Bone marrow (BM) niche responds to chemotherapy-induced cytokines secreted from acute lymphoblastic leukemia (ALL) cells and protects the residual cells from chemotherapeutics in vivo. However, the ...underlying molecular mechanisms for the induction of cytokines by chemotherapy remain unknown. Here, we found that chemotherapeutic drugs (e.g., Ara-C, DNR, 6-MP) induced the expression of niche-protecting cytokines (GDF15, CCL3 and CCL4) in both ALL cell lines and primary cells in vitro. The ATM and NF-κB pathways were activated after chemotherapy treatment, and the pharmacological or genetic inhibition of these pathways significantly reversed the cytokine upregulation. Besides, chemotherapy-induced NF-κB activation was dependent on ATM-TRAF6 signaling, and NF-κB transcription factor p65 directly regulated the cytokines expression. Furthermore, we found that both pharmacological and genetic perturbation of ATM and p65 significantly decreased the residual ALL cells after Ara-C treatment in ALL xenograft mouse models. Together, these results demonstrated that ATM-dependent NF-κB activation mediated the cytokines induction by chemotherapy and ALL resistance to chemotherapeutics. Inhibition of ATM-dependent NF-κB pathway can sensitize ALL to chemotherapeutics, providing a new strategy to eradicate residual chemo-resistant ALL cells.
Therapeutic peptides have been widely concerned, but their efficacy is limited by the inability to penetrate cell membranes, which is a key bottleneck in peptide drugs delivery. Herein, an in vivo ...self‐assembly strategy is developed to induce phase separation of cell membrane that improves the peptide drugs internalization. A phosphopeptide KYp is synthesized, containing an anticancer peptide KLAKLAK2 (K) and a responsive moiety phosphorylated Y (Yp). After interacting with alkaline phosphatase (ALP), KYp can be dephosphorylated and self‐assembles in situ, which induces the aggregation of ALP and the protein‐lipid phase separation on cell membrane. Consequently, KYp internalization is 2‐fold enhanced compared to non‐responsive peptide, and IC50 value of KYp is approximately 5 times lower than that of free peptide. Therefore, the in vivo self‐assembly induced phase separation on cell membrane promises a new strategy to improve the drug delivery efficacy in cancer therapy.
An in vivo self‐assembly strategy is developed to induce phase separation of cell membrane that improves the peptide drugs internalization and anticancer efficacy. KYp self‐assembles in situ, which induces the aggregation of ALP and the protein‐lipid phase separation and leakage on the cell membrane. The peptide drugs internalization is 2‐fold enhanced compared to non‐responsive peptide nanoparticle.
Preparing super-hydrophobic surfaces with additive manufacturing (AM) and multi-step processes improves corrosion resistance of Al alloys. But the incorporation of dissimilar metals accelerates ...matrix corrosion, additive polymers cannot offer a long-term structural stability, and multi-step methods are complicated and costly. Hereon, stable micro-craters and nano-terraces on AA5052 sheet with enhanced water repellence and durable corrosion resistance are fabricated via low-cost subtractive manufacturing (SM) strategy. After fluoridation process, as-fabricated hierarchical structures possess highlighted self-cleaning and anti-adhesion capabilities. The following electrochemical test shows that the resultant surface effectively acts as a barrier against seawater infiltration suggesting superior anti-corrosion capacity. Meanwhile, the bacterial colony count test shows that the surface also possesses excellent resistance to microbiological adhesion. Such economic, efficient and environmental SM process is of great potential in fabricating multifunctional Al alloys with durable anti-corrosion, super-hydrophobic and bacteriostatic behaviors.
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•One-step electron discharge machining of stable hierarchical micro-nano structures is achieved.•The machined surface shows enhanced water-repellent, self-cleaning and anti-adhesion behaviors.•The surface acts as a durable barrier against seawater corrosion and bacteria adhesion.•Anti-corrosion mechanisms of various wetting states are systematically investigated.
Abstract
Background
The epigenetic regulation of immune response has been demonstrated in recent studies. Nonetheless, potential roles of RNA N6-methyladenosine (m
6
A) modification in tumor ...microenvironment (TME) cell infiltration remain unknown.
Methods
We comprehensively evaluated the m
6
A modification patterns of 1938 gastric cancer samples based on 21 m
6
A regulators, and systematically correlated these modification patterns with TME cell-infiltrating characteristics. The m6Ascore was constructed to quantify m
6
A modification patterns of individual tumors using principal component analysis algorithms.
Results
Three distinct m
6
A modification patterns were determined. The TME cell-infiltrating characteristics under these three patterns were highly consistent with the three immune phenotypes of tumors including immune-excluded, immune-inflamed and immune-desert phenotypes. We demonstrated the evaluation of m
6
A modification patterns within individual tumors could predict stages of tumor inflammation, subtypes, TME stromal activity, genetic variation, and patient prognosis. Low m6Ascore, characterized by increased mutation burden and activation of immunity, indicated an inflamed TME phenotype, with 69.4% 5-year survival. Activation of stroma and lack of effective immune infiltration were observed in the high m6Ascore subtype, indicating a non-inflamed and immune-exclusion TME phenotype, with poorer survival. Low m6Ascore was also linked to increased neoantigen load and enhanced response to anti-PD-1/L1 immunotherapy. Two immunotherapy cohorts confirmed patients with lower m6Ascore demonstrated significant therapeutic advantages and clinical benefits.
Conclusions
This work revealed the m
6
A modification played a nonnegligible role in formation of TME diversity and complexity. Evaluating the m
6
A modification pattern of individual tumor will contribute to enhancing our cognition of TME infiltration characterization and guiding more effective immunotherapy strategies.
Graphical abstract
Patients with critical illness due to infection with the 2019 coronavirus disease (COVID-19) show rapid disease progression to acute respiratory failure. The study aimed to screen the most useful ...predictive factor for critical illness caused by COVID-19.
The study prospectively involved 61 patients with COVID-19 infection as a derivation cohort, and 54 patients as a validation cohort. The predictive factor for critical illness was selected using LASSO regression analysis. A nomogram based on non-specific laboratory indicators was built to predict the probability of critical illness.
The neutrophil-to-lymphocyte ratio (NLR) was identified as an independent risk factor for critical illness in patients with COVID-19 infection. The NLR had an area under receiver operating characteristic of 0.849 (95% confidence interval CI, 0.707 to 0.991) in the derivation cohort and 0.867 (95% CI 0.747 to 0.944) in the validation cohort, the calibration curves fitted well, and the decision and clinical impact curves showed that the NLR had high standardized net benefit. In addition, the incidence of critical illness was 9.1% (1/11) for patients aged ≥ 50 and having an NLR < 3.13, and 50% (7/14) patients with age ≥ 50 and NLR ≥ 3.13 were predicted to develop critical illness. Based on the risk stratification of NLR according to age, this study has developed a COVID-19 pneumonia management process.
We found that NLR is a predictive factor for early-stage prediction of patients infected with COVID-19 who are likely to develop critical illness. Patients aged ≥ 50 and having an NLR ≥ 3.13 are predicted to develop critical illness, and they should thus have rapid access to an intensive care unit if necessary.
Vitiligo is a skin depigmentation disorder. GATA3 expression is downregulated in vitiligo patients, and its role and regulatory mechanism in vitiligo are unclear. GATA3 and HMGB1 levels were detected ...by qRT‐PCR in peripheral blood cells of vitiligo patients and healthy controls, as well as H2O2‐treated PIG1 cells. Their expression correlation was assessed by Pearson analysis. qRT‐PCR, MTT assay, Ki67 immunostaining, flow cytometry, ELISA and Western blot were applied to determine GATA3 expression, cell survival, cell proliferation, cell apoptosis, melanin contents, and melanin‐related protein expressions. The cellular distributions of HMGB1 and its deacetylation levels were detected by Western blot. The binding of GATA3 to SIRT3 promoter and effects on SIRT3 expression and HMGB1 deacetylation was determined by dual‐luciferase assay, ChIP assay, and Western blot. GATA3 was decreased, and HMGB1 was increased in vitiligo. Pearson correlation assay showed that they were negatively correlated. H2O2 significantly inhibited cell survival, proliferation, melanin secretion, and melanin‐related protein expressions but remarkably increased cell apoptosis. GATA3 overexpression could distinctly reverse the effects of H2O2 through decreasing HMGB1 expression and retained HMGB1 in nuclear due to the decreased HMGB1 acetylation. GATA3 bound to the SIRT3 and subsequently decreased H2O2‐induced HMGB1 acetylation. Overexpressing HMGB1 or knockdown of SIRT3 could reverse the effects of GATA3 overexpression. GATA3 inhibited H2O2‐induced injury in PIG1 cells and enhanced melanin secretion by SIRT3‐regulated HMGB1 deacetylation, which might provide new evidence to treat vitiligo.
This paper discusses the generalized theory of phase-shifted carrier pulsewidth modulation (PSC-PWM) for cascaded H-bridge (CHB) converters and modular multilevel converters (MMCs), provides a ...reasonable classification of the PSC-PWM, and extends the possible phase-shift angles to full range. First, the PSC-PWM for CHB converter is classified into two categories by phase-shift pattern. In addition, by rigorous mathematical derivation, the impact law of the full-range phase-shift angles on harmonic minimization is obtained. And then, it is proved that the generalized theory is equally applicable to MMC, which also merges the former proposed PSC-PWM for MMCs into itself. Moreover, the harmonic analysis of the dead-time error voltage is discussed, which is found to have the same harmonic distribution as the ideal voltage, except for the emerging of odd-order harmonics. In summary, this generalized theory offers a general perspective of the PSC-PWM for CHB converter and MMC, and builds up a scientific and comprehensive understanding for researchers from both academia and industry. Finally, the analytical findings are sufficiently validated by simulation and experimental results.
Non-invasive stimulation of biological tissue is highly desirable for several biomedical applications. Of specific interest are methods for tumor treatment, endometrial ablation, and ...neuro-modulation. In traditional neuro-modulation, single- and multi-coil transcranial stimulation techniques in low oscillation frequencies are utilized to non-invasively penetrate the skull and elicit action potentials in cortical neurons. Although these methods have been proven effective, tightly focusing these signals to localized regions is difficult. In recent years, microwave (MW) methods have seen an increase usage as a minimally invasive treatment modality for ablation and neuro-stimulation. Unlike low frequency signals, MW signals can be focused to localized sub-centimeter regions. In this work we demonstrate that a three-dimensional array of MW antennas can be used to tightly focus signals to a localized region in space within the human body with MW frequencies. Assuming an array of small MW loop antennas are placed around the body, the optimal amplitude and phase of each array element can be accurately determined to match an arbitrary desired field profile. The major innovation of the presented method is that the fields that penetrate the biological region are determined via computing numerical Green's functions (NGF) that are then used to drive an optimization algorithm. Using simplified models of regions in the human body, it is shown that the MW fields at 1 GHz can be focused to sub-centimeter sized "hot spots" at depths of several centimeters. The algorithm can be easily extended to more realistic models of the human body or for non-biological applications.
Abstract
Noble metal electrocatalysts (e.g., Pt, Ru, etc.) suffer from sluggish kinetics of water dissociation for the electrochemical reduction of water to molecular hydrogen in alkaline and neutral ...pH environments. Herein, we found that an integration of Ru nanoparticles (NPs) on oxygen-deficient WO
3-x
manifested a 24.0-fold increase in hydrogen evolution reaction (HER) activity compared with commercial Ru/C electrocatalyst in neutral electrolyte. Oxygen-deficient WO
3-x
is shown to possess large capacity for storing protons, which could be transferred to the Ru NPs under cathodic potential. This significantly increases the hydrogen coverage on the surface of Ru NPs in HER and thus changes the rate-determining step of HER on Ru from water dissociation to hydrogen recombination.
Background Hypomethylation of the perforin gene promoter in CD4 + T cells, inflammation and oxidative stress, might be involved in alveolar septal cell apoptosis associated with emphysema in rats. ...This study aimed to investigate the effects of S-adenosylmethionine (SAM) on this kind of apoptosis in rats with autoimmune emphysema. Methods Twenty-four rats were randomly divided into three groups: a normal control group, a model group, and a SAM group. Pathological changes in lung tissues were observed, and the mean linear intercept (MLI) and mean alveolar number (MAN) were measured. The levels of anti-endothelial cell antibodies (AECA) in serum, alveolar septal cell apoptosis, perforin gene promotor methylation in CD4 + T cells in the spleen, and the levels of cytokines, malondialdehyde (MDA), and glutathione (GSH) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in bronchoalveolar lavage fluid (BALF) were investigated. Results The MLI, apoptosis index (AI) of alveolar septal cells, levels of AECA in serum, and levels of tumour necrosis factor-alpha (TNF-alpha), matrix metalloproteinase-9 (MMP-9) and MDA in BALF were increased, while the MAN, methylation levels, and the activities of GSH, SOD and GSH-Px in BALF were decreased in the model group compared with those in the normal control group and the SAM group (all P < 0.05). The levels of interleukin-8 (IL-8) in BALF were greater in the model group than in the normal control group (P < 0.05). Conclusions SAM protects against alveolar septal cell apoptosis, airway inflammation and oxidative stress in rats with autoimmune emphysema possibly by partly reversing the hypomethylation of the perforin gene promoter in CD4 + T cells. Keywords: S-Adenosylmethionine, Autoimmune emphysema, DNA methylation, Cell apoptosis, Rat
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