Appraising non-linear association between pre-diagnostic platelet counts and cancer survival outcomes: observational and genetic analysis.

Previous studies have reported inconsistent associations between platelet count (PLT) and cancer survival. However, whether there is linear causal effect merits in-depth investigations. We conducted a cohort study using the UK Biobank and a two-sample Mendelian randomization (MR) analysis. PLT levels were measured prior to cancer diagnosis. We adopted overall survival (OS) as the primary outcome. Cox models were utilized to estimate the effects of PLTs on survival outcomes at multiple lag times for cancer diagnosis. We employed 34 genetic variants as PLT proxies for MR analysis. Linear and non-linear effects were modeled. Prognostic effects of gene expression harboring the instrumental variants were also investigated. A total of 65 471 cancer patients were included. We identified a significant association between elevated PLTs (per 100 × 109/L) and inferior OS (HR: 1.07; 95% CI: 1.04-1.10; p < .001). Similar significant associations were observed for several cancer types. We further observed a U-shaped relationship between PLTs and cancer survival (p < .001). Our MR analysis found null evidence to support a causal association between PLTs and overall cancer survival (HR: 1.000; 95% CI: 0.998-1.001; p = .678), although non-linear MR analysis unveiled a potential greater detrimental effect at lower PLT range. Expression of eleven PLT-related genes were associated with cancer survival. Early detection of escalated PLTs indicated possible occult cancer development and inferior subsequent survival outcomes. The observed associations could potentially be non-linear. However, PLT is less likely to be a promising therapeutic target.

What is the context? Previous studies have reported inconsistent associations between platelet counts (PLTs) and cancer survival. However, it is unclear whether there is a linear causal effect, as most studies measured PLTs at the time of cancer diagnosis, which could be influenced by the cancer itself.This study aimed to investigate the association and potential causality between pre-diagnostic PLTs and cancer survival outcomes using a large prospective cohort and genetic analysis.What is new? The observational cohort study found a significant association between elevated pre-diagnostic PLTs and poorer overall and cancer-specific survival. We also identified a U-shaped relationship between PLTs and cancer survival, suggesting that both high and low PLTs may be detrimental.The Mendelian randomization analysis did not support a causal effect of PLTs on overall cancer survival, although it hinted at potential non-linear effects at lower PLT ranges.The study also identified several genes (TPM4, PDIA5, PSMD13, TMCC2, ZFPM2, BAZ2A, CDKN2A, GP1BA, TAOK1, CABLES1, and THPO) related to PLTs that were associated with cancer survival.What is the impact? The findings suggest that early detection of elevated PLTs may indicate occult cancer development and poorer subsequent survival outcomes. However, PLTs are less likely to be a promising therapeutic target for improving cancer survival, as the observed associations could be influenced by confounding factors.The study highlights the need for further research into the complex relationship between PLTs and cancer prognosis, as well as the exploration of other platelet-related traits as potential drug targets.

Integrated Network Analysis to Determine CNN1, MYL9, TAGLN, and SORBS1 as Potential Key Genes Associated with Prostate Cancer.

BACKGROUND: Prostate cancer (PCa) is challenging to treat. It is necessary to screen for related biological markers to accurately predict the prognosis and recurrence of prostate cancer. METHODS: Three data sets, GSE28204, GSE30521, and GSE69223, from the Gene Expression Omnibus (GEO) database were integrated into this study. After the identification of differentially expressed genes (DEGs) between PCa and normal prostate tissues, network analyses including protein-protein interaction (PPI) network, and weighted gene co-expression network analysis (WGCNA) were used to select hub genes. Gene Ontology (GO) term analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to annotate the functions of DEGs and hub modules of the networks. Survival analysis was performed to validate the correlation between the key genes and PCa relapse. RESULTS: In total, 867 DEGs were identified, including 201 upregulated and 666 downregulated genes. Three hub modules of the PPI network and one hub module of the weighted gene co-expression network were determined. Moreover, four key genes (CNN1, MYL9, TAGLN, and SORBS1) were significantly associated with PCa relapse (p < 0.05). CONCLUSIONS: CNN1, MYL9, TAGLN, and SORBS1 may be potential biomarkers for PCa development.

Total neoadjuvant therapy versus chemoradiotherapy for locally advanced rectal cancer: Bayesian network meta-analysis.

BACKGROUND: Total neoadjuvant therapy is a promising treatment for locally advanced rectal cancer, utilizing either short-course radiotherapy or long-course chemoradiotherapy, but their relative efficacy remains unclear. The aim of this Bayesian network meta-analysis was to investigate clinical outcomes amongst patients receiving total neoadjuvant therapy with short-course radiotherapy or long-course chemoradiotherapy, and those receiving long-course chemoradiotherapy alone. METHODS: A systematic literature search was performed. All studies that compared at least two of these three treatments for locally advanced rectal cancer were included. The primary endpoint was the pathological complete response rate, and survival outcomes were adopted as secondary outcomes. RESULTS: Thirty cohorts were included. Compared with long-course chemoradiotherapy, both total neoadjuvant therapy with long-course chemoradiotherapy (OR 1.78, 95 per cent c.i. 1.43 to 2.26) and total neoadjuvant therapy with short-course radiotherapy (OR 1.75, 95 per cent c.i. 1.23 to 2.50) improved the pathological complete response rate. Similar benefits were observed in the sensitivity and subgroup analyses, except for short-course radiotherapy with one to two cycles of chemotherapy. No significant differences in survival outcomes were found amongst the three treatments. Long-course chemoradiotherapy with consolidation chemotherapy (HR 0.44, 95 per cent c.i. 0.20 to 0.99) exhibited higher disease-free survival than long-course chemoradiotherapy alone. CONCLUSION: Compared with long-course chemoradiotherapy, both short-course radiotherapy with greater than or equal to three cycles of chemotherapy and total neoadjuvant therapy with long-course chemoradiotherapy can improve the pathological complete response rate, and long-course chemoradiotherapy with consolidation chemotherapy may lead to a marginal benefit in disease-free survival. The pathological complete response rate and survival outcomes are similar for total neoadjuvant therapy with short-course radiotherapy or long-course chemoradiotherapy.

Application of quorum sensing system in microbial synthesis of valuable chemicals: a mini-review.

With advantages of low substrates cost, high optical purity of end products and environmentally friendly fermentation process, microbial production of valuable chemicals grow rapidly. Compared with static microbial strain engineering strategies, such as gene deletion, overexpression and mutation, dynamic pathway regulation is a new approach that balances cellular growth and chemical production. Quorum sensing is a natural microbial communication system responsible for cell-density-related cell behaviors. Accordingly, quorum sensing systems can be employed to achieve dynamic regulation in microorganisms without the need for manual intervention or the use of chemical inducers. In this review, natural quorum sensing systems are firstly summarized. Then, recent progress in using quorum sensing circuits in the field of metabolic engineering is highlighted. The current application challenges of quorum sensing systems and future perspectives in microbial synthesis of chemicals are also discussed.

Altered Salivary Microbiota in Patients with Obstructive Sleep Apnea Comorbid Hypertension.

Purpose: Microorganisms contribute to the pathogenesis of obstructive sleep apnea (OSA)-associated hypertension (HTN), while more studies focus on intestinal microbiome. However, the relationship between oral microbiota and OSA-associated HTN has yet to be elucidated. This study aimed to identify differences in salivary microbiota between patients with OSA comorbid HTN compared with OSA patients, and furthermore evaluate the relationship between oral microbiome changes and increased blood pressure in patients with OSA. Patients and Methods: This study collected salivary samples from 103 participants, including 27 healthy controls, 27 patients with OSA, 23 patients with HTN, and 26 patients with OSA comorbid HTN, to explore alterations of the oral microbiome using 16S rRNA gene V3-V4 high-throughput sequencing. And ultra-high-performance liquid chromatography was used for metabolomic analysis. Results: Alpha- and beta-diversity analyses revealed a substantial difference in community structure and diversity in patients with OSA comorbid HTN compared with patients with OSA or HTN. The relative abundance of the genus Actinomyces was significantly decreased in patients with HTN compared with healthy controls, and those with OSA concomitant HTN compared with the patients in OSA, but was not significantly different between patients with OSA and healthy controls. Linear discriminant analysis effect size and variance analysis also indicated that the genera Haemophilus, Neisseria, and Lautropia were enriched in HTN. In addition, Oribacterium was an unique taxa in the OSA comorbid HTN group compared with the control group. Metabolomic analysis of saliva identified compounds associated with cardiovascular disease in patients with OSA comorbid HTN.2-hydroxyadenine, was significantly increased in the group of patients with OSA compared with controls, and L-carnitine was significantly decreased in patients with OSA comorbid HTN compared with OSA patients. Conclusion: This study highlighted noninvasive biomarkers for patients with OSA comorbid HTN. As the first study to find alterations of the salivary microbiome in patients with OSA comorbid HTN, it may provide a theoretical foundation for clinical diagnosis and treatment of this condition.

Biosynthesis of vanillin by different microorganisms: a review.

Vanillin is a popular flavoring agent widely used around the world. Vanillin is generated by natural extraction, chemical synthesis, or tissue culture technology, but these production methods no longer meet the increasing worldwide demand for vanillin. Accordingly, a biotechnological approach may provide an effective replacement route to obtaining vanillin. Processes for environmentally friendly production of vanillin in microorganisms from different carbon sources, such as eugenol, isoeugenol, lignin, ferulic acid, sugars, and waste residues, with high productivity and yield have been developed. However, challenges remain for optimizing the vanillin biosynthesis process and further improving production titer and yield. In this review, successful and applicable strategies for increasing vanillin titer and yield in different microorganisms are summarized. Additionally, perspectives for further optimizing the production of vanillin are discussed.

Discovery of novel 2-phenylamino-4-prolylpyrimidine derivatives as TRK/ALK dual inhibitors with promising antitumor effects.

In order to explore novel TRK and ALK dual inhibitors, a series of 2-phenylamino-4-prolylpyrimidine derivatives were designed, synthesized and evaluated for their in vitro cytotoxicity and enzymatic activities. Delightfully, most compounds were detected moderated to excellent activities in cellular assay. Among them, compound 21 exhibited encouraging cytotoxicity on KM12, H2228 and KARPAS299 cells with IC50 values of 0.86, 0.141 and 0.072 µM. Meanwhile, the performances of 21 in the enzymatic assays were in good accordance with anti-proliferative activity with IC50 values of 2.2, 9.3 and 38 nM towards TRKA, ALKWT and ALKL1196M, respectively. Compared with Entrectinib, compound 21 not only ensured the inhibitory activity on TRKA, but also improved the affinity with ALK and ALKL1196M to a certain extent. Ultimately, the binding model of 21 with TRKA and ALK were ideally established through molecular docking, which further confirmed the SARs analysis.

Comparative Analysis of the Lignification Process of Two Bamboo Shoots Stored at Room Temperature.

Two types of bamboo shoots, high bamboo (Phyllostachys prominens) shoots (HBSes) and moso bamboo (Phyllostachys edulis) shoots (MBSes), underwent a fast post-harvest lignification process under room temperature storage. To explore the mechanism of lignification in two types of bamboo shoots after post-harvest during room temperature storage, the measurement of cell wall polymers (lignin and cellulose) and enzyme activities of phenylalanine ammonialyase (PAL) and peroxidase (POD), and relative expression of related transcription networks factors (TFs) were performed. The results suggested that the lignification process in HBSes is faster than that in MBSes because of incremental increase in lignin and cellulose contents within 6 days and the shorter shelf-life. Additionally, compared with the expression pattern of lignification-related TFs and correlation analysis of lignin and cellulose contents, MYB20, MYB43, MYB85 could function positively in the lignification process of two types of bamboo shoots. A negative regulator, KNAT7, could negatively regulate the lignin biosynthesis in two types of bamboo shoots. In addition, MYB63 could function positively in HBSes, and NST1 could function negatively in MBSes. Notably, MYB42 may function differently in the two types of bamboo shoots, that is, a positive regulator in HBSes, but a negative regulator in MBSes. Transcription networks provide a comprehensive analysis to explore the mechanism of lignification in two types of bamboo shoots after post-harvest during room temperature storage. These results suggest that the lignification of bamboo shoots was mainly due to the increased activity of POD, higher expression levels of MYB20, MYB43, MYB63, and MYB85 genes, and lower expression levels of KNAT7 and NST1 genes, and the lignification process of HBSes and MBSes had significant differences.

Discovery of Novel Indole-Based Allosteric Highly Potent ATX Inhibitors with Great In Vivo Efficacy in a Mouse Lung Fibrosis Model.

Autotaxin (ATX) is the dominant catalytic enzyme accounting for the lipid mediator lysophosphatidic acid (LPA) through hydrolysis of lysophosphatidylcholine (LPC). There is great interest in developing nonacidic ATX inhibitors with a specific binding mode to serve as potential in vivo effective therapeutic tools. Herein, dating from a high-throughput screening (HTS) product Indole-1 (740 nM), a dedicated optimization campaign was implemented through derivatizing the -COOH group to versatile linkers that well-bridged the indole skeleton and the hydrophobic pocket binding groups. Ultimately, it was established that the coexistence of a carbamate linker and -OH-group-containing amines could generally furnish excellent indole-based ATX inhibitors with even below 1 nM in vitro activities. Two optimal entities were advanced to a bleomycin-induced mice pulmonary fibrosis model, which exerted promising efficacy in alleviating the damaged lung texture caused by bleomycin exposure. The novel carbamate-containing indole-based ATX inhibitors with a concrete binding mode may contribute to the identification of potential therapeutic agents to intervene in fibrotic diseases.

Structure guided design of potent indole-based ATX inhibitors bearing hydrazone moiety with tumor suppression effects.

ATX was capable of catalyzing the hydrolysis of LPC to the lipid mediator LPA which attracted considerable attention on the development of potent ATX inhibitors. Herein, driven by the HTS product indole-based lead 1, a hybridization strategy was utilized to construct the trifluoroacetyl hydrazone moiety through assembling the phenyl thiazole fragment to the indole skeleton of lead 1. After a systematic structure guided optimization, by cycling the phenyl thiazole to the compacted benzothiazole or decreasing the lipophilicity, two promising ATX inhibitors (9j and 25a) were identified with IC50 values of 2.1 nM and 19.0 nM, respectively. All compounds were tested a panel of cancer cell lines and a preliminary affinity on breast cancer cell lines (SI > 16.5) were observed which shed a light on their potential application of breast cancer relevant cases. Through a dedicated docking study, the intramolecular pseudo-ring within the trifluoroacetylhydrazone moiety played a significant role in constraining the binding poses of 9j and 25a. Finally, a binding free energy calculation was conducted to examine the contribution of different interactions in binding affinity.

Galectin-3 may serve as a marker for poor prognosis in colorectal cancer: A meta-analysis.

Galectin-3 has an important function in the development of tumors. The purpose of this meta-analysis was to explore the relationships between the expression of galectin-3 on clinicopathological features and prognosis of colorectal cancer (CRC). A comprehensive literature search was used to identify eligible studies, and Stata software was conducted using in this meta-analysis. A total of 15 studies, including 1661 cases, were matched in the inclusion criteria. The pooled analysis indicated that galectin-3 expression was related to the poor overall survival (OS) in CRC patients (HR: 1.77, 95% CI: 1.36-2.31, P < 0.0001). Our meta-analysis also showed that cancerous tissues have higher levels of galectin-3 expression than normal tissues. Besides, positive galectin-3 expression was also related to advanced TNM stages(III/IV vs. I/II: OR 5.30, 95% CI: 2.42-11.61, P < 0.0001), higher Duke's stages (C/D vs. A/B: OR 4.00, 95% CI: 2.22-7.22, P < 0.0001), venous invasion (venous invasion vs. not: OR 3.02, 95%CI: 1.75-5.22, P < 0.0001) and higher CEA level (CEA≥5 ng/ml vs. ≤ 5 ng/ml: OR 2.09, 95% CI: 1.09-4.03, P = 0.03). In summary, our results indicated that overexpression of galectin-3 is significantly related to the tumor progression and could be a efficient in predicting the prognosis of patients with CRC.

C3 -Symmetric Assemblies from Trigonal Polycarbene Ligands and MI Ions for the Synthesis of Three-Dimensional Polyimidazolium Cations.

Metallosupramolecular poly-NHC-metal assemblies were prepared from trigonal hexakis (H6 -1 a(PF6 )6 and H6 -1 b(PF6 )6 ) or nonakis (H9 -3(BF4 )9 ) imidazolium salts and Ag2 O. Complexes [Ag6 (1 a)2 ](PF6 )6 and [Ag6 (1 b)2 ](PF6 )6 are built from six Ag+ ions sandwiched between two trigonal hexacarbene ligands with an inner and an outer NHC donor in each of the three ligand arms. The metal atoms are arranged in two triangles. The hexakis-NHC ligands bear cinnamic ester groups at the outlying NHC donors, used in postsynthetic [2+2] cycloaddition reactions linking two hexakis-NHC ligands by three cyclobutane units to give complexes [Ag6 (2 a)](PF6 )6 and [Ag6 (2 b)](PF6 )6 bearing a dodecacarbene ligand. From the related nonakisimidazolium salt H9 -3(BF4 )9 , complex [Ag9 (4)](BF4 )9 bearing an octadecacarbene ligand was obtained. Removal of the template metals yielded very large, stable, polyimidazolium cations with 12 or 18 internal imidazolium groups.

Molecular Mechanism of Xylogenesis in Moso Bamboo (Phyllostachys edulis) Shoots during Cold Storage.

A bamboo shoot is the immature stem of the woody grass and a nutritious and popular vegetable in East Asia. However, it undergoes a rapid xylogenesis process right after harvest, even being stored in a cold chamber. To investigate the molecular regulation mechanisms of xylogenesis in Moso bamboo (Phyllostachys edulis) shoots (MBSes) during cold storage, the measurement of cell wall polymers (cellulose, hemicellulose, and lignin) and related enzyme activities (phenylalanine ammonia lyase (PAL), cinnamyl alcohol dehydrogenase (CAD), peroxidase (POD), and xylan xylosyltransferase (XylT)) and transcriptomic analysis were performed during cold storage. It was noticed that cellulose and lignin contents increased, while hemicellulose content exhibited a downward trend. PAL, CAD, and POD activity presented an upward trend generally in MBS when stored at 4 °C for 16 days. XylT activity showed a descending trend during the stages of storage, but slightly increased during the 8th to 12th days after harvest at 4 °C. Transcriptomic analysis identified 72, 28, 44, and 31 functional unigenes encoding lignin, cellulose, xylan biosynthesis enzymes, and transcription factors (TFs), respectively. Many of these secondary cell wall (SCW)-related genes showed higher expression levels in the later period of cold storage. Quantitative RT-PCR analysis of the selected genes conformed to the expression pattern. Our study provides a comprehensive analysis of MBS secondary wall biosynthesis at the molecular level during the cold storage process. The results give insight into the xylogenesis process of this economically important vegetable and shed light on solving this problem of the post-harvest industry.

Clinical application of E-MAX glass ceramic onlays in the restorations of the nonvital posterior teeth / 口腔疾病防治

Objective @# To investigate the clinical use of glass ceramic onlay in the restoration of the non-vital posterior teeth with computer aided design and computer-aided manufacturing technique (CAD/CAM). @*Methods @# 70 patients with 75 teeth of residual crown were selected and restored with CAD/CAM glass-ceramic onlay after completely root canal therapy. Marginal adaptation, anatomic form, adjacent relation, contour appearance, color match were checked in 12-month follow-up. @*Results @# Marginal adaptation, anatomic form, adjacent relation, contour appearance, color match of 73 teeth were satisfactory and 2 cases was excluded because of lost to follow-up. There were no significant differences in the number of cases which met clinical criterion A or B between immediate restoration and 12-month follow-up (P > 0.05), and more than 95% of cases met clinical criterion A.@*Conclusion @#The CAD/CAM glass-ceramic onlay in the restoration of non-vital posterior teeth can provide better effect of retention and esthetics in a short term observation of 12 months.