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Non-small cell lung cancer (NSCLC), as the main type of lung cancer, has a long history of high incidence and mortality. Despite the continuous updates to the American Joint Committee on Cancer (AJCC) staging system, which adapt to evolving treatment modalities and diagnostic advancements, it is evident that patients at the same stage exhibit varying prognoses. The heterogeneity of tumors underscores the need for molecular diagnostics to assume a pivotal role in tumor staging and patient stratification. In our investigation, we meticulously analyzed the data of the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, incorporating clinical patients and scrutinizing pathological specimens. Through this comprehensive approach, we established a correlation between the expression of the Thymosin beta 4 X-linked (TMSB4X) gene and poorer disease-free survival (DFS) and overall survival (OS) post-surgery. Compared to the TMSB4X positive expression group, patients in the negative expression group had a better prognosis, with longer DFS (median disease-free survival (median DFS): 16.2 months vs. 11.3 months, P  = 0.032) and OS (median overall survival (mOS): 29.8 months vs. 18.5 months, P  = 0.033). Furthermore, our findings suggest that TMSB4X may facilitate immune evasion in non-small cell lung cancer cells by influencing the activation of infiltrating dendritic cells (DCs) in tumor infiltrating immune cells (TIICs) (R = 0.27, P  = 4.8E+08). In summary, TMSB4X emerges as an unfavorable prognostic factor for NSCLC, potentially modulating the tumor immune microenvironment through its regulatory impact on dendritic cell function, thus facilitating tumor immune escape., Competing Interests: Ze Yang, Jihang Luo, Mengmei Zhang, Meixiao Zhan, Yuju Bai, Yi Yang, Wei Wang and Ligong Lu declare that they have no conflict of interest.All authors declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (© 2023 The Authors. Published by Elsevier Ltd.)

N 6 -methyladenosine (m 6 A), the most common and abundant epigenetic RNA modification, governs mRNA metabolism to determine cell differentiation, proliferation and response to stimulation. m 6 A methyltransferase METTL3 has been reported to control T cell homeostasis and sustain the suppressive function of regulatory T cells (Tregs). However, the role of m 6 A methyltransferase in other subtypes of T cells remains unknown. T helper cells 17 (Th17) play a pivotal role in host defense and autoimmunity. Here, we found that the loss of METTL3 in T cells caused serious defect of Th17 cell differentiation, and impeded the development of experimental autoimmune encephalomyelitis (EAE). We generated Mettl3 f/f Il17a Cre mice and observed that METTL3 deficiency in Th17 cells significantly suppressed the development of EAE and displayed less Th17 cell infiltration into central nervous system (CNS). Importantly, we demonstrated that depletion of METTL3 attenuated IL-17A and CCR5 expression by facilitating SOCS3 mRNA stability in Th17 cells, leading to disrupted Th17 cell differentiation and infiltration, and eventually attenuating the process of EAE. Collectively, our results highlight that m 6 A modification sustains Th17 cell function, which provides new insights into the regulatory network of Th17 cells, and also implies a potential therapeutic target for Th17 cell mediated autoimmune disease., (© 2023. Science China Press.)

Aim: This study aimed to explore whether the addition of sarcopenia and visceral adiposity could improve the accuracy of model predicting progression-free survival (PFS) in hepatocellular carcinoma (HCC)., Methods: In total, 394 patients with HCC from five hospitals were divided into the training and external validation datasets. Patients were initially treated by liver resection or transarterial chemoembolization. We evaluated adipose and skeletal muscle using preoperative computed tomography imaging and then constructed three predictive models, including metabolic (Model MA ), clinical-imaging (Model CI ), and combined (Model MA-CI ) models. Their discrimination, calibration, and decision curves were compared, to identify the best model. Nomogram and subgroup analysis was performed for the best model., Results: Model MA-CI containing sarcopenia and visceral adiposity had good discrimination and calibrations (integrate area under the curve for PFS was 0.708 in the training dataset and 0.706 in the validation dataset). Model MA-CI had better accuracy than Model CI and Model MA . The performance of Model MA-CI was not affected by treatments or disease stages. The high-risk subgroup (scored > 198) had a significantly shorter PFS (p < 0.001) and poorer OS (p < 0.001)., Conclusions: The addition of sarcopenia and visceral adiposity improved accuracy in predicting PFS in HCC, which may provide additional insights in prognosis for HCC in subsequent studies., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The composition of kidney stones is related to the hardness of the stones. Knowing the composition of the stones before surgery can help plan the laser power and operation time of percutaneous nephroscopic surgery. Moreover, patients can be treated with medications if the kidney stone is compounded by uric acid before treatment, which can relieve the patients of the pain of surgery. However, although the literature generally reports the kidney stone composition analysis method base on dual-energy CT images, the accuracy of these methods is not enough; they need manual delineation of the kidney stone location, and these methods cannot analyze mixed composition kidney stones., Objective: This study aimed to overcome the problem related to identifying kidney stone composition; we need an accurate method to analyze the composition of kidney stones., Methods: In this paper, we proposed the automatic kidney stone composition analysis algorithm based on a dual-energy CT image. The algorithm first segmented the kidney stone mask by deep learning model, then analyzed the composition of each stone by machine learning model., Results: The experimental results indicate that the proposed algorithm can segment kidney stones accurately (AUC=0.96) and predict kidney stone composition accurately (mean Acc=0.86, mean Se=0.75, mean Sp=0.9, mean F1=0.75, mean AUC=0.83, MR (Exact match ratio)=0.6)., Conclusion: The proposed method can predict the composition and location of kidney stones, which can guide its treatment. Experimental results show that the weighting strategy can improve kidney stone segmentation performance. In addition, the multi-label classification model can predict kidney stone composition precisely, including the mixed composition kidney stones., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: N6-methyladenine modification of RNA, a critical component of the regulatory role at the post-transcriptional level, has a crucial effect on tumor development and progression. vir-Like m6A methyltransferase associated (VIRMA) has been recently discovered as an N6-methyladenine methyltransferase; however, its specific role in intrahepatic cholangiocarcinoma (ICC) remains to be investigated in-depth., Methods: VIRMA expression and its association with clinicopathological characteristics were evaluated using The Cancer Genome Atlas (TCGA) dataset and tissue microarrays. In vivo and in vitro assays were performed to determine the role of VIRMA in ICC proliferation and metastasis. The underlying mechanism by which VIRMA influences ICC was clarified by RNA sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), SLAM sequencing (SLAM-seq), RNA immunoprecipitation, a luciferase reporter assay, and chromatin immunoprecipitation assay., Results: VIRMA showed high expression in ICC tissues, and this finding predicted a dismal prognostic outcome. The high expression of VIRMA in ICC was due to the demethylation of H3K27me3 modification in the promoter region. Functionally, VIRMA is required for the endothelial-mesenchymal transition (EMT) process in ICC cells, as shown by multiple ICC models in in vitro and in vivo experiments. Mechanistically, multi-omics analysis using ICC cells demonstrated that TMED2 and PARD3B were the direct downstream target of VIRMA. The methylated TMED2 and PARD3B transcripts were directly recognized by HuR, which exerted stabilizing effects on its bound RNA. VIRMA-induced expression of TMED2 and PARD3B activated the Akt/GSK/β-catenin and MEK/ERK/Slug signaling pathways, thereby promoting ICC proliferation and metastasis., Conclusions: The present study showed that VIRMA plays a critical role in ICC development by stabilizing TMED2 and PARD3B expression through the m6A-HuR-mediated mechanism. Thus, demonstrating VIRMA and its pathway as candidate therapeutic targets for ICC treatment., (© 2023. Japanese Society of Gastroenterology.)

To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity., (© 2023. The Author(s).)

Although the Hedgehog (Hh) pathway plays an evolutionarily conserved role from Drosophila to mammals, some divergences also exist. Loss of Sufu, an important component of the Hh pathway, does not lead to an obvious developmental defect in Drosophila. However, in mammals, loss of SUFU results in serious disorder, even various cancers. This divergence suggests that SUFU plays additional roles in mammalian cells, besides regulating the Hh pathway. Here, we identify that the transcription factor ZNF281 is a novel binding partner of SUFU. Intriguingly, the Drosophila genome does not encode any homologs of ZNF281. SUFU is able to suppress ZNF281-induced tumor cell migration and DNA damage repair by inhibiting ZNF281 activity. Mechanistically, SUFU binds ZNF281 to mask the nuclear localization signal of ZNF281, culminating in ZNF281 cytoplasmic retention. In addition, SUFU also hampers the interactions between ZNF281 and promoters of target genes. Finally, we show that SUFU is able to inhibit ZNF281-induced tumor cell migration using an in vivo model. Taken together, these results uncover a Hh-independent mechanism of SUFU exerting the anti-tumor role, in which SUFU suppresses tumor cell migration through antagonizing ZNF281. Therefore, this study provides a possible explanation for the functional divergence of SUFU in mammals and Drosophila., (© 2022. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

COVID-19 has been spreading continuously since its outbreak, and the detection of its manifestations in the lung via chest computed tomography (CT) imaging is essential to investigate the diagnosis and prognosis of COVID-19 as an indispensable step. Automatic and accurate segmentation of infected lesions is highly required for fast and accurate diagnosis and further assessment of COVID-19 pneumonia. However, the two-dimensional methods generally neglect the intraslice context, while the three-dimensional methods usually have high GPU memory consumption and calculation cost. To address these limitations, we propose a two-stage hybrid UNet to automatically segment infected regions, which is evaluated on the multicenter data obtained from seven hospitals. Moreover, we train a 3D-ResNet for COVID-19 pneumonia screening. In segmentation tasks, the Dice coefficient reaches 97.23% for lung segmentation and 84.58% for lesion segmentation. In classification tasks, our model can identify COVID-19 pneumonia with an area under the receiver-operating characteristic curve value of 0.92, an accuracy of 92.44%, a sensitivity of 93.94%, and a specificity of 92.45%. In comparison with other state-of-the-art methods, the proposed approach could be implemented as an efficient assisting tool for radiologists in COVID-19 diagnosis from CT images., (© 2022. International Federation for Medical and Biological Engineering.)

Pulsed laser can excite light absorber to generate photoacoustic (PA) effect, that is, when the absorber is irradiated with pulsed laser, the absorbed light energy is converted into local heat to cause rapid thermoelastic expansion and generate acoustic wave. The generated PA signal has been widely employed for the diagnosis of many diseases with superb contrast, high penetrability and sensitivity. In addition, with the increase of pulsed laser energy, the resulting PA shockwave and cavitation can promote efficient drug release at lesion sites to potentiate the resulting therapeutic efficacy. Furthermore, the PA shockwave/cavitation can mechanically inhibit disease and produce reactive species. In this Concept article, the principle and research status of pulsed laser excited disease theranostics are briefly summarized, extra suggestions are proposed to inspire extensive PA probes and photodynamic materials as well as novel methodologies., (© 2022 Wiley-VCH GmbH.)

RNA-binding proteins (RBPs) can recognize thousands of RNAs that help to maintain cell homeostasis, and RBP dysfunction is frequently observed in various cancers. However, whether specific RBPs are involved in tumor immune evasion by regulating programmed death ligand-1 (PD-L1) is unclear. Here, we perform targeted RBP CRISPR/Cas9 screening and identify density regulated re-initiation and release factor (DENR) as a PD-L1 regulator. DENR-depleted cancer cells exhibit reduced PD-L1 expression in vitro and in vivo. DENR depletion significantly suppresses tumor growth and enhances the tumor-killing activity of CD8 + T cells. Mechanistically, DENR antagonizes the translational repression of three consecutive upstream open reading frames (uORFs) upstream of Janus kinase 2 (Jak2); thus, DENR deficiency impairs JAK2 translation and the IFNγ-JAK-STAT signaling pathway, resulting in reduced PD-L1 expression in tumors. Overall, we discover an RBP DENR that could regulate PD-L1 expression for tumor immune evasion, and highlight the potential of DENR as a therapeutic target for immunotherapy., (© 2022. The Author(s).)

Background: Main challenges for COVID-19 include the lack of a rapid diagnostic test, a suitable tool to monitor and predict a patient's clinical course and an efficient way for data sharing among multicenters. We thus developed a novel artificial intelligence system based on deep learning (DL) and federated learning (FL) for the diagnosis, monitoring, and prediction of a patient's clinical course., Methods: CT imaging derived from 6 different multicenter cohorts were used for stepwise diagnostic algorithm to diagnose COVID-19, with or without clinical data. Patients with more than 3 consecutive CT images were trained for the monitoring algorithm. FL has been applied for decentralized refinement of independently built DL models., Results: A total of 1,552,988 CT slices from 4804 patients were used. The model can diagnose COVID-19 based on CT alone with the AUC being 0.98 (95% CI 0.97-0.99), and outperforms the radiologist's assessment. We have also successfully tested the incorporation of the DL diagnostic model with the FL framework. Its auto-segmentation analyses co-related well with those by radiologists and achieved a high Dice's coefficient of 0.77. It can produce a predictive curve of a patient's clinical course if serial CT assessments are available., Interpretation: The system has high consistency in diagnosing COVID-19 based on CT, with or without clinical data. Alternatively, it can be implemented on a FL platform, which would potentially encourage the data sharing in the future. It also can produce an objective predictive curve of a patient's clinical course for visualization., Key Points: • CoviDet could diagnose COVID-19 based on chest CT with high consistency; this outperformed the radiologist's assessment. Its auto-segmentation analyses co-related well with those by radiologists and could potentially monitor and predict a patient's clinical course if serial CT assessments are available. It can be integrated into the federated learning framework. • CoviDet can be used as an adjunct to aid clinicians with the CT diagnosis of COVID-19 and can potentially be used for disease monitoring; federated learning can potentially open opportunities for global collaboration., (© 2021. European Society of Radiology.)

Background: As reported, preclinical animal models differ greatly from the human body. The evaluation model may be the colossal obstacle for scientific research and anticancer drug development. Therefore, it is essential to propose efficient evaluation systems similar to clinical practice for cancer research., Main Body: While it has emerged for decades, the development of patient-derived xenografts, patient-derived organoid and patient-derived cell used to be limited. As the requirements for anticancer drug evaluation increases, patient-derived models developed rapidly recently, which is widely applied in basic research, drug development, and clinical application and achieved remarkable progress. However, there still lack systematic comparison and summarize reports for patient-derived models. In the current review, the development, applications, strengths, and challenges of patient-derived models in cancer research were characterized., Conclusion: Patient-derived models are an indispensable approach for cancer research and human health., (© 2022. The Author(s).)

Background: Cervical cancer is the most fatal gynecological carcinoma in the world. It is urgent to explore novel prognostic biomarkers and intervention targets for cervical cancer., Methods: Through integrated quantitative proteomic strategy, we investigated the protein expression profiles of cervical cancer; 28 fresh frozen tissue samples (11 adenocarcinoma (AC), 12 squamous cell carcinoma (SCC) and 5 normal cervixes (HC)) were included in discover cohort; 45 fresh frozen tissue samples (19 AC, 18 SCC and 8 HC) were included in verification cohort; 140 paraffin-embedded tissues samples of cervical cancer (85 AC and 55 SCC) were used for immunohistochemical evaluation (IHC) of coatomer protein subunit alpha (COPA) as a prognostic biomarker for cervical cancer; how deficiency of COPA affects cell viability and tumorigenic ability of cervical cancer cells (SiHa cells and HeLa cells) were evaluated by cell counting kit-8 and clone formation in vitro., Results: We identified COPA is a potential prognostic biomarker for cervical cancer in quantitative proteomics analysis. By retrospective IHC analysis, we additionally verified the proteomics results and demonstrated moderate or strong IHC staining for COPA is an unfavourable independent prognostic factor for cervical cancer. We also identified COPA is a potential pharmacological intervention target of cervical cancer by a series of in vitro experiments., Conclusion: This study is the first to demonstrate that COPA may contribute to progression of cervical cancer. It can serve as a potential prognostic biomarker and promising intervention target for cervical cancer., (© 2022. The Author(s).)

Regulation of stimulator of interferon genes (STING) pathway using agonists can boost antitumor immunity for cancer treatment, while the rapid plasma clearance, limited membrane permeability, and inefficient cytosolic transport of STING agonists greatly compromise their therapeutic efficacy. In this study, we describe an extracellular matrix (ECM)-degrading nanoagonist (dNAc) with second near-infrared (NIR-II) light controlled activation of intracellular STING pathway for mild photothermal-augmented chemodynamic-immunotherapy of breast cancer. The dNAc consists of a thermal-responsive liposome inside loading with ferrous sulfide (FeS 2 ) nanoparticles as both NIR-II photothermal converters and Fenton catalysts, 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) as the STING agonist, and an ECM-degrading enzyme (bromelain) on the liposome surface. Mild heat generated by dNAc upon NIR-II photoirradiation improves Fenton reaction efficacy to kill tumor cells and cause immunogenic cell death (ICD). Meanwhile, the generated heat triggers a controlled release of cGAMP from thermal-responsive liposomes to active STING pathway. The mild photothermal activation of STING pathway combined with ICD promotes anti-tumor immune responses, which leads to improved infiltration of effector T cells into tumor tissues after bromelain-mediated ECM degradation. As a result, after treatment with dNAc upon NIR-II photoactivation, both primary and distant tumors in a murine mouse model are inhibited and the liver and lung metastasis are effectively suppressed. This work presents a photoactivatable system for STING pathway and combinational immunotherapy with improved therapeutic outcome., (© 2022. The Author(s).)

Gas therapy (GT) has attracted increasing attention in recent years as a new cancer treatment method with favorable therapeutic efficacy and reduced side effects. Several gas molecules, such as nitric oxide (NO), carbon monoxide (CO), hydrogen (H 2 ), hydrogen sulfide (H 2 S) and sulfur dioxide (SO 2 ), have been employed to treat cancers by directly killing tumor cells, enhancing drug accumulation in tumors or sensitizing tumor cells to chemotherapy, photodynamic therapy or radiotherapy. Despite the great progress of gas therapy, most gas molecules are prone to nonspecific distribution when administered systemically, resulting in strong toxicity to normal tissues. Therefore, how to deliver and release gas molecules to targeted tissues on demand is the main issue to be considered before clinical applications of gas therapy. As a specific and noninvasive stimulus with deep penetration, near-infrared (NIR) light has been widely used to trigger the cleavage and release of gas from nano-prodrugs via photothermal or photodynamic effects, achieving the on-demand release of gas molecules with high controllability. In this review, we will summarize the recent progress in cancer gas therapy triggered by NIR light. Furthermore, the prospects and challenges in this field are presented, with the hope for ongoing development., (© 2021. The Author(s).)

Metastasis is an important cause of death from malignant tumors. It is of great significance to explore the molecular mechanism of metastasis for the development of anti-cancer drugs. Here, we find that the Hippo pathway hampers tumor cell metastasis in vivo. Silence of hpo or its downstream wts promotes tumor cell migration in a Yki-dependent manner. Furthermore, we identify that inhibition of the Hippo pathway promotes tumor cell migration through transcriptional activating src42A, a Drosophila homolog of the SRC oncogene. Yki activates src42A transcription through direct binding its intron region. Intriguingly, Src42A further increases Yki transcriptional activity to form a positive feedback loop. Finally, we show that SRC is also a target of YAP and important for YAP to promote the migration of human hepatocellular carcinoma cells. Together, our findings uncover a conserved Yki/YAP-Src42A/SRC positive feedback loop promoting tumor cell migration and provide SRC as a potential therapeutic target for YAP-driven metastatic tumors., (© 2021. The Author(s).)

Nicotinamide, the amide form of Vitamin B3, is a common nutrient supplement that plays important role in human fetal development. Nicotinamide has been widely used in clinical treatments, including the treatment of diseases during pregnancy. However, its impacts during embryogenesis have not been fully understood. In this study, we show that nicotinamide plays multiplex roles in mesoderm differentiation of human embryonic stem cells (hESCs). Nicotinamide promotes cardiomyocyte fate from mesoderm progenitor cells, and suppresses the emergence of other cell types. Independent of its functions in PARP and Sirtuin pathways, nicotinamide modulates differentiation through kinase inhibition. A KINOMEscan assay identifies 14 novel nicotinamide targets among 468 kinase candidates. We demonstrate that nicotinamide promotes cardiomyocyte differentiation through p38 MAP kinase inhibition. Furthermore, we show that nicotinamide enhances cardiomyocyte survival as a Rho-associated protein kinase (ROCK) inhibitor. This study reveals nicotinamide as a pleiotropic molecule that promotes the derivation and survival of cardiomyocytes, and it could become a useful tool for cardiomyocyte production for regenerative medicine. It also provides a theoretical foundation for physicians when nicotinamide is considered for treatments for pregnant women., (© 2021. The Author(s).)

Background: A large number of variants have been employed in various medical applications, such as providing medication instructions, disease susceptibility testing, paternity testing, and tumour diagnosis. A high multiplicity PCR will outperform other technologies because of its lower cost, reaction time and sample consumption. To conduct a multiplex PCR with higher than 100 plex multiplicity, primers need to be carefully designed to avoid the formation of secondary structures and nonspecific amplification between primers, templates and products. Thus, a user-friendly, highly automated and highly user-defined web-based multiplex PCR primer design software is needed to minimize the work of primer design and experimental verification., Results: Ultiplex was developed as a free online multiplex primer design tool with a user-friendly web-based interface ( http://ultiplex.igenebook.cn ). To evaluate the performance of Ultiplex, 294 out of 295 (99.7%) target primers were successfully designed. A total of 275 targets produced qualified primers after primer filtration, and 271 of those targets were successfully clustered into one compatible PCR group and could be covered by 108 primers. The designed primer group stably detected the rs28934573(C > T) mutation at lower than a 0.25% mutation rate in a series of samples with different ratios of HCT-15 and HaCaT cell line DNA., Conclusion: Ultiplex is a web-based multiplex PCR primer tool that has several functions, including batch design and compatibility checking for the exclusion of mutual secondary structures and mutual false alignments across the whole genome. It offers flexible arguments for users to define their own references, primer Tm values, product lengths, plex numbers and tag oligos. With its user-friendly reports and web-based interface, Ultiplex will provide assistance for biological applications and research involving genomic variants., (© 2021. The Author(s).)

New Delhi metallo-β-lactamases (NDMs), including at least 28 variants, are a rapidly emerging family of β-lactamases worldwide, with a variety of infections caused by NDM-positive strains usually associated with very poor prognosis and high mortality. NDMs are the most prevalent carbapenemases in Escherichia coli ( E. coli ) worldwide, especially in China. The vast majority of bla NDM cases occur on plasmids, which play a vital role in the dissemination of bla NDM . To systematically explore the relationships between plasmids and bla NDM genes in E. coli and obtain an overall picture of the conjugative and mobilizable bla NDM -positive plasmids, we analyzed the variants of bla NDM , replicon types, phylogenetic patterns, conjugative transfer modules, host STs, and geographical distributions of 114 bla NDM -positive plasmids, which were selected from 3786 plasmids from 1346 complete whole genomes of E. coli from the GenBank database. We also established links among the characteristics of bla NDM -positive plasmids in E. coli . Eight variants of bla NDM were found among the 114 bla NDM -positive plasmids, with bla NDM - 5 (74 bla NDM - 5 genes in 73 plasmids), and bla NDM - 1 (31 bla NDM - 1 genes in 28 plasmids) being the most dominant. The variant bla NDM - 5 was mainly carried by the IncX3 plasmids and IncF plasmids in E. coli , the former were mainly geographically distributed in East Asia (especially in China) and the United States, and the latter were widely distributed worldwide. IncC plasmids were observed to be the predominant carriers of bla NDM - 1 genes in E. coli , which were mainly geographically distributed in the United States and China. Other bla NDM - 1 -carrying plasmids also included IncM2, IncN2, and IncHI1. Moreover, the overall picture of the conjugative and mobilizable bla NDM -positive plasmids in E. coli was described in our study. Our findings enhance our understanding of the genetic diversity and characteristics of bla NDM -positive plasmids in in E. coli ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Guo, Li, Li, Yang, Ni, Zhan, Lu, Zhang, Li and Zhou.)

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people and caused tremendous morbidity and mortality worldwide. Effective treatment for coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 infection is lacking, and different therapeutic strategies are under testing. Host humoral and cellular immunity to SARS-CoV-2 infection is a critical determinant for patients' outcomes. SARS-CoV-2 infection results in seroconversion and production of anti-SARS-CoV-2 antibodies. The antibodies may suppress viral replication through neutralization but might also participate in COVID-19 pathogenesis through a process termed antibody-dependent enhancement. Rapid progress has been made in the research of antibody response and therapy in COVID-19 patients, including characterization of the clinical features of antibody responses in different populations infected by SARS-CoV-2, treatment of COVID-19 patients with convalescent plasma and intravenous immunoglobin products, isolation and characterization of a large panel of monoclonal neutralizing antibodies and early clinical testing, as well as clinical results from several COVID-19 vaccine candidates. In this review, we summarize the recent progress and discuss the implications of these findings in vaccine development.

The Hippo pathway is an evolutionarily conserved regulator of organ growth and tumorigenesis. In Drosophila , oncogenic Ras V12 cooperates with loss-of-cell polarity to promote Hippo pathway-dependent tumor growth. To identify additional factors that modulate this signaling, we performed a genetic screen utilizing the Drosophila Ras V12 /lgl -/- in vivo tumor model and identified Rox8, a RNA-binding protein (RBP), as a positive regulator of the Hippo pathway. We found that Rox8 overexpression suppresses whereas Rox8 depletion potentiates Hippo-dependent tissue overgrowth, accompanied by altered Yki protein level and target gene expression. Mechanistically, Rox8 directly binds to a target site located in the yki 3' UTR, recruits and stabilizes the targeting of miR-8-loaded RISC, which accelerates the decay of yki messenger RNA (mRNA). Moreover, TIAR, the human ortholog of Rox8, is able to promote the degradation of yki mRNA when introduced into Drosophila and destabilizes YAP mRNA in human cells. Thus, our study provides in vivo evidence that the Hippo pathway is posttranscriptionally regulated by the collaborative action of RBP and microRNA (miRNA), which may provide an approach for modulating Hippo pathway-mediated tumorigenesis., Competing Interests: The authors declare no competing interest.

Long non-coding RNAs (lncRNAs) act important roles in several tumors including cholangiocarcinoma. However, the expression pattern and function of PCAT6 in intrahepatic cholangiocarcinoma remains unknown. In our research, we showed that the PCAT6 expression level was upregulated in intrahepatic cholangiocarcinoma cell lines. The expression of PCAT6 in intrahepatic cholangiocarcinoma tissues than that in noncancerous samples and the higer expression of PCAT6 was associated with advanced stage. Ectopic expression of PCAT6 induced cell proliferation and invasion in cholangiocarcinoma cell. Moreover, we demonstrated that PCAT6 interacts with miR-330-5p by directly targeting and PCAT6 overexpression inhibited the expression of miR-330-5p in the ICC-9810 cell. We also showed that the expression level of miR-330-5p in intrahepatic cholangiocarcinoma samples was downregulated compared to noncancerous tissues. Interesting, we proved that the miR-330-5p expression was negative correlated with PCAT6 expression in intrahepatic cholangiocarcinoma. Ectopic expression of miR-330-5p suppressed cell proliferation and invasion. Finally, we showed that PCAT6 induced cell proliferation and invasion by decreasing miR-330-5p in cholangiocarcinoma cell. Taken together, these data suggested that lncRNA PCAT6 was an oncogenic player in the development of intrahepatic cholangiocarcinoma., Competing Interests: None., (AJTR Copyright © 2019.)

Objective: To explore the clinical application of serum GP73 in the diagnosis and progress of hepatocellular carcinoma (HCC)., Methods: Enzyme-linked immunosorbent assay was employed to quantitatively detect serum GP73 in 59 HCC patients, 23 cases of hepatitis B virus (HBV)-related cirrhosis and 33 normal controls. The relationship between GP73 and diagnosis as well as progress of HCC was examined., Results: Significant differences existed when serum GP73 was categorized by Child-Pugh class A and B (P < 0.01). There was no correlation between GP73 levels and other parameters including age, gender, BCLC staging, HBV infection, tumor size, extrahepatic metastasis and tumor numbers. The serum GP73 with a mean level of [127 (147) µg/L, M(QR)] in HCC patients was significantly higher than that in normal controls or those with HBV-liver cirrhosis (P < 0.01). Based on the ROC curve analysis, the cut-off value was 99 µg/L with 64.4% sensitivity and 96.4% specificity. The sensitivity of diagnosing HCC with GP73 plus AFP improved (P = 0.025) , but not in specificity.Serum GP73 and AFP did not change greatly in terms of response assessment in mRECIST from baseline to progressive disease (P = 0.959, P = 0.788).No correlation existed between baseline concentration of GP73 with AFP and time to progression (r = 0.119, P = 0.608; r = 0.142, P = 0.540) ., Conclusion: GP73 may become a potential serum marker for diagnosing HCC. And a combination of AFP yields better outcomes. The exact relationship between mRECIST and GP73 as well as AFP shall be proved by large-scale clinical trials.