Terahertz Photons Inhibit Cancer Cells Long Term by Suppressing Nano Telomerase Activity.

Telomeres are nanoscale DNA-protein complexes to protect and stabilize chromosomes. The reexpression of telomerase in cancer cells is a key determinant crucial for the infinite proliferation and long-term survival of most cancer cells. However, the use of telomerase inhibitors for cancer treatment may cause problems such as poor specificity, drug resistance, and cytotoxicity. Here, we discovered a nondrug and noninvasive terahertz modulation strategy capable of the long-term suppression of cancer cells by inhibiting telomerase activity. First, we found that an optimized frequency of 33 THz photon irradiation effectively inhibited the telomerase activity by molecular dynamics simulation and frequency filtering experiments. Moreover, in vitro experiments showed that telomerase activity in 4T1 and MCF-7 cells significantly decreased by 77% and 80% respectively, after 21 days of regular 33 THz irradiation. Furthermore, two kinds of cells were found to undergo aging, apoptosis, and DNA double-strand breaks caused by telomere crisis, which seriously affected the survival of cancer cells. In addition, the tumorigenicity of 4T1 cells irradiated with 33 THz waves for 21 days in in vivo mice decreased by 70%. In summary, this study demonstrates the potential application of THz modulation in nano therapy for cancer.

Immune-related risk prognostic model for clear cell renal cell carcinoma: Implications for immunotherapy.

Clear cell renal cell carcinoma (ccRCC) is associated with complex immune interactions. We conducted a comprehensive analysis of immune-related differentially expressed genes in patients with ccRCC using data from The Cancer Genome Atlas and ImmPort databases. The immune-related differentially expressed genes underwent functional and pathway enrichment analysis, followed by COX regression combined with LASSO regression to construct an immune-related risk prognostic model. The model comprised 4 IRGs: CLDN4, SEMA3G, CAT, and UCN. Patients were stratified into high-risk and low-risk groups based on the median risk score, and the overall survival rate of the high-risk group was significantly lower than that of the low-risk group, confirming the reliability of the model from various perspectives. Further comparison of immune infiltration, tumor mutation load, and immunophenoscore (IPS) comparison between the 2 groups indicates that the high-risk group could potentially demonstrate a heightened sensitivity towards immunotherapy checkpoints PD-1, CTLA-4, IL-6, and LAG3 in ccRCC patients. The proposed model not only applies to ccRCC but also shows potential in developing into a prognostic model for renal cancer, thus introducing a novel approach for personalized immunotherapy in ccRCC.

Upregulated expression of long non-coding RNA MEG3 serves as a prognostic biomarker in severe pneumonia children and its regulatory mechanism.

Severe pneumonia is a high-mortality disorder in children. The expression and underlying effects of lncRNA maternally expressed 3 (MEG3) were detected. The relationships between MEG3 and other parameters were reported by Pearson correlation. The prognostic importance of MEG3 was assessed by Kaplan-Meier (K-M) curve and COX analysis and its diagnostic potential was uncovered by the receiver operating characteristic (ROC) curve. Luciferase activity assay was performed to demonstrate the target gene of MEG3. Elevated expression of MEG3 and reduced microRNA-29 c (miR-29 c) were evaluated in severe pneumonia children, and a negative relationship between MEG3 and miR-29 c was propounded. MEG3 might function as an independent prognostic indicator. The diagnostic efficiency of MEG3 was also indicated for severe pneumonia children. In MRC-5 cell models and MH-S cell models, lipopolysaccharide (LPS) contributed to the increased expression of MEG3. Interference of MEG3 restricted the upregulation of MEG3 triggered by LPS. Silenced MEG3 protected MRC-5 and MH-S cells against damages managed by LPS on cell apoptosis, viability, and inflammation. MiR-29 c was a ceRNA of MEG3 and the absence of MEG3 abrogated the decreased expression of miR-29 c caused by LPS. Overall, the increased expression of MEG3 and the reduced levels of miR-29 c were identified in severe pneumonia. Prognostic and diagnostic significances of MEG3 provided a novel perspective for severe pneumonia. Disruption of MEG3 alleviated cell injury and inflammation as characterized by high LPS by binding miR-29 c.

Imaging biomarkers of contrast-enhanced computed tomography predict survival in oesophageal cancer after definitive concurrent chemoradiotherapy.

BACKGROUND: This study aimed to evaluate the predictive potential of contrast-enhanced computed tomography (CT)-based imaging biomarkers (IBMs) for the treatment outcomes of patients with oesophageal squamous cell carcinoma (OSCC) after definitive concurrent chemoradiotherapy (CCRT). METHODS: Altogether, 154 patients with OSCC who underwent definitive CCRT were included in this retrospective study. All patients were randomised to the training cohort (n = 99) or the validation cohort (n = 55). Pre-treatment contrast-enhanced CT scans were obtained for all patients and used for the extraction of IBMs. An IBM score, was constructed by using the least absolute shrinkage and selection operator with Cox regression analysis, which was equal to the log-partial hazard of the Cox model in the training cohort and tested in the validation cohort. IBM nomograms were built based on IBM scores for individualised survival estimation. Finally, a decision curve analysis was performed to estimate the clinical usefulness of the nomograms. RESULTS: Altogether, 96 IBMs were extracted from each contrast-enhanced CT scan. IBM scores were constructed from 11 CT-based IBMs for overall survival (OS) and 8 IBMs for progression-free survival (PFS), using the LASSO-Cox regression method in the training cohort. Multivariate analysis revealed that IBM score was an independent prognostic factor correlated with OS and PFS. In the training cohort, the C-indices of IBM scores were 0.734 (95% CI 0.664-0.804) and 0.658 (95% CI 0.587-0.729) for OS and PFS, respectively. In the validation cohort, C-indices were 0.672 (95% CI 0.578-0.766) and 0.666 (95% CI 0.574-0.758) for OS and PFS, respectively. Kaplan-Meier survival analysis showed a significant difference between risk subgroups in the training and validation cohorts. Decision curve analysis confirmed the clinical usefulness of the IBM score. CONCLUSIONS: The IBM score based on pre-treatment contrast-enhanced CT could predict the OS and PFS for patients with OSCC after definitive CCRT. Further multicentre studies with larger sample sizes are warranted.

In vitro study on the effect of peucedanol on the activity of cytochrome P450 enzymes.

CONTEXT: Peucedanol is a major extract of Peucedanum japonicum Thunb. (Apiaceae) roots, which is a commonly used herb in paediatrics. Its interaction with cytochrome P450 enzymes (CYP450s) would lead to adverse effects or even failure of therapy. OBJECTIVE: The interaction between peucedanol and CYP450s was investigated. MATERIALS AND METHODS: Peucedanol (0, 2.5, 5, 10, 25, 50, and 100 µM) was incubated with eight human liver CYP isoforms (CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1), in pooled human liver microsomes (HLMs) for 30 min with specific inhibitors as positive controls and untreated HLMs as negative controls. The enzyme kinetics and time-dependent study (0, 5, 10, 15, and 30 min) were performed to obtain corresponding parameters in vitro. RESULTS: Peucedanol significantly inhibited the activity of CYP1A2, 2D6, and 3A4 in a dose-dependent manner with IC50 values of 6.03, 13.57, and 7.58 µM, respectively. Peucedanol served as a non-competitive inhibitor of CYP3A4 with a Ki value of 4.07 µM and a competitive inhibitor of CYP1A2 and 2D6 with a Ki values of 3.39 and 6.77 µM, respectively. Moreover, the inhibition of CYP3A4 was time-dependent with the Ki/Kinact value of 5.44/0.046 min/µM. DISCUSSION AND CONCLUSIONS: In vitro inhibitory effect of peucedanol on the activity of CYP1A2, 2A6, and 3A4 was reported in this study. As these CYPs are involved in the metabolism of various drugs, these results implied potential drug-drug interactions between peucedanol and drugs metabolized by CYP1A2, 2D6, and 3A4, which needs further in vivo validation.

Clinical significance of miR-181a in patients with neonatal sepsis and its regulatory role in the lipopolysaccharide-induced inflammatory response.

Neonatal sepsis (NS) poses a serious threat to the health of neonates worldwide. The present study aimed to investigate the diagnostic value of microRNA (miR)-181a in patients with NS and the regulatory role of miR-181a in lipopolysaccharide (LPS)-induced inflammation. A total of 102 neonates with NS and 50 neonates without sepsis were enrolled in the present study. The serum levels of miR-181a were estimated using reverse transcription-quantitative PCR. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic value of miR-181a for NS. The effect of miR-181a on the expression of Toll-like receptor (TLR)4 was assessed after modification of the expression of miR-181a in monocytes isolated from the blood of neonates in vitro. An ELISA was used to measure the concentration of inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-8 in the supernatant of monocytes. The serum levels of miR-181a were decreased in patients with NS compared with those in the controls. The area under the ROC curve of miR-181a was 0.893 with a sensitivity of 83.3% and a specificity of 84.0%. LPS stimulation in monocytes also led to a decrease in the expression of miR-181a. TLR4 was proven to be a direct target gene of miR-181a, according to the results of a luciferase reporter assay, and overexpression of miR-181a suppressed TLR4 expression in monocytes. Regarding LPS-induced inflammation, it was revealed that the upregulated levels of TNF-α and IL-8 induced by LPS were reduced by overexpression of miR-181a in monocytes. In conclusion, decreased serum levels of miR-181a may serve as a diagnostic biomarker in patients with NS and overexpression of miR-181a inhibits the LPS-induced inflammatory response at least partially by targeting TLR4. Aberrant miR-181a may be a non-invasive biomarker for NS patients, and provide a novel insight into the pathologic mechanisms of action behind the development of NS.

A primary model of THz and far-infrared signal generation and conduction in neuron systems based on the hypothesis of the ordered phase of water molecules on the neuron surface I: signal characteristics.

In this paper, we use the theory of quantum optics and electrodynamics to study the electromagnetic field problem in the nervous system based on the assumption of an ordered arrangement of water molecules on the neuronal surface. Using the Lagrangian of the water molecule-field ion, the dynamic equations for neural signal generation and transmission are derived. Perturbation theory and the numerical method are used to solve the dynamic equations, and the characteristics of high-frequency signals (the dispersion relation, the time domain of the field, the frequency domain waveform, etc.) are discussed. This model predicts some intrinsic vibration modes of electromagnetic radiation on the neuronal surface. The frequency range of these vibration modes is in the THz and far-infrared ranges.

Effects of astragaloside IV on the pharmacokinetics of omeprazole in rats.

Context: Omeprazole and astragaloside IV (AS-IV) are widely used for the treatment of gastric ulcers in China clinics. Objective: This study investigates the effects of AS-IV on the pharmacokinetics of omeprazole in rats. Materials and methods: The pharmacokinetics of orally administered omeprazole (2 mg/kg), with or without AS-IV (100 mg/kg/day for 7 days) pretreatment, were investigated in male Sprague-Dawley rats (two groups of six animals each) using LC-MS/MS. A Caco-2 cell transwell model and rat liver microsome incubation systems were also used to support the in vivo pharmacokinetic data and investigate its potential mechanism. Results: The results indicated that co-administration of AS-IV could decrease the systemic exposure of omeprazole significantly (p < 0.05), including AUC0-t (717.20 ± 177.63 vs. 1166.25 ± 186.65 ng h/mL) and Cmax (272.35 ± 25.81 vs. 366.34 ± 32.57 ng/mL). The t1/2 of omeprazole also decreased significantly (1.78 ± 0.15 vs. 2.23 ± 0.27 h, p < 0.05). The efflux ratio of omeprazole across the Caco-2 cell transwell model increased significantly from 1.73 to 2.67 (p < 0.05), and the metabolic stability of omeprazole was decreased from 42.6 ± 7.8 to 26.2 ± 5.1 min with the pretreatment of AS-IV (p < 0.05). Discussion and conclusions: AS-IV could decrease the systemic exposure of omeprazole in rats when AS-IV and omeprazole were co-administered, and it might exert these effects through decreasing the absorption of omeprazole by inducing P-gp, or through accelerating the metabolism of omeprazole in rat liver by inducing the activity of CYP3A4.

Improvement of Glucose Metabolism Following Long-Term Taurocholic Acid Gavage in a Diabetic Rat Model.

BACKGROUND Bile acids (BAs) are signaling molecules that participate in maintaining glucose homeostasis. Acute enteral infusion of BAs potently reduces the glycemic response to glucose, associated with an increase of incretin hormones. However, the effect of long-term supplementation of BAs on glucose metabolism has not been fully investigated. MATERIAL AND METHODS Thirty diabetic rats were assigned to a control group (n=10), a low TCA group (L-TCA group, n=10), and a high TCA group (H-TCA group, n=10). Rats in the control group were fed a regular high-fat diet (HFD), while rats in the L-TCA group and H-TCA group were fed a TCA (taurocholic acid)-mixed HFD with the concentrations of 0.05% and 0.3%, respectively, to control the intake of HFD and TCA. Energy intake, body weight, serum insulin, glucose tolerance, insulin sensitivity, GLP-1, and total serum BAs were measured at week 2 and week 12. RESULTS At week 2 there were no significant differences in body weight, daily energy intake, glucose tolerance, serum insulin, insulin sensitivity, GLP-1, or fasting total serum BAs between the 3 groups. At week 12, fasting blood glucose and intragastric glucose tolerance were better in the H-TCA group, with significantly greater insulin and GLP-1 secretion and better insulin sensitivity; no significant differences in body weight, energy intake, or total fasting serum BAs were observed. CONCLUSIONS Long-term supplementation with small doses of TCA was demonstrated to improve glucose metabolism in a diabetic rat model and may be a potential target for diabetes control.

High-efficiency coaxial relativistic backward wave oscillator.

This paper studies the coaxial relativistic backward wave oscillator (CRBWO) through analytical, numerical, and experimental methods. This new type of device is remarked by its high efficiency of more than 35%, which is predicted by the theoretical calculation and the numerical simulation and validated by experiment. The two primary hindrances preventing CRBWO from achieving the expected high efficiency, the poor coaxiality and the power capacity, are discussed in detail and some advanced methods are developed. The theoretical and numerical conclusions agree with the experiment results, which are obtained from the electric probe and the calorimeter simultaneously for each shot of CRBWO. Employing the electron beam pulse of the full width at half maximum 28 ns, a microwave pulse of the width about 20 ns is generated in the experiment; the power is 710 MW and the efficiency is higher than 33%.

All-solid-state repetitive semiconductor opening switch-based short pulse generator.

The operating characteristics of a semiconductor opening switch (SOS) are determined by its pumping circuit parameters. SOS is still able to cut off the current when pumping current duration falls to the order of tens of nanoseconds and a short pulse forms simultaneously in the output load. An all-solid-state repetitive SOS-based short pulse generator (SPG100) with a three-level magnetic pulse compression unit was successfully constructed. The generator adopts magnetic pulse compression unit with metallic glass and ferrite cores, which compresses a 600 V, 10 mus primary pulse into short pulse with forward pumping current of 825 A, 60 ns and reverse pumping current of 1.3 kA, 30 ns. The current is sent to SOS in which the reverse pumping current is interrupted. The generator is capable of providing a pulse with the voltage of 120 kV and duration of 5-6 ns while output load being 125 Omega. The highest repetition rate is up to 1 kHz.