Dual-Responsive Turn-On T1 Imaging-Guided Mild Photothermia for Precise Apoptotic Cancer Therapy.

Apoptosis has gained increasing attention in cancer therapy as an intrinsic signaling pathway, which leads to minimal leakage of waste products from a dying cell to neighboring normal cells. Among various stimuli to trigger apoptosis, mild hyperthermia is attractive but confronts limitations of non-specific heating and acquired resistance from elevated expression of heat shock proteins. Here, a dual-stimulation activated turn-on T1 imaging-based nanoparticulate system (DAS) is developed for mild photothermia (≈43 °C)-mediated precise apoptotic cancer therapy. In the DAS, a superparamagnetic quencher (ferroferric oxide nanoparticles, Fe3 O4 NPs) and a paramagnetic enhancer (Gd-DOTA complexes) are connected via the N6-methyladenine (m6 A)-caged, Zn2+ -dependent DNAzyme molecular device. The substrate strand of the DNAzyme contains one segment of Gd-DOTA complex-labeled sequence and another one of HSP70 antisense oligonucleotide. When the DAS is taken up by cancer cells, overexpressed fat mass and obesity-associated protein (FTO) specifically demethylates the m6 A group, thereby activating DNAzymes to cleave the substrate strand and simultaneously releasing Gd-DOTA complex-labeled oligonucleotides. The restored T1 signal from the liberated Gd-DOTA complexes lights up the tumor to guide the location and time of deploying 808 nm laser irradiation. Afterward, locally generated mild photothermia works in concert with HSP70 antisense oligonucleotides to promote apoptosis of tumor cells. This highly integrated design provides an alternative strategy for mild hyperthermia-mediated precise apoptotic cancer therapy.

DNA strand displacement based computational systems and their applications.

DNA computing has become the focus of computing research due to its excellent parallel processing capability, data storage capacity, and low energy consumption characteristics. DNA computational units can be precisely programmed through the sequence specificity and base pair principle. Then, computational units can be cascaded and integrated to form large DNA computing systems. Among them, DNA strand displacement (DSD) is the simplest but most efficient method for constructing DNA computing systems. The inputs and outputs of DSD are signal strands that can be transferred to the next unit. DSD has been used to construct logic gates, integrated circuits, artificial neural networks, etc. This review introduced the recent development of DSD-based computational systems and their applications. Some DSD-related tools and issues are also discussed.

Pin1/YAP pathway mediates matrix stiffness-induced epithelial-mesenchymal transition driving cervical cancer metastasis via a non-Hippo mechanism.

Cervical cancer metastasis is an important cause of death in cervical cancer. Previous studies have shown that epithelial-mesenchymal transition (EMT) of tumors promotes its invasive and metastatic capacity. Alterations in the extracellular matrix (ECM) and mechanical signaling are closely associated with cancer cell metastasis. However, it is unclear how matrix stiffness as an independent cue triggers EMT and promotes cervical cancer metastasis. Using collagen-coated polyacrylamide hydrogel models and animal models, we investigated the effect of matrix stiffness on EMT and metastasis in cervical cancer. Our data showed that high matrix stiffness promotes EMT and migration of cervical cancer hela cell lines in vitro and in vivo. Notably, we found that matrix stiffness regulates yes-associated protein (YAP) activity via PPIase non-mitotic a-interaction 1 (Pin1) with a non-Hippo mechanism. These data indicate that matrix stiffness of the tumor microenvironment positively regulates EMT in cervical cancer through the Pin1/YAP pathway, and this study deepens our understanding of cervical cancer biomechanics and may provide new ideas for the treatment of cervical cancer.

A Telomerase-Activated Magnetic Resonance Imaging Probe for Consecutively Monitoring Tumor Growth Kinetics and In Situ Screening Inhibitors.

Telomerase has long been considered as a biomarker for cancer diagnosis and a therapeutic target for drug discovery. Detecting telomerase activity in vivo could provide more direct information of tumor progression and response to drug treatment, which, however, is hampered by the lack of an effective probe that can generate an output signal without a tissue penetration depth limit. In this study, using the principle of distance-dependent magnetic resonance tuning, we constructed a telomerase-activated magnetic resonance imaging probe (TAMP) by connecting superparamagnetic ferroferric oxide nanoparticles (SPFONs) and paramagnetic Gd-DOTA (Gd(III) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) complexes via telomerase-responsive DNA motifs. Upon telomerase-catalyzed extension of the primer in TAMP, Gd-DOTA-conjugated oligonucleotides can be liberated from the surface of SPFONs through a DNA strand displacement reaction, restoring the T1 signal of the Gd-DOTA for a direct readout of the telomerase activity. Here we show that, by tracking telomerase activity, this probe provides consistent monitoring of tumor growth kinetics during progression and in response to drug treatment and enables in situ screening of telomerase inhibitors in whole-animal models. This study provides an alternative toolkit for cancer diagnosis, treatment response assessment, and anticancer drug screening.

Individualized dynamic PEEP (dynPEEP) vs. positive pressure ventilation in delivery room management: A retrospective cohort study.

Objective: Although nasal continuous positive airway pressure (nCPAP) is recommended in delivery room (DR) management for preterm infants, the effect of delivering nCPAP at 6-8 cmH2O is not satisfactory. Therefore, we conducted this retrospective cohort study to compare the effects of individualized dynamic positive end-expiratory pressure (dynPEEP) vs. positive pressure ventilation (PPV) in the DR on clinical outcomes. Methods: Preterm infants with a gestational age (GA) less than 30 weeks who received PPV (peak inspiratory pressure, PIP/PEEP 15-25/6-8 cmH2O) from August 2018 to July 2020 were included as Cohort 1 (PPV group, n = 55), and those who received dynPEEP (nCPAP 8-15 cmH2O) from June 2020 to April 2022 were included as Cohort 2 (dynPEEP group, n = 62). Primary outcomes included the DR intubation rate and the bronchopulmonary dysplasia (BPD) rate. The secondary outcomes included DR stabilization, transfer, admission, respiratory function, and other outcomes. Results: The percentage of singleton infants was higher in the PPV group (63.6%) than in the dynPEEP group (22.6%, p = 0.000). The DR intubation and chest compression rates were higher in the PPV group (80.0% and 18.2%, respectively) than in the dynPEEP group (45.2%, p = 0.000; 3.0%, p = 0.008, respectively). The percentage of patients with 5-min Apgar scores < 5 was higher in the PPV group (9.1%) than in the dynPEEP group (0%, p = 0.016). The partial pressure of carbon dioxide was lower in the PPV group (49.77 ± 11.28) than in the dynPEEP group (56.44 ± 13.17, p = 0.004), and lactate levels were higher in the PPV group (3.60 (2.10, 5.90)) than in the dynPEEP group (2.25 (1.38, 3.33), p = 0.002). No significant differences in the BPD rate or other secondary outcomes were noted. Conclusions: In this retrospective cohort study, the dynPEEP strategy reduced the need for DR intubation compared with PPV. The dynPEEP strategy is feasible and potentially represents an alternative respiratory strategy to PPV. Nevertheless, a randomized control trial is needed to evaluate the dynPEEP strategy.

Cardiac Protection of Valsartan on Juvenile Rats with Heart Failure by Inhibiting Activity of CaMKII via Attenuating Phosphorylation.

Background. This study was undertaken to determine relative contributions of phosphorylation and oxidation to the increased activity of calcium/calmodulin-stimulated protein kinase II (CaMKII) in juveniles with cardiac myocyte dysfunction due to increased pressure overload. Methods. Juvenile rats underwent abdominal aortic constriction to induce heart failure. Four weeks after surgery, rats were then randomly divided into two groups: one group given valsartan (HF + Val) and the other group given placebo (HF + PBO). Simultaneously, the sham-operated rats were randomly given valsartan (Sham + Val) or placebo (Sham + PBO). After 4 weeks of treatment, Western blot analysis was employed to quantify CaMKII and relative calcium handling proteins (RyR2 and PLN) in all groups. Results. The deteriorated cardiac function was reversed by valsartan treatment. In ventricular muscle cells of group HF + PBO, Thr287 phosphorylation of CaMKII and S2808 phosphorylation of RyR2 and PLN were increased and S16 phosphorylation of PLN was decreased compared to the other groups, while Met281 oxidation was not significantly elevated. In addition, these changes in the expression of calcium handling proteins were ameliorated by valsartan administration. Conclusions. The phosphorylation of Thr286 is associated with the early activation of CaMKII rather than the oxidation of Met281.

[Role of nuclear factor-κB activation in bilirubin-induced rat hippocampal neuronal apoptosis and the effect of TAT-NBD intervention].

OBJECTIVE: To investigate the role of nuclear factor-κB (NF-κB) activation in bilirubin-induced apoptosis of rat hippocampal neurons and the effect of TAT-NBD intervention on bilirubin neurotoxicity. METHODS: Primary-cultured rat hippocampal neurons were treated with TAT-NBD in the initial 6 or 24 h or in the latter 6 h during a 24-h bilirubin exposure of the cells (early, continuous and late intervention groups, respectively). Immunocytochemistry was performed to detect NF-κB p65 protein expression, and the cell survival and apoptosis were assessed with a modified MTT assay, Annexin V-FITC/PI and TUNEL assay. IL-1ß concentration in the supernatant was determined with ELISA. RESULTS: Compared with the control cells, bilirubin-treated cells showed a significantly increased NF-κB p65 protein expression (P<0.01), which reached the peak level at 6 and 24 h (P<0.01). The cell survival rate in early TAT-NBD intervention group was (80.784∓9.767)%, significantly lower than that of the control group (P<0.01) but higher than that of bilirubin group (P<0.01); the apoptotic rate in early TAT-NBD intervention group was significantly higher than that of control group (P<0.01) but lower than that of bilirubin group (P<0.01). IL-1ß concentration was significantly lower in early TAT-NBD intervention group (15.348∓0.812 pg/ml) than in bilirubin group (P<0.05). The continuous and late TAT-NBD intervention groups showed comparable cell survival rate, apoptotic rate and IL-1ß concentration with bilirubin group (P>0.05). CONCLUSION: NF-κB bidirectionally regulates bilirubin-induced apoptosis of rat hippocampal neurons. Selective inhibition of the early peak of NF-κB by TAT-NBD offers neuroprotective effect. TAT-NBD can be potentially used for prophylaxis of bilirubin-induced brain injury.