Nucleophosmin (NPM1) is the most commonly mutated gene in acute myeloid leukemia (AML) resulting in aberrant cytoplasmic translocation of the encoded nucleolar protein (NPM1c
). NPM1c
maintains a ...unique leukemic gene expression program, characterized by activation of HOXA/B clusters and MEIS1 oncogene to facilitate leukemogenesis. However, the mechanisms by which NPM1c
controls such gene expression patterns to promote leukemogenesis remain largely unknown. Here, we show that the activation of HOXBLINC, a HOXB locus-associated long non-coding RNA (lncRNA), is a critical downstream mediator of NPM1c
-associated leukemic transcription program and leukemogenesis. HOXBLINC loss attenuates NPM1c
-driven leukemogenesis by rectifying the signature of NPM1c
leukemic transcription programs. Furthermore, overexpression of HoxBlinc (HoxBlincTg) in mice enhances HSC self-renewal and expands myelopoiesis, leading to the development of AML-like disease, reminiscent of the phenotypes seen in the Npm1 mutant knock-in (Npm1
) mice. HoxBlincTg and Npm1
HSPCs share significantly overlapped transcriptome and chromatin structure. Mechanistically, HoxBlinc binds to the promoter regions of NPM1c
signature genes to control their activation in HoxBlincTg HSPCs, via MLL1 recruitment and promoter H3K4me3 modification. Our study reveals that HOXBLINC lncRNA activation plays an essential oncogenic role in NPM1c
leukemia. HOXBLINC and its partner MLL1 are potential therapeutic targets for NPM1c
AML.
Nanomaterials and nanoparticles have received considerable attention recently because of their unique properties and diverse biotechnology and life sciences applications. Nanosilver products, which ...have well-known antimicrobial properties, have been used extensively in a range of medical settings. Despite the widespread use of nanosilver products, relatively few studies have been undertaken to determine the biological effects of nanosilver exposure. The purpose of this study was to evaluate the toxicity of nanosilver and to elucidate possible molecular mechanisms underlying the biological effects of nanosilver. Here, we show that nanosilver is cytotoxic, inducing apoptosis in NIH3T3 fibroblast cells. Treatment with nanosilver induced the release of cytochrome
c into the cytosol and translocation of Bax to mitochondria, indicating that nanosilver-mediated apoptosis is mitochondria-dependent. Nanosilver-induced apoptosis was associated with the generation of reactive oxygen species (ROS) and JNK activation, and inhibition of either ROS or JNK attenuated nanosilver-induced apoptosis. In nanosilver-resistant HCT116 cells, up-regulation of the anti-apoptotic proteins, Bcl-2 appeared to be associated with a diminished apoptotic response. Taken together, our results provide the first evidence for a molecular mechanism of nanosilver cytotoxicity, showing that nanosilver acts through ROS and JNK to induce apoptosis via the mitochondrial pathway.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Drug-eluting contact lenses (DCLs) have attracted considerable attention as potential therapeutic ophthalmic drug delivery devices. In this study, we propose, fabricate, and investigate pH-triggered ...DCLs that are combined with large-pore mesoporous silica nanoparticles (LPMSNs). Compared to reference DCLs, LPMSN-laden DCLs can prolong the residence time of glaucoma drugs in an artificial lacrimal fluid (ALF) environment at pH 7.4. Additionally, LPMSN-laden DCLs do not require drug preloading and are compatible with current contact lens manufacturing processes. LPMSN-laden DCLs soaked at pH 6.5 exhibit better drug loading than reference DCLs due to their specific adsorption. The sustained and extended release of glaucoma drugs by LPMSN-laden DCLs was successfully monitored in ALF, and the drug release mechanism was further explained. We also evaluated the cytotoxicity of LPMSN-laden DCLs, and qualitative and quantitative results showed no cytotoxicity. Our experimental results demonstrate that LPMSNs are excellent nanocarriers that have the potential to be used as safe and stable nanocarriers for the delivery of glaucoma drugs or other drugs. pH-triggered LPMSN-laden DCLs can significantly improve drug loading efficiency and control prolonged drug release, indicating that they have great potential for future biomedical applications.
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IJS, KILJ, NUK, PNG, UL, UM
Atrial fibrosis is an essential contributor to atrial fibrillation (AF). It remains unclear whether atrial endocardial endothelial cells (AEECs) that undergo endothelial-mesenchymal transition ...(EndMT) are among the sources of atrial fibroblasts. We studied human atria, TGF-β–treated human AEECs, cardiac-specific TGF-β–transgenic mice, and heart failure rabbits to identify the underlying mechanism of EndMT in atrial fibrosis. Using isolated AEECs, we found that miR-181b was induced in TGF-β–treated AEECs, which decreased semaphorin 3A (Sema3A) and increased EndMT markers, and these effects could be reversed by a miR-181b antagomir. Experiments in which Sema3A was increased by a peptide or decreased by a siRNA in AEECs revealed a mechanistic link between Sema3A and LIM-kinase 1/phosphorylated cofilin (LIMK/p-cofilin) signaling and suggested that Sema3A is upstream of LIMK in regulating actin remodeling through p-cofilin. Administration of the miR-181b antagomir or recombinant Sema3A to TGF-β–transgenic mice evoked increased Sema3A, reduced EndMT markers, and significantly decreased atrial fibrosis and AF vulnerability. Our study provides a mechanistic link between the induction of EndMT by TGF-β via miR-181b/Sema3A/LIMK/p-cofilin signaling to atrial fibrosis. Blocking miR-181b and increasing Sema3A are potential strategies for AF therapeutic intervention.
The loss of semaphorin 3A (Sema3A), which is related to endothelial‐to‐mesenchymal transition (EndMT) in atrial fibrosis, is implicated in the pathogenesis of atrial fibrillation (AF). To explore the ...mechanisms by which EndMT affects atrial fibrosis and assess the potential of a Sema3A activator (naringin) to prevent atrial fibrosis by targeting transforming growth factor‐beta (TGF‐β)‐induced EndMT, we used human atria, isolated human atrial endocardial endothelial cells (AEECs), and used transgenic mice expressing TGF‐β specifically in cardiac tissues (TGF‐β transgenic mice). We evaluated an EndMT marker (Twist), a proliferation marker (proliferating cell nuclear antigen; PCNA), and an endothelial cell (EC) marker (CD31) through triple immunohistochemistry and confirmed that both EndMT and EC proliferation contribute to atrial endocardial fibrosis during AF in TGF‐β transgenic mice and AF patient tissue sections. Additionally, we investigated the impact of naringin on EndMT and EC proliferation in AEECs and atrial fibroblasts. Naringin exhibited an antiproliferative effect, to which AEECs were more responsive. Subsequently, we downregulated Sema3A in AEECs using small interfering RNA to clarify a correlation between the reduction in Sema3A and the elevation of EndMT markers. Naringin treatment induced the expression of Sema3A and a concurrent decrease in EndMT markers. Furthermore, naringin administration ameliorated AF and endocardial fibrosis in TGF‐β transgenic mice by stimulating Sema3A expression, inhibiting EndMT markers, reducing atrial fibrosis, and lowering AF vulnerability. This suggests therapeutic potential for naringin in AF treatment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
The 23‐valent pneumococcal polysaccharide vaccine (PPSV23) is indicated for adults who have a high risk of pneumonia; however, its effectiveness in patients with prostate cancer who are at ...a risk of pneumonia because of age and cancer treatments, including androgen‐deprivation therapy, is unknown.
Methods
Between 2000 and 2010, 38,735 patients with prostate cancer were diagnosed in Taiwan. After exclusions and exact matching for age, previous pneumonia, and influenza vaccination, 2188 vaccinated patients and 2188 unvaccinated patients were recruited. The incidence density of all‐cause bacterial pneumonia hospitalizations was analyzed.
Results
Over 7 years of follow‐up, patients who received the PPSV23 had a significantly lower incidence density, with 142.8 per 1000 person‐years versus 162.0 per 1000 person‐years for unvaccinated patients. More patients in the vaccinated cohort were never hospitalized for pneumonia compared with those in the unvaccinated cohort (64.2% vs 62.2%, respectively). After adjusting for the Charlson comorbidity index, cancer treatment modalities, and socioeconomic levels, the risk of pneumonia‐related hospitalization in the PPSV23 vaccination cohort was 0.48 times lower than that in the unvaccinated cohort (adjusted incidence rate ratio, 0.48; P = .046). For patients who received the influenza vaccination, subgroup analysis demonstrated that PPSV23 vaccination significantly decreased the risk (adjusted incidence rate ratio, 0.45; P < .001). Compared with unvaccinated controls, PPSV23‐vaccinated patients had a lower cumulative incidence for the first occurrence of pneumonia‐related hospitalization (34.49% vs 36.36%; P = .178) and higher overall survival (47.5% and 42.3%, respectively; P < .001).
Conclusions
Vaccination of elderly patients who have prostate cancer with the relatively common and inexpensive PPSV23 can decrease the risk of pneumonia and prolong survival.
Elderly patients and those undergoing treatments for cancer, such as androgen‐deprivation therapy or chemotherapy, are at increased risk of developing pneumonia that requires hospitalization. In elderly patients who have prostate cancer, vaccination with the 23‐valent pneumococcal polysaccharide vaccine is associated with lower rates of pneumonia‐related hospitalization and better survival outcomes compared with unvaccinated patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In the long history of traditional Chinese medicine, single herbs and complex formulas have been suggested to increase lifespan. However, the identification of single molecules responsible for ...lifespan extension has been challenging. Here, we collected a list of traditional Chinese medicines with potential longevity properties from pharmacopeias. By utilizing the mother enrichment program, we systematically screened these traditional Chinese medicines and identified a single herb, Psoralea corylifolia, that increases lifespan in Saccharomyces cerevisiae. Next, twenty-two pure compounds were isolated from Psoralea corylifolia. One of the compounds, corylin, was found to extend the replicative lifespan in yeast by targeting the Gtr1 protein. In human umbilical vein endothelial cells, RNA sequencing data showed that corylin ameliorates cellular senescence. We also examined an in vivo mammalian model, and found that corylin extends lifespan in mice fed a high-fat diet. Taken together, these findings suggest that corylin may promote longevity.
Electrical manipulation of skyrmions attracts considerable attention for its rich physics and promising applications. To date, such a manipulation is realized mainly via spin-polarized current based ...on spin-transfer torque or spin-orbital torque effect. However, this scheme is energy consuming and may produce massive Joule heating. To reduce energy dissipation and risk of heightened temperatures of skyrmion-based devices, an effective solution is to use electric field instead of current as stimulus. Here, we realize an electric-field manipulation of skyrmions in a nanostructured ferromagnetic/ferroelectrical heterostructure at room temperature via an inverse magneto-mechanical effect. Intriguingly, such a manipulation is non-volatile and exhibits a multistate feature. Numerical simulations indicate that the electric-field manipulation of skyrmions originates from strain-mediated modification of effective magnetic anisotropy and Dzyaloshinskii-Moriya interaction. Our results open a direction for constructing low-energy-dissipation, non-volatile, and multistate skyrmion-based spintronic devices.
Quantum dot white light‐emitting diodes (QD‐WLEDs) have a potential for wide color gamut displays. Their applications to QD‐on‐chip package are limited by their poor stability. In this study, highly ...dense protective layers of Na‐poly(Al‐O‐Si) nanocomposite (NPAS NC) coating on QDs are developed for the first time. They enhanced the photoluminescence quantum yield at ≈1.74‐fold and stability. In addition, the effects of specific surface area (SSA) of NC structures on the reliability of QD‐WLEDs are investigated. The synthesized NPAS NCs via a sol‐gel method with catalyst showed the lowest SSA (2.39 m2 g−1) with almost no pore, thereby demonstrating the best reliability analysis (RA) results for QD‐WLEDs. QDs@NPAS WLEDs present a highly luminous efficacy of 133 lm W−1 compared with pristine QD‐WLEDs (79 lm W−1) under an electric input power of 21.4 mW. RA test on the QDs@NPAS WLEDs with an operational lifetime of 1,560 h is performed. A 16.6‐fold enhancement is observed compared with pristine QD‐WLEDs (≈94 h). QDs@NPAS WLEDs also exhibit an excellent display performance with a wide color gamut (≈91%) based on Rec. 2020 color standard. This approach can enhance the reliability of QDs for display applications, thereby providing a strategy for mini‐ and micro‐QD‐WLEDs.
This study proposes QDs@Na‐poly(Al‐O‐Si) white light‐emitting diodes (WLEDs) with excellent stability, high luminous efficacy, and wide color gamut for backlight displays. QDs@Na‐poly(Al‐O‐Si) WLEDs demonstrate a Rec. 2020 standard of ≈91% (a NTSC value of 122%) and are not visibly degraded during the reliability analysis test after 1560 h. A highly dense coating layer technology for protecting QDs is implemented.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
High reliability and wide color gamut light-emitting diodes (LEDs) that use composite quantum dot films (CQDFs) protected by chip-scale package (CSP) structures are presented. CQDFs containing ...CdZnSeS/ZnS core-shell QDs and the K
SiF
:Mn
phosphors were mixed with silicone gel and used as color converters in the CSP QD-LEDs. The CSP QD-LEDs, used for backlight displays, transmitted through a color filter and exhibited ITU-R Recommendation BT.2020 of approximately 86% (a National Television System Committee value of 115%). Furthermore, we performed a long-term reliability analysis test on the CSP QD-LEDs for 2352 h to verify whether the optical performance of CSP QD-LEDs does not significantly degrade relative to that of a conventional plastic leaded chip carrier QD-LEDs. We implemented a highly reliable package technology that can protect the QDs, solve the moisture/oxygen problems in defective QD-LEDs, and produce a backlight source for display with a wide color gamut.
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IJS, KILJ, NUK, UL, UM, UPUK
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