoding RNA LONA.

The most frequent genetic alteration in acute myeloid leukemia (AML) is the mutation of nucleophosmin 1 (NPM1). Yet, its downstream oncogenic routes are not fully understood. Here, we report the identification of one long noncoding RNA (lncRNA) overexpressed in NPM1-mutated AML patients (named LONA) whose intracellular localization inversely reflects that of NPM1. While NPM1 is nuclear and LONA cytoplasmic in wild-type NPM1 AML cells, LONA becomes nuclear as mutant NPM1 moves toward the cytoplasm. Gain or loss of function combined with a genome-wide RNA-seq search identified a set of LONA mRNA targets encoding proteins involved in myeloid cell differentiation (including THSB1, MAFB, and ASB2) and interaction with its microenvironment. Consistently, LONA overexpression in mutant NPM1 established cell lines and primary AML cells exerts an anti-myeloid differentiation effect, whilst it exerts an opposite pro-myeloid differentiation effect in a wild type NPM1 setting. In vivo, LONA overexpression acts as an oncogenic lncRNA reducing the survival of mice transplanted with AML cells and rendering AML tumors more resistant to AraC chemotherapy.These data indicate that mutation-dependent nuclear export of NPM1 leads to nuclear retention and consequent oncogenic functions of the overexpressed lncRNA LONA, thus uncovering a novel NPM1 mutation-dependent pathway in AML pathogenesis.

A Pin1/PML/P53 axis activated by retinoic acid in NPM-1c acute myeloid leukemia.

Retinoic acid (RA) was proposed to increase survival of chemotherapy- treated patients with nucleophosmin-1 (NPM-1c)-mutated acute myeloid leukemia. We reported that, ex vivo, RA triggers NPM-1c degradation, P53 activation and growth arrest. PML organizes domains that control senescence or proteolysis. Here, we demonstrate that PML is required to initiate RA-driven NPM-1c degradation, P53 activation and cell death. Mechanistically, RA enhances PML basal expression through inhibition of activated Pin1, prior to NPM-1c degradation. Such PML induction drives P53 activation, favoring blast response to chemotherapy or arsenic in vivo. This RA/PML/P53 cascade could mechanistically explain RA-facilitated chemotherapy response in patients with NPM-1c mutated acute myeloid leukemia.

Dactinomycin induces complete remission associated with nucleolar stress response in relapsed/refractory NPM1-mutated AML.

Acute myeloid leukemia (AML) with mutated NPM1 accounts for one-third of newly diagnosed AML. Despite recent advances, treatment of relapsed/refractory NPM1-mutated AML remains challenging, with the majority of patients eventually dying due to disease progression. Moreover, the prognosis is particularly poor in elderly and unfit patients, mainly because they cannot receive intensive treatment. Therefore, alternative treatment strategies are needed. Dactinomycin is a low-cost chemotherapeutic agent, which has been anecdotally reported to induce remission in NPM1-mutated patients, although its mechanism of action remains unclear. Here, we describe the results of a single-center phase 2 pilot study investigating the safety and efficacy of single-agent dactinomycin in relapsed/refractory NPM1-mutated adult AML patients, demonstrating that this drug can induce complete responses and is relatively well tolerated. We also provide evidence that the activity of dactinomycin associates with nucleolar stress both in vitro and in vivo in patients. Finally, we show that low-dose dactinomycin generates more efficient stress response in cells expressing NPM1 mutant compared to wild-type cells, suggesting that NPM1-mutated AML may be more sensitive to nucleolar stress. In conclusion, we establish that dactinomycin is a potential therapeutic alternative in relapsed/refractory NPM1-mutated AML that deserves further investigation in larger clinical studies.

Usp11 controls cortical neurogenesis and neuronal migration through Sox11 stabilization.

The role of protein stabilization in cortical development remains poorly understood. A recessive mutation in the USP11 gene is found in a rare neurodevelopmental disorder with intellectual disability, but its pathogenicity and molecular mechanism are unknown. Here, we show that mouse Usp11 is expressed highly in embryonic cerebral cortex, and Usp11 deficiency impairs layer 6 neuron production, delays late-born neuronal migration, and disturbs cognition and anxiety behaviors. Mechanistically, these functions are mediated by a previously unidentified Usp11 substrate, Sox11. Usp11 ablation compromises Sox11 protein accumulation in the developing cortex, despite the induction of Sox11 mRNA. The disease-associated Usp11 mutant fails to stabilize Sox11 and is unable to support cortical neurogenesis and neuronal migration. Our findings define a critical function of Usp11 in cortical development and highlight the importance of orchestrating protein stabilization mechanisms into transcription regulatory programs for a robust induction of cell fate determinants during early brain development.

Analyzing the Impact of Vaccine Availability on Alternative Supplier Selection Amid the COVID-19 Pandemic: A cFGM-FTOPSIS-FWI Approach.

The supply chain disruption caused by the coronavirus disease 2019 (COVID-19) pandemic has forced many manufacturers to look for alternative suppliers. How to choose a suitable alternative supplier in the COVID-19 pandemic has become an important task. To fulfill this task, this research proposes a calibrated fuzzy geometric mean (cFGM)-fuzzy technique for order preference by similarity to ideal solution (FTOPSIS)-fuzzy weighted intersection (FWI) approach. In the proposed methodology, first, the cFGM method is proposed to accurately derive the priorities of criteria. Subsequently, each expert applies the FTOPSIS method to compare the overall performances of alternative suppliers in the COVID-19 pandemic. The sensitivity of an expert to any change in the overall performance of the alternative supplier is also considered. Finally, the FWI operator is used to aggregate the comparison results by all experts, for which an expert's authority level is set to a value proportional to the consistency of his/her pairwise comparison results. The cFGM-FTOPSIS-FWI approach has been applied to select suitable alternative suppliers for a Taiwanese foundry in the COVID-19 pandemic.

Chlorella sorokiniana Extract Prevents Cisplatin-Induced Myelotoxicity In Vitro and In Vivo.

Cisplatin chemotherapy causes myelosuppression and often limits treatment duration and dose escalation in patients. Novel approaches to circumvent or lessen myelotoxicity may improve clinical outcome and quality of life in these patients. Chlorella sorokiniana (CS) is a freshwater unicellular green alga and exhibits encouraging efficacy in immunomodulation and anticancer in preclinical studies. However, the efficacy of CS on chemoprotection remains unclear. We report here, for the first time, that CS extract (CSE) could protect normal myeloid cells and PBMCs from cisplatin toxicity. Also, cisplatin-induced apoptosis in HL-60 cells was rescued through reservation of mitochondrial function, inhibition of cytochrome c release to cytosol, and suppression of caspase and PARP activation. Intriguingly, cotreatment of CSE attenuated cisplatin-evoked hypocellularity of bone marrow in mice. Furthermore, we observed the enhancement of CSF-GM activity in bone marrow and spleen in mice administered CSE and cisplatin, along with increased CD11b levels in spleen. In conclusion, we uncovered a novel mechanism of CSE on myeloprotection, whereby potentially supports the use of CSE as a chemoprotector against cisplatin-induced bone marrow toxicity. Further clinical investigation of CSE in combination with cisplatin is warranted.

PML nuclear bodies, membrane-less domains acting as ROS sensors?

PML Nuclear bodies (PML NBs) are spherical domains associated with a broad range of activities upon stress responses such as apoptosis, senescence DNA repair, epigenetic control, as well as control of oncogenesis. These bodies are considered as privileged sites for post-translational modifications, where sumoylation plays a key role. Here we summarize recent in vitro and in vivo findings on the link between PML NBs and ROS, in particular PML contributions to oxidative stress response. We discuss how it may regulate switch from cell protection against stress to cell arrest/cell death.

Erratum: USP11 regulates PML stability to control Notch-induced malignancy in brain tumours.

This corrects the article DOI: 10.1038/ncomms4214.

Insights into the coordinated interplay of the sHP hairpin and its co-existing and mutually-exclusive dengue virus terminal RNA elements for viral replication.

Terminal RNA elements of the dengue virus (DENV) genome are necessary for balanced stability of linear and circular conformations during replication. We examined the small hairpin (sHP) and co-existing and mutually-exclusive terminal RNA elements by mutagenesis analysis, compensatory mutation screening, and by probing with RNA fragments to explore localized RNA folding and long-range RNA interactions. We found that the first base pair of the sHP and the stability of SLB and the 3'SL bottom stem affected circularization; sHPgc/C10631G+G10644C prohibited circularization, sHPuG accelerated and stabilized 5'-to-3' RNA hybridization, while C94A and A97G and C10649 mutations loosened SLB and 3'SL, respectively, for circularization. sHPuG+C10649G induced circularization and impeded replication, whereas point mutations that loosened the UAR or DAR ds region, strengthened the sHP, or reinforced the 3'SL bottom stem, rescued the replication deficiency. Overall, we reveal structural and sequence features and interplay of DENV genome terminal RNA elements essential to viral replication.

Imidazoquinoxaline derivative EAPB0503: A promising drug targeting mutant nucleophosmin 1 in acute myeloid leukemia.

BACKGROUND: Nucleophosmin 1 (NPM1) is a nucleocytoplasmic shuttling protein mainly localized in the nucleolus. NPM1 is frequently mutated in acute myeloid leukemia (AML). NPM1c oligomerizes with wild-type nucleophosmin 1 (wt-NPM1), and this leads to its continuous cytoplasmic delocalization and contributes to leukemogenesis. Recent studies have shown that Cytoplasmic NPM1 (NPM1c) degradation leads to growth arrest and apoptosis of NPM1c AML cells and corrects wt-NPM1 normal nucleolar localization. METHODS: AML cells expressing wt-NPM1 or NPM1c or transfected with wt-NPM1 or NPM1c as well as wt-NPM1 and NPM1c AML xenograft mice were used. Cell growth was assessed with trypan blue or a CellTiter 96 proliferation kit. The cell cycle was studied with a propidium iodide (PI) assay. Caspase-mediated intrinsic apoptosis was assessed with annexin V/PI, the mitochondrial membrane potential, and poly(adenosine diphosphate ribose) polymerase cleavage. The expression of NPM1, p53, phosphorylated p53, and p21 was analyzed via immunoblotting. Localization was performed with confocal microscopy. The leukemia burden was evaluated by flow cytometry with an anti-human CD45 antibody. RESULTS: The imidazoquinoxaline 1-(3-methoxyphenyl)-N-methylimidazo[1,2-a]quinoxalin-4-amine (EAPB0503) induced selective proteasome-mediated degradation of NPM1c, restored wt-NPM1 nucleolar localization in NPM1c AML cells, and thus yielded selective growth arrest and apoptosis. Introducing NPM1c to cells normally harboring wt-NPM1 sensitized them to EAPB0503 and led to their growth arrest. Moreover, EAPB0503 selectively reduced the leukemia burden in NPM1c AML xenograft mice. CONCLUSIONS: These findings further reinforce the idea of targeting the NPM1c oncoprotein to eradicate leukemic cells and warrant a broader preclinical evaluation and then a clinical evaluation of this promising drug. Cancer 2017;123:1662-1673. © 2017 American Cancer Society.