Clinical application of ctDNA in early diagnosis, treatment and prognosis of patients with non-small cell lung cancer.

Lung cancer is one of the most common malignancies worldwide, with non-small cell lung cancer (NSCLC) being the most common type. As understanding of precise treatment options for NSCLC deepens, circulating tumor DNA (ctDNA) has emerged as a potential biomarker that has become a research hotspot and may represent a new approach for the individualized diagnosis and treatment of NSCLC. This article reviews the applications of ctDNA for the early screening of patients with NSCLC, guiding targeted therapy and immunotherapy, evaluating chemotherapy and postoperative efficacy, assessing prognosis and monitoring recurrence. With the in-depth study of the pathogenesis of NSCLC, plasma ctDNA may become an indispensable part of the precise treatment of NSCLC, which has great clinical application prospects.

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Transcriptome Dynamics and Cell Dialogs Between Oocytes and Granulosa Cells in Mouse Follicle Development.

The development and maturation of follicles is a sophisticated and multistage process. The dynamic gene expression of oocytes and their surrounding somatic cells and the dialogs between these cells are critical to this process. In this study, we accurately classified the oocyte and follicle development into nine stages and profiled the gene expression of mouse oocytes and their surrounding granulosa cells and cumulus cells. The clustering of the transcriptomes showed the trajectories of two distinct development courses of oocytes and their surrounding somatic cells. Gene expression changes precipitously increased at Type 4 stage and drastically dropped afterward within both oocytes and granulosa cells. Moreover, the number of differentially expressed genes between oocytes and granulosa cells dramatically increased at Type 4 stage, most of which persistently passed on to the later stages. Strikingly, cell communications within and between oocytes and granulosa cells became active from Type 4 stage onward. Cell dialogs connected oocytes and granulosa cells in both unidirectional and bidirectional manners. TGFB2/3, TGFBR2/3, INHBA/B, and ACVR1/1B/2B of TGF-ß signaling pathway functioned in the follicle development. NOTCH signaling pathway regulated the development of granulosa cells. Additionally, many maternally DNA methylation- or H3K27me3-imprinted genes remained active in granulosa cells but silent in oocytes during oogenesis. Collectively, Type 4 stage is the key turning point when significant transcription changes diverge the fate of oocytes and granulosa cells, and the cell dialogs become active to assure follicle development. These findings shed new insights on the transcriptome dynamics and cell dialogs facilitating the development and maturation of oocytes and follicles.

OLFM4 promotes the progression of intestinal metaplasia through activation of the MYH9/GSK3ß/ß-catenin pathway.

BACKGROUND: Intestinal metaplasia (IM) is classified into complete intestinal metaplasia (CIM) and incomplete intestinal metaplasia (IIM). Patients diagnosed with IIM face an elevated susceptibility to the development of gastric cancer, underscoring the critical need for early screening measures. In addition to the complexities associated with diagnosis, the exact mechanisms driving the progression of gastric cancer in IIM patients remain poorly understood. OLFM4 is overexpressed in several types of tumors, including colorectal, gastric, pancreatic, and ovarian cancers, and its expression has been associated with tumor progression. METHODS: In this study, we used pathological sections from two clinical centers, biopsies of IM tissues, precancerous lesions of gastric cancer (PLGC) cell models, animal models, and organoids to explore the role of OLFM4 in IIM. RESULTS: Our results show that OLFM4 expression is highly increased in IIM, with superior diagnostic accuracy of IIM when compared to CDX2 and MUC2. OLFM4, along with MYH9, was overexpressed in IM organoids and PLGC animal models. Furthermore, OLFM4, in combination with Myosin heavy chain 9 (MYH9), accelerated the ubiquitination of GSK3ß and resulted in increased ß-catenin levels through the Wnt signaling pathway, promoting the proliferation and invasion abilities of PLGC cells. CONCLUSIONS: OLFM4 represents a novel biomarker for IIM and could be utilized as an important auxiliary means to delimit the key population for early gastric cancer screening. Finally, our study identifies cell signaling pathways involved in the progression of IM.

Advances in systemic immune inflammatory indices in non-small cell lung cancer: A review.

Lung cancer is one of the most prevalent cancers globally, with non-small cell lung cancers constituting the majority. These cancers have a high incidence and mortality rate. In recent years, a growing body of research has demonstrated the intricate link between inflammation and cancer, highlighting that inflammation and cancer are inextricably linked and that inflammation plays a pivotal role in cancer development, progression, and prognosis of cancer. The Systemic Immunoinflammatory Index (SII), comprising neutrophil, lymphocyte, and platelet counts, is a more comprehensive indicator of the host's systemic inflammation and immune status than a single inflammatory index. It is widely used in clinical practice due to its cost-effectiveness, simplicity, noninvasiveness, and ease of acquisition. This paper reviews the impact of SII on the development, progression, and prognosis of non-small cell lung cancer.

Cholesteryl ester transfer protein knock-down in conjunction with a cholesterol-depleting agent decreases tamoxifen resistance in breast cancer cells.

The cholesterogenic phenotype, encompassing de novo biosynthesis and accumulation of cholesterol, aids cancer cell proliferation and survival. Previously, the role of cholesteryl ester (CE) transfer protein (CETP) has been implicated in breast cancer aggressiveness, but the molecular basis of this observation is not clearly understood, which this study aims to elucidate. CETP knock-down resulted in a >50% decrease in cell proliferation in both 'estrogen receptor-positive' (ER+; Michigan Cancer Foundation-7 (MCF7) breast cancer cells) and 'triple-negative' breast cancer (TNBC; MDA-MB-231) cell lines. Intriguingly, the abrogation of CETP together with the combination treatment of tamoxifen (5 µM) and acetyl plumbagin (a cholesterol-depleting agent) (5 µM) resulted in twofold to threefold increase in apoptosis in both cell lines. CETP knockdown also showed decreased intracellular CE levels, lipid raft and lipid droplets in both cell lines. In addition, RT2 Profiler PCR array (Qiagen, Germany)-based gene expression analysis revealed an overall downregulation of genes associated in cholesterol biosynthesis, lipid signalling and drug resistance in MCF7 cells post-CETP knock-down. On the contrary, resistance in MDA-MB-231 cells was reduced through increased expression in cholesterol efflux genes and the expression of targetable surface receptors by endocrine therapy. The pilot xenograft mice study substantiated CETP's role as a cancer survival gene as knock-down of CETP stunted the growth of TNBC tumour by 86%. The principal findings of this study potentiate CETP as a driver in breast cancer growth and aggressiveness and thus targeting CETP could limit drug resistance via the reduction in cholesterol accumulation in breast cancer cells, thereby reducing cancer aggressiveness.

Predictive value of plasma sICAM-1 and sP-Selectins in the risk of death in patients with acute respiratory distress syndrome.

Background: To evaluate the predictive value of sICAM-1 and sP-Selectins in the risk of death in a prospective cohort of adult acute respiratory distress syndrome (ARDS). Methods: Adult ARDS patients were included. Plasma sICAM-1, sP-Selectins, and inflammatory cytokines (TNF-α, IL-1b, IL-6, IL-8, and IL-17A) were detected in ARDS subjects. The correlation between different factors and the potential of sICAM-1 and sP-Selectins as endothelial markers to predict the risk of deathfrom ARDS was analyzed.

Defining a TFAP2C-centered transcription factor network during murine peri-implantation.

Transcription factors (TFs) play important roles in early embryonic development, but factors regulating TF action, relationships in signaling cascade, genome-wide localizations, and impacts on cell fate transitions during this process have not been clearly elucidated. In this study, we used uliCUT&RUN-seq to delineate a TFAP2C-centered regulatory network, showing that it involves promoter-enhancer interactions and regulates TEAD4 and KLF5 function to mediate cell polarization. Notably, we found that maternal retinoic acid metabolism regulates TFAP2C expression and function by inducing the active demethylation of SINEs, indicating that the RARG-TFAP2C-TEAD4/KLF5 axis connects the maternal-to-zygotic transition to polarization. Moreover, we found that both genomic imprinting and SNP-transferred genetic information can influence TF positioning to regulate parental gene expressions in a sophisticated manner. In summary, we propose a ternary model of TF regulation in murine embryonic development with TFAP2C as the core element and metabolic, epigenetic, and genetic information as nodes connecting the pathways.

The role of tumor parenchyma and brain cortex signal intensity ratio in differentiating solitary fibrous tumors and meningiomas.

BACKGROUND: Solitary fibrous tumors (SFT) and meningiomas (MA) have similar clinical and radiographic presentations but require different treatment approaches and have different prognoses. This emphasizes the importance of a correct preoperative diagnosis of SFT versus MA. OBJECTIVE: In this study, investigated the differences in imaging characteristics between SFT and MA to improve the accuracy of preoperative imaging diagnosis of SFT. METHODS: The clinical and imaging data of 26 patients with SFT and 104 patients with MA who were pathologically diagnosed between August 2017 and December 2022, were retrospectively analyzed. The clinical and imaging differences between SFT and MA, as well as between the various pathological grades of SFT, were analyzed. RESULTS: Age, gender, cystic change, flow void phenomenon, yin-yang sign, lobulation, narrow base, tumor/cortex signal ratio (TCSR) > 1.0 in T1-weighted imaging (T1WI), TCSR ≥ 1.1 in T2-weighted imaging (T2WI), peritumoral edema, and absence of dural tail sign varied between SFT and MA. As per the receiver operating characteristic (ROC) curve analysis, TCSR > 1 in T1WI has the maximum diagnostic accuracy for SFT. Cranial or venous sinus invasion had a positive effect on SFT (Grade III, World Health Organization (WHO) grading). CONCLUSION: Among the many radiological and clinical distinctions between SFT and MA, TCSR ≥ 1 exhibits the highest predictive efficacy for SFT; while cranial or venous sinus invasion may be a predictor of WHO grade III SFT.

Electroacupuncture Promotes Skeletal Muscle Myogenic Differentiation and Protein Synthesis by Reducing Let-7c-5p Levels.

Objective: Acupuncture with low-frequency electrical stimulation (Acu-LFES) can attenuate muscle atrophy. Previous studies have found that Acu-LFES reduces the let-7 family in serum exosomes. This study explored the effects of let-7c-5p in chronic kidney disease (CKD) muscle atrophy. Methods: A total of 24 mice were randomly divided into control group, Acu-LFES group, CKD group, and CKD/Acu-LFES group (n = 6/group). The 5/6 nephrectomy was performed to establish the CKD model in mice. After 20 weeks, the Acu-LFES group and CKD/Acu-LFES group were treated with electroacupuncture at the "Zu San Li" and "Yang Ling Quan" bilaterally points for 15 minutes once. Surface sensing of translation (SUnSET), Reverse Transcription-quantitative PCR(RT-qPCR), immunofluorescence staining, and Western blot were performed to examine each group's state of protein production and myogenic differentiation. we knocked down or exogenously expressed let-7c-5p in C2C12 myoblast, RT-qPCR, and Western blot were performed to examine protein synthesis and myogenic differentiation. Results: The protein expressions of MyoD and Myogenin (MyoG) were decreased in the CKD group (P = .029 and P = .026) concomitant with a decrease in the muscle fiber cross-sectional area. Acu-LFES prevented muscle atrophy in CKD mice. The protein expressions of MyoD and MyoG were increased in the CKD/Acu-LFES group (P = .006 and P = .001). In muscle of CKD mice, IGF1, IGF1R, IRS1, phosphorylated mTOR and P70S6K proteins were decreased compared with control muscle (P = .001, P = .007, P < .001, P < .001 and P < .001), whereas atrogin-1/MAFbx and MuRF1 were dramatically increased (P < .001). Acu-LFES reversed these phenomena, indicating IGF1/mTOR signaling pathway was induced to promote muscle protein synthesis and myogenic differentiation. Meanwhile, Acu-LFES caused a decrease of let-7c-5p in skeletal muscle of CKD mice (P = .034). Inhibiting let-7c-5p promoted C2C12 myogenic differentiation (P = .002 and P = .001) and increased IGF1, IGF1R, IRS1 levels while upregulating mTOR and P70S6K phosphorylation (P < .001, P = .002, P = .009, P < .001 and P = .007). It is interesting to observe that the abundance of atrogin-1/MAFbx and MuRF-1 was unaffected by let-7c-5p (P > .05). Conclusions: Acu-LFES-reduced expression of let-7c-5p can ameliorate CKD-induced skeletal muscle atrophy by upregulating the IGF1/mTOR signaling pathway, which enhances skeletal muscle protein synthesis and myogenic differentiation. Let-7c-5p may be a potential regulator for the treatment of muscle atrophy.

Pumilio1 regulates NPM3/NPM1 axis to promote PD-L1-mediated immune escape in gastric cancer.

Abnormal regulation of RNA binding proteins (RBPs) plays an essential role in tumorigenesis and progression, but their functions and mechanisms remain largely elusive. Previously, we reported that Pumilio 1 (PUM1), a RBP, could regulate glycolysis metabolism and promote the progression of gastric cancer (GC). However, the role of PUM1 in tumor immune regulation remains largely elusive. In this study, we report that PUM1 induces immune escape through posttranscriptional regulation of PD-L1 in GC. We used multiplexed immunohistochemistry to analyze the correlation between PUM1 expression and immune microenvironment in GC. The effect of PUM1 deficiency on tumor killing of T cells was examined in vitro and in vivo. The molecular mechanism of PUM1 was evaluated via RNA immunoprecipitation, chromatin immunoprecipitation, Western blot, co-immunoprecipitation, and RNA stability assays. Clinically, elevated PUM1 expression is associated with high-expression of PD-L1, lack of CD8+ T cell infiltration and poor prognosis in GC patients. PUM1 positively regulates PD-L1 expression and PUM1 reduction enhances T cell killing of tumors. Mechanistically, PUM1 directly binds to nucleophosmin/nucleoplasmin 3 (NPM3) mRNA and stabilizes NPM3. NPM3 interacts with NPM1 to promote NPM1 translocation into the nucleus and increase the transcription of PD-L1. PUM1 inhibits the anti-tumor activity of T cells through the PUM1/NPM3/PD-L1 axis. In summary, this study reveals the critical post-transcriptional effect of PUM1 in the modulation of PD-L1-dependent GC immune escape, thus provides a novel indicator and potential therapeutic target for cancer immunotherapy.

Development and Validation of a Nomogram for Renal Survival Prediction in Patients with Autosomal Dominant Polycystic Kidney Disease.

Introduction: Due to the wide variation in the prognosis of autosomal dominant polycystic kidney disease (ADPKD), prediction of risk of renal survival in ADPKD patients is a tough challenge. We aimed to establish a nomogram for the prediction of renal survival in ADPKD patients. Methods: We conducted a retrospective observational cohort study in 263 patients with ADPKD. The patients were randomly assigned to a training set (N = 198) and a validation set (N = 65), and demographic and statistical data at baseline were collected. The total kidney volume was measured using stereology. A clinical prediction nomogram was developed based on multivariate Cox regression results. The performance and clinical utility of the nomogram were assessed by calibration curves, the concordance index (C-index), and decision curve analysis (DCA). The nomogram was compared with the height-adjusted total kidney volume (htTKV) model by receiver operating characteristic curve analysis and DCA. Results: The five independent factors used to construct the nomogram for prognosis prediction were age, htTKV, estimated glomerular filtration rate, hypertension, and hemoglobin. The calibration curve of predicted probabilities against observed renal survival indicated excellent concordance. The model showed very good discrimination with a C-index of 0.91 (0.83-0.99) and an area under the curve of 0.94, which were significantly higher than those of the htTKV model. Similarly, DCA demonstrated that the nomogram had a better net benefit than the htTKV model. Conclusion: The risk prediction nomogram, incorporating easily assessable clinical parameters, was effective for the prediction of renal survival in ADPKD patients. It can be a useful clinical adjunct for clinicians to evaluate the prognosis of ADPKD patients and provide individualized decision-making.

Imaging and pathological characteristics, treatment, and prognosis of pulmonary sequestration-A retrospective study of 13 cases.

OBJECTIVE: This study aimed to summarize and analyze the characteristics of pulmonary sequestration to improve our understanding of this disease. METHODS: Between January 2019 and April 2023, the clinical data of 13 patients with pulmonary sequestration underwent surgical treatment at the First Affiliated Hospital of Gannan Medical University. RESULTS: The male-to-female ratio was 4:9, the age was 0.5 to 60 years, and the average age was 38 ± 19 years. There were 10 and 3 cases of intralobar and extralobar pulmonary sequestration, respectively. Chest enhanced computed tomography (CT) and three-dimensional vascular reconstruction showed that the abnormal blood vessels were derived from the descending thoracic aorta in nine cases and from other blood vessels in four cases. Three patients underwent thoracoscopic lobectomy, two underwent thoracoscopic segmentectomy, and eight underwent thoracoscopic wedge resection. All the patients successfully completed the surgery and were discharged postoperatively. CONCLUSIONS: Some patients with pulmonary sequestration exhibit no obvious symptoms. Patients with clinical symptoms are easily confused for pneumonia, bronchial cysts, lung abscesses, and lung tumors; therefore, patients with pulmonary sequestration are prone to missed diagnosis and misdiagnosis. Currently, enhanced chest CT combined with three-dimensional vascular reconstruction can accurately show the course, branches, and relationship with the mass of the feeding artery. Routine pathological examination is helpful to further clarify the diagnosis of pulmonary sequestration. Minimally invasive thoracoscopic surgery is the preferred treatment for patients with pulmonary sequestration. Surgical resection is safe and feasible, and satisfactory results are typically obtained.

PUM1 Promotes Tumor Progression by Activating DEPTOR-Meditated Glycolysis in Gastric Cancer.

RNA-binding proteins (RBPs) play essential roles in tumorigenesis and progression, but their functions in gastric cancer (GC) remain largely elusive. Here, it is reported that Pumilio 1 (PUM1), an RBP, induces metabolic reprogramming through post-transcriptional regulation of DEP domain-containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR) in GC. In clinical samples, elevated expression of PUM1 is associated with recurrence, metastasis, and poor survival. In vitro and in vivo experiments demonstrate that knockdown of PUM1 inhibits the proliferation and metastasis of GC cells. In addition, RNA-sequencing and bioinformatics analyses show that PUM1 is enriched in the glycolysis gene signature. Metabolomics studies confirm that PUM1 deficiency suppresses glycolytic metabolism. Mechanistically, PUM1 binds directly to DEPTOR mRNA pumilio response element to maintain the stability of the transcript and prevent DEPTOR degradation through post-transcriptional pathway. PUM1-mediated DEPTOR upregulation inhibits mTORC1 and alleviates the inhibitory feedback signal transmitted from mTORC1 to PI3K under normal conditions, thus activating the PI3K-Akt signal and glycolysis continuously. Collectively, these results reveal the critical epigenetic role of PUM1 in modulating DEPTOR-dependent GC progression. These conclusions support further clinical investigation of PUM1 inhibitors as a metabolic-targeting treatment strategy for GC.

Interplay between the renin angiotensin system and oxidative stress contributes to alcohol addiction by stimulating dopamine accumulation in the mesolimbic pathway.

The brain renin-angiotensin system (RAS) has recently been implicated in the development of substance abuse and addiction. However, the integrative roles of the two counter-regulating RAS arms, including the ACE1/Ang II/AT1R axis and the ACE2/Ang(1-7)/MasR axis, in alcohol addiction remain unclear. Using the 20% ethanol intermittent-access two-bottle-choice (IA2BC) paradigm, we observed significant alcohol preference and addictive behaviors in rats. Additionally, we observed significant disruption in the RAS and redox homeostasis in the ventral tegmental area (VTA), as indicated by upregulation of ACE1 activities, Ang II levels, AT1R expression, and glutathione disulfide contents, as well as downregulation of ACE2 activities, Ang(1-7) levels, MasR expression and glutathione content. Moreover, dopamine accumulated in the VTA and nucleus accumbens of IA2BC rats. Intra-VTA infusion of the antioxidant tempol substantially attenuated RAS imbalance and addictive behaviors. Intra-VTA infusion of the ACE1 inhibitor captopril significantly reduced oxidative stress, alcohol preference, addictive behaviors, and dopamine accumulation, whereas intra-VTA infusion of the ACE2 inhibitor MLN4760 had the opposite effects. The anti-addictive effects of the ACE2/Ang(1-7)/MasR axis were further observed using intra-VTA infusion of Ang(1-7) and a MasR-specific antagonist A779. Therefore, our findings suggest that excessive alcohol intake causes RAS imbalance via oxidative stress, and that a dysregulated RAS in the VTA contributes to alcohol addiction by stimulating oxidative stress and dopaminergic neurotransmission. Breaking the vicious cycle of RAS imbalance and oxidative stress using brain-permeable antioxidants, ACE1 inhibitors, ACE2 activators, or Ang(1-7) mimetics thus represents a promising strategy for combating alcohol addiction.

Transcriptome profiles and chromatin states in mouse androgenetic haploid embryonic stem cells.

Haploid embryonic stem cells (haESCs) are derived from the inner cell mass of the haploid blastocyst, containing only one set of chromosomes. Extensive and accurate chromatin remodelling occurs during haESC derivation, but the intrinsic transcriptome profiles and chromatin structure of haESCs have not been fully explored. We profiled the transcriptomes, nucleosome positioning, and key histone modifications of four mouse haESC lines, and compared these profiles with those of other closely-related stem cell lines, MII oocytes, round spermatids, sperm, and mouse embryonic fibroblasts. haESCs had transcriptome profiles closer to those of naïve pluripotent stem cells. Consistent with the one X chromosome in haESCs, Xist was repressed, indicating no X chromosome inactivation. haESCs and ESCs shared a similar global chromatin structure. However, a nucleosome depletion region was identified in 2056 promoters in ESCs, which was absent in haESCs. Furthermore, three characteristic spatial relationships were formed between transcription factor motifs and nucleosomes in both haESCs and ESCs, specifically in the linker region, on the nucleosome central surface, and nucleosome borders. Furthermore, the chromatin state of 4259 enhancers was off in haESCs but active in ESCs. Functional annotation of these enhancers revealed enrichment in regulation of the cell cycle, a predominantly reported mechanism of haESC self-diploidization. Notably, the transcriptome profiles and chromatin structure of haESCs were highly preserved during passaging but different from those of differentiated cell types.

Discovery of therapeutic targets of quercetin for endometrial carcinoma patients infected with COVID-19 through network pharmacology.

Purpose: Aimed to identify the anti-uterine corpus endometrial carcinoma (UCEC) function and characterize the mechanism of quercetin in the treatment of patients infected with COVID-19 via integrated in silico analysis. Methods: The Cancer Genome Atlas and Genotype Tissue Expression databases were applied to obtain differentially expressed genes of UCEC and non-tumor tissue. Several in silico methods such as network pharmacology, functional enrichment analysis, Cox regression analyses, somatic mutation analysis, immune infiltration and molecular docking were used to investigate and analysis the biological targets, functions and mechanisms of anti-UCEC/COVID-19 of quercetin. Multiple methods such as CCK8 assay, Transwell assay and western blotting were performed to test proliferation, migration, and protein level of UCEC (HEC-1 and Ishikawa) cells. Results: Functional analysis disclosed that quercetin against UCEC/COVID-19 mainly by 'biological regulation', 'response to stimulus', and 'regulation of cellular process'. Then, regression analyses indicated that 9 prognostic genes (including ANPEP, OAS1, SCGB1A1, HLA-A, NPPB, FGB, CCL2, TLR4, and SERPINE1) might play important roles in quercetin for treating UCEC/COVID-19. Molecular docking analysis revealed that the protein products of 9 prognostic genes were the important anti-UCEC/COVID-19 biological targets of quercetin. Meanwhile, the proliferation and migration of UCEC cells were inhibited by quercetin. Moreover, after treatment with quercetin, the protein level of ubiquitination-related gene ISG15 was decreased in UCEC cells in vitro. Conclusions: Taken together, this study provides new treatment option for UCEC patients infected with COVID-19. Quercetin may work by reducing the expression of ISG15 and participating in ubiquitination-related pathways.

APOC1 predicts a worse prognosis for esophageal squamous cell carcinoma and is associated with tumor immune infiltration during tumorigenesis.

Background: Esophageal carcinoma (ESCA), a common malignant tumor of the digestive tract with insidious onset, is a serious threat to human health. Despite multiple treatment modalities for patients with ESCA, the overall prognosis remains poor. Apolipoprotein C1 (APOC1) is involved in tumorigenesis as an inflammation-related molecule, and its role in esophageal cancer is still unknown. Methods: We downloaded documents and clinical data using The Cancer Genome Atlas (TCGA)and Gene Expression Omnibus (GEO) databases. We also conducted bioinformatics studies on the diagnostic value, prognostic value, and correlation between APOC1 and immune infiltrating cells in ESCA through STRING (https://cn.string-db.org/), the TISIDB (http://cis.hku.hk/TISIDB/) website, and various other analysis tools. Results: In patients with ESCA, APOC1 was significantly more highly expressed in tumor tissues than in normal tissues (p < 0.001). APOC1 could diagnose ESCA more accurately and determine the TNM stage and disease classification with high accuracy (area under the curve, AUC≥0.807). The results of the Kaplan-Meier curve analysis showed that APOC1 has prognostic value for esophageal squamous carcinoma (ESCC) (p = 0.043). Univariate analysis showed that high APOC1 expression in ESCC was significantly associated with worse overall survival (OS) (p = 0.043), and multivariate analysis shows that high APOC1 expression was an independent risk factor for the OS of patients with ESCC (p = 0.030). In addition, the GO (gene ontology)/KEGG (Kyoto encyclopedia of genes and genomes) analysis showed a concentration of gene enrichment in the regulation of T-cell activation, cornification, cytolysis, external side of the plasma membrane, MHC protein complex, MHC class II protein complex, serine-type peptidase activity, serine-type endopeptidase activity, Staphylococcus aureus infection, antigen processing and presentation, and graft-versus-host disease (all p < 0.001). GSEA (gene set enrichment analysis) showed that enrichment pathways such as immunoregulatory-interactions between a lymphoid and non-lymphoid cell (NES = 1.493, p. adj = 0.023, FDR = 0.017) and FCERI-mediated NF-KB activation (NES = 1.437, p. adj = 0.023, FDR = 0.017) were significantly enriched in APOC1-related phenotypes. In addition, APOC1 was significantly associated with tumor immune infiltrating cells and immune chemokines. Conclusion: APOC1 can be used as a prognostic biomarker for esophageal cancer. Furthermore, as a novel prognostic marker for patients with ESCC, it may have potential value for further investigation regarding the diagnosis and treatment of this group of patients.

Design, synthesis, and biological evaluation of pleuromutilin derivatives containing 1,2,4-triazole linker.

A series of thioether pleuromutilin derivatives containing 1,2,4-triazole on the side chain of C14 were designed and synthesized. The in vitro antibacterial activities experiments of the synthesized derivatives showed that compounds 72 and 73 displayed superior in vitro antibacterial effect against MRSA minimal inhibitory concentration (MIC = 0.0625 µg/mL) than tiamulin (MIC = 0.5 µg/mL). The results of time-kill study and postantibiotic effect study indicated that compound 72 could inhibit the growth of MRSA quickly (-2.16 log10 CFU/mL) and showed certain postantibiotic effect (PAE) time (exposure to 2 × MIC and 4 × MIC for 2 h, the PAE was 1.30 and 1.35 h) against MRSA. Furthermore, the binding mode between compound 72 and 50S ribosome of MRSA was explored by molecular docking and five hydrogen bonds were formed between compound 72 and 50S ribosome.

The role of USP51 in attenuating chemosensitivity of lung cancer cells to cisplatin by regulating DNA damage response.

Lung cancer is the most frequent type of cancer affecting both men and women globally, and it is associated with a high mortality rate. It is clinically treated with cisplatin, a platinum-based drug that works by generating DNA lesions, which activates DNA damage response and induces cell death. However, chemoresistance by cancer cells limits the clinical usefulness of cisplatin as an anticancer drug. Here, we uncovered a role of ubiquitin-specific protease 51 (USP51) in the chemosensitivity of lung cancer cells to cisplatin by regulating DNA damage response. USP51 was more upregulated in lung cancer tissues of chemotherapy-resistant patients than those of chemotherapy-sensitive patients with adjacent, nontumor tissues. USP51 overexpression in lung cancer cells in vitro reduced γ-H2AX formation and promoted checkpoint kinase 1 (CHK1) phosphorylation, whereas USP51 knockdown showed opposite effects, indicating that USP51 played an important role in promoting DNA damage repair. Finally, USP51 knockdown weakened cisplatin resistance in A549/DDP cells and significantly suppressed tumor growth in vivo, suggesting that a USP51 inhibitor combined with cisplatin may be considered as an effective treatment strategy to eliminate drug-resistant lung cancer cells.

CRISPR/Cas9-mediated knock-in strategy at the Rosa26 locus in cattle fetal fibroblasts.

The genetic modification of cattle has many agricultural and biomedical applications. However, random integration often leads to the unstable or differentially expression of the exogenous genes, which limit the application and development of transgenic technologies. Finding a safe locus suitable for site-specific insertion and efficient expression of exogenous genes is a good way to overcome these hurdles. In this study, we efficiently integrated three targeted vector into the cattle Rosa26 (cRosa26) by CRISPR/Cas9 technology in which EGFP was driven by CAG, EF1a, PGK and cRosa26 endogenous promoter respectively. The CRISPR/Cas9 knock-in system allows highly efficient gene insertion of different expression units at the cRosa26 locus. We also find that in the four cell lines, EGFP was stable expressed at different times, and the CAG promoter has the highest activity to activate the expression of EGFP, when compared with the cRosa26, EF1a and PGK promoter. Our results proved that cRosa26 was a locus that could integrate different expression units efficiently, and supported the friendly expression of different expression units. Our findings described here will be useful for a variety of studies using cattle.