Roles of RNA m5C modification patterns in prognosis and tumor microenvironment infiltration of diffuse large B-cell lymphoma.

Genetic and epigenetic aberrations display an essential role in the initiation and progression of diffuse large B-cell lymphoma (DLBCL). 5-methylcytosine (m5C), a common RNA modification, regulates various cellular processes and contributes to tumorigenesis and cancer progression. However, m5C alterations in DLBCL remain unclear. Our research constructed an m5C prognostic model utilizing GEO data sets, which can efficiently predict the prognosis of patients with DLBCL, and verified the m5C prognostic model genes by immunohistochemistry analysis. This model was constructed using unsupervised consensus clustering analyses, Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses. Based on the expression of m5C genes in the model, patients with DLBCL could be effectively divided into groups with significant survival time differences. The m5C risk-score signature demonstrated a highly significant independent prognostic value. Results from tumor microenvironment analyses revealed that m5C genes altered the infiltration of eosinophils, Tregs, and M2 macrophages. Additionally, they regulated T cell activation by modulating the expression of CTLA4, PDL1, B2M, CD8A, ICOS, and other relevant immune checkpoint expressions. In conclusion, our study presents a robust m5C prognostic model that effectively predicts prognosis in DLBCL. This model may offer a new approach for prognostic stratification and potential therapeutic interventions for patients with DLBCL.

Association of gene polymorphisms and the decreased expression of long non-coding RNA LOC553103 with rheumatoid arthritis.

BACKGROUND: Long non-coding RNAs (lncRNAs) are involved in many key bioprocesses, including the occurrence and development of rheumatoid arthritis (RA). We aimed to analyze the association of genetic variants of long non-coding RNA LOC553103 and its peripheral blood mononuclear cells (PBMC) expression with RA. METHODS: We enrolled 457 RA patients and 551 healthy controls and conducted a case-control study to analyze the relationship between LOC553103 gene rs272879 and the susceptibility of RA by TaqMan single nucleotide polymorphism genotyping. Among them, we sampled 92 cases and 92 controls, respectively, to detect the PBMC level of LOC553103 using quantitative real-time polymerase chain reaction technology. We explored the association between LOC553103 rs272879 and its PBMC expression levels in 71 RA patients. Mann-Whitney, Chi-square, and Spearman correlation analysis were used for statistical analysis and P-value <.05 was considered statistically significant. RESULTS: The genotype frequency of LOC553103 rs272879 CC was increased, and CG was decreased in RA patients compared to the control group (χ2 = 6.772, P = .034). The LOC553103 expression level in PBMC of RA patients was downregulated compared to healthy control (Z = -4.497, P < .001). Moreover, negative correlations were observed between the PBMC level of LOC553103 and erythrocyte sedimentation rate (rs = -0.262, P = .018), white blood cell count (rs = -0.382, P = .004), platelet (rs = -0.293, P = .030), and disease activity score in 28 joints (rs = -0.271, P = .016) in RA patients. CONCLUSIONS: This study provides the first evidence supporting an association between LOC553103 gene polymorphisms and susceptibility of RA and a relationship of PBMC level of LOC553103 with clinical manifestations and laboratory indicators of RA patients.

Network pharmacology combined with experimental validation to investigate the effect of Rongjin Niantong Fang on chondrocyte apoptosis in knee osteoarthritis.

Knee osteoarthritis (KOA) is a chronic degenerative disease that affects the quality of life of middle­aged and elderly individuals, and is one of the major factors leading to disability. Rongjin Niantong Fang (RJNTF) can alleviate the clinical symptoms of patients with KOA, but the molecular mechanism underlying its beneficial effects on KOA remains unknown. Using pharmacological analysis and in vitro experiments, the active components of RJNTF were analyzed to explore their potential therapeutic targets and mechanisms in KOA. The potential targets and core signaling pathways by which RJNTF exerts its effects on KOA were obtained from databases such as Gene Expression Omnibus, Traditional Chinese Medicine Systems Pharmacology and Analysis Platform. Subsequently, chondrocyte apoptosis was modeled using hydrogen peroxide (H2O2). Cell Counting Kit­8 assay involving a poly [ADP­ribose] polymerase­1 (PARP1) inhibitor, DAPI staining, reverse transcription­quantitative PCR, Annexin V­FITC/PI staining and flow cytometry, western blotting and co­immunoprecipitation analysis were used to determine the therapeutic efficacy of RJNTF on KOA and to uncover the molecular mechanism. It was found that PARP1­knockdown lentivirus, incubation with PARP1 inhibitor PJ34, medium and high doses of RJNTF significantly reduced H2O2­induced chondrocyte apoptosis. Medium and high doses of RJNTF downregulated the expression of cleaved caspase­3, cleaved PARP1 and PAR total proteins, as well as nucleus proteins of apoptosis­inducing factor (AIF) and migration inhibitory factor (MIF), and upregulated the expression of caspase­3, PARP1 total protein, as well as the cytoplasmic expression of AIF and MIF, suggesting that RJNTF may inhibit chondrocyte apoptosis through the PARP1/AIF signaling pathway.

Integrated transcriptomic and CGAs analysis revealed IbGLK1 is a key transcription factor for chlorogenic acid accumulation in sweetpotato (Ipomoea batatas [L.] Lam.) blades.

Sweetpotato blades are rich in the functional secondary metabolite chlorogenic acid (CGA), which deepen potential for effective utilization of the blade in industry. In this study, we evaluated the type and content of CGA in the blades of 16 sweetpotato genotypes and analyzed the correlation between CGA content and antioxidant capacity. Then we isolated and characterized IbGLK1, a GARP-type transcription factor, by comparative transcriptome analysis. A subcellular localization assay indicated that IbGLK1 is located in the nucleus. Overexpression and silencing of IbGLK1 in sweetpotato blade resulted in a 0.90-fold increase and 1.84-fold decrease, respectively, in CGA content compared to the control. Yeast one-hybrid and dual-luciferase assays showed that IbGLK1 binds and activates the promoters of IbHCT, IbHQT, IbC4H, and IbUGCT, resulting in the promotion of CGA biosynthesis. In conclusion, our study provides insights into a high-quality gene for the regulation of CGA metabolism and germplasm resources for breeding sweetpotato.

Biosynthesis of Scopoletin in Sweet Potato Confers Resistance against Fusarium oxysporum.

Fusarium wilt is a severe fungal disease caused by Fusarium oxysporum in sweet potato. We conducted transcriptome analysis to explore the resistance mechanism of sweet potato against F. oxysporum. Our findings highlighted the role of scopoletin, a hydroxycoumarin, in enhancing resistance. In vitro experiments confirmed that scopoletin and umbelliferone had inhibitory effects on the F. oxysporum growth. We identified hydroxycoumarin synthase genes IbF6'H2 and IbCOSY that are responsible for scopoletin production in sweet potatoes. The co-overexpression of IbF6'H2 and IbCOSY in tobacco plants produced the highest scopoletin levels and disease resistance. This study provides insights into the molecular basis of sweet potato defense against Fusarium wilt and identifies valuable genes for breeding wilt-resistant cultivars.

Seed and Soil: Consensus Molecular Subgroups (CMS) and Tumor Microenvironment Features Between Primary Lesions and Metastases of Different Organ Sites in Colorectal Cancer.

Purpose: Consensus molecular subtypes (CMS) are mainly used for biological interpretability and clinical stratification of colorectal cancer (CRC) in primary tumors (PT) but few in metastases. The heterogeneity of CMS distribution in metastases and the concordance of CMS between PT and metastases still lack sufficient study. We used CMS to classify CRC metastases and combine it with histopathological analysis to explore differences between PT and distant metastases. Patients and Methods: We obtained gene expression profiles for 942 PT samples from TCGA database (n=376) and GEO database (n=566), as well as 442 metastasis samples from GEO database. Among these, 765 PT samples and 442 metastasis samples were confidently identified with CMS using the "CMS classifier" and enrolled for analysis. Clinicopathological manifestation and CMS classification of CRC metastases were assessed with data from GEO, TCGA, and cBioPortal. Overall, 105 PT-metastasis pairs were extracted from 10 GEO datasets to assess CMS concordance. Tumor microenvironment (TME) features between PT and metastases were analyzed by immune-stromal infiltration with ESTIMATE and xCell algorithms. Finally, TME features were validated with multiplex immunohistochemistry in 27 PT-metastasis pairs we retrospectively collected. Results: Up to 64% of CRC metastases exhibited concordant CMS groups with matched PT, and the TME of metastases was similar to that of PT. For most common distant metastases, liver metastases were predominantly CMS2 and lung and peritoneal metastases were mainly CMS4, highlighting "seed" of tumor cells of different CMS groups had a preference for metastasis to "soil" of specific organs. Compared with PT, cancer-associated fibroblasts (CAF) reduced in liver metastases, CD4+T cells and M2-like macrophages increased in lung metastases, and M2-like macrophages and CAF increased in peritoneal metastases. Conclusion: Our findings underscore the importance of CMS-guided specific organ monitoring and treatment post-primary tumor surgery for patients. Differences in immune-stromal infiltration among different metastases provide targeted therapeutic opportunities for metastatic CRC.

The Index sAGP is Valuable for Distinguishing Atypical Hepatocellular Carcinoma from Atypical Benign Focal Hepatic Lesions.

Purpose: The differential diagnosis of atypical hepatocellular carcinoma (aHCC) and atypical benign focal hepatic lesions (aBFHL) usually depends on pathology. This study aimed to develop non-invasive approaches based on conventional blood indicators for the differential diagnosis of aHCC and aBFHL. Patients and Methods: Hospitalized patients with pathologically confirmed focal hepatic lesions and their clinical data were retrospectively collected, in which patients with HCC with serum alpha-fetoprotein (AFP) levels of ≤200 ng/mL and atypical imaging features were designated as the aHCC group (n = 224), and patients with benign focal hepatic lesions without typical imaging features were designated as the aBFHL group (n = 178). The performance of indexes (both previously reported and newly constructed) derived from conventional blood indicators by four mathematical operations in distinguishing aHCC and aBFHL was evaluated using the receiver operating characteristic (ROC) curve and diagnostic validity metrics. Results: Among ten previously reported derived indexes related to HCC, the index GPR, the ratio of γ-glutamyltransferase (GGT) to platelet (PLT), showed the best performance in distinguishing aHCC from aBFHL with the area under ROC curve (AUROC) of 0.853 (95% CI 0.814-0.892), but the other indexes were of little value (AUROCs from 0.531 to 0.700). A new derived index, sAGP [(standardized AFP + standardized GGT)/standardized PLT], was developed and exhibited AUROCs of 0.905, 0.894, 0.891, 0.925, and 0.862 in differentiating overall, BCLC stage 0/A, TNM stage I, small, and AFP-negative aHCC from aBFHL, respectively. Conclusion: The sAGP index is an efficient, simple, and practical metric for the non-invasive differentiation of aHCC from aBFHL.

ZBTB20 mediates stress-induced visceral hypersensitivity via activating the NF-κB/transient receptor potential channel pathway.

BACKGROUND: Psychological stress is a major trigger for visceral hypersensitivity (VH) in irritable bowel syndrome. The zinc finger protein ZBTB20 (ZBTB20) is implicated in somatic nociception via modulating transient receptor potential (TRP) channels, but its role in the development of VH is unclear. This study aimed to investigate the role of ZBTB20/TRP channel axis in stress-induced VH. METHODS: Rats were subjected to water avoidance stress (WAS) for 10 consecutive days. Small interfering RNA (siRNA) targeting ZBTB20 was intrathecally administered. Inhibitors of TRP channels, stress hormone receptors, and nuclear factor kappa-B (NF-κB) were administered. Visceromotor response to colorectal distension was recorded. Dorsal root ganglia (DRGs) were dissected for Western blot, coimmunoprecipitation, and chromatin immunoprecipitation. The DRG-derived neuron cell line was applied for specific research. KEY RESULTS: WAS-induced VH was suppressed by the inhibitor of TRPV1, TRPA1, or TRPM8, with enhanced expression of these channels in L6-S2 DRGs. The inhibitor of glucocorticoid receptor or ß2-adrenergic receptor counteracted WAS-induced VH and TRP channel expression. Concurrently, WAS-induced stress hormone-dependent ZBTB20 expression and NF-κB activation in DRGs. Intrathecally injected ZBTB20 siRNA or an NF-κB inhibitor repressed WAS-caused effect. In cultured DRG-derived neurons, stress hormones promoted nuclear translocation of ZBTB20, which preceded p65 nuclear translocation. And, ZBTB20 siRNA suppressed stress hormone-caused NF-κB activation. Finally, WAS enhanced p65 binding to the promoter of TRPV1, TRPA1, or TRPM8 in rat DRGs. CONCLUSIONS AND INFERENCES: ZBTB20 mediates stress-induced VH via activating NF-κB/TRP channel pathway in nociceptive sensory neurons.

DHRS4-AS1 regulate gastric cancer apoptosis and cell proliferation by destabilizing DHX9 and inhibited the association between DHX9 and ILF3.

Gastric cancer (GC) causes millions of cancer-related deaths due to anti-apoptosis and rapid proliferation. However, the molecular mechanisms underlying GC cell proliferation and anti-apoptosis remain unclear. The expression levels of DHRS4-AS1 in GC were analyzed based on GEO database and recruited GC patients in our institution. We found that DHRS4-AS1 was significantly downregulated in GC. The expression of DHRS4-AS1 in GC tissues showed a significant correlation with tumor size, advanced pathological stage, and vascular invasion. Moreover, DHRS4-AS1 levels in GC tissues were significantly associated with prognosis. DHRS4-AS1 markedly inhibited GC cell proliferation and promotes apoptosis in vitro and in vivo assays. Mechanically, We found that DHRS4-AS1 bound to pro-oncogenic DHX9 (DExH-box helicase 9) and recruit the E3 ligase MDM2 that contributed to DHX9 degradation. We also confirmed that DHRS4-AS1 inhibited DHX9-mediated cell proliferation and promotes apoptosis. Furthermore, we found DHX9 interact with ILF3 (Interleukin enhancer Binding Factor 3) and activate NF-kB Signaling in a ILF3-dependent Manner. Moreover, DHRS4-AS1 can also inhibit the association between DHX9 and ILF3 thereby interfered the activation of the signaling pathway. Our results reveal new insights into mechanisms underlying GC progression and indicate that LncRNA DHRS4-AS1 could be a future therapeutic target and a biomarker for GC diagnosis.

Transcriptome-Based WGCNA Analysis Reveals the Mechanism of Drought Resistance Differences in Sweetpotato (Ipomoea batatas (L.) Lam.).

Sweetpotato (Ipomoea batatas (L.) Lam.) is a globally significant storage root crop, but it is highly susceptible to yield reduction under severe drought conditions. Therefore, understanding the mechanism of sweetpotato resistance to drought stress is helpful for the creation of outstanding germplasm and the selection of varieties with strong drought resistance. In this study, we conducted a comprehensive analysis of the phenotypic and physiological traits of 17 sweetpotato breeding lines and 10 varieties under drought stress through a 48 h treatment in a Hoagland culture medium containing 20% PEG6000. The results showed that the relative water content (RWC) and vine-tip fresh-weight reduction (VTFWR) in XS161819 were 1.17 and 1.14 times higher than those for the recognized drought-resistant variety Chaoshu 1. We conducted RNA-seq analysis and weighted gene co-expression network analysis (WGCNA) on two genotypes, XS161819 and 18-12-3, which exhibited significant differences in drought resistance. The transcriptome analysis revealed that the hormone signaling pathway may play a crucial role in determining the drought resistance in sweetpotato. By applying WGCNA, we identified twenty-two differential expression modules, and the midnight blue module showed a strong positive correlation with drought resistance characteristics. Moreover, twenty candidate Hub genes were identified, including g47370 (AFP2), g14296 (CDKF), and g60091 (SPBC2A9), which are potentially involved in the regulation of drought resistance in sweetpotato. These findings provide important insights into the molecular mechanisms underlying drought resistance in sweetpotato and offer valuable genetic resources for the development of drought-resistant sweetpotato varieties in the future.

[Administration of a single chain variable fragments chimeric protein (SD) of ovalbumin epitopes internalizing receptor DEC-205 antibody inhibits food allergy in mice].

Objective To investigate the preventive therapeutic effect and possible mechanism of single chain variable fragments chimeric protein (SD) of ovalbumin epitopes internalizing receptor DEC-205 antibody on food allergy in mice. Methods Mice were randomly divided to five groups (control, PBS, scFv DEC 100 µg, SD 50 µg, SD 100 µg) and treated for 24 hours before OVA administration. After challenge, the serum level of OVA-specific IgE, IgG1, IgG2a and IL-4 were detected by ELISA. Infiltration of eosinophils and mast cells in the jejunum was observed by HE staining and toluidine blue staining respectively. The bone marrow of tibia and femur was isolated and cultured to obtain immature dendritic cells(BMDCs), which were further treated with LPS (10 ng/mL), TSLP (50 ng/mL), scFv DEC protein (1000 ng/mL) and SD protein (10,100,1000)ng/mL for 24 hours, and the IL-10 level of supernatant was assayed by ELISA. Results Compared with PBS group, the number of SD-treated mice with diarrhea was markedly reduced. The difference in rectal temperature and the levels of serum OVA-specific IgE, IgG1, IgG2a and IL-4 decreased significantly after prophylactic administration of SD; The number of eosinophils and mast cells in jejunum also decreased significantly while the IL-10 level in the supernatant of BMDCs increased significantly after SD intervention. Conclusion SD mitigates experimental FA response by fosters the immune tolerance property of dendritic cells.

Discovery of novel S6K1 inhibitors by an ensemble-based virtual screening method and molecular dynamics simulation.

Ribosomal protein S6 kinase beta-1 (S6K1) is considered a potential target for the treatment of various diseases, such as obesity, type II diabetes, and cancer. Development of novel S6K1 inhibitors is an urgent and important task for the medicinal chemists. In this research, an effective ensemble-based virtual screening method, including common feature pharmacophore model, 3D-QSAR pharmacophore model, naïve Bayes classifier model, and molecular docking, was applied to discover potential S6K1 inhibitors from BioDiversity database with 29,158 compounds. Finally, 7 hits displayed considerable properties and considered as potential inhibitors against S6K1. Further, carefully analyzing the interactions between these 7 hits and key residues in the S6K1 active site, and comparing them with the reference compound PF-4708671, it was found that 2 hits exhibited better binding patterns. In order to further investigate the mechanism of the interactions between 2 hits and S6K1 at simulated physiological conditions, the molecular dynamics simulation was performed. The ΔGbind energies for S6K1-Hit1 and S6K1-Hit2 were - 111.47 ± 1.29 and - 54.29 ± 1.19 kJ mol-1, respectively. Furthermore, deep analysis of these results revealed that Hit1 was the most stable complex, which can stably bind to S6K1 active site, interact with all of the key residues, and induce H1, H2, and M-loop regions changes. Therefore, the identified Hit1 may be a promising lead compound for developing new S6K1 inhibitor for various metabolic diseases treatment.

Maternal hyperglycemia inhibits pulmonary vasculogenesis during mouse fetal lung development by promoting GßL Ubiquitination-dependent mammalian target of Rapamycin assembly.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with retarded lung development and poor lung health in offspring. Mammalian target of rapamycin (mTOR) is a key regulator of vasculogenesis and angiogenesis. The aim of this study was to investigate the role mTOR plays in pulmonary vasculogenesis during fetal lung development under maternal hyperglycemia. METHODS: First, GDM was induced via streptozotocin injection in pregnant C57BL/6 mice before the radial alveolar count (RAC) in the fetal lungs was assessed using hematoxylin and eosin staining. The angiogenic ability of the cultured primary mouse fetal lung endothelial cells (MFLECs) was then assessed using the tube formation assay technique, while western blot and real-time polymerase chain reaction were performed to determine the expression of mTOR, regulatory-associated protein of mTOR (Raptor), rapamycin-insensitive companion of mTOR (Rictor), stress-activated protein kinase interacting protein 1 (Sin1), G protein beta subunit-like protein (GßL), Akt, tumor necrosis receptor associated factor-2 (TRAF2), and OTU deubiquitinase 7B (OTUD7B) in both the fetal lung tissues and the cultured MFLECs. Immunoprecipitation assays were conducted to evaluate the status of GßL-ubiquitination and the association between GßL and mTOR, Raptor, Rictor, and Sin1 in the cultured MFLECs. RESULTS: The GDM fetal lungs exhibited a decreased RAC and reduced expression of von Willebrand factor, CD31, and microvessel density. The high glucose level reduced the tube formation ability in the MFLECs, with the mTOR, p-mTOR, p-Raptor, and TRAF2 expression upregulated and the p-Rictor, p-Sin1, p-Akt, and OTUD7B expression downregulated in both the GDM fetal lungs and the high-glucose-treated MFLECs. Meanwhile, GßL-ubiquitination was upregulated in the high-glucose-treated MFLECs along with an increased GßL/Raptor association and decreased GßL/Rictor and GßL/Sin1 association. Furthermore, TRAF2 knockdown inhibited the high-glucose-induced GßL-ubiquitination and GßL/Raptor association and restored the tube formation ability of the MFLECs. CONCLUSION: Maternal hyperglycemia inhibits pulmonary vasculogenesis during fetal lung development by promoting GßL-ubiquitination-dependent mTORC1 assembly.

Peroxisomal trans-2-enoyl-CoA inhibits proliferation, migration and invasion of hepatocellular carcinoma cells.

OBJECTIVES: Peroxisomal trans-2-enoyl-CoA reductase (PECR) encodes proteins related to fatty acid metabolism and synthesis. It has been confirmed that PECR has decreased expression in colon cancer and breast cancer, while the role of PECR in liver cancer is unknown. We aimed to study the role and mechanism of PECR in the genesis and development of liver cancer. METHODS: In this study, the expression of PECR was queried in the Cancer Genome Atlas Database and Western Blotting and RT-PCR experiments were carried out in paired liver cancer tissues to detect the expression of PECR. Functional tests were evaluated by cell count kit-8 (CCK-8), Flow cytometry, wound healing assay, Transwell, migration. In vivo study, we constructed a nude mouse tumorigenic model to observe the effect of PECR on the proliferation of liver cancer. And the tumor body of the mouse was taken out for histochemistry (IHC). Multiple Cox regression was used to analyze the correlation between PECR and Clinicopathology. RESULTS: We confirmed that the overexpression of PECR inhibited the proliferation, migration and invasion of hepatocellular carcinoma and promoted the apoptosis of hepatocellular carcinoma. The low expression group of PECR promoted the proliferation and metastasis of liver cancer. In vivo, overexpression of PECR inhibits the proliferation of mouse tumors. In addition, the mechanism study shows that PECR may indirectly affect the proliferation of hepatocellular carcinoma cells through ERK pathway. CONCLUSION: In general, PECR may be a new diagnostic marker and a potential therapeutic target for hepatocellular carcinoma.

Discovery of potent microtubule-destabilizing agents targeting for colchicine site by virtual screening, biological evaluation, and molecular dynamics simulation.

Microtubule has been considered as attractive therapeutic target for various cancers. Although numerous of chemically diverse compounds targeting to colchicine site have been reported, none of them was approved by Food and Drug Administration. In this investigation, the virtual screening methods, including pharmacophore model, molecular docking, and interaction molecular fingerprints similarity, were applied to discover novel microtubule-destabilizing agents from database with 324,474 compounds. 22 compounds with novel scaffolds were identified as microtubule-destabilizing agents, and then submitted to the biological evaluation. Among these 22 hits, hit4 with novel scaffold represents the best anti-proliferative activity with IC50 ranging from 4.51 to 14.81 µM on four cancer cell lines. The in vitro assays reveal that hit4 can effectively inhibit tubulin assembly, and disrupt the microtubule network in MCF-7 cell at a concentration-dependent manner. Finally, the molecular dynamics simulation analysis exhibits that hit4 can stably bind to colchicine site, interact with key residues, and induce αT5 and ßT7 regions changes. The values of ΔGbind for the tubulin-colchicine and tubulin-hit4 are -172.9±10.5 and -166.0±12.6 kJ·mol-1, respectively. The above results indicate that the hit4 is a novel microtubule destabilizing agent targeting to colchicine-binding site, which could be developed as a promising tubulin polymerization inhibitor with higher activity for cancer therapy.

New indexes derived from routine blood tests and their clinical application in hepatocellular carcinoma.

Considerable efforts have been made in the diagnosis and treatment of hepatocellular carcinoma (HCC), but the prognosis of patients with HCC remains poor. The development of officious and easy-to-use indicators that are applicable to all levels of hospitals for the diagnosis, prognosis and risk prediction of HCC may play an important role in improving the current undesirable situation. The occurrence of HCC can cause a series of local and systemic changes, involving liver function, inflammation, immunity, and nutrition, which can be reflected in routine clinical indicators, especially laboratory metrics. A comprehensive analysis of these routine indicators is capable of providing important information for the clinical management of HCC. Routine clinical indicators are daily medical data that are readily available, easily repeatable, and highly acceptable, which has attracted clinicians to derive a number of comprehensive indexes from routine clinical indicators by means of four arithmetic operations, scoring system, and mathematical modeling. These indexes integrate several clinical indicators into a new single indicator that performs better than any of original individual indicators in the risk prediction, clinical diagnosis and prognostic evaluation of HCC and is easy to use. Herein, we reviewed recent indexes derived from routine clinical indicators for the diagnosis, prognosis and risk prediction of HCC.

The optimal first-line treatment for patients with left-sided RAS wild-type metastatic colorectal cancer: Double-drug regimen or triple-drug regimen therapy.

There are many treatments for metastatic colorectal cancer (mCRC). Among them, uncertainty remains especially concerning the clinical benefit of different regimens for left-sided RAS wild-type (WT) mCRC in the triple-drug therapy era. No studies have been conducted to answer this critical clinical issue. We performed a comprehensive analysis of published data and real-world data. First, we conducted analyses of the published trials to show the landscape of efficacy and safety in the treatments of left-sided RAS WT mCRC. Then, we initiated a multicenter real-world study as the validation dataset. This study included six published randomized controlled trials (RCTs) and a total of 1925 patients. The double-drug regimen plus cetuximab/panitumumab (D + C/P) achieved the longest overall survival (OS) in patients with left-sided mCRC (HR = 0.74, 95%CI: 0.57-0.98), while triple-drug regimen with bevacizumab (T + B, HR = 1.1, 95%CI: 0.63-2.0), compared with double-drug with bevacizumab (D + B). The D + C/P had the highest overall response rate (ORR) in patients with left-sided mCRC (OR = 1.8, 95%CI: 0.89-3.8), while T + B (OR = 1.8, 95%CI: 0.70-4.8), compared with D + B. The multicenter real-world cohort showed the double-drug regimen plus cetuximab had longer progression-free survival (PFS) in left-sided mCRC patients than the triple-drug regimen with bevacizumab. The safety analysis showed the incidence of the adverse events (grade≥3) in the triple-drug therapy plus bevacizumab was higher than that in the double-drug therapy plus cetuximab/panitumumab. This work demonstrates the ranking of three regimens for therapeutic efficacy and safety in patients with left-sided RAS WT mCRC. The double-drug regimen plus cetuximab/panitumumab appears more effective and safer than double-drug and triple-drug based regimens with bevacizumab. Further trials and cohort analyses on this topic would increase confidence in these results.

Plasma Exosomal miR-199a-5p Derived from Preeclampsia with Severe Features Impairs Endothelial Cell Function via Targeting SIRT1.

Preeclampsia (PE) is a pregnancy complication with high maternal and fetal morbidity and mortality rates. During pregnancy, the concentration of exosomes in the maternal blood circulation would increase, establishing that plasma exosomes play a role in the development of pregnancy. Our previous study implied the important role of exosomal miR-199a-5p in preeclampsia with severe features (sPE). This study aims to reveal the role of exosomal miR-199a-5p in contribution to the development of sPE. The results showed that the expression of miR-199a-5p was significantly higher in plasma exosomes and placenta tissue from patients with sPE than that in normal pregnant women. Additionally, hydrogen peroxide (H2O2) could upregulate the expression of miR-199a-5p in BeWo cells and cell-derived exosomes. In terms of the regulatory effect, exosomal miR-199a-5p was observed to inhibit the expression of SIRT1 in human umbilical venous endothelial cells (HUVECs). Moreover, the treatment of both miR-199a-5p-overexpressed exosomes and SIRT1 inhibitor EX527 could decrease the nitric oxide production, elevate the intracellular reactive oxygen species level, and enhance the expressions of ICAM-1 and VCAM-1 of HUVECs. Thus, our findings suggest that the upregulated plasma exosomal miR-199a-5p in sPE might result from the trophoblast of the impaired placenta under oxidative stress. Furthermore, exosomal miR-199a-5p could impair the endothelial cell function via targeting SIRT1, contributing to the development of preeclampsia.