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Abstract Cancer cells alter their metabolism and epigenetics to support cancer progression. However, very few modulators connecting metabolism and epigenetics have been uncovered. Here, we reveal that serine hydroxymethyltransferase-2 (SHMT2) generates S-adenosylmethionine (SAM) to epigenetically repress phosphatase and tensin homolog (PTEN), leading to papillary thyroid cancer (PTC) metastasis depending on activation of AKT signaling. SHMT2 is elevated in PTC, and is associated with poor prognosis. Overexpressed SHMT2 promotes PTC metastasis both in vitro and in vivo. Proteomic enrichment analysis shows that AKT signaling is activated, and is positively associated with SHMT2 in PTC specimens. Blocking AKT activation eliminates the effects of SHMT2 on promoting PTC metastasis. Furthermore, SHMT2 expression is negatively associated with PTEN, a negative AKT regulator, in PTC specimens. Mechanistically, SHMT2 catalyzes serine metabolism and produces activated one-carbon units that can generate SAM for the methylation of CpG islands in PTEN promoter for PTEN suppression and following AKT activation. Importantly, interference with PTEN expression affects SHMT2 function by promoting AKT signaling activation and PTC metastasis. Collectively, our research demonstrates that SHMT2 connects metabolic reprogramming and epigenetics, contributing to the poor progression of PTC.

Thyroid cancer (TC) is the most prevalent malignancy of the endocrine system. PANoptosis, a newly discovered cell death pathway, is of interest in tumor research. However, the relationship between PANoptosis-related lncRNAs (PRlncRNAs) and TC remains unclear. The study aimed to develop a prognostic model based on PRlncRNAs in TC. Gene expression data of PANoptosis-associated genes and clinical information on TC from The Cancer Genome Atlas (TCGA) database were analyzed by Pearson correlation analysis, univariate/multivariate Cox analysis, and Lasso Cox regression analysis. A PRlncRNA signature was constructed and used to develop a nomogram to predict overall survival (OS). We further explored the correlation between the risk score and tumor immune microenvironment, immune checkpoints, and drug sensitivity. Moreover, we verified the expression and biological function of lncRNAs in TC cell lines. Finally, seven PRlncRNAs were used to construct a prognostic model for predicting the OS of TC patients. We found that the risk score was associated with the tumor microenvironment (TME) and the expression of critical immune checkpoints. In addition, we screened for drugs that high- or low-risk TC groups might be sensitive to. Quantitative real-time polymerase chain reaction (qRT-PCR) results showed differential expression of four PRlncRNAs (GAPLINC, IDI2-AS1, LINC02154, and RBPMS-AS1) between tumor and normal tissues. Besides, a GEO database (GSE33630) was used to verify the expression differences of PRLncRNAs in THCA tissues and normal tissues. Finally, RBPMS-AS1 was found to inhibit the proliferation and migration of TC cells. In conclusion, we developed a PANoptosis-related lncRNA prognostic risk model that offers a comprehensive understanding of TME status in patients with TC and establishes a foundation for the choice of sensitive medications and immunotherapy.

Abstract Background The increase in drug-resistant opportunistic pathogenic bacteria, especially of antibiotic-resistant Staphylococcus epidermidis (S. epidermidis), has led to difficulties in the treatment of skin and soft tissue infections (SSTI). The major reason for bacterial resistance is the formation of bacterial biofilm. Here, we report a promising combination therapy of flavaspidic acid BB (BB) and mupirocin, which can effectively eradicate the biofilm of S. epidermidis and eliminate its drug resistance. Result The susceptibility test showed that the combination of BB and mupirocin has good antibacterial and antibiofilm activities, and the fractional inhibitory concentration index (FICI) of BB combined with mupirocin was 0.51 ± 0.00 ~ 0.75 ± 0.05, showing synergistic effect. Moreover, the time-kill curve assay results indicated that the combination of drugs can effectively inhibit the planktonic S. epidermidis. After drugs treatment, the drug-combination showed significantly inhibitory effects on the metabolic activity and total biomass in each stage of biofilm formation. The synergistic effect is likely related to the adhesion between bacteria, which is confirmed by field emission scanning electron microscope. And the expression level of aap, sarA and agrA genes were detected by real-time quantitative PCR (qRT-PCR). Conclusion Our study provides the experimental data for the use of BB for the clinical treatment of skin infections and further demonstrate the potential of BB as a novel biofilm inhibitor.

Abstract Background Thyroid cancer is the most common malignant endocrine tumour, and metastasis has become the main reason for treatment failure. However, the underlying molecular mechanism of thyroid cancer metastasis remains poorly understood. We investigated the role of the tumour suppressor zinc fingers and homeoboxes 2 (ZHX2) in the metastasis of thyroid cancer. Methods To study the role of ZHX2 in thyroid cancer metastasis, we evaluated the EMT process using cell migration, wound healing and lung metastatic tumour formation in vitro and in vivo models. Results ZHX2 expression was significantly decreased in thyroid cancer tissues, which correlated with poor prognosis of thyroid cancer patients. ZHX2 knockdown significantly promoted the migration of thyroid cancer cells. Mechanistically, ZHX2 associated with the S100 calcium binding protein A14 (S100A14) promoter to decrease the transcription of S100A14. Moreover, S100A14 was highly expressed in human thyroid cancer samples, and its expression negatively correlated with ZHX2 expression. Conclusions Inhibition of S100A14 attenuated the ZHX2 knockdown-induced enhanced metastasis of thyroid cancer cells both in vitro and in vivo. The evidence presented here suggests that ZHX2 inhibits the progression of thyroid cancer by blocking S100A14-mediated metastasis.

Background & Aims: Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV), existing as a stable minichromosome in the hepatocyte, is responsible for persistent HBV infection. Maintenance and sustained replication of cccDNA require its interaction with both viral and host proteins. However, the cccDNA-interacting host factors that limit HBV replication remain elusive. Methods: Minicircle HBV (MC-HBV), a recombinant cccDNA, was constructed based on chimeric intron and minicircle DNA technology. By mass spectrometry based on pull-down with biotinylated MC-HBV, the cccDNA-hepatocyte interaction profile was mapped. HBV replication was assessed in different cell models that support cccDNA formation. Results: MC-HBV supports persistent HBV replication and mimics the cccDNA minichromosome. The MC-HBV–based screen identified cohesin complex as a cccDNA binding host factor, leading to reduced HBV replication. Mechanistically, with the help of CCCTC-binding factor (CTCF), which has specific binding sites on cccDNA, cohesin loads on cccDNA and reshapes cccDNA confirmation to prevent RNA polymerase II enrichment. Interestingly, HBV X protein transcriptionally reduces structural maintenance of chromosomes complex expression to partially relieve the inhibitory role of the cohesin complex on HBV replication. Conclusions: Our data not only provide a feasible approach to explore cccDNA-binding factors, but also identify cohesin/CTCF complex as a critical host restriction factor for cccDNA-driven HBV replication. These findings provide a novel insight into cccDNA–host interaction and targeted therapeutic intervention for HBV infection.

Abstract Background Infection of Helcococcus kunzii(H. kunzii) from diabetic foot wound is rarely reported. This case report describes the infection of H.kunzii and highlights the therapeutic effect on H.kunzii from a diabetic foot wound. Case presentation In this study, one H. kunzii strain was isolated from a patient with diabetic foot, which was confirmed by 16S rRNA gene analysis and MALDI-TOF-MS. It is the first Chinese case of H. kunzii in a patient with diabetic foot. As a result of the lack of antibiotic sensitivity data and multiple comorbidities, antibiotics were used cautiously, and those administered during the first 3 months were ineffective. Then, vacuum sealing drainage (VSD) was applied during hospitalization; no antibiotics were used and the wound healed well. Conclusions VSD alone may be more effective in treating diabetic feet infected with H. kunzii, which may provide reference for clinical treatment of H. kunzii infection from diabetic foot.

Abstract Covalently closed circular DNA (cccDNA) is the transcriptional template of hepatitis B virus (HBV), which interacts with both host and viral proteins to form minichromosome in the nucleus and is resistant to antiviral agents. Identification of host factors involved in cccDNA transcriptional regulation is expected to prove a new venue for HBV therapy. Recent evidence suggests the involvement of long noncoding RNAs (lncRNAs) in mediating the interaction of host factors with various viruses, however, lncRNAs that HBV targets and represses cccDNA transcription have not been fully elucidated. Here, the authors identified LINC01431 as a novel host restriction factor for HBV transcription. Mechanically, LINC01431 competitively bound with type I protein arginine methyltransferase (PRMT1) to block the HBx‐mediated PRMT1 ubiquitination and degradation. Consequently, LINC01431 increased the occupancy of PRMT1 on cccDNA, leading to enhanced H4R3me2a modification and reduced acetylation of cccDNA‐bound histones, thereby repressing cccDNA transcription. In turn, to facilitate viral replication, HBV transcriptionally repressed LINC01431 expression by HBx‐mediated repression of transcription factor Zinc fingers and homeoboxes 2 (ZHX2). Collectively, the study demonstrates LINC01431 as a novel epigenetic regulator of cccDNA minichromosome and highlights a feedback loop of HBx‐LINC01431‐PRMT1 in HBV replication, which provides potential therapeutic targets for HBV treatment.

MicroRNAs (miRNAs) are short noncoding RNAs that can regulate target gene expression at the posttranscriptional level. It has been reported that bta-miR-145 shows differential expression between the different lactation stages of bovine mammary glands, but the function of bta-miR-145 in normal mammary glands remains unknown. The overexpression of bta-miR-145 significantly decreased the proliferation of mammary epithelial cells (p .05), whereas the IRS1 protein level was changed significantly after bta-miR-145 mimic or inhibitor transfection for 72 h (p

Although suppliers can sell their goods on e-retailers’ e-platforms through either a wholesale or agency contract, suppliers that produce complementary goods and have different channel roles have been confused as to how to choose an optimal distribution contract. This paper aims to study this problem by considering the combined impacts of suppliers’ channel roles, e-retailer’s referral fees, goods’ differences in the level of complementarity and goods’ differences in potential demand. Our results show that, regardless of one supplier’s distribution contract choice, the other supplier always prefers agency contract, which is independent of two suppliers’ channel roles, the e-retailer’s referral fees, two goods’ differences in the level of complementarity and two goods’ differences in the potential demand. Moreover, when two suppliers use different distribution contracts to sell goods with different levels of complementarity on the same e-retailer’s e-platform, low-complementarity goods have a larger optimal retail price only if the two goods’ differences in the level of complementarity are sufficiently high, and the supplier can obtain more profits by producing low-complementarity goods regardless of the supplier’s distribution contract and channel role.

Abstract Background The purpose of this study was to investigate the value of wavelet-transformed radiomic MRI in predicting the pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) for patients with locally advanced breast cancer (LABC). Methods Fifty-five female patients with LABC who underwent contrast-enhanced MRI (CE-MRI) examination prior to NAC were collected for the retrospective study. According to the pathological assessment after NAC, patient responses to NAC were categorized into pCR and non-pCR. Three groups of radiomic textures were calculated in the segmented lesions, including (1) volumetric textures, (2) peripheral textures, and (3) wavelet-transformed textures. Six models for the prediction of pCR were Model I: group (1), Model II: group (1) + (2), Model III: group (3), Model IV: group (1) + (3), Model V: group (2) + (3), and Model VI: group (1) + (2) + (3). The performance of predicting models was compared using the area under the receiver operating characteristic (ROC) curves (AUC). Results The AUCs of the six models for the prediction of pCR were 0.816 ± 0.033 (Model I), 0.823 ± 0.020 (Model II), 0.888 ± 0.025 (Model III), 0.876 ± 0.015 (Model IV), 0.885 ± 0.030 (Model V), and 0.874 ± 0.019 (Model VI). The performance of four models with wavelet-transformed textures (Models III, IV, V, and VI) was significantly better than those without wavelet-transformed textures (Model I and II). In addition, the inclusion of volumetric textures or peripheral textures or both did not result in any improvements in performance. Conclusions Wavelet-transformed textures outperformed volumetric and/or peripheral textures in the radiomic MRI prediction of pCR to NAC for patients with LABC, which can potentially serve as a surrogate biomarker for the prediction of the response of LABC to NAC.

ObjectivePapillary thyroid carcinoma (PTC) accounts for the majority of thyroid cancer and affects a large number of individuals. The pathogenesis of PTC has not been completely elucidated thus far. Metabolic reprogramming is a common feature in tumours. Our previous research revealed the reprogramming of lipid metabolism in PTC. Further studies on lipid metabolism reprogramming may help elucidate the pathogenesis of PTC.MethodsClinical samples of PTC and para-tumour tissue were analysed using lipidomic, proteomic, and metabolomic approaches. A multi-omics integrative strategy was adopted to identify the important pathways in PTC. The findings were further confirmed using western blotting, tissue microarray, bioinformatics, and cell migration assays.ResultsMulti-omics data and the results of integrated analysis revealed that the three steps of fatty acid metabolism (hydrolysis, transportation, and oxidation) were significantly enhanced in PTC. Especially, the expression levels of LPL, FATP2, and CPT1A, three key enzymes in the respective steps, were elevated in PTC. Moreover, LPL, FATP2 and CPT1A expression was associated with the TNM stage, lymph node metastasis of PTC. Moreover, high levels of FATP2 and CPT1A contributed to poor prognosis of PTC. In addition, ectopic overexpression of LPL, FATP2 and CPT1A can each promote the migration of thyroid cancer cells.ConclusionsOur data suggested that enhanced fatty acid metabolism supplied additional energy and substrates for PTC progression. This may help elucidating the underlying mechanism of PTC pathogenesis and identifying the potential therapeutic targets for PTC.

A good understanding of the fading characteristics in high speed railway environment is essential for the design of a high reliable railway wireless network. In this paper, measurements have been taken in both high speed viaduct and terrain cutting scenarios using track side base stations (BSs) of the railway wireless network in China. The measurement sites have been chosen with special care; thus the whole measured route can be characterized either by viaduct or terrain cutting. Kolmogorov-Smirnov (K-S) test has been first introduced in the statistical analysis to find out which is the most appropriate model for the small scale fading envelope. Though both Rice and Nakagami distributions provide a good fit to the first-order envelope data in both scenarios, only the Rice model generally fits the second-order statistics data accurately. For the viaduct scenario, higher Rice K factor can be observed. The change tendency of the K factor as a function of distance in the two scenarios is completely different. It can be concluded that the over bridges which span the railway tracks in terrain cutting scenario would affect the Rice K value severely.