Clinical application of liquid biopsy in colorectal cancer: detection, prediction, and treatment monitoring.

Colorectal cancer (CRC) is one of the most prevalent malignancies affecting the gastrointestinal tract and is ranked third among cancers with the highest incidence and second-highest mortality rate worldwide. CRC exhibits a slow progression providing a wide treatment window. The currently employed CRC screening methods have shown great potential to prevent CRC and reduce CRC-related morbidity and mortality. The diagnosis of CRC is achieved by colonoscopy and tissue biopsy, with studies showing that liquid biopsy is more effective in detecting and diagnosing early CRC patients. Increasing number of studies have shown that the tumor components shed into circulating blood can be detected in liquid form, and can be applied in the clinical management of CRC. Analysis of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), or tumor-associated platelets (TEPs) in the blood can be used for early screening and diagnosis of CRC, aid tumor staging, treatment response monitoring, and prediction of CRC recurrence and metastasis in a minimally invasive manner. This chapter provides an updated review of CTCs, ctDNA, and TEPs as novel biomarkers for CRC, highlighting their strengths and limitations.

Liver transcriptome analysis reveal the metabolic and apoptotic responses of Trachinotus ovatus under acute cold stress.

Trachinotus ovatus is an economically important fish and has been recommended as a high-quality aquaculture fish breed for the high-quality development of sea ranches in the South China Sea. However, T. ovatus shows intolerance to low temperature, greatly limiting the extension of farming scale, reducing production efficiency in winter, and increasing farming risks. In this study, liver transcriptome analysis was investigated in T. ovatus under acute low temperature conditions (20 and 15 °C) using RNA sequencing (RNA-Seq) technology. Inter-groups differential expression analysis and trend analysis screened 1219 DEGs and four significant profiles (profiles 0, 3, 4, and 7), respectively. GO enrichment analysis showed that these DEGs were mainly related to metabolic process and cell growth and death process. KEGG enrichment analysis found that DEGs were mainly associated with lipid metabolism, carbohydrate metabolism, and cell growth and death, such as gluconeogenesis, glycolysis, fatty acid oxidation, cholesterol biosynthesis, p53 signaling pathway, cell cycle arrest, and apoptotic cell death. Moreover, protein-protein interaction networks identified two hub genes (FOS and JUNB) and some important genes related to metabolic process and cell growth and death process, that corresponding to enrichment analysis. Overall, gluconeogenesis, lipid mobilization, and fatty acid oxidation in metabolic process and cell cycle arrest and apoptotic cell death in cell growth and death process were enhanced, while glycolysis, liver glycogen synthesis and cholesterol biosynthesis in metabolic process were inhibited. The enhancement or attenuatment of metabolic process and cell growth and death process is conducive to maintain energy balance, normal fluidity of cell membrane, normal physiological functions of liver cell, enhancing the tolerance of T. ovatus to cold stress. These results suggested that metabolic process and cell growth and death process play important roles in response to acute cold stress in the liver of T. ovatus. Gene expreesion level analysis showed that acute cold stress at 15 °C was identified as a critical temperature point for T. ovatus in term of cellular metabolism alteration and apoptosis inducement, and rewarming intervention should be timely implemented above 15 °C. Our study can provide theoretical support for breeding cold-tolerant cultivars of T. ovatus, which is contributed to high-quality productions fish production.

Oncoprotein LAMTOR5-mediated CHOP silence via DNA hypermethylation and miR-182/miR-769 in promotion of liver cancer growth.

C/EBP homologous protein (CHOP) triggers the death of multiple cancers via endoplasmic reticulum (ER) stress. However, the function and regulatory mechanism of CHOP in liver cancer remain elusive. We have reported that late endosomal/lysosomal adapter, mitogen-activated protein kinase and mTOR activator 5 (LAMTOR5) suppresses apoptosis in various cancers. Here, we show that the transcriptional and posttranscriptional inactivation of CHOP mediated by LAMTOR5 accelerates liver cancer growth. Clinical bioinformatic analysis revealed that the expression of CHOP was low in liver cancer tissues and that its increased expression predicted a good prognosis. Elevated CHOP contributed to destruction of LAMTOR5-induced apoptotic suppression and proliferation. Mechanistically, LAMTOR5-recruited DNA methyltransferase 1 (DNMT1) to the CpG3 region (-559/-429) of the CHOP promoter and potentiated its hypermethylation to block its interaction with general transcription factor IIi (TFII-I), resulting in its inactivation. Moreover, LAMTOR5-enhanced miR-182/miR-769 reduced CHOP expression by targeting its 3'UTR. Notably, lenvatinib, a first-line targeted therapy for liver cancer, could target the LAMTOR5/CHOP axis to prevent liver cancer progression. Accordingly, LAMTOR5-mediated silencing of CHOP via the regulation of ER stress-related apoptosis promotes liver cancer growth, providing a theoretical basis for the use of lenvatinib for the treatment of liver cancer.

Advancements in the Regulation of Different-Intensity Exercise Interventions on Arterial Endothelial Function.

Normal-functioning endothelium is crucial to maintaining vascular homeostasis and inhibiting the development and progression of cardiovascular diseases such as atherosclerosis. Exercise training has been proven effective in regulating arterial endothelial function, and the effect of this regulation is closely related to exercise intensity and the status of arterial endothelial function. With this review, we investigated the effects of the exercise of different intensity on the function of arterial endothelium and the underlying molecular biological mechanisms. Existing studies indicate that low-intensity exercise improves arterial endothelial function in individuals who manifest endothelial dysfunction relative to those with normal endothelial function. Most moderate-intensity exercise promotes endothelial function in individuals with both normal and impaired arterial endothelial function. Continuous high-intensity exercise can lead to impaired endothelial function, and high-intensity interval exercise can enhance both normal and impaired endothelial function. In addition, it was demonstrated that the production of vasomotor factors, oxidative stress, and inflammatory response is involved in the regulation of arterial endothelial function under different-intensity exercise interventions. We posit that this synthesis will then provide a theoretical basis for choosing the appropriate exercise intensity and optimize the prescription of clinical exercise for persons with normal and impaired endothelium.

Mechanistic insights into DNA damage recognition and checkpoint control in plants.

The plant DNA damage response (DDR) pathway safeguards genomic integrity by rapid recognition and repair of DNA lesions that, if unrepaired, may cause genome instability. Most frequently, DNA repair goes hand in hand with a transient cell cycle arrest, which allows cells to repair the DNA lesions before engaging in a mitotic event, but consequently also affects plant growth and yield. Through the identification of DDR proteins and cell cycle regulators that react to DNA double-strand breaks or replication defects, it has become clear that these proteins and regulators form highly interconnected networks. These networks operate at both the transcriptional and post-transcriptional levels and include liquid-liquid phase separation and epigenetic mechanisms. Strikingly, whereas the upstream DDR sensors and signalling components are well conserved across eukaryotes, some of the more downstream effectors are diverged in plants, probably to suit unique lifestyle features. Additionally, DDR components display functional diversity across ancient plant species, dicots and monocots. The observed resistance of DDR mutants towards aluminium toxicity, phosphate limitation and seed ageing indicates that gaining knowledge about the plant DDR may offer solutions to combat the effects of climate change and the associated risk for food security.

Causal associations between circulating cytokines and risk of sepsis and related outcomes: a two-sample Mendelian randomization study.

Introduction: Sepsis represents a critical medical condition that arises due to an imbalanced host reaction to infection. Central to its pathophysiology are cytokines. However, observational investigations that explore the interrelationships between circulating cytokines and susceptibility to sepsis frequently encounter challenges pertaining to confounding variables and reverse causality. Methods: To elucidate the potential causal impact of cytokines on the risk of sepsis, we conducted two-sample Mendelian randomization (MR) analyses. Genetic instruments tied to circulating cytokine concentrations were sourced from genome-wide association studies encompassing 8,293 Finnish participants. We then evaluated their links with sepsis and related outcomes using summary-level data acquired from the UK Biobank, a vast multicenter cohort study involving over 500,000 European participants. Specifically, our data spanned 11,643 sepsis cases and 474,841 controls, with subsets including specific age groups, 28-day mortality, and ICU-related outcomes. Results and Discussion: MR insights intimated that reduced genetically-predicted interleukin-10 (IL-10) levels causally correlated with a heightened sepsis risk (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.52-0.90, P=0.006). An inverse relationship emerged between monocyte chemoattractant protein-1 (MCP-1) and sepsis-induced mortality. Conversely, elevated macrophage inflammatory protein 1 beta (MIP1B) concentrations were positively linked with both sepsis incidence and associated mortality. These revelations underscore the causal impact of certain circulating cytokines on sepsis susceptibility and its prognosis, hinting at the therapeutic potential of modulating these cytokine levels. Additional research is essential to corroborate these connections.

Six new species of Margattea Shelford, 1911 (Blaberoidea, Pseudophyllodromiidae, Neoblattellini) from China.

Six Margattea species are established and described: three are cryptic species, namely, M.parabisignata Li & Che, sp. nov., M.semicircularis Li & Che, sp. nov., and M.forcipata Li & Che, sp. nov. They are distinguished from known species M.bisignata, M.spinifera, and M.paratransversa by their male genitalia with the aid of molecular species delimitation method (ABGD) using COI as the molecular marker. The other three new species are M.pedata Li & Che, sp. nov., M.undulata Li & Che, sp. nov., and M.bisphaerica Li & Che, sp. nov. Morphological and genitalia photographs of these new species of Margattea, as well as a key to the species of Margattea from China, are provided.

Mendelian randomization analysis identifies causal associations between serum lipidomic profile, amino acid biomarkers and sepsis.

Background: Sepsis is a life-threatening condition marked by a severe systemic response to infection, leading to widespread inflammation, cellular signaling disruption, and metabolic dysregulation. The role of lipid and amino acid metabolism in sepsis is not fully understood, but aberrations in this pathway could contribute to the disease's pathophysiology. Methods: To explore the potential of lipid and amino acid compounds as biomarkers for the diagnosis and prognosis of sepsis, a two-sample Mendelian Randomization (MR) study was conducted, examining the relationship between sepsis and 249 serum lipid and amino acid-related markers. Key enzymes involved in synthesis of phosphatidylcholine, including choline/ethanolamine phosphotransferase 1 (CEPT1), choline phosphotransferase 1 (CPT1), and ethanolamine phosphotransferase 1 (EPT1), were also targeted for drug-target Mendelian randomization. Results: The study found that phosphatidylcholines (OR IVW: 0.88, 95%CI: 0.80-0.96, p = 0.005) and phospholipids in medium HDL (OR IVW: 0.86, 95%CI: 0.77-0.96, p = 0.007) potentially exhibit a protective effect against sepsis nominally. However, the potential drug target of CEPT1, CPT1, and EPT1 was found to be unrelated to septic outcomes. Conclusion: Our findings suggest that increasing levels of phosphatidylcholines and medium HDL phospholipids may reduce the incidence of sepsis. This highlights the potential of lipid-based biomarkers in the diagnosis and management of sepsis, opening avenues for new therapeutic strategies.

Helicobacter pylori infection alters gastric microbiota structure and biological functions in patients with gastric ulcer or duodenal ulcer.

BACKGROUND: Helicobacter pylori (H. pylori) infection is closely associated with gastrointestinal diseases. Our preliminary studies have indicated that H. pylori infection had a significant impact on the mucosal microbiome structure in patients with gastric ulcer (GU) or duodenal ulcer (DU). AIM: To investigate the contributions of H. pylori infection and the mucosal microbiome to the pathogenesis and progression of ulcerative diseases. METHODS: Patients with H. pylori infection and either GU or DU, and healthy individuals without H. pylori infection were included. Gastric or duodenal mucosal samples was obtained and subjected to metagenomic sequencing. The compositions of the microbial communities and their metabolic functions in the mucosal tissues were analyzed. RESULTS: Compared with that in the healthy individuals, the gastric mucosal microbiota in the H. pylori-positive patients with GU was dominated by H. pylori, with significantly reduced biodiversity. The intergroup differential functions, which were enriched in the H. pylori-positive GU patients, were all derived from H. pylori, particularly those concerning transfer RNA queuosine-modification and the synthesis of demethylmenaquinones or menaquinones. A significant enrichment of the uibE gene was detected in the synthesis pathway. There was no significant difference in microbial diversity between the H. pylori-positive DU patients and healthy controls. CONCLUSION: H. pylori infection significantly alters the gastric microbiota structure, diversity, and biological functions, which may be important contributing factors for GU.

Whole-Genome Sequencing Analyses Reveal the Evolution Mechanisms of Typical Biological Features of Decapterus maruadsi.

Decapterus maruadsi is a typical representative of small pelagic fish characterized by fast growth rate, small body size, and high fecundity. It is a high-quality marine commercial fish with high nutritional value. However, the underlying genetics and genomics research focused on D. maruadsi is not comprehensive. Herein, a high-quality chromosome-level genome of a male D. maruadsi was assembled. The assembled genome length was 716.13 Mb with contig N50 of 19.70 Mb. Notably, we successfully anchored 95.73% contig sequences into 23 chromosomes with a total length of 685.54 Mb and a scaffold N50 of 30.77 Mb. A total of 22,716 protein-coding genes, 274.90 Mb repeat sequences, and 10,060 ncRNAs were predicted, among which 22,037 (97%) genes were successfully functionally annotated. The comparative genome analysis identified 459 unique, 73 expanded, and 52 contracted gene families. Moreover, 2804 genes were identified as candidates for positive selection, of which some that were related to the growth and development of bone, muscle, cardioid, and ovaries, such as some members of the TGF-ß superfamily, were likely involved in the evolution of typical biological features in D. maruadsi. The study provides an accurate and complete chromosome-level reference genome for further genetic conservation, genomic-assisted breeding, and adaptive evolution research for D. maruadsi.

The delivery of PD-L1 siRNA by neutrophil-targeted lipid nanoparticles effectively ameliorates sepsis.

BACKGROUND: Sepsis, a complex and life-threatening disease, poses a significant global burden affecting over 48 million individuals. Recently, it has been reported that programmed death-ligand 1 (PD-L1) expressed on neutrophils is involved in both inflammatory organ dysfunction and immunoparalysis in sepsis. However, there is a dearth of strategies to specifically target PD-L1 in neutrophils in vivo. METHODS: We successfully developed two lipid nanoparticles (LNPs) specifically targeting neutrophils by delivering PD-L1 siRNA via neutrophil-specific antibodies and polypeptides. In vivo and in vitro experiments were performed to detect lipid nanoparticles into neutrophils. A mouse cecal ligation and puncture (CLP) model was used to detect neutrophil migration, neutrophil extracellular traps (NETs) level, and organ damage. RESULT: The PD-L1 siRNA-loaded LNPs that target neutrophils suppressed inflammation, reduced the release of NETs, and inhibited T-lymphocyte apoptosis. This approach could help maintain homeostasis of both the immune and inflammatory responses during sepsis. Furthermore, the PD-L1 siRNA-loaded LNPs targeting neutrophils have the potential to ameliorate the multi-organ damage and lethality resulting from CLP. CONCLUSIONS: Taken together, our data identify a previously unknown drug delivery strategy targeting neutrophils, which represents a novel, safe, and effective approach to sepsis therapy.