Response and adaptation mechanisms of Apostichopus japonicus to single and combined anthropogenic stresses of polystyrene microplastics or cadmium.

Microplastics (MPs) have become pervasive in marine ecosystems, exerting detrimental effects on marine life. The concurrent presence and interaction of MPs and heavy metals in aquatic environments could engender more insidious toxicological impacts. This study aimed to elucidate the potential impacts and underlying mechanisms of polystyrene microplastics (PS-MPs), cadmium (Cd), and their combined stress (MPs-Cd) on sea cucumbers (Apostichopus japonicus). It focused on the growth, Cd bioaccumulation, oxidative stress responses, immunoenzymatic activities, and metabolic profiles, specifically considering PS-MPs sizes preferentially ingested by these organisms. The high-dose MPs (MH) treatment group exhibited an increase in cadmium bioavailability within the sea cucumbers. Exposure to PS-MPs or Cd triggered the activation of antioxidant defenses and immune responses. PS-MPs and Cd exhibited a synergistic effect on lysozyme (LZM) activity. A total of 149, 316, 211, 197, 215, 619, 434, and 602 differentially expressed metabolites were identified, distinguishing the low-dose MPs (ML), high-dose MPs (MH), low-dose Cd (LCd), low-dose MPs and low-dose Cd (MLLCd), high-dose MPs and low-dose Cd (MHLCd), high-dose Cd (HCd), low-dose MPs and high-dose Cd (MLHCd), high-dose MPs and high-dose Cd (MHHCd) groups, respectively. Metabolomic analyses revealed disruptions in lipid metabolism, nervous system function, signal transduction, and transport and catabolism pathways following exposure to PS-MPs, Cd, and MPs-Cd. Correlation analyses among key differentially expressed metabolites (DEMs) underscored the interregulation among these metabolic pathways. These results offer new perspectives on the distinct and synergistic toxicological impacts of microplastics and cadmium on aquatic species, highlighting the complex interplay between environmental contaminants and their effects on marine life.

Development and validation of a risk prediction model for invasiveness of pure ground-glass nodules based on a systematic review and meta-analysis.

BACKGROUND: Assessing the aggressiveness of pure ground glass nodules early on significantly aids in making informed clinical decisions. OBJECTIVE: Developing a predictive model to assess the aggressiveness of pure ground glass nodules in lung adenocarcinoma is the study's goal. METHODS: A comprehensive search for studies on the relationship between computed tomography(CT) characteristics and the aggressiveness of pure ground glass nodules was conducted using databases such as PubMed, Embase, Web of Science, Cochrane Library, Scopus, Wanfang, CNKI, VIP, and CBM, up to December 20, 2023. Two independent researchers were responsible for screening literature, extracting data, and assessing the quality of the studies. Meta-analysis was performed using Stata 16.0, with the training data derived from this analysis. To identify publication bias, Funnel plots and Egger tests and Begg test were employed. This meta-analysis facilitated the creation of a risk prediction model for invasive adenocarcinoma in pure ground glass nodules. Data on clinical presentation and CT imaging features of patients treated surgically for these nodules at the Third Affiliated Hospital of Kunming Medical University, from September 2020 to September 2023, were compiled and scrutinized using specific inclusion and exclusion criteria. The model's effectiveness for predicting invasive adenocarcinoma risk in pure ground glass nodules was validated using ROC curves, calibration curves, and decision analysis curves. RESULTS: In this analysis, 17 studies were incorporated. Key variables included in the model were the largest diameter of the lesion, average CT value, presence of pleural traction, and spiculation. The derived formula from the meta-analysis was: 1.16×the largest lesion diameter + 0.01 × the average CT value + 0.66 × pleural traction + 0.44 × spiculation. This model underwent validation using an external set of 512 pure ground glass nodules, demonstrating good diagnostic performance with an ROC curve area of 0.880 (95% CI: 0.852-0.909). The calibration curve indicated accurate predictions, and the decision analysis curve suggested high clinical applicability of the model. CONCLUSION: We established a predictive model for determining the invasiveness of pure ground-glass nodules, incorporating four key radiological indicators. This model is both straightforward and effective for identifying patients with a high likelihood of invasive adenocarcinoma.

Directed evolution-based discovery of ligands for in vivo restimulation of CAR-T cells.

Chimeric antigen receptor (CAR) T cell therapy targeting CD19 elicits remarkable clinical efficacy in B-cell malignancies, but many patients relapse due to failed expansion and/or progressive loss of CAR-T cells. We recently reported a strategy to potently restimulate CAR-T cells in vivo, enhancing their functionality by administration of a vaccine-like stimulus comprised of surrogate peptide ligands for a CAR linked to a lymph node-targeting amphiphilic PEG-lipid (termed CAR-T-vax). Here, we demonstrate a general strategy to generate and optimize peptide mimotopes enabling CAR-T-vax generation for any CAR. Using the clinical CD19 CAR FMC63 as a test case, we employed yeast surface display to identify peptide binders to soluble IgG versions of FMC63, which were subsequently affinity matured by directed evolution. CAR-T vaccines using these optimized mimotopes triggered marked expansion of both murine CD19 CAR-T cells in a syngeneic model and human CAR-T cells in a humanized mouse model of B cell acute lymphoblastic leukemia (B-ALL), and enhanced control of leukemia progression. This approach thus enables vaccine boosting to be applied to any clinically-relevant CAR-T cell product.

Duodenal-jejunal bypass improves hypothalamic oxidative stress and inflammation in diabetic rats via glucagon-like peptide 1-mediated Nrf2/HO-1 signaling.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is often accompanied by impaired glucose utilization in the brain, leading to oxidative stress, neuronal cell injury and infla-mmation. Previous studies have shown that duodenal jejunal bypass (DJB) surgery significantly improves brain glucose metabolism in T2DM rats, the role and the metabolism of DJB in improving brain oxidative stress and inflammation condition in T2DM rats remain unclear. AIM: To investigate the role and metabolism of DJB in improving hypothalamic oxidative stress and inflammation condition in T2DM rats. METHODS: A T2DM rat model was induced via a high-glucose and high-fat diet, combined with a low-dose streptozotocin injection. T2DM rats were divided into DJB operation and Sham operation groups. DJB surgical intervention was carried out on T2DM rats. The differential expression of hypothalamic proteins was analyzed using quantitative proteomics analysis. Proteins related to oxidative stress, inflammation, and neuronal injury in the hypothalamus of T2DM rats were analyzed by flow cytometry, quantitative real-time PCR, Western blotting, and immunofluorescence. RESULTS: Quantitative proteomics analysis showed significant differences in proteins related to oxidative stress, inflammation, and neuronal injury in the hypothalamus of rats with T2DM-DJB after DJB surgery, compared to the T2DM-Sham groups of rats. Oxidative stress-related proteins (glucagon-like peptide 1 receptor, Nrf2, and HO-1) were significantly increased (P < 0.05) in the hypothalamus of rats with T2DM after DJB surgery. DJB surgery significantly reduced (P < 0.05) hypothalamic inflammation in T2DM rats by inhibiting the activation of NF-κB and decreasing the expression of interleukin (IL)-1ß and IL-6. DJB surgery significantly reduced (P < 0.05) the expression of factors related to neuronal injury (glial fibrillary acidic protein and Caspase-3) in the hypothalamus of T2DM rats and upregulated (P < 0.05) the expression of neuroprotective factors (C-fos, Ki67, Bcl-2, and BDNF), thereby reducing hypothalamic injury in T2DM rats. CONCLUSION: DJB surgery improve oxidative stress and inflammation in the hypothalamus of T2DM rats and reduce neuronal cell injury by activating the glucagon-like peptide 1 receptor-mediated Nrf2/HO-1 signaling pathway.

3D genome structural variations play important roles in regulating seed oil content of Brassica napus.

Dissecting the complex regulatory mechanism of seed oil content (SOC) is one of the main research goals in Brassica napus. Increasing evidence suggests that genome architecture is linked to multiple biological functions. However, the effect of genome architecture on SOC regulation remains unclear. Here, we used high-throughput chromatin conformation capture to characterize differences in the three-dimensional (3D) landscape of genome architecture of seeds from two B. napus lines, N53-2 (with high SOC) and Ken-C8 (with low SOC). Bioinformatics analysis demonstrated that differentially accessible regions and differentially expressed genes between N53-2 and Ken-C8 were preferentially enriched in regions with quantitative trait loci (QTLs)/associated genomic regions (AGRs) for SOC. A multi-omics analysis demonstrated that expression of SOC-related genes was tightly correlated with genome structural variations in QTLs/AGRs of B. napus. The candidate gene BnaA09g48250D, which showed structural variation in a QTL/AGR on chrA09, was identified by fine-mapping of a KN double-haploid population derived from hybridization of N53-2 and Ken-C8. Overexpression and knockout of BnaA09g48250D led to significant increases and decreases in SOC, respectively, in the transgenic lines. Taken together, our results reveal the 3D genome architecture of B. napus seeds and the roles of genome structural variations in SOC regulation, enriching our understanding of the molecular mechanisms of SOC regulation from the perspective of spatial chromatin structure.

Low UPB1 Level Correlates With Poor Prognosis in Lung Adenocarcinoma.

OBJECTIVES: Lung adenocarcinoma (LUAD) is a critical cancer with high mortality, worse prognosis, and crucial lymphatic metastasis. Consequently, prognostic biomarkers for LUAD are truly required. ß-Ureidopropionase (UPB1) is abnormally expressed in various cancers. However, the function of UPB1 in LUAD is still ambiguous. This study aimed to explore the expression profile and prognostic significance of UPB1 in LUAD. MATERIALS AND METHODS: The differential UPB1 levels in pan cancers and their prognostic significance were comprehensively investigated through Gene Expression Profiling Interactive Analysis, UALCAN, Tumor Immune Estimation Resource, and Kaplan-Meier plotter platform. The correlation between UPB1 and tumor infiltration immune cells was explored using Tumor Immune Estimation Resource, Gene Expression Profiling Interactive Analysis, and Tumor-Immune System Interactions and Drug Bank database databases. RESULTS: The UPB1 level was abnormally expressed in pan-tumor tissue than in adjacent tissue from The Cancer Genome Atlas tool. Low UPB1 level was correlated with poor overall survival in patients with LUAD. Furthermore, a comparison of the various pathologic characteristics of LUAD between high and low UPB1 level subgroups revealed that low UPB1 expression was correlated with lymph node metastasis. Kaplan-Meier survival analysis indicated that a low UPB1 level was associated with worse progression­free survival and overall survival in patients with LUAD. Univariate and multivariate analyses suggested that UPB1 could be a useful prognostic indicator for LUAD. Abnormal UPB1 may be correlated with aberrant LUAD immune infiltration, prompting a worse survival outcome. CONCLUSIONS: Results showed that low UPB1 is correlated with a worse prognosis of LUAD and may be a valuable prognostic indicator for LUAD.

Effects of recombinant human brain natriuretic peptide combined with tolvaptan on cardiac and renal function and serum inflammatory factors in patients with severe heart failure.

This study examined the effects of recombinant human brain natriuretic peptide (rhBNP) combined with tolvaptan on cardiac and renal function and serum inflammatory factors in patients with severe heart failure (HF). This retrospective study included 90 patients with severe HF who were treated at our hospital between January 2019 and August 2021. Patients treated with tolvaptan tablets were assigned to the control group, and those treated with rhBNP combined with tolvaptan were assigned to the observation group. Efficacy, cardiac function, levels of inflammatory factors, renal function, 6 minutes walking test, Minnesota Living with Heart Failure Questionnaire score, and adverse reactions were assessed. The curative effect (97.78% vs 77.78%) and improvement in cardiac function were greater in the observation group than in the control group (P < .05). Decreased levels of inflammatory factors were seen in both groups after treatment, and the levels of tumor necrosis factor-α, interleukin-33, and intercellular adhesion factor-1 in the observation group were lower than those in the control group (P < .05). The 6 minutes walking test was higher and the Minnesota Living with Heart Failure Questionnaire score was lower in the observation group compared with the control group (P < .05). The incidence of adverse reactions such as dry mouth, nausea, polyuria, hypotension, and headache in the observation group was lower than that in the control group (P < .05). In conclusion, for patients with severe HF, rhBNP combined with tolvaptan can improve cardiac function, alleviate symptoms of dyspnea, protect renal function, and reduce serum inflammatory factor levels when compared with tolvaptan alone.

MYH16 upregulation is associated with lung adenocarcinoma aggressiveness and immune infiltration.

Myosin heavy chain 16 (MYH16) may significantly affect cell cycle progression. Nevertheless, there is a lack of evidence about the clinical relevance of MYH16 upregulation in pan cancers, including lung adenocarcinoma (LUAD). MYH16 expression patterns were evaluated in various bioinformatics databases using The Cancer Genome Atlas data set. Clinical and pathological factor data were employed to risk-stratify patients. The Kaplan-Meier plotter approach was used to estimate survival rates. Tumor immune infiltration was explored via the TIMER tool, and gene set enrichment analysis (GSEA) was used to identify the pathways involved in MYH16 upregulation. The results showed that MYH16 was abnormally upregulated in pan cancers, including LUAD. MYH16 expression induction in LUAD was found to be related to the tumor stage. Furthermore, MYH16 upregulation was correlated with LUAD development and worse overall survival, particularly in women. Notably, MYH16 overexpression in LUAD tissues corresponded to the amount of immune infiltration in the tumor. Additionally, univariate Cox hazard regression analysis revealed that MYH16 may be an independent prognostic indicator for LUAD. Furthermore, a nomogram was constructed according to MYH16 expression and clinical characteristics. BMP6 expression deficiency may be a key factor contributing to MYH16 upregulation in LUAD. Finally, GSEA demonstrated that MYH16 might mediate meiosis and gene silencing through RNA signaling pathways. This study, for the first time, showed that MYH16 upregulation in LUAD is associated with various risk factors, increased cancer aggressiveness, enhanced infiltration of tumor immune cells, and reduced survival rates.

New insight into the genetic basis of oil content based on noninvasive three-dimensional phenotyping and tissue-specific transcriptome in Brassica napus.

BACKGROUND: Increasing seed oil content is the most important breeding goal in Brassica napus, and phenotyping is crucial to dissect its genetic basis in crops. To date, QTL mapping for oil content has been based on whole seeds, and the lipid distribution is far from uniform in different tissues of seeds in B. napus. In this case, the phenotype based on whole seeds was unable to sufficiently reveal the complex genetic characteristics of seed oil content. RESULTS: Here, the three-dimensional (3D) distribution of lipid was determined for B. napus seeds by magnetic resonance imaging (MRI) and 3D quantitative analysis, and ten novel oil content-related traits were obtained by subdividing the seeds. Based on a high-density genetic linkage map, 35 QTLs were identified for 4 tissues, the outer cotyledon (OC), inner cotyledon (IC), radicle (R) and seed coat (SC), which explained up to 13.76% of the phenotypic variation. Notably, 14 tissue-specific QTLs were reported for the first time, 7 of which were novel. Moreover, haplotype analysis showed that the favorable alleles for different seed tissues exhibited cumulative effects on oil content. Furthermore, tissue-specific transcriptomes revealed that more active energy and pyruvate metabolism influenced carbon flow in the IC, OC and R than in the SC at the early and middle seed development stages, thus affecting the distribution difference in oil content. Combining tissue-specific QTL mapping and transcriptomics, 86 important candidate genes associated with lipid metabolism were identified that underlie 19 unique QTLs, including the fatty acid synthesis rate-limiting enzyme-related gene CAC2, in the QTLs for OC and IC. CONCLUSIONS: The present study provides further insight into the genetic basis of seed oil content at the tissue-specific level.

Single and combined effects of microplastics and cadmium on the sea cucumber Apostichopus japonicus.

Microplastic pollution of the ocean has received extensive attention as plastic pollution increases globally, but the potential ecological risks caused by microplastic interactions with trace metals still require further research. In this study, Apostichopus japonicus was used to explore the individual and combined toxicities of cadmium (Cd) and microplastics and their effects on growth, Cd tissue accumulation, digestive enzymes, and gut microbes. The body weight gain and specific growth rate of animals exposed to a combination of high concentrations of Cd and microplastics decreased. The addition of high concentrations of cadmium to the diet led to an increase in cadmium content in the respiratory tree, digestive tract and body wall. Amylase, lipase and trypsin decreased to different degrees in the group treated with high concentrations of Cd/microplastics. Firmicutes were significantly reduced across multiple treatment groups, with the order Lactobacillales being the most significantly affected. Cd is the pollutant causing the greatest negative impact, but the presence of microplastics undoubtedly increases its toxicity.

The effect of 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) on locomotor behaviour and muscle physiology of the sea cucumber Apostichopus japonicus.

The 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is the predominant congener of polybrominated diphenyl ethers, and it is also a persistent organic pollutant that with a higher detection rate in samples from environment and animals. To date, there have been few studies of the effects of BDE-47 on locomotion in sea cucumbers. In this study, we investigated the influence of different concentrations of BDE-47 (low: 0.1 µg/L; moderate: 1.0 µg/L; high: 10.0 µg/L) on locomotion of Apostichopus japonicus and evaluated changes in their muscle physiology using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. The behavioural studies showed that the average and maximum velocity of movement decreased significantly in both the moderate and high BDE-47 groups after 1 day of exposure. In addition, levels of 55 metabolites were identified and characterized in the longitudinal muscle of A. japonicus exposed to BDE-47. The alteration of taurine and norepinephrine levels indicated that BDE-47 had drastic physiological effects on the longitudinal muscle of A. japonicus.

Ryanodine receptor (RYR) mutational status correlates with tumor mutational burden, age and smoking status and stratifies non-small cell lung cancer patient prognosis.

Background: The ryanodine receptors (RYRs) have been implicated in many muscular, cardiac and neurological diseases. However, there are almost no studies so far focusing on RYR genetic alterations and its roles in cancer, especially in non-small cell lung cancer (NSCLC). Methods: The whole-exome sequencing (WES) data, demographic and clinical data of 1,052 NSCLC patients was downloaded from The Cancer Genome Atlas (TCGA) database and analyzed using the corresponding packages of the R software. Mutational profile was established and its correlation with tumor mutational burden (TMB), prognosis, age and smoking status was analyzed and compared. Results: RYR mutations were found in 502 NSCLC patients, in which mutations of RYR1, RYR2 and RYR3 were found in 17.3% (182/1,052), 40.0% (421/1,052) and 21.3% (224/1,052) of patients, respectively. Random distribution of mutations without hotspot mutations were observed with all three RYR isoforms. Significant co-mutations were found between RYR1 and RYR3, while mutual exclusive mutations were found between RYR1 and RYR2, and between RYR2 and RYR3. Significant correlation was found between cumulative number of mutations and cumulative TMB for all three RYR isoforms, and patients with RYR mutations exhibited significantly higher TMB than those without RYR mutations. Significant correlation was also found between mutational status and age in RYR2 and RYR3, and between mutational status and smoking history grading in all three isoforms, and between mutational status and number of pack years in RYR3. More interestingly, significant stratification of patient survival was revealed by RYR2 mutational status, which was found to be one of the independent risk factors for patient prognosis in multivariate Cox analysis. Conclusions: The mutational profile of RYR in NSCLC has been characterized for the first time. Strong correlation was found between RYR mutational status and TMB, age and smoking status. RYR2 mutational status was an independent risk factor for NSCLC patient prognosis.

Oncogenic Role of Heterogeneous Nuclear Ribonucleoprotein C in Multiple Cancer Types, with a Particular Focus on Lung Adenocarcinoma, Using a Pan-Cancer Analysis and Cell Line Experiments.

Although some evidence has validated the connection between heterogeneous nuclear ribonucleoprotein C (HNRNPC) and the progression of tumors, a pan-cancer investigation is still required. Thus, we explored the oncogenic effect of HNRNPC across many tumors using The Cancer Genome Atlas datasets. Moreover, short hairpin RNAs (shRNAs) were found to repress HNRNPC in lung adenocarcinoma (LUAD) cells, and the effect on LUAD cells proliferation and metastasis was examined using a Cell Counting Kit-8, transwell, and invasion test. HNRNPC was found to be overexpressed in most cancers, and a divergent relationship was observed between the abnormal levels of HNRNPC and tumor prognosis. HNRNPC level was observed to correlate with the cancer-associated fibroblast infiltration, such as lung cancer. Furthermore, higher HNRNPC levels were found in LUAD tissues and cells. Subsequently, Kaplan-Meier analysis revealed that the increased HNRNPC level was connected with worse overall survival and disease-free survival in LUAD patients. Moreover, HNRNPC silencing reduced the progression of A549 and H1299 cells, including proliferation, migration, and invasion. This is the first pan-cancer investigation that presents a relatively systematic finding of the oncogenic effect of HNRNPC among many cancer types. Our data indicate that HNRNPC facilitates the biological processes of LUAD cells; nevertheless, further research on the mechanism underlying the role of HNRNPC in LUAD development is warranted.

MiR-223-3p affects myocardial inflammation and apoptosis following myocardial infarction via targeting FBXW7.

Background: Myocardial infarction (MI) is one of the main causes of disability and death in the world, leading to myocarditis and cardiomyocyte apoptosis. Studies have shown that microRNA (miRNA) is involved in myocarditis and apoptosis. The main purpose of this study was to explore the regulatory mechanism of miR-223-3p on myocarditis and apoptosis after MI. Methods: We cultured H9c2 cells and detected the expression of miR-223-3p in cells treated with different concentrations of H2O2. Sprague Dawley (SD) rats were fed with normal diet, constructed an MI model and detect the expression of miR-223-3p in heart tissue. Overexpression or inhibition of miR-223-3p was conducted in MI model cells in vitro, and the contents of the inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) in cell supernatant were detected by enzyme-linked immunosorbent assay (ELISA). Cell apoptosis was detected by flow cytometry. Luciferase activity assay was used to detect the targeting relationship between miR-223-3p and FBXW7, and the expression of FBXW7 in cells was also detected. Overexpression of miR-223-3p was performed in MI rats to detect the expression of inflammatory factors, FBXW7, and apoptosis in rat cardiac tissue. Results: The expression of miR-223-3p was down regulated in MI models established in vitro and in vivo. Overexpression of miR-223-3p can inhibit inflammatory response and apoptosis in H9c2 cells and cardiac tissues. It was revealed that miR-223-3p can inhibit the expression of FBXW7, reduce myocarditis and apoptosis after MI, and improve cardiac function. Conclusions: It is possible that miR-223-3p reduces myocarditis and apoptosis after MI and improves cardiac function by targeted inhibition of FBXW7 expression.

Assessment of radial artery atherosclerosis in acute coronary syndrome patients: an in vivo study using optical coherence tomography.

BACKGROUND: Radial artery (RA) atherosclerosis in acute coronary syndrome (ACS) patients has not been systematically observed in vivo. The study aims to characterize plaque morphology and intimal hyperplasia of the RA in patients with ACS, using optical coherence tomography (OCT). METHODS: In this retrospective study involving 239 ACS patients underwent RA OCT without guidewire shadow, 3 groups were divided according to the following criteria: radial artery plaque (RAP) group included patients with fibrous, lipid or calcified plaque; patients without RAP were further classified into radial intimal hyperplasia (RIH) group (intima media thickness ratio [IMR] ≥ 1) or normal group (IMR < 1). The presence and characteristics of RAP and its related risk factors were identified. RESULTS: The RAP, RIH and normal groups included 76 (31.8%), 69 (28.9%) and 94 (39.3%) patients, respectively. Patients in RAP group were the oldest, compared with those in the RIH and normal groups (p < 0.001), and more frequently had triple vessel disease (p = 0.004). The percentage of plaque rupture (72.4% vs. 56.4%, p = 0.018) and calcification (42.1% vs. 27.6%, p = 0.026) at culprit lesion were significantly higher in patients with RAP than those without RAP. A total of 148 RAP were revealed by OCT, including fibrous (72, 48.6%), lipid (50, 33.8%) and calcified plaques (26, 17.6%). The microvessels were also frequently observed in the RAP group than that in RIH and normal groups (59.2% vs. 8.7% vs. 9.6%, p < 0.001). Multivariate logistic regression analysis showed that age, diabetes, and smoking history (all p < 0.05) were independent risk factors for RAP. CONCLUSIONS: In terms of insights gained from OCT, RA atherosclerosis is not uncommon in ACS patients by OCT, sharing several morphological characters with early coronary atherosclerosis. Aging, diabetes, and smoking are risk factors for RAP.

Identification of DNA Repair-Related Genes Predicting Clinical Outcome for Thyroid Cancer.

Recent studies have demonstrated the utility and superiority of DNA repair-related genes as novel biomarkers for cancer diagnosis, prognosis, and therapy. Here, we aimed to screen the potential survival-related DNA repair-related genes in thyroid cancer (TC). TCGA datasets were utilized to analyze the differentially expressed DNA repair-related genes between TC and nontumor tissues. The K-M approach and univariate analysis were employed to screen survival-related genes. RT-PCR was employed to examine the expression of DNA repair-related genes in TC samples and matched noncancer samples. CCK-8 analyses were used to determine cellular proliferation. Herein, our team discovered that the expression of four DNA repair-related genes was remarkably upregulated in TC samples in contrast to noncancer samples. Survival assays identified 14 DNA repair-related genes. In our cohort, we observed that the expression of TAF13 and DCTN4 was distinctly elevated in TC specimens in contrast to nontumor specimens. Moreover, knockdown of TAF13 and DCTN4 was observed to inhibit the TC cellular proliferation. Overall, the upregulation of TAF13 and DCTN4 is related to decreased overall survival in TC patients. Therefore, the assessment of TAF13 and DCTN4 expression may be useful for predicting prognosis in these patients.

Circular RNA SOX13 promotes malignant behavior and cisplatin resistance in non-small cell lung cancer through targeting microRNA-3194-3p/microtubule-associated protein RP/EB family member 1.

Circular RNA (circRNA) presents an essential regulatory role in affecting the occurrence and acquired resistance in non-small cell lung cancer (NSCLC), but how circSOX13 impacts NSCLC is unclear. In this work it was found that compared with adjacent normal tissues, circSOX13 and the microtubule-associated protein RP/EB family member 1 (MAPRE1) were signally up-regulated in NSCLC while miR-3194-3p was signally lowered. Pulmonary function tests (PETs) revealed that knocking down circSOX13 or overexpressing miR-3194-3p inhibited NSCLC proliferation, invasion and migration but promoted its apoptosis. The promoting effect of overexpressing circSOX13 on NSCLC was reversed via knocking down MAPRE1. Additionally, knocking down circSOX13 reduced cisplatin resistance in NSCLC. Furthermore, circSOX13 mediated MAPRE1 expression via competitively binding miR-3194-3p to exert its tumorigenic impact. To conclude, this work clarified the carcinogenic impact of circSOX13-miR-3194-3p-MAPRE1 axis on NSCLC and DDP resistance. CircSOX13 can be a potential diagnostic marker and therapeutic target for NSCLC, thus providing a new insight for clinically reversing its acquired resistance.

Efficacy and safety of rivaroxaban in patients with inferior vena cava filter placement without anticoagulation contraindications (EPICT): a prospective randomised controlled trial study protocol.

INTRODUCTION: Inferior vena cava (IVC) filters are commonly used in patients with venous thromboembolism to prevent fatal pulmonary embolism, but the thrombosis risk increases after filter placement. Warfarin is a widely anticoagulant, but long-term monitoring and dose adjustments are required. Anticoagulation with rivaroxaban is more straightforward as it dose not require laboratory monitoring. This study compares the efficacy and safety of rivaroxaban and warfarin as an in anticoagulation therapy for patients with IVC filter placement. METHODS AND ANALYSIS: This is a multicentre, randomised controlled trial. In total, 200 patients with deep vein thrombosis (DVT) with IVC filter implantation from 10 hospitals will be recruited. The patients will be randomised to the experimental group (rivaroxaban) or the control group (nadroparin overlapped with warfarin). The primary outcomes include death of any cause, pulmonary embolism (PE)-related death, bleeding and recurrent PE/DVT. The secondary outcomes include the percentage of other vascular events, IVC filter retrieval failure and net clinical benefits. This study aims to provide reliable, verification for the efficacy and safety of rivaroxaban antithrombotic therapy after IVC filter placement. ETHICS AND DISSEMINATION: The study was approved by the Human Research Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine (approval number: (2019) 295). The results will be disseminated through presentations at scientific conferences and publications in peer-reviewed journals TRIAL REGISTRATION NUMBER: NCT04066764.

Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational burden in lung cancer.

BACKGROUND: Programmed cell death ligand 1 (PD-L1) expressed on tumor and immune cells are both associated with the response to programmed cell death 1 (PD-1) pathway blockade therapy. Here, we examine the role of CD8+PD-L1+ tumor-infiltrating lymphocyte (Tils) in the tumor microenvironment of non-small cell lung cancer (NSCLC). METHODS: Tumor tissue samples of a total of 378 patients from two NSCLC cohorts were collected retrospectively. Tumor genetic variations were measured by targeted next-generation sequencing of 543 oncogenes. Tils were assessed by multiplex immunohistochemistry assay. Correlations among Tils, tumor genetic variations, and clinicopathological characteristics were analyzed. RESULTS: The levels of CD8+PD-L1+ Tils varied in NSCLC tumor tissues. Tumor samples with high CD8+PD-L1+ Tils had higher levels of CD8+ Tils, CD68+ macrophages, PD-L1+ tumor cells, PD-1+ Tils, and CD163+ M2-type macrophages, and also had a higher tumor mutation burden, all of which collectively constituted a typically hot but immunosuppressive tumor microenvironment. Therefore, in a non-immunotherapy cohort, we observed that the higher the CD8+PD-L1+ Tils level in the tumor tissue, the worse the prognosis (progression-free survival; cohort A, stage I-II tumor; p=0.005). Contrarily, in an immunotherapy cohort, where the immune suppression was blocked by anti-PD-1 treatment, the higher the CD8+PD-L1+ Tils level, the better the response to the anti-PD-1 treatment (complete response/partial response vs stable disease/progressive disease; cohort B; p=0.0337). CONCLUSIONS: CD8+PD-L1+ Tils may be an indicator of the hot but immunosuppressive tumor microenvironment which is related to a high tumor mutation burden. PD-1 pathway blockade therapy can help to mitigate this immunosuppression and obtain better curative effects.