Changes in the Glucose Concentration Affect the Formation of Humic-like Substances in Polyphenol-Maillard Reactions Involving Gibbsite.

The polyphenol-Maillard reaction is considered one of the important pathways in the formation of humic-like substances (HLSs). Glucose serves as a microbial energy source that drives the humification process. However, the effects of changes in glucose, particularly its concentration, on abiotic pathways remain unclear. Given that the polyphenol-Maillard reaction requires high precursor concentrations and elevated temperatures (which are not present in soil), gibbsite was used as a catalyst to overcome energetic barriers. Catechol and glycine were introduced in fixed concentrations into a phosphate-buffered solution containing gibbsite using the liquid shake-flask incubation method, while the concentration of glucose was controlled in a sterile incubation system. The supernatant fluid and HLS components were dynamically extracted over a period of 360 h for analysis, thus revealing the influence of different glucose concentrations on abiotic humification pathways. The results showed the following: (1) The addition of glucose led to a higher degree of aromatic condensation in the supernatant fluid. In contrast, the supernatant fluid without glucose (Glu0) and the control group without any Maillard precursor (CK control group) exhibited lower degrees of aromatic condensation. Although the total organic C (TOC) content in the supernatant fluid decreased in all treatments during the incubation period, the addition of Maillard precursors effectively mitigated the decreasing trend of TOC content. (2) While the C content of humic-like acid (CHLA) and the CHLA/CFLA ratio (the ratio of humic-like acid to fulvic-like acid) showed varying increases after incubation, the addition of Maillard precursors resulted in a more noticeable increase in CHLA content and the CHLA/CFLA ratio compared to the CK control group. This indicated that more FLA was converted into HLA, which exhibited a higher degree of condensation and humification, thus improving the quality of HLS. The addition of glycine and catechol without glucose or with a glucose concentration of 0.06 mol/L was particularly beneficial in enhancing the degree of HLA humification. Furthermore, the presence of glycine and catechol, as well as higher concentrations of glucose, promoted the production of N-containing compounds in HLA. (3) The presence of Maillard precursors enhanced the stretching vibration of the hydroxyl group (-OH) of HLA. After the polyphenol-Maillard reaction of glycine and catechol with glucose concentrations of 0, 0.03, 0.06, 0.12, or 0.24 mol/L, the aromatic C structure in HLA products increased, while the carboxyl group decreased. The presence of Maillard precursors facilitated the accumulation of polysaccharides in HLA with higher glucose concentrations, ultimately promoting the formation of Al-O bonds. However, the quantities of phenolic groups and phenols in HLA decreased to varying extents.

Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin-4-IgG4-Fc in healthy subjects: A phase 1, single-centre, randomized, double-blind, dose escalation study.

AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.

Modified response evaluation criteria in solid tumors: A better response evaluation criteria for patients with non-squamous non-small cell lung cancer after bevacizumab treatment.

AIM: Cavitation of lesions is common in non-squamous non-small cell lung cancer (non-squamous-NSCLC) patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFRIs). However, traditional response evaluation criteria in solid tumors (RECIST) do not take cavitation into consideration and may no longer be accurate for potentially reflecting the real clinical efficacy of anti-vessel growth therapy. Here, we aimed to optimize the traditional RECIST version 1.1 by adding cavitation into the evaluation criteria. METHODS: We performed a post-hoc radiologic review of 517 patients in a phase III clinical trial of bevacizumab biosimilar (SIBP04) combined with chemotherapy for the treatment of non-squamous NSCLC. Tumor responses were assessed by RECIST1.1 and mRECIST criteria (modified RECIST, a novel alternate method where the longest diameter of the cavity was subtracted from the overall longest diameter of that lesion to measure target lesions), respectively, and correlated with clinical outcomes. RESULTS: Cavitations of pulmonary lesions were seen in nine (2%) patients at baseline, and 97 (19%) during treatment. The use of mRECIST resulted in an alteration of the response category. For patients with post-therapy cavitation, the objective response rate was 56% using RECIST1.1 and 67% by mRECIST. In addition, the survival rates between partial response, stable disease, and progressive disease when the mRECIST was applied were significantly different (p < 0.05), while RECIST1.1 failed to show survival differences (p = 0.218). CONCLUSION: For patients with post-therapy cavitation, mRECIST exhibited higher predictability of survival than RECIST1.1. Response assessment might be improved by incorporating cavitation into assessment, potentially altering outcomes of key clinical efficacy parameters.

Outcome benefits of bevacizumab biosimilar (SIBP04) combined with carboplatin and paclitaxel in advanced non-squamous non-small-cell lung cancer patients with EGFR mutation: subgroup analysis of a prospective, randomized phase III clinical trial.

PURPOSE: SIBP04 is a bevacizumab biosimilar, and bevacizumab combined with carboplatin and paclitaxel in advanced non-squamous non-small-cell lung cancer (nsqNSCLC) has been recommended as the first-line treatment choice. However, the efforts of bevacizumab combined with carboplatin and paclitaxel for nsqNSCLC patients with EGFR mutation remained unclear. Here we report an EGFR mutation subgroup analysis of a prospective, randomized phase III clinical trial (NCT05318443). METHODS: In this randomized, double-blind, multi-center, parallel controlled, phase III clinical trial, locally advanced, metastatic NSCLC patients were enrolled, and EGFR expression was examined and considered as a stratification factor. All patients received 4 to 6 cycles of paclitaxel and carboplatin plus SIBP04 or bevacizumab 15 mg/kg intravenously followed by SIBP04 15 mg/kg maintenance until intolerable toxicity, disease progression or death. Patients with EGFR mutation and wild-type were assessed for progression-free survival (PFS) and overall survival (OS). RESULTS: EGFR expression was examined in 398 NSCLC patients (142 with EGFR mutation, 256 with EGFR wild type). PFS in EGFR mutation patients was significantly longer than EGFR wild-type patients (10.91 vs. 7.82 months; HR = 0.692, 95% CI 0.519-0.921, P = 0.011). The median OS in patients with EGFR mutation was not reached while that of EGFR wild-type group was 17.54 months (HR = 0.398, 95% CI 0.275-0.575, P < 0.001). However, there were no significant differences in objective response rate (61.97% vs. 55.86%, P = 0.237) or disease control rate (90.14% vs. 89.84%, P = 0.925). CONCLUSION: Bevacizumab combined with chemotherapy significantly prolonged the PFS and OS of advanced nsqNSCLC patients with EGFR mutation.

Study of Microstructure and Fatigue in Aluminum/Steel Butt Joints Made by CMT Fusion-Brazing Technology.

Cold metal transfer (CMT) fusion brazing technology was used to weld 6061 aluminum alloy and Q235 galvanized steel with ER4043 welding wire. The microstructure, hardness, tensile performance, and fatigue performance of the welded joint were observed and analyzed. The results show that the tensile strength of the welded joint is 110.83 MPa and the fatigue strength limit is 170 MPa. In the fatigue process, the coupon first undergoes cyclic hardening and then cyclic softening and a ratchet effect occurs. The coupon was broken at the interface layer or weld zone where the fatigue strength limit is the lowest. The fatigue crack initiation is mainly caused by: (1) inclusions and second-phase particles; and (2) porosity and incomplete fusion. When cracks encounter holes during expansion, the expansion direction will change. The fatigued coupon displays a toughness fracture in the instantaneous fracture zone.

Circ_0000467 Exerts an Oncogenic Role in Colorectal Cancer via miR-330-5p-Dependent Regulation of TYRO3.

Colorectal cancer (CRC) remains one of the most frequent neoplasms of digestive tract worldwide. Circular RNAs (circRNAs) have been identified to serve crucial regulatory roles in the pathogenesis of human cancers. However, the role and regulatory mechanism of circ_0000467 in the progression of CRC are still unclear. The expression levels of circ_0000467, microRNA-330-5p (miR-330-5p), and tyrosine receptor kinase 3 (TYRO3) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The interaction between miR-330-5p and circ_0000467 or TYRO3 was validated by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Xenograft tumor assay and Immunohistochemistry (IHC) assay were implemented to analyze CRC tumor growth in vivo. Circ_0000467 was a stable circRNA and was highly expressed in CRC tumor tissues and cells. Silencing of circ_0000467 could inhibit the proliferation, migration, invasion, and glycolysis and accelerated the apoptosis of CRC cells in vitro and hindered tumor growth in vivo. Mechanistically, circ_0000467 directly interacted with miR-330-5p and circ_0000467 depletion inhibited CRC cell malignant progression by regulating miR-330-5p. Furthermore, TYRO3 was a target of miR-330-5p and circ_0000467 upregulated TYRO3 expression by sponging miR-330-5p. Moreover, TYRO3 overexpression counteracted the inhibitory effect of miR-330-5p overexpression or circ_0000467 knockdown on CRC cell progression. Altogether, circ_0000467 knockdown suppressed CRC cell malignant development through modulating the miR-330-5p/TYRO3 network, providing a novel molecular target of CRC therapy.

Microstructure and Fatigue Damage of 316L Stainless Steel Manufactured by Selective Laser Melting (SLM).

In this paper, 316L stainless steel powder was processed and formed by selective laser melting (SLM). The microstructure of the sample was studied using an optical microscope, and the fatigue failure of the sample and the characteristics of crack initiation and propagation were analyzed, providing a research basis for the application of SLM-316L. Due to the influence of microstructure and SLM process defects, the fatigue cracks of SLM-316L mainly emerged due to defects such as lack of fusion and pores, while the cracks of rolled 316L initiated at the inclusions near the surface of the specimen. After fatigue microcrack initiation of the SLM-316L specimen, due to the existence of shear stress and tear stress, the crack tip was passivated and Z-shaped propagation was formed. The existence of internal defects in SLM-316L made the microcrack initiation random and diverse. At the same time, the existence of defects affected the crack propagation in the form of bending, bifurcation and bridge, which made the main crack propagation deviate from the maximum load direction.

Jagged1 is Clinically Prognostic and Promotes Invasion of Glioma-Initiating Cells by Activating NF-κB(p65) Signaling.

BACKGROUND/AIMS: Jagged1 is the ligands of the Notch signaling and has been shown to promote glioma-initiating cells (GICs) in glioblastoma. The role of Jagged1 in GICs invasion and underlying molecular mechanisms remain unclear. METHODS: Survival data from R2 genomics analysis, the Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA) and visualization platform database were used to evaluate the effects of Jagged1 on overall patient survival. we investigated Jagged1 induced the GICs cells' invasion by matrix degradation assays and Transwell cell invasion assays in vitro, then we further explored the underlying molecular mechanisms using Co-immunoprecipitation (co-IP) analysis. RESULTS: High expression of Jagged1 in human glioma was associated with poor survival. Clinical data analysis showed that the Jagged1 was positively correlated with NF-κB(p65). Jagged1-induced invasion of GICs cells through activation of NF-κB(p65) pathway. In vivo, knockdown of Jagged1 could suppress the tumorigenicity of GICs cells through NF-κB(p65) signaling. CONCLUSION: Insights gained from these findings suggest that Jagged1 plays an important oncogenic role in GICs malignancy by activation of NF-κB(p65) signaling, and Jagged1 could be employed as an effective therapeutic target for GICs.

Tumour cell dormancy as a contributor to the reduced survival of GBM patients who received standard therapy.

Glioblastoma multiforme (GBM) is a fatal cancer with varying life expectancy, even for patients undergoing the same standard therapy. Identification of differentially expressed genes in GBM patients with different survival rates may benefit the development of effective therapeutic strategies. In the present study, key pathways and genes correlated with survival in GBM patients were screened with bioinformatic analysis. Included in the study were 136 eligible patients who had undertaken surgical resection of GBM followed by temozolomide (TMZ) chemoradiation and long-term therapy with TMZ. A total of 383 differentially expressed genes (DEGs) related to GBM survival were identified. Gene Ontology and pathway enrichment analysis as well as hub gene screening and module analysis were performed. As expected, angiogenesis and migration of GBM cells were closely correlated with a poor prognosis. Importantly, the results also indicated that cell dormancy was an essential contributor to the reduced survival of GBM patients. Given the lack of specific targeted genes and pathways known to be involved in tumour cell dormancy, we proposed enriched candidate genes related to the negative regulation of cell proliferation, signalling pathways regulating pluripotency of stem cells and neuroactive ligand-receptor interaction, and 3 hub genes (FTH1, GRM1 and DDIT3). Maintaining persistent cell dormancy or preventing tumour cells from entering dormancy during chemoradiation should be a promising therapeutic strategy.

Notch1 is a prognostic factor that is distinctly activated in the classical and proneural subtype of glioblastoma and that promotes glioma cell survival via the NF-κB(p65) pathway.

Glioblastomas (GBMs) are the most prevalent and devastating primary intracranial malignancies and have extensive heterogeneity. Notch1 signaling is a more complex process in the development of numerous cell and tissue types, including gliomagenesis and progression, and is upregulated in glioma-initiating cells. However, the contradictory expression of Notch1 among lower grade gliomas and GBMs confounds our understanding of GBM biology and has made identifying effective therapies difficult. In this study, we validated that Notch1 and NF-κB(p65) are highly expressed in the classical and proneural subtypes of GBM using the data set from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). DAPT and shRNA targeting Notch1 decreased NF-κB(p65) expression, suppressed cell proliferation, and induced apoptosis of GBM cells in vitro and in vivo. Furthermore, we illustrated that the intracellular Notch could bind with NF-κB(p65) in GBM cells. These findings suggest that the cross-talk between Notch1 signaling and NF-κB(p65) could contribute to the proliferation and apoptosis of glioma, and this discovery could help drive the design of more effective therapies in Notch1-targeted clinical trials.

The interactome and spatial redistribution feature of Ca2+ receptor protein calmodulin reveals a novel role in invadopodia-mediated invasion.

Numerous studies have shown that calmodulin (CaM) is a major regulator of calcium-dependent signaling, which regulates cell proliferation, programmed cell death, and autophagy in cancer. However, limited information is available on mechanisms underlying the effect of CaM on the invasive property of glioblastoma multiforme (GBM) cells, especially with respect to invadopodia formation. In this study, we find that CaM serves as a prognostic factor for GBM, and it is strongly associated with the invasive nature of this tumor. Results of preliminary experiments indicated that CaM concentration was significantly correlated with the invasive capacity of and invadopodia formation by different GBM cell lines. CaM inhibition via a small hairpin RNA or a pharmacological inhibitor significantly disrupted invadopodia formation and MMP activity and downregulated vimentin expression. Moreover, CaM knockdown exerted a strong anti-invasive effect on GBM in vivo. Interestingly, epidermal growth factor treatment promoted CaM redistribution from the nucleus to the cytoplasm, eventually activating invadopodia-associated proteins by binding to them via their cytosolic-binding sites. Moreover, CaM inhibition suppressed the activation of invadopodia-associated proteins. Thus, our findings provide a novel therapeutic strategy to impede GBM invasion by inhibiting invadopodia formation, and shed light on the spatial organization of CaM signals during GBM invasion.

Three-dimensional hydrogel is suitable for targeted investigation of amoeboid migration of glioma cells.

Glioblastoma (GBM) invasion and migration are key biological behaviors leading to refractoriness to current therapies and infiltration into the non­tumor brain parenchyma. GBM cell migration is strongly dependent on tumor architecture in vivo, which is absent in traditional two­dimensional (2D) monolayer culture. The present study applied a three­dimensional (3D) hydrogel model to rebuild the tumor architecture in vitro. Treatment with NSC23766, a specific inhibitor of Ras­related C3 botulinum toxin substrate 1 (Rac1), inhibited the mesenchymal invasiveness however triggered the amoeboid motility called mesenchymal­amoeboid transition (MAT). Notably, NSC23766 stimulated U87 GBM cell migration in the 3D hydrogel. However, this compound inhibited cell motility in 2D monolayer culture without tumor architecture for MAT, suggesting the advantage of 3D hydrogel to investigate tumor cell invasion. Due to the inverse interaction of Rac1 and Ras homolog family member A (RhoA) signaling in the transition between mesenchymal and amoeboid morphology, simultaneous treatment of NSC23766 and Y27632 (selective Rho associated coiled­coil containing protein kinase 1 inhibitor), abolished U87 GBM cell migration through inhibiting MAT and amoeboid­mesenchymal transition. In addition, Y27632 induced integrin expression which gave rise to the focal adhesion to facilitate the mesenchymal invasion. The results of the present study demonstrated that the 3D hydrogel was a preferable model in vitro to study tumor cell invasion and migration. The combined inhibition of Rac1 and RhoA signaling would be a promising strategy to suppress GBM invasion.

Actin cytoskeleton regulator Arp2/3 complex is required for DLL1 activating Notch1 signaling to maintain the stem cell phenotype of glioma initiating cells.

Glioblastoma (GBM) is the most common and lethal primary intracranial tumor. Actin cytoskeleton regulator Arp2/3 complex stimulates glioma cell motility and migration, and thus triggers tumor invasion. However, little is known regarding the role of actin cytoskeleton in maintaining the stem cell phenotype. Here, we showed that Arp2/3 complex improved stem cell phenotype maintenance through sustaining the activated Notch signaling. ShRNA targeting Notch ligand Delta-like 1 (DLL1) decreased CD133 and Nestin expression, and impaired the self-renewal ability of CD133+ U87-MG and U251-MG glioma cells, indicating DLL1/Notch1 signaling promoted stem cell phenotype maintenance. Interestingly, inhibiting Arp2/3 complex also induced the similar effect of shDLL1. Silencing DLL1 in the Arp2/3 inhibited CD133+ cells did not further abrogate the stem cell phenotype, suggesting DLL1 function requires Arp2/3 complex in glioma initiating cells (GICs). However, exogenous soluble DLL1 (sDLL1) instead of endogenous DLL1 rescued the Arp2/3 inhibition-induced stem cell phenotype suppression. The underlying mechanism was that Arp2/3 inhibition impeded DLL1 vesicular transport from cytoplasm to cell membrane, which resulted in DLL1 unable to activate Notch pathway. Furthermore, we illustrated that Arp2/3 inhibition abolished the tumorigenicity of CD133+ U87-MG neurosphere cells in the intracranial model. These findings suggested that cytoskeleton maintained the stem cell phenotype in GBM, which provide novel therapeutic strategy that anti-invasive targeted therapies may help eliminate GICs.

[Quantitative analysis of the exposure of suboccipital far-lateral approach and postauricular transtemporal approach to the jugular foramen region].

OBJECTIVE: To study the exposure of suboccipital far-lateral approach and postauricular transtemporal approach to the jugular foramen region based on quantitative measurements, and provide reliable anatomic data for selecting surgical approach individually and protecting the function of important structures. METHODS: The complete approach of the suboccipital far-lateral approach and the postauricular transtemporal approach were reproduced in twelve (twenty-four sides) head-neck specimens of adults be fixed in 10% formalin. The exposure area to the jugular foramen region was obtained using a stereotactic device, and the length of exposure of the clivus and the trigeminal nerve were measured using a vernier caliper. RESULTS: In the suboccipital far-lateral approach, the significant increase in exposure was noted after removal of the jugular process and partial resection of occipital condyle. In the postauricular transtemporal approach, the exposure increased significantly after complete retrolabyrinthine approach, partial labyrinthectomy and transcochlear approach. CONCLUSIONS: Resection of jugular process is the key to expose the jugular foramen through the far-lateral approach. The infralabyrinthine approach and the partial labyrinthectomy approach are ideal approaches to expose the jugular foramen region laterally.

[Total mesorectal excision versus conventional radical surgery for rectal cancer: a meta analysis].

OBJECTIVE: To compare treatment outcomes of total mesorectal excision (TME) with those of conventional radical surgery (CRS) for rectal cancer. METHODS: Literature reviews were performed with key words, such as rectal cancer, total mesorectal excision, TME on all studies reported on TME versus CRS for rectal cancer between January 1986 to May 2006. According to the same screening criteria, 17 clinical studies were included in our systematic reviews. Two of our co-authors drew the details of trial design, characteristics of participants, results and so on from the studies included. Data analyses were performed by using RevMan 4.2. RESULTS: Sample volume in this Meta analysis was 5267 rectal cancer cases. Quality and quantity analyses were performed within all included studies, prospective studies (prospective nonrandomized studies and multicenter prospective nonrandomized studies) and retrospective studies. The results showed that postoperative survival rate was significantly increased [OR 1.81 (95%CI 1.55-2.11, P<0.00001), OR 1.79 (95%CI 1.49-2.15, P<0.00001) and OR 1.84 (95%CI 1.39-2.45, P<0.00001)] and local recurrence rate was significantly reduced [OR 0.35 (95%CI 0.29-0.43, P<0.00001), OR 0.41 (95%CI 0.32-0.53, P<0.00001) and OR 0.29 (95%CI 0.22-0.39, P<0.00001)] after TME was used. The results of all study analyses agreed with those from prospective studies analyses, in which postoperative mortality was significantly reduced [OR 0.51 (95%CI 0.32-0.87, P=0.007) and OR 0.56 (95%CI 0.33-0.94, P=0.04)] after TME treatment, meanwhile the results of retrospective study analyses indicated that there was no significant difference between TME group and CRS group in postoperative mortality [OR 0.39 (95%CI 0.14-1.10, P=0.07)]. TME was a risk factor for postoperative anastomotic leak according to the results of all included studies and prospective study analyses, but no difference between TME group and CRS group had been found [OR 1.24 (95%CI 0.84-1.83, P=0.29) OR 1.98 (95%CI 0.85-4.61, P=0.11)]. CONCLUSIONS: TME is still the standard operative technique for rectal cancer. As compared with CRS, TME results in lower postoperative local recurrence rate and higher survival rate.