The CD44high Subpopulation of Multifraction Irradiation-Surviving NSCLC Cells Exhibits Partial EMT-Program Activation and DNA Damage Response Depending on Their p53 Status

Ionizing radiation (IR) is used for patients diagnosed with unresectable non-small cell lung cancer (NSCLC). However, radiotherapy remains largely palliative due to the survival of specific cell subpopulations. In the present study, the sublines of NSCLC cells, A549IR (p53wt) and H1299IR (p53null) survived multifraction X-ray radiation exposure (MFR) at a total dose of 60 Gy were investigated three weeks after the MFR course. We compared radiosensitivity (colony formation), expression of epithelial-mesenchymal transition (EMT) markers, migration activity, autophagy, and HR-dependent DNA double-strand break (DSB) repair in the bulk and entire CD44high/CD166high CSC-like populations of both parental and MFR survived NSCLC cells. We demonstrated that the p53 status affected: the pattern of expression of N-cadherin, E-cadherin, Vimentin, witnessing the appearance of EMT-like phenotype of MFR-surviving sublines; 1D confined migratory behavior (wound healing); the capability of an irradiated cell to continue to divide and form a colony of NSCLC cells before and after MFR; influencing the CD44/CD166 expression level in MFR-surviving NSCLC cells after additional single irradiation. Our data further emphasize the impact of p53 status on the decay of γH2AX foci and the associated efficacy of the DSB repair in NSCLC cells survived after MFR. We revealed that Rad51 protein might play a principal role in MFR-surviving of p53 null NSCLC cells promoting DNA DSB repair by homologous recombination (HR) pathway. The proportion of Rad51 + cells elevated in CD44high/CD166high population in MFR-surviving p53wt and p53null sublines and their parental cells. The p53wt ensures DNA-PK-mediated DSB repair for both parental and MFR-surviving cells irrespectively of a subsequent additional single irradiation. Whereas in the absence of p53, a dose-dependent increase of DNA-PK-mediated non-homologous end joining (NHEJ) occurred as an early post-irradiation response is more intensive in the CSC-like population MFR-surviving H1299IR, compared to their parental H1299 cells. Our study strictly observed a significantly higher content of LC3 + cells in the CD44high/CD166high populations of p53wt MFR-surviving cells, which enriched the CSC-like cells in contrast to their p53null counterparts. The additional 2 Gy and 5 Gy X-ray exposure leads to the dose-dependent increase in the proportion of LC3 + cells in CD44high/CD166high population of both parental p53wt and p53null, but not MFR-surviving NSCLC sublines. Our data indicated that autophagy is not necessarily associated with CSC-like cells’ radiosensitivity, emphasizing that careful assessment of other milestone processes (such as senescence and autophagy-p53-Zeb1 axis) of primary radiation responses may provide new potential targets modulated for therapeutic benefit through radiosensitizing cancer cells while rescuing normal tissue. Our findings also shed light on the intricate crosstalk between autophagy and the p53-related EMT, by which MFR-surviving cells might obtain an invasive phenotype and metastatic potential.     

Early angiotensin converting enzyme inhibitor therapy after experimental myocardial infarction prevents left ventricular dilation by reducing infarct expansion: a possible mechanism of clinical benefits

OBJECTIVE: To examine the effects of early angiotensin-converting enzyme (ACE) inhibitor therapy after myocardial infarction on infarct expansion in an experimental rat model. BACKGROUND: ACE inhibitor therapy within 24 h of acute myocardial infarction (AMI) reduces mortality by unknown mechanism(s). METHODS: Rats underwent permanent coronary artery occlusion. A treated group received enalapril (1.9+/-0.2 mg/kg) daily in drinking water beginning 2 h after coronary artery occlusion, a time too late to reduce infarct size. Rats were sacrificed 2 days or 2 weeks after myocardial infarction. Hearts were arrested and fixed at a constant pressure, then sectioned and photographed for morphometric analysis. RESULTS: Infarcts in the control group expanded between 2 days and 2 weeks after myocardial infarction (expansion index 0.7+/-0.1 versus 2.5+/-0.4, P< 0.05). However, infarct expansion remained unchanged in the enalapril group between 2 days and 2 weeks after myocardial infarction (expansion index 0.8+/-0.1 versus 1.3+/-0.1, NS). Two weeks after myocardial infarction, the enalapril group had fewer expanded infarcts than the control group (expansion index 1.3+/-0.1 versus 2.5+/-0.4, P< 0.05). While left ventricular volume increased in the control group between 2 days and 2 weeks after myocardial infarction (0.17+/-0.01 ml versus 0.36+/-0.03 ml, P< 0.05), it remained constant in the enalapril group (0.22+/-0.02 ml versus 0.25+/-0.03 ml, NS). Two weeks after myocardial infarction, the left ventricles were larger in the control group than in the enalapril group (0.36+/-0.03 ml versus 0.25+/-0.03 ml, P< 0.05). CONCLUSIONS: Treatment with enalapril initiated 2 h after AMI prevented left ventricular dilation by limiting infarct expansion. This may explain the mechanism by which ACE inhibitor therapy started within 24 h of an AMI improves survival 5-6 weeks after infarction.     

Microneedle-Based Local Delivery of CCL22 and IL-2 Enriches Treg Homing to the Skin Allograft and Enables Temporal Monitoring of Immunotherapy Efficacy

Skin allografts only serve as temporary dressing for patients suffering major burns due to their high immunogenicity and rejection by the immune system, requiring systemic immunosuppressive therapies that lead to deleterious side effects. Microneedle arrays composed of hyaluronic acid (HA) and placed on skin allografts can locally deliver immunomodulators and simultaneously sample immune cells in interstitial fluid to monitor the response to the therapy. The cells can be retrieved from the microneedles for downstream analysis by degrading the HA using a reducing agent. Using an allogeneic skin transplantation model, it is shown that the microneedle-mediated local delivery of the chemokine CCL22 (to attract T_regs) and the cytokine IL-2 (to promote their expansion) increases the local immune suppression in the allograft. Moreover, immune cell population in the allograft correlates with that seen in the microneedles. The delivery and sampling functions of the microneedle arrays can help regulate the immune system locally, without inducing systemic immune suppression, and facilitate the monitoring of the response to the therapy following skin transplantation.     

La-doped NaTaO3 perovskite nanocrystals supported with α-Fe2O3 for sustainable visible-light-driven elimination of ciprofloxacin in water

To date, the emergence of antibiotic waste in water has become an important issue for humans and other living organisms. The spread of such waste will influence human health and the effectiveness of such antibiotics. Accordingly, several research approaches are offered for the clean and safe elimination of such waste. Herein, we present a facile synthesis of visible-light-activated La-doped NaTaO₃ perovskite nanocrystals (LNTO) supported with small amounts (1.0–4.0 wt %) of Fe₂O₃ (FO) nanoparticles to produce x%FO@LNTO nanocomposites. These FO@LNTO samples exhibited a mesostructured crystalline surface with a high surface area (200–230 m² g^?1). Additionally, the loading of FO nanoparticles onto LNTO resulted in a broad visible-light absorption and reduction of the bandgap (E_g) to 2.35 eV compared to 4.40 eV for the parent LNTO. The produced nanocomposite was tested for the photodegradation of ciprofloxacin (CIP) as an emerging probe of antibiotic waste in water. The 3% FO@LNTO displayed a total elimination of 10 ppm CIP after 90 min of visible-light illumination with sustainable recyclability. This fascinating action of FO@LNTO is referred to as the formation of a close heterojunction between FO and LNTO that decreases the E_g value and enhances photocharge separation. This work implies the use of perovskite-based photocatalysts for reasonable elimination of antibiotic waste in water.     

Towards a linear general type-2 fuzzy logic based approach for computing with words

Within the last two decades, the paradigm of Computing With Words (CWW) has been gaining more attention. Mainly, CWW has an exciting vision which tries to tackle the problem of human intelligence by taking the human mind as a role model. The human intelligence has been investigated by various disciplines including psychology, philosophy, neuroscience, linguistics, computer science, and cognitive sciences. Notably, it is not a straightforward task to map the human’s brain reasoning into computer processes. In this paper, we propose to facilitate such mapping by investigating a key element, which is to identify the step-by-step formation of perceptual judgments. Herein, we first introduce an approach that employs general type-2 fuzzy logic to dynamically model the human perceptions based on the human experience. This approach can be regarded as a step to enable the CWW vision. We have deployed the proposed approach in real-world settings and we will present two sets of real-world experiments which were conducted in the intelligent apartment (iSpace) in the University of Essex. The first set of experiments demonstrates the results of the proposed approach for the adaptive modeling of ambient luminance perception. In the second set of experiments, we show that our approach performs better in the rule base evaluation processing time and in output accuracy with comparison to an interval type-2 fuzzy logic system.     

Facile Fabrication of Pt-Doped Mesoporous ZnS as High Efficiency for Photocatalytic CO2 Conversion

Developing high efficiency, environmentally friendly, and low-cost mesoporous Pt/ZnS photocatalyst for CO₂ conversion to CH₃OH is significant for clean energy conversion. Herein, we described a facile synthesis of mesoporous ZnS framework decorated Pt NPs as high efficiency for CO₂ conversion through visible light illumination. The results indicated that Pt/ZnS nanocomposites showed that the structural and crystallinity integrity of polyhedral heterojunction obviously maintain after incorporating Pt NPs, and they are well-distributed on the ZnS surface with particles size about 3–5 nm. The optimized photocatalyst 1.5% Pt/ZnS nanocomposite could prominently exhibit a high photocatalytic efficiency compared to undoped ZnS. Remarkably, the yield of CH₃OH of 400 µmolg^??1 in 9 h over 1.5% Pt/ZnS nanocomposite indicated a significantly promoted CH₃OH formation, nearly 22-fold greater than that of the undoped ZnS NPs, which substantially verified the great promoting potential for conversion of clean energy. The CH₃OH formation rate over mesoporous 1.5% Pt/ZnS nanocomposite (44.5 µmolg^?1 h^?1) is larger 24 times than that of undoped ZnS NPs (1.86 µmolg^?1 h^?1). The recycled Pt/ZnS photocatalyst does not alter the CH₃OH formation remarkably after five repeating cycles with excellent durability. Electrochemical impedance spectroscopy, photocurrent response, and photoluminescence analyses were investigated to support our results and suggested mechanism for enhancement of CO₂ conversion to CH₃OH.

     

Nanodiamond as a vector for siRNA delivery to Ewing sarcoma cells

The ability of diamond nanoparticles (nanodiamonds, NDs) to deliver small interfering RNA (siRNA) into Ewing sarcoma cells is investigated with a view to the possibility of in-vivo anticancer nucleic-acid drug delivery. siRNA is adsorbed onto NDs that are coated with cationic polymer. Cell uptake of NDs is demonstrated by taking advantage of the NDs' intrinsic fluorescence from embedded color-center defects. Cell toxicity of these coated NDs is shown to be low. Consistent with the internalization efficacy, a specific inhibition of EWS/Fli-1 gene expression is shown at the mRNA and protein level by the ND-vectorized siRNA in a serum-containing medium.