CACNA2D3 Enhances the Chemosensitivity of Esophageal Squamous Cell Carcinoma to Cisplatin via Inducing Ca2+-Mediated Apoptosis and Suppressing PI3K/Akt Pathways

Resistance to platinum-based combination chemotherapy is the main cause of poor prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC). Previously, we showed that CACNA2D3 (voltage-dependent subunit alpha 2 delta 3 of a calcium channel complex) was significantly downregulated and functioned as a tumor suppressor in ESCC, but its role in the chemosensitivity of ESCC to cisplatin remained unknown. Here, we found that the expression of CACNA2D3 was significantly associated with poor platinum response in ESCC patients from the Gene Expression Omnibus database. Overexpression of CACNA2D3 increased sensitivity to cisplatin in ESCC in vitro, whereas knockdown of CACNA2D3 increased cisplatin resistance. CACNA2D3 promoted cisplatin-induced apoptosis by modulating intracellular Ca2+ stores. In vivo experiments further showed that overexpression of CACNA2D3 enhanced cisplatin anti-tumor effects in a xenograft mouse model. CACNA2D3 overexpression also resulted in the attenuation of PI3K and Akt phosphorylation. Treatment with the PI3K/Akt inhibitor LY294002 restored the chemosensitivity of CACAN2D3-knockdown cells to cisplatin. In conclusion, the results of the current study indicate that CACAN2D3 enhances the chemosensitivity of ESCC to cisplatin via inducing Ca2+-mediated apoptosis and suppressing PI3K/Akt pathways. Therefore, regulating the expression of CACNA2D3 is a potential new strategy to increase the efficacy of cisplatin in ESCC patients

Discovery and Characterization of a High-Affinity Small Peptide Ligand, H1, Targeting FGFR2IIIc for Skin Wound Healing

Background/Aims: How to aid recovery from severe skin injuries, such as burns, chronic or radiation ulcers, and trauma, is a critical clinical problem. Current treatment methods remain limited, and the discovery of ideal wound-healing therapeutics has been a focus of research. Functional recombinant proteins such as basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) have been developed for skin repair, however, some disadvantages in their use remain. This study reports the discovery of a novel small peptide targeting fibroblast growth factor receptor 2 IIIc (FGFR2IIIc) as a potential candidate for skin wound healing. Methods: A phage-displayed peptide library was used for biopanning FGFR2IIIc-targeting small peptides. The selected small peptides binding to FGFR2IIIc were qualitatively evaluated by an enzyme-linked immunosorbent assay. Their biological function was detected by a cell proliferation assay. Among them, an optimized small peptide named H1 was selected for further study. The affinity of the H1 peptide and FGFR2IIIc was determined by an isothermal titration calorimetry device. The ability of theH1 peptide to promote skin wound repair was investigated using an endothelial cell tube formation assay and wound healing scratch assay in vitro. Subsequently, the H1 peptide was assessed using a rat skin full-thickness wound model and chorioallantoic membrane (CAM) assays in vivo. To explore its molecular mechanisms, RNA-Seq, quantitative real-time PCR, and western blot assays were performed. Computer molecular simulations were also conducted to analyze the binding model. Results: We identified a novel FGFR2IIIc-targeting small peptide, called H1, with 7 amino acid residues using phage display. H1 had high binding affinity with FGFR2IIIc. The H1 peptide promoted the proliferation and motility of fibroblasts and vascular endothelial cells in vitro. In addition, the H1 peptide enhanced angiogenesis in the chick chorioallantoic membrane and accelerated wound healing in a rat full-thickness wound model in vivo. The H1 peptide activated both the PI3K-AKT and MAPK-ERK1/2 pathways and simultaneously increased the secretion of vascular endothelial growth factor. Computer analysis demonstrated that the model of H1 peptide binding to FGFR2IIIc was similar to that of FGF2 and FGFR2IIIc. Conclusion: The H1 peptide has a high affinity for FGFR2IIIc and shows potential as a wound healing agent. As a substitute for bFGF, it could be developed into a novel therapeutic candidate for skin wound repair in the future

PRMT inhibition induces a viral mimicry response in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and few effective therapies. Here we identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), which has antitumor growth activity in TNBC. Pathway analysis of TNBC cell lines indicates that the activation of interferon responses before and after MS023 treatment is a functional biomarker and determinant of response, and these observations extend to a panel of human-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway with the induction of double-stranded RNA, which is derived, at least in part, from inverted repeat Alu elements. Together, our results represent a shift in understanding the antitumor mechanism of type I PRMT inhibitors and provide a rationale and biomarker approach for the clinical development of type I PRMT inhibitors

An Aluminum-Lithium Allloy Produced by Laser Powder Bed Fusion

Aluminum-lithium (Al-Li) alloys are promising to replace traditional high-strength aluminum alloys in aerospace and military industries due to their low density, high specific strength, and excellent corrosion resistance. However, there is little research focused on the laser powder bed fusion (LPBF) of Al-Li alloys due to their poor weldability and high crack susceptibility. In this study, the feasibility of the Al-Li alloy fabricated by LPBF was investigated. The effect of the processing parameters on the densification and crack formation behavior was studied. Finally, after optimizing the processing parameters, crack-free and nearly fully dense 2195 Al-Li alloy 3D-printed samples were obtained. A relative density of 99.92% and a microhardness of 89.1 HV were achieved.Mechanical Engineerin

The Effect of Processing Parameter on Zirconium Modified Al-Cu-Mg Alloys Fabricated by Selective Laser Melting

The newly designed alloy compositions for selective laser melting (SLM) have aroused great interest. In this study, zirconium modified Al-Cu-Mg alloys were fabricated by SLM. Results show that crack-free samples with relative density of nearly 100% were obtained by optimizing the processing parameters. With the increase of scanning speed, the relative density decreases due to insufficient energy input. In addition, the microstructure transforms from homogeneous to bio-modal, the reason is the unstable flows caused by the high scanning speed. The small hatching space will provide more energy input and preheat, leading to the coarse surface.Mechanical Engineerin

Investigation on Selective Laser Melting AlSi10Mg Cellular Lattice Strut: Molten Pool Morphology, Surface Roughness and Dimensional Accuracy

AlSi10Mg inclined struts with angle of 45° were fabricated by selective laser melting (SLM) using different scanning speed and hatch spacing to gain insight into the evolution of the molten pool morphology, surface roughness, and dimensional accuracy. The results show that the average width and depth of the molten pool, the lower surface roughness and dimensional deviation decrease with the increase of scanning speed and hatch spacing. The upper surface roughness is found to be almost constant under different processing parameters. The width and depth of the molten pool on powder-supported zone are larger than that of the molten pool on the solid-supported zone, while the width changes more significantly than that of depth. However, if the scanning speed is high enough, the width and depth of the molten pool and the lower surface roughness almost keep constant as the density is still high. Therefore, high dimensional accuracy and density as well as good surface quality can be achieved simultaneously by using high scanning speed during SLMed cellular lattice strut

Effect of defocusing distance on laser powder bed fusion of high strength Al–Cu–Mg–Mn alloy

The influence of the defocusing distance on melt pool morphology, defect, microstructure and mechanical properties of the laser powder bed fusion (L-PBF) of high strength Al–Cu–Mg–Mn alloy was studied. It is found that because of the different laser energy distribution, the defocusing distance has significant effects on melt pool morphology, defects, microstructure and mechanical properties of the L-PBF parts using same process parameters and laser spot size. When defocusing distance in the range of −3.0 to 0 mm, specimens with cracks, fine grains and keyhole or transition melt mode are obtained. When defocusing distance is positive or −3.0 mm, specimens with no cracks, columnar grains and conduction mode are obtained. The best mechanical properties are obtained when defocusing distance is 1.0 mm in this experiment. This paper provides a novel method for tailoring the microstructure and mechanical properties of L-PBF parts

Esophagogastroduodenoscopy Outcomes Variated by the Time of the Day: A Single-Center Experience

(1) Background: To assess whether the start time influences the outcomes of esophagogastroduodenoscopy (EGD). (2) Methods: We retrospectively analyzed the clinical data of patients who underwent EGD between January 2021 and December 2021 in our endoscopy center. The EGD were divided into three shifts, according to the start time. The lesion detection rate (LDR) and endoscopy biopsy rate (EBR) were used to evaluate the quality of the EGD. (3) Results: A total of 14,597 procedures were included in this study. The LDR of shift 2 was significantly lower than that of shift 1 (62.4% vs. 58.5%; p < 0.001). The EBR of shift 1 (37.4% vs. 31.5%; p < 0.001) and shift 3 (35.5% vs. 31.5%; p = 0.024) were significantly higher than that of shift 2; the EBR in shift 1 did not differ significantly from shift 3 (p = 0.280). The multivariable analysis for the EGD performed before 14:00 demonstrated a graded decrease in the LDR and EBR after adjusting the confounders (p < 0.001). (4) Conclusion: In a continuous working period, the lesion detection and biopsy submission of EGD are superior to those in the first three hours compared to the last three hours; the LDR and EBR decreased as the day progressed, probably due to the endoscopists’ fatigue

Adjuvant Therapy of Oral Chinese Herbal Medicine for Menopausal Depression: A Systematic Review and Meta-Analysis

Objective. The aim of this meta-analysis was to evaluate the effectiveness of oral Chinese herbal medicine (OCHM) combined with pharmacotherapy for menopausal depression. Methods. The electronic databases were searched from their inception to December 25, 2016, comprising PubMed, Embase, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure (CNKI), Wanfang database, and Chinese Biomedical (CBM) database. Randomized controlled trials investigating the effectiveness of OCHM combined with pharmacotherapy for the people with menopausal depression were eligible. Risk of bias was evaluated according to the Cochrane handbook. Meta-analyses were performed to pool the effect size. Heterogeneity and publication bias were also examined. Results. Twenty-two RCTs with 1770 participants were included in the review. None of the studies used placebo as the control and the risk of bias was high in blinding the participants and personnel. Overall, the meta-analysis demonstrated that adjuvant therapy of OCHM was effective in reducing the Hamilton Rating Scale for Depression (HAMD) scores compared to pharmacotherapy (MD = −3.75; 95% CI = −5.22, −2.29; P < 0.00001). The meta-analysis also suggested that OCHM adjuvant therapy for menopausal depression was superior to pharmacotherapy in terms of response rate of reducing HAMD scores (RR = 1.17; 95% CI = 1.10, 1.25; I2 = 55%). Conclusions. OCHM may provide additional effectiveness to pharmacotherapy for the people with menopausal depression. RCTs including the placebo control were required to further determine the additional efficacy of OCHM for menopausal depression