Myeloid/natural killer (NK) cell precursor acute leukemia as a distinct leukemia type.

Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is no consensus on the characteristics for identifying this disease type because of its rarity and lack of defined distinctive molecular characteristics. In this study, multiomics analysis revealed that MNKPL is distinct from acute myeloid leukemia, T cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia (MPAL), and NOTCH1 and RUNX3 activation and BCL11B down-regulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, the results of our single-cell analysis using MNKPL cells suggest that NK cells and myeloid cells share common progenitor cells. Treatment outcomes for MNKPL are unsatisfactory, even when hematopoietic cell transplantation is performed. Multiomics analysis and in vitro drug sensitivity assays revealed increased sensitivity to l-asparaginase and reduced levels of asparagine synthetase (ASNS), supporting the clinically observed effectiveness of l-asparaginase.

Targeting Poly(ADP)ribose polymerase in BCR/ABL1-positive cells.

BCR/ABL1 causes dysregulated cell proliferation and is responsible for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL). In addition to the deregulatory effects of its kinase activity on cell proliferation, BCR/ABL1 induces genomic instability by downregulating BRCA1. PARP inhibitors (PARPi) effectively induce cell death in BRCA-defective cells. Therefore, PARPi are expected to inhibit growth of CML and Ph1-ALL cells showing downregulated expression of BRCA1. Here, we show that PARPi effectively induced cell death in BCR/ABL1 positive cells and suppressed colony forming activity. Prevention of BCR/ABL1-mediated leukemogenesis by PARP inhibition was tested in two in vivo models: wild-type mice that had undergone hematopoietic cell transplantation with BCR/ABL1-transduced cells, and a genetic model constructed by crossing Parp1 knockout mice with BCR/ABL1 transgenic mice. The results showed that a PARPi, olaparib, attenuates BCR/ABL1-mediated leukemogenesis. One possible mechanism underlying PARPi-dependent inhibition of leukemogenesis is increased interferon signaling via activation of the cGAS/STING pathway. This is compatible with the use of interferon as a first-line therapy for CML. Because tyrosine kinase inhibitor (TKI) monotherapy does not completely eradicate leukemic cells in all patients, combined use of PARPi and a TKI is an attractive option that may eradicate CML stem cells.

Internal Wireless Electrical Stimulation from Piezoelectric Barium Titanate Nanoparticles as a New Strategy for the Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive BC subtype with a higher metastatic rate and a worse 5-year survival ratio than the other BC. It is an urgent need to develop a noninvasive treatment with high efficiency to resist TNBC cell proliferation and invasion. Internal wireless electric stimulation (ES) based on piezoelectric materials is an emerging noninvasive strategy, with adjustable ES intensity and excellent biosafety. In this study, three different barium titanate nanoparticles (BTNPs) with different crystal phases and piezoelectric properties were studied. Varying intensities of internal ES were generated from the three BTNPs (i.e., BTO, U-BTO, P-BTO). In vitro tests revealed that the internal ES from BTNPs was efficient at reducing the proliferative potential of cancer cells, particularly BC cells. In vitro experiments on MDA-MB-231, a typical TNBC cell line, further revealed that the internal wireless ES from BTNPs significantly inhibited cell growth and migration up to about 82% and 60%, respectively. In vivo evaluation of MDA-MB-231 tumor-bearing mice indicated that internal ES not only resisted almost 70% tumor growth but also significantly inhibited lung metastasis. More importantly, in vitro and in vivo studies demonstrated a favorable correlation between the anticancer impact and the intensities of ES. The underlying mechanism of MDA-MB-231 cell proliferation and metastasis inhibition caused by internal ES was also investigated. In summary, our results revealed the effect and mechanism of internal ES from piezoelectric nanoparticles on TNBC cell proliferation and migration regulation and proposed a promising noninvasive therapeutic strategy for TNBC with minimal side effects while exhibiting good therapeutic efficiency.

Modulating p-Orbital of Bismuth Nanosheet by Nickel Doping for Electrocatalytic Carbon Dioxide Reduction Reaction.

Electrochemical reduction of CO2 (CO2 RR) to value-added chemicals is an effective way to harvest renewable energy and utilize carbon dioxide. However, the electrocatalysts for CO2 RR suffer from insufficient activity and selectivity due to the limitation of CO2 activation. In this work, a Ni-doped Bi nanosheet (Ni@Bi-NS) electrocatalyst is synthesized for the electrochemical reduction of CO2 to HCOOH. Physicochemical characterization methods are extensively used to investigate the composition and structure of the materials. Electrochemical results reveal that for the production of HCOOH, the obtained Ni@Bi-NS exhibits an equivalent current density of 51.12 mA cm-2 at -1.10 V, which is much higher than the pure Bi-NS (18.00 mA cm-2 at -1.10 V). A high Faradaic efficiency over 92.0 % for HCOOH is achieved in a wide potential range from -0.80 to -1.10 V, and particularly, the highest efficiency of 98.4 % is achieved at -0.90 V. Both experimental and theoretical results reveal that the superior activity and selectivity are attributed to the doping effect of Ni on the Bi nanosheet. The density functional theory calculation reveals that upon doping, the charge is transferred from Ni to the adjacent Bi atoms, which shifts the p-orbital electronic density states towards the Fermi level. The resultant strong orbital hybridization between Bi and the π* orbitals of CO2 facilitates the formation of *OCHO intermediates and favors its activation. This work provides an effective strategy to develop active and selective electrocatalysts for CO2 RR by modulating the electronic density state.

mRNA based vaccines provide broad protection against different SARS-CoV-2 variants of concern.

In order to overcome the pandemic of COVID-19, messenger RNA (mRNA)-based vaccine has been extensively researched as a rapid and versatile strategy. Herein, we described the immunogenicity of mRNA-based vaccines for Beta and the most recent Omicron variants. The homologous mRNA-Beta and mRNA-Omicron and heterologous Ad5-nCoV plus mRNA vaccine exhibited high-level cross-reactive neutralization for Beta, original, Delta, and Omicron variants. It indicated that the COVID-19 mRNA vaccines have great potential in the clinical use against different SARS-CoV-2 variants.

Evaluation of the context of downstream N- and free N-glycomic alterations induced by swainsonine in HepG2 cells.

Swainsonine (SWA), a potent inhibitor of class II α-mannosidases, is present in a number of plant species worldwide and causes severe toxicosis in livestock grazing these plants. The mechanisms underlying SWA-induced animal poisoning are not fully understood. In this study, we analyzed the alterations that occur in N- and free N-glycomic upon addition of SWA to HepG2 cells to understand better SWA-induced glycomic alterations. After SWA addition, we observed the appearance of SWA-specific glycomic alterations, such as unique fucosylated hybrid-type and fucosylated M5 (M5F) N-glycans, and a remarkable increase in all classes of Gn1 FNGs. Further analysis of the context of these glycomic alterations showed that (fucosylated) hybrid type N-glycans were not the precursors of these Gn1 FNGs and vice versa. Time course analysis revealed the dynamic nature of glycomic alterations upon exposure of SWA and suggested that accumulation of free N-glycans occurred earlier than that of hybrid-type N-glycans. Hybrid-type N-glycans, of which most were uniquely core fucosylated, tended to increase slowly over time, as was observed for M5F N-glycans. Inhibition of swainsonine-induced unique fucosylation of hybrid N-glycans and M5 by coaddition of 2-fluorofucose caused significant increases in paucimannose- and fucosylated paucimannose-type N-glycans, as well as paucimannose-type free N-glycans. The results not only revealed the gross glycomic alterations in HepG2 cells induced by swainsonine, but also provide information on the global interrelationships between glycomic alterations.

Wireless electrical stimulation at the nanoscale interface induces tumor vascular normalization.

Pathological angiogenesis frequently occurs in tumor tissue, limiting the efficiency of chemotherapeutic drug delivery and accelerating tumor progression. However, traditional vascular normalization strategies are not fully effective and limited by the development of resistance. Herein, inspired by the intervention of endogenous bioelectricity in vessel formation, we propose a wireless electrical stimulation therapeutic strategy, capable of breaking bioelectric homeostasis within cells, to achieve tumor vascular normalization. Polarized barium titanate nanoparticles with high mechano-electrical conversion performance were developed, which could generate pulsed open-circuit voltage under low-intensity pulsed ultrasound. We demonstrated that wireless electrical stimulation significantly inhibited endothelial cell migration and differentiation in vitro. Interestingly, we found that the angiogenesis-related eNOS/NO pathway was inhibited, which could be attributed to the destruction of the intracellular calcium ion gradient by wireless electrical stimulation. In vivo tumor-bearing mouse model indicated that wireless electrical stimulation normalized tumor vasculature by optimizing vascular structure, enhancing blood perfusion, reducing vascular leakage, and restoring local oxygenation. Ultimately, the anti-tumor efficacy of combination treatment was 1.8 times that of the single chemotherapeutic drug doxorubicin group. This work provides a wireless electrical stimulation strategy based on the mechano-electrical conversion performance of piezoelectric nanoparticles, which is expected to achieve safe and effective clinical adjuvant treatment of malignant tumors.

Radical Stabilization of a Tripyridinium-Triazine Molecule Enables Reversible Storage of Multiple Electrons.

A novel organic molecule, 2,4,6-tris[1-(trimethylamonium)propyl-4-pyridiniumyl]-1,3,5-triazine hexachloride, was developed as a reversible six-electron storage electrolyte for use in an aqueous redox flow battery (ARFB). Physicochemical characterization reveals that the molecule evolves from a radical to a biradical and finally to a quinoid structure upon accepting four electrons. Both the diffusion coefficient and the rate constant were sufficiently high to run a flow battery with low concentration and kinetics polarization losses. In a demonstration unit, the assembled flow battery affords a high specific capacity of 33.0 Ah L-1 and a peak power density of 273 mW cm-2 . This work highlights the rational design of electroactive organics that can manipulate multi-electron transfer in a reversible way, which will pave the way to development of energy-dense, manageable and low-cost ARFBs.

Fabrication and application of a novel electrochemical biosensor based on a mesoporous carbon sphere@UiO-66-NH2/Lac complex enzyme for tetracycline detection.

The overuse of tetracycline results in a threat to human, poultry and livestock health. An enzymatic electrochemical biosensor is an ideal alternative method for accurate and rapid tetracycline detection, while the unstable and easily deactivated nature of the enzyme limits its development. To overcome these limitations, a highly sensitive enzymatic electrochemical biosensor for the determination of tetracycline is developed in this work based on a complex enzyme which was constructed using a mesoporous carbon sphere@UiO-66-NH2 (MCS@UiO-66-NH2) core-shell composite with embedded laccase (Lac). Compared to pure MCS and UiO-66-NH2, the MCS@UiO-66-NH2 core-shell composite has an advantageous mesoporous structure (pore diameter >8 nm), which is suitable for the immobilization of small laccase. The biosensor based on the complex enzyme exhibits a superior activity and enhanced stability as compared with that made using a pure enzyme because the mesoporous structure of the MCS@UiO-66-NH2 composite can effectively protect the laccase against inactivation and denaturation. Besides, its high specific surface area and good conductivity are beneficial to enzyme immobilization and electron transfer in the modified electrode. The biosensor based on this complex enzyme exhibits a relatively low detection limit of 8.94 × 10-7 mol L-1 and a detection range of 1.0 × 10-6-6.0 × 10-5 mol L-1 for tetracycline detection. Furthermore, the developed biosensor possesses good long-term stability, selectivity and reproducibility, indicating its potential application for tetracycline determination in actual food. This research work provides a prospective solution to resolve the stability and inactivation problems of enzymatic electrochemical biosensors in different application scenarios.

Decrease of ABCB1 protein expression and increase of G1 phase arrest induced by oleanolic acid in human multidrug-resistant cancer cells.

Oleanolic acid (OA) is a natural compound that can be found in a number of edible and medicinal plants and confers diverse biological actions. However, the direct target of OA in human tumor cells remains poorly understood, preventing its application in clinical and health settings. A previous study revealed that overexpression of caveolin-1 in human leukemia HL-60 cells can increase its sensitivity to OA. The present study aimed to investigate the effects of OA on the doxorubicin-resistant human breast cancer MCF-7 cell line (MCF-7/DOX), harringtonine-resistant human leukemia HL-60 cells (HL-60/HAR) and their corresponding parental cell lines. Western blotting was performed to measure protein expression levels, whilst Cell Counting Kit-8 (CCK-8) assays, cell cycle analysis (by flow cytometry) and apoptosis assays (with Annexin V/PI staining) were used to assess drug sensitivity. CCK-8 assay results suggested that MCF-7/DOX cells, which overexpress the caveolin-1 protein, have similar OA susceptibility to their parent line. In addition, sensitivity of MCF-7/DOX cells to OA was not augmented by knocking down caveolin-1 using RNA interference. HL-60/HAR cells exhibited a four-fold increased sensitivity to OA compared with that in their parental HL-60 cells according to CCK-8 assay. Both of the resistant cell lines exhibited higher numbers of cells at G1 phase arrest compared with those in their parent lines, as measured via flow cytometry. Treatment of both MCF-7 cell lines with 100 µM OA for 48 h induced apoptosis, with increased effects observed in resistant cells. However, no PARP-1 or caspase-3 cleavage was observed, with some positive Annexin V staining found after HL-60/HAR cells were treated with OA, suggesting that cell death occurred via non-classical apoptosis or through other cell death pathways. It was found that OA was not a substrate of ATP-binding cassette subfamily B member 1 (ABCB1) in drug-resistant cells, as indicated by the accumulation of rhodamine 123 assessed using flow cytometry. However, protein expression of ABCB1 in both of the resistant cell lines was significantly decreased after treatment with OA in a concentration-dependent manner. Collectively, these results suggest that OA could reduce ABCB1 protein expression and induce G1 phase arrest in multidrug-resistant cancer cells. These findings highlight the potential of OA for cancer therapy.

Structural characteristic of a sulfated polysaccharide from Gracilaria Lemaneiformis and its lipid metabolism regulation effect.

A sulfated polysaccharide extracted from Gracilaria lemaneiformis (GLP) with a prominent effect in regulating lipid metabolism was isolated. The molecular weight was 31.5 kDa and it was composed mainly of galactose, glucose and xylose. Fourier-transform infrared (FT-IR) spectrum and nuclear magnetic resonance (NMR) analysis suggested that GLP was composed of the following repeating unit: [3-ß-Gal-4(OSO3)-1→4-α-3,6-anhydrogal-2(OSO3)-1→]. GLP could significantly decrease serum total cholesterol, triglyceride and free fatty acid levels and lower alanine aminotransferase and aspartate aminotransferase activities in high-fat-diet mice. Additionally, GLP could keep the body weight and attenuate accumulation of fat surrounding the liver and epididymis induced by high-fat diet. Results of RT-PCR indicated that GLP might regulate lipid metabolism and accelerate free fatty acid oxidation by up-regulating the expression of the PPARα, ACS and CPT1a gene. The present study suggests that GLP may be potentially useful for regulating lipid metabolism.

Improved stability of ß-CsPbI3 inorganic perovskite using π-conjugated bifunctional surface capped organic cations for high performance photovoltaics.

Multiple-ring naphthalenediammonium is employed for the first time to overcome the intrinsic instability of ß-CsPbI3 perovskite via anchoring the ammonium groups occupying A-site vacancies. It improves charge transport and moisture stability giving out a champion power conversion efficiency of 16.69% for an excellent inorganic perovskite solar cell.

Surface Roughed and Pt-Rich Bimetallic Electrocatalysts for Hydrogen Evolution Reaction.

Platinum-based alloys with low cost transition metals have been considered as promising electrocatalysts in the field of sustainable energy conversion and storage. Herein, chloroplatinic acid, cobalt chloride, and carbon nanotubes are used as platinum, cobalt precursors, and carriers, respectively, to prepare rich Pt dealloying PtCo nanoparticles (SD-PtCo/CNT) via co-liquid phase reduction and chemical dealloying methods. The characterization and test results confirm that PtCo alloy nanoparticles are evenly dispersed on carbon nanotubes, further dealloying and resulting in the partial dissolving of cobalt, simultaneously generating a rich Pt layer and roughly active surface. Benefiting from the unique structure, the SD-PtCo/CNT catalyst displays obviously enhanced HER activity in both acidic and alkaline conditions. In 1.0 M KOH, SD-PtCo/CNT exhibits a low overpotential of 78 mV at 10 mA/cm2 and a small tafel slope (38.28 mV/dec). In 0.5 M H2SO4, SD-PtCo/CNT still shows the superior performance compared with un-dealloying PtCo/CNT, with an overpotential of 17 mV at 10 mA/cm2 and corresponding tafel slope of 21.35 mV/dec. The high HER activity of SD-PtCo/CNT can be attributed to the formation of a platinum rich layer and the uniformly dispersed PtCo nanoparticles supported on superior conductive carbon nanotubes, suggesting its great potential for hydrogen generation via water splitting.

MicroRNA302-367-PI3K-PTEN-AKT-mTORC1 pathway promotes the development of cardiac hypertrophy through controlling autophagy.

Cardiac hypertrophy at a decompensated state eventually leads to heart failure that mostly contributes to deaths globally. Dysregulated cardiac autophagy is a hallmark of a diseased heart, and a close contact between cardiac autophagy and cardiac hypertrophy is emerging. MicroRNAs (miRNAs) have been recently reported to be prominently implicated in cardiac hypertrophy through regulating cardiac autophagy. However, the role and function of miR302-367 clusters in cardiac autophagy and cardiac hypertrophy remain largely masked. Therefore, to investigate the performance of miR302-367 in cardiac hypertrophy, the specific in vitro hypertrophic model was established in H9c2 cells upon Ang II treatment. Consequently, we discovered a distinct inhibition on autophagy and a remarkable upregulation of miR302-367 expression in hypertrophic H9c2 cells. Besides, loss- and gain-of-function assays demonstrated miR302-367 inhibited autophagy and then aggravated cardiac hypertrophy. Mechanically, PTEN was predicted and confirmed as the shared target of miR302-367. Further, we recognized the apparent inactivation of PI3K/AKT/mTORC1 signaling in the face of miR302-367 suppression in Ang II-induced hypertrophic H9c2 cells. Moreover, co-treatment of PTEN inhibitor re-activated the PI3K/AKT/mTORC1 pathway, therefore counteracting the pro-autophagic and anti-hypertrophic effects of miR302-367 depletion on cardiomyocytes. These findings unveiled the pivotal role of the miR302-367 cluster in regulating cardiac autophagy and therefore modulating cardiac hypertrophy through PTEN/PI3K/AKT/mTORC1 signaling, indicating a promising therapeutic strategy for cardiac hypertrophy and even heart failure. Graphical abstract .

Adrenal Angiosarcoma: A Diagnostic Dilemma.

Primary angiosarcoma of the adrenal gland is both a rare and aggressive malignancy. Differentiating it from more common adrenal masses such as adrenal adenomas, adrenal cortical carcinomas, and metastatic carcinomas is one of several diagnostic challenges. Immunohistochemical analysis is imperative to arrive at the correct diagnosis. Treatment typically involves surgery and adjuvant chemotherapy, but prognosis remains poor.

Tumor necrosis factor-α-308 polymorphism is not associated with Kawasaki disease: A meta-analysis of case-control studies.

BACKGROUND: Genetic factors in the pathogenesis of Kawasaki disease (KD) have received a lot of attention during the past decade. Some studies have reported that tumor necrosis factor (TNF)-α-308 polymorphism has been associated with KD. However, there have been inconsonant results among different studies. To increase the power for clarifying the influence of TNF on KD, a meta-analysis of case-control studies were performed. METHODS: The following databases were searched to identify related studies: PubMed, Embase, Cochrane Library, CNKI, Wanfang, and VIP databases according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Search terms included "Kawasaki disease" or "KD," "tumor necrosis factor-alpha" or "TNF-α," and "polymorphism" or "mutation." Two reviewers independently extracted data and assessed study quality using Newcastle-Ottawa Scale. Odds ratios (ORs) with corresponding 95% confidence intervals (CI) were used to assess the strength of the association. Accounting for heterogeneity, a fixed or random effects model was respectively adopted. Heterogeneity was checked using the Q test and the I statistic. A cumulative meta-analysis was conducted to estimate the tendency of pooled OR. Funnel plots and Egger tests were performed to test for possible publication bias and sensitivity analyses were done to ensure authenticity of the outcome. RESULTS: Eleven separate studies were suitable for the inclusion criterion. The selected studies contained 2582 participants, including 841 in KD group and 1741controls. The pooled odds ratio of G versus A with the random effect model was 1.09 (95% CI = 0.69-1.70, P = .72) and the genotype effects for GG versus GA+AA was 1.14 (95% CI = 0.68-1.90, P = .62) in the whole population separately. Unfortunately, no significant association was detected between the TNF-α-308 polymorphism and KD risk under allele and genotype model. CONCLUSION: No association between the TNF-α-308 polymorphism and KD was found in our meta-analysis and further studies with larger sample size and more ethnicities are expected to be conducted in the future to validate the results.

Efficient Nitrogen-Doped Carbon for Zinc-Bromine Flow Battery.

The zinc-bromine flow battery (ZBFB) is one of the most promising technologies for large-scale energy storage. Here, nitrogen-doped carbon is synthesized and investigated as the positive electrode material in ZBFBs. The synthesis includes the carbonization of the glucose precursor and nitrogen doping by etching in ammonia gas. Physicochemical characterizations reveal that the resultant carbon exhibits high electronic conductivity, large specific surface area, and abundant heteroatom-containing functional groups, which benefit the formation and exposure of the active sites toward the Br2 /Br- redox couple. As a result, the assembled ZBFB achieves a voltage efficiency of 83.0% and an energy efficiency of 82.5% at a current density of 80 mA cm-2 , which are among the top values in literature. Finally, the ZBFB does not yield any detectable degradation in performance after a 200-cycle charging/discharging test, revealing its high stability. In summary, this work provides a highly efficient electrode material for the zinc-bromine flow battery.

Foamy Histiocyte-like Esophageal Adenocarcinoma: Unusual Morphology and Diagnostic Pitfalls.

In the United States and other western countries, the vast majority of primary esophageal malignancies are adenocarcinomas arising in the lower esophagus within a background of Barrett's esophagus. The microscopic feature of esophageal adenocarcinoma varies, with the tubular or papillary adenocarcinoma of intestinal pattern being the most common, and other less common morphological patterns include adenosquamous, signet ring cell, mucinous, mucoepidermoid, and adenoid cystic carcinoma. This is a case report of esophageal adenocarcinoma with foamy histiocyte-like feature in a 71-year-old male with a history of smoking and Barrett's esophagus who presented with dysphagia and weight loss. The tumor cells showed an abundant foamy cytoplasm, low N/C ratio and irregular nuclear contour. They were arranged in single, trabecular and glandular patterns and deeply invaded adventitia. Lymphovascular invasion and perineural invasion were present. The foamy histiocyte like-tumor cells were negative for CD68, but strongly and diffusely positive for CK7. E-Cadherin was maintained in the tumor cells, and p53 immunostaining revealed a wild-type staining pattern. To the best of our knowledge, this is the first documented case of primary esophageal adenocarcinoma with foamy-histiocyte-like phenotype. The clinical course, diagnosis and prognosis of this entity are discussed.