Induction of autophagic death in cancer cells is one of the promising strategies for the development of anti-cancer therapeutics. In the present study, we designed and synthesized a series of isatin ...Schiff base derivatives containing thioether structures. After discovering the highly active target compound H13 (IC50 = 4.83 μM) based on in vitro antiproliferation, we also found it had a high safety against normal cells HEK293 with CC50 of 69.01 μM, indicating a sufficient therapeutic window. In addition, to provide reference for subsequent studies, a model was successfully constructed by Sybyl software. Preliminary mechanistic studies suggested that H13-induced apoptosis may be closely related to ROS accumulation and mitochondrial dysfunction. Subsequent studies revealed that H13 inhibited cell proliferation by inducing cellular autophagy mainly through blocking signal of the PI3K/AKT/mTOR pathway. Altogether, these results suggested that H13 was potentially valuable as a lead compound.Induction of autophagic death in cancer cells is one of the promising strategies for the development of anti-cancer therapeutics. In the present study, we designed and synthesized a series of isatin Schiff base derivatives containing thioether structures. After discovering the highly active target compound H13 (IC50 = 4.83 μM) based on in vitro antiproliferation, we also found it had a high safety against normal cells HEK293 with CC50 of 69.01 μM, indicating a sufficient therapeutic window. In addition, to provide reference for subsequent studies, a model was successfully constructed by Sybyl software. Preliminary mechanistic studies suggested that H13-induced apoptosis may be closely related to ROS accumulation and mitochondrial dysfunction. Subsequent studies revealed that H13 inhibited cell proliferation by inducing cellular autophagy mainly through blocking signal of the PI3K/AKT/mTOR pathway. Altogether, these results suggested that H13 was potentially valuable as a lead compound.
A series of high-quality, large-sized (maximum size of 16 × 16 × 32 mm(3)) K1-xNaxTa1-yNbyO3 (x = 0.61, 0.64, and 0.70 and corresponding y = 0.58, 0.60, and 0.63) single crystals were grown using the ...top-seed solution growth method. The segregation of the crystals, which allowed for precise control of the individual components of the crystals during growth, was investigated. The obtained crystals exhibited excellent properties without being annealed, including a low dielectric loss (0.006), a saturated hysteresis loop, a giant piezoelectric coefficient d33 (d33 = 416 pC/N, determined by the resonance method and d33(*) = 480 pC/N, measured using a piezo-d33 meter), and a large electromechanical coupling factor, k33 (k33 = 83.6%), which was comparable to that of lead zirconate titanate. The reason the piezoelectric coefficient d33 of K0.39Na0.61Ta0.42Nb0.58O3 was larger than those of the other two crystals grown was elucidated through first-principles calculations. The obtained results indicated that K1-xNaxTa1-yNbyO3 crystals can be used as a high-quality, lead-free piezoelectric material.
Faults play an intricate role in hydrocarbon migration and accumulation since they can serve either as a conduit or a seal. Quantitative evaluation of fault opening/sealing properties requires the ...selection of valid and optimal parameters among numerous geological factors to characterize the hydraulic behaviors of faults. The present study focuses on the Chengbei Step-Fault Area in the Qikou Depression, Bohai Bay Basin, NE China, because hydrocarbon migration and accumulation in this area occurred in a relatively short period so that accumulated hydrocarbons can be used as an indicator to deduce hydraulic connectivity of a fault zone between two sites. Various geological parameters pertinent to a fault, such as burial depth, dip angle, throw, strike, percentage of sandstone of faulted intervals, fluid pressure in faulted mudstone, stress normal to the fault plane, and shale gouge ratio, are analyzed to assess their effectiveness in characterizing fault connectivity. An index, the fault-connectivity probability (N
p), is proposed to evaluate the possibility that a fault has been once serving as a migration pathway. The statistical relationship between N
p and any a geological parameter may be used to indicate the effectiveness of this parameter in characterizing the connectivity of a fault during hydrocarbon migration. The correlation coefficient of a relationship is a good indicator of the effectiveness; and the results are generally in agreement with qualitative assessments. Parameters representing a single geological factor are generally ineffective, whereas those representing implicitly or explicitly two or more factors, such as shale gouge ratio, stress normal to the fault plane, and fault opening index, are more effective.
► In this study we evaluate if a fault may serve as a conduit for oil migration. ► Geoparameters pertinent to a fault are assessed for characterizing fault sealing. ► Accumulated oils are used as indicators to deduce hydraulic connectivity of a fault. ► A concept of fault-connectivity probability offers a conduit for statistical analyses.
By using a photosensitizer as a molecular catalyst, chromogenic 3,3′,5,5′‐tetramethylbenzidine (TMB) can be directly oxidized by oxygen with green LED irradiation, avoiding expensive and unstable ...peroxidase and hydrogen peroxidase. For more information on demonstrating its application for detection of cancer biomarkers, see the Full Paper by P. Wu and J. Liu et al. on page 2602 ff.
Two unusual ring C-seco and ring D-aromatic nor-triterpenoids, ebracpenes A (1) and B (2), were obtained from Euphorbia ebracteolata roots and elucidated by widely spectroscopic data analyses, such ...as 1D, 2D NMR, HRESIMS, and X-ray crystallography analysis. Compound 2 showed a significant inhibitory activity on lipase (IC50 = 0.89 μM as well as the K i determined to be 0.69 μM). Enzyme kinetics analysis and molecular docking experiments revealed that compound 2 was a competitive inhibitor, binding to the active site of lipase.
The taxonomic classification of Dactylispa, a large genus of leaf-mining beetles, is problematic because it is currently based on morphology alone. Here, the first eight mitochondrial genomes of ...Dactylispa species, which were used to construct the first molecular phylogenies of this genus, are reported. The lengths of the eight mitogenomes range from 17,189 bp to 20,363 bp. All of the mitochondrial genomes include 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), 2 ribosomal RNA genes (rRNAs), and 1 A + T-rich region. According to the nonsynonymous/synonymous mutation ratio (Ka/Ks) of all PCGs, the highest and the lowest evolutionary rates were found for atp8 and cox1, respectively, which is a common phenomenon among animals. According to relative synonymous codon usage, UUA(L) has the highest frequency. With two Gonophorini species as the outgroup, mitogenome-based phylogenetic trees of the eight Dactylispa species were constructed using maximum likelihood (ML) and Bayesian inference (BI) methods based on the PCGs, tRNAs, and rRNAs. Two DNA-based phylogenomic inferences and one protein-based phylogenomic inference support the delimitation of the subgenera Dactylispa s. str. and Platypriella as proposed in the system of Chen et al. (1986). However, the subgenus Triplispa is not recovered as monophyletic. The placement of Triplispa species requires further verification and testing with more species. We also found that both adult body shape and host plant relationship might explain the subgeneric relationships among Dactylispa beetles to a certain degree.
The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance despite having extensive T-cell infiltration. Elucidation of the ...mechanisms underlying immune evasion could help identify therapeutic strategies to boost the efficacy of immune checkpoint blockade (ICB) in RCC. This study uncovered a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine 2,3-dioxygenase 1 (IDO1), a prospective target for immunotherapy. PABPC1L was markedly upregulated in RCC, and high PABPC1L expression correlated with unfavorable prognosis and resistance to ICB. PABPC1L bolstered tryptophan metabolism by upregulating IDO1, inducing T-cell dysfunction and Treg infiltration. PABPC1L enhanced the stability of JAK2 mRNA, leading to increased JAK2-STAT1 signaling that induced IDO1 expression. Additionally, PABPC1L-induced activation of the JAK2-STAT1 axis created a positive feedback loop to promote PABPC1L transcription. Conversely, loss of PABPC1L diminished IDO1 expression, mitigated cytotoxic T-cell suppression, and enhanced responsiveness to anti-PD-1 therapy in patient-derived xenograft models. These findings reveal the crucial role of PABPC1L in facilitating immune evasion in RCC and indicate that inhibiting PABPC1L could be a potential immunotherapeutic approach in combination with ICB to improve patient outcomes.
PABPC1L functions as a key factor in renal cell carcinoma immune evasion, enhancing IDO1 and impeding T-cell function, and represents a potential target to enhance the efficacy of immune checkpoint blockade therapy.
Long non-coding RNAs (lncRNAs) are actively involved in various carcinomas. The purpose of this experiment is to explore the function of long intergenic non-protein coding RNA 01106 (LINC01106) in ...non-small cell lung cancer (NSCLC). LINC01106 expression in NSCLC was determined by RT-qPCR. Next, the distribution of LINC01106 in A549 cells was observed using subcellular fractionation. Subsequently, functional assays were performed to access NSCLC cell biological behaviors, with epithelial–mesenchymal transition detected by the western blot analysis. After that xenograft tumors were established in nude mice to analyze the inhibitory role of LINC01106 knockdown in NSCLC. In addition, gain-of-function and loss-of-function assays were carried out to confirm the interaction between LINC01106 and microRNA (miR)-765 and between miR-765 and collagen type III (COL3A1) in NSCLC cells. LINC01106 was overexpressed in NSCLC cells, and it existed in both cytoplasm and nuclei in A549 cells. Then, it was further discovered that LINC01106 knockdown greatly reduced NSCLC cell expansion and tumor growth in vivo. Furthermore, it was identified that LINC01106 could serve as a sponge of miR-765 to promote COL3A1 expression. miR-765 overexpression inhibited A549 cell activities. This study unmasked that LINC01106 knockdown suppressed NSCLC progression by serving as a sponge of miR-765 to downregulate COL3A1 expression.
Purpose
To investigate the optimal threshold for measuring thyroid volume in patients with Grave's hyperthyroidism (GH) by SPECT/CT.
Materials and methods
A 53 mL butterfly-shaped hollow container ...made of two 45-degree transparent elbows was put into a NEMA IEC phantom tank. The butterfly-shaped container and the tank were then filled with Na
99m
TcO4 of different radioactive concentrations, respectively, which could simulate thyroid gland with GH by different target-to-background ratios (T/B) (200:1, 600:1, 1000:1). The different T/B of planar imaging and SPECT/CT were acquired by a Discovery NM/CT 670 Pro SPECT/CT. With Thyroid software (Version 4.0) of GE-Xeleris workstation, the region of the thyroid gland in planar imaging was delineated. The thyroid area and average long diameter of both lobes were substituted into the Allen formula to calculate the thyroid volume. The calculation error was compared with the actual volume. Q-Metrix software was used to perform CT-based attenuation correction, scatter correction, resolution recovery. Ordered-subsets expectation maximization was used to reconstruct SPECT data. 20%, 25%, 30%, 40%, 50%, 60% thresholds were selected to automatically delineate the volume of interest and compared with the real volume, which determinated the optimal threshold. We measured the thyroid volume of 40 GH patients using the threshold and compared the volumes obtained by planar imaging and ultrasound three-dimensional. The differences of the volumes with different T/B and thresholds were compared by the ANOVA and least significant difference
t
test. The volumes delineated by SPECT/CT were evaluated using ANOVA, least significant difference
t
test, correlation analysis and, linear regression and Bland–Altman concordance test plot. The differences and consistency of thyroid volume were compared among the above three methods.
Results
There was no significant difference in the results between different T/B models (
P
> 0.05). The thyroid volume calculated by the planar imaging formula method was higher than the real volume, with an average overestimation of 22.81%. The volumes delineated by SPECT/CT threshold automatically decreased while the threshold increased. There were significant differences between groups with different thresholds (
P
< 0.001). With an average error of 3.73%, the thyroid volume analyzed by the threshold of 25% was close to the results of ultrasound measurement (
P
> 0.05). Thyroid volume measured by planar imaging method was significantly higher than ultrasound and SPECT/CT threshold automatic delineation method (
P
< 0.05). The agreement between the SPECT/CT 25% threshold and ultrasound (
r
= 0.956,
b
= 0.961) was better than that between the planar imaging and ultrasound (
r
= 0.590,
b
= 0.574). The Bland–Altman plot also showed that the thyroid volume measured by the 25% threshold automatic delineation method was in good agreement with the ultrasound measurement.
Conclusions
The T/B has no effect on the measurement of thyroid volume in GH patients; planar imaging method can significantly overestimate thyroid volume in GH patients, and 25% threshold automatic delineation method can obtain more accurate thyroid volume in GH patients.
This paper develops a decision-making model to assist the improvement of the carrying capacity of ship locks by combing fuzzy logic, the analytic hierarchy process (AHP) method, and the technique for ...order preference by similarity to an ideal solution (TOPSIS). A three-level hierarchical structure is constructed to identify the key factors influencing the carrying capacity of ship locks from the aspects of ship locks, vessels, environment, and administration. On this basis, a series of targeted strategies have been put forward to improve the carrying capacity of ship locks, and the TOPSIS method is applied to rank these strategies in terms of their performance. A case study of the five-stage dual-track ship lock of the Three Gorges Dam in China has been conducted to demonstrate the feasibility and rationality of the proposed model, and correlation analysis is conducted to verify the identified influencing factors in order to eliminate potential bias which may be generated from using AHP. The results obtained from the proposed methods are consistent with the real-life situation to a certain extent, indicating that the proposed method can provide a useful reference for improving the carrying capacity of ship locks.
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