Systematic analysis of the expression profiles and prognostic significance of the MED gene family in renal clear cell carcinoma.

The mediator complex (MED) family is a contributing factor in the regulation of transcription and proliferation of cells, and is closely associated with the development of various types of cancer. However, the significance of the expression levels and prognostic value of MED genes in kidney renal clear cell carcinoma (KIRC) have rarely been reported. The present study analyzed the expression and prognostic potential of MED genes in KIRC. The Search Tool for the Retrieval of Interacting Genes/Proteins was used to construct the protein-protein interaction network (PPI), the Assistant for Clinical Bioinformatics database was used to perform correlation analysis, GEPIA 2 was utilized to draw the Kaplan-Meier plot and analyze prognostic significance and the Tumor Immune Estimation Resource was used to assess the association of MED genes with the infiltration of immune cells in patients with KIRC. A total of 30 MED genes were identified, and among these genes, 11 were selected for the creation of a prognostic gene signature based on the results of a LASSO Cox regression analysis. Furthermore, according to univariate and multivariate analyses, MED7, MED16, MED21, MED25 and MED29 may be valuable independent predictive biomarkers for the prognosis of individuals with KIRC. Furthermore, there were significant differences in the expression levels of MED7, MED21 and MED25 in KIRC among different tumor grades. Additionally, patients with KIRC with high transcription levels of MED7, MED21 and MED29 had considerably longer overall survival times. The expression levels of MED genes were also linked to the infiltration of several immune cells. Overall, MED genes may have potential significance in predicting the prognosis of patients with KIRC.

TRPML1 triggers ferroptosis defense and is a potential therapeutic target in AKT-hyperactivated cancer.

Targeting ferroptosis for cancer therapy has slowed because of an incomplete understanding of ferroptosis mechanisms under specific pathological contexts such as tumorigenesis and cancer treatment. Here, we identify TRPML1-mediated lysosomal exocytosis as a potential anti-ferroptotic process through genome-wide CRISPR-Cas9 activation and kinase inhibitor library screening. AKT directly phosphorylated TRPML1 at Ser343 and inhibited K552 ubiquitination and proteasome degradation of TRPML1, thereby promoting TRPML1 binding to ARL8B to trigger lysosomal exocytosis. This boosted ferroptosis defense of AKT-hyperactivated cancer cells by reducing intracellular ferrous iron and enhancing membrane repair. Correlation analysis and functional analysis revealed that TRPML1-mediated ferroptosis resistance is a previously unrecognized feature of AKT-hyperactivated cancers and is necessary for AKT-driven tumorigenesis and cancer therapeutic resistance. TRPML1 inactivation or blockade of the interaction between TRPML1 and ARL8B inhibited AKT-driven tumorigenesis and cancer therapeutic resistance in vitro and in vivo by promoting ferroptosis. A synthetic peptide targeting TRPML1 inhibited AKT-driven tumorigenesis and enhanced the sensitivity of AKT-hyperactivated tumors to ferroptosis inducers, radiotherapy, and immunotherapy by boosting ferroptosis in vivo. Together, our findings identified TRPML1 as a therapeutic target in AKT-hyperactivated cancer.

Corrigendum: Therapeutic strategies targeting folate receptor α for ovarian cancer.

[This corrects the article DOI: 10.3389/fimmu.2023.1254532.].

The nexus of dynamic T cell states and immune checkpoint blockade therapy in the periphery and tumor microenvironment.

Immune checkpoint blockade (ICB) therapies, that is, using monoclonal antibodies to reinvigorate tumor-reactive, antigen-specific T cells from the inhibitory effects of CTLA-4, PD-1 and PD-L1 immune checkpoints, have revolutionized the therapeutic landscape of modern oncology. However, only a subset of patients can benefit from the ICB therapy. Biomarkers associated with ICB response, resistance and prognosis have been subjected to intensive research in the past decade. Early studies focused on the analysis of tumor specimens and their residing microenvironment. However, biopsies can be challenging to obtain in clinical practice, and do not reflect the dynamic changes of immunological parameters during the ICB therapy. Recent studies have investigated profiles of antigen-specific T cells derived from the peripheral compartment using multi-omics approaches. By tracking the clonotype and diversity of tumor-reactive T cell receptor repertoire, these studies collectively establish that de novo priming of antigen-specific T cells in peripheral blood occurs throughout the course of ICB, whereas preexisting T cells prior to ICB are exhausted to various degrees. Here, we review what is known about ICB-induced T cell phenotypic and functional changes in cancer patients both within the tumor microenvironment and in the peripheral compartment. A better understanding of parameters influencing the response to ICBs will provide rationales for developing novel diagnostics and combinatorial therapeutic strategies to maximize the clinical efficacies of ICB therapies.

Therapeutic strategies targeting folate receptor α for ovarian cancer.

Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer, and presents a major clinical challenge due to limited treatment options. Folate receptor alpha (FRα), encoded by the FOLR1 gene, is an attractive therapeutically target due to its prevalent and high expression in EOC cells. Recent basic and translational studies have explored several modalities, such as antibody-drug conjugate (ADC), monoclonal antibodies, small molecules, and folate-drug conjugate, to exploit FRα for EOC treatment. In this review, we summarize the function of FRα, and clinical efficacies of various FRα-based therapeutics. We highlight mirvetuximab soravtansine (MIRV), or Elahere (ImmunoGen), the first FRα-targeting ADC approved by the FDA to treat platinum-resistant ovarian cancer. We discuss potential mechanisms and management of ocular adverse events associated with MIRV administration.

The possibility of automatic capillary blood testing in routine blood tests: an evaluation of the automatic mode of the Mindray BC-7500 CRP Auto Hematology Analyzer for capillary blood testing.

Background: Capillary blood is a common specimen type used for infant blood routine tests. Until now, this specimen type could only be tested with the manual mode in hematology analyzers. Manual sample mixing and loading increases the amount labor force and can be more easily affected by human factors. This study was designed to investigate the proficiency of the automatic mode of the Mindray BC-7500 CRP Auto Hematology Analyzer for capillary blood testing. Methods: The complete blood count (CBC) results for capillary blood were compared between the automatic and manual modes. Special types of samples, including samples with high or low volume, thalassemia red cells, high fibrinogen, high hematocrit (HCT), or high triglyceride levels, were compared and evaluated. The intraclass correlation coefficient (ICC) was used to define the agreement between the 2 modes. The industry standard Analytical Quality Specifications for Routine Tests in Clinical Hematology (WS/T 406-2012), published by the National Health Commission of China, was used to evaluate the correlation between the results from the 2 modes. Results: There was good correlation between the automatic and manual modes for every type of sample, and the ICCs were all higher than 0.9. Except for high HCT or high triglyceride samples, there were no differences found between the 2 modes based on the WS/T 406-2012 standard. Conclusions: This new automatic mode utilized in the Mindray BC-7500 CRP Auto Hematology Analyzer for capillary blood yielded the same results as the manual mode except in the case of samples with high HCT or triglycerides. Capillary blood might be routinely tested automatically with hematology analyzers in the near future, which might reduce the labor required and improve standardization.

A Rare Hemoglobin Variant Detected in a Pregnant Chinese Woman.

BACKGROUND: Hemoglobin Variant (HBB:c.155 C>A) is a rare mutation caused by ß-globin gene mutation called Hemoglobin North Manchester. So far, its existence has no adverse effect on human body, and it is a rare benign hemoglobin variant. METHODS: We reported a 32-year-old pregnant woman with discordant HbA1c and glucose measurements. In 75 g oral glucose tolerance test (OGTT), the pregnant woman got hyperglycemia at 1h-OGTT and 2h-OGTT. However, the pregnant woman had a low HbA1c of 3.9%. Subsequently, gene sequencing identified a rare mutation in the gene (HBB:c.155 C>A). RESULTS: We report for the first time that a case of North Manchester mutation in a Chinese female patient. In this case, it was found that the North Manchester variant could affect the examination of HbA1c when measured by ion-exchange high-performance liquid chromatography (HPLC), causing in falsely low HbA1c. CONCLUSIONS: Hemoglobin variants may lead to false HbA1c measurement. Clinicians should consider hemoglobin variants when HbA1c results are inconsistent with other laboratory tests.

Activation of CB1R alleviates central sensitization by regulating HCN2-pNR2B signaling in a chronic migraine rat model.

BACKGROUND: Central sensitization has been widely accepted as an underlying pathophysiological mechanism of chronic migraine (CM), activation of cannabinoid type-1 receptor (CB1R) exerts antinociceptive effects by relieving central sensitization in many pain models. However, the role of CB1R in the central sensitization of CM is still unclear. METHODS: A CM model was established by infusing inflammatory soup (IS) into the dura of male Wistar rats for 7 days, and hyperalgesia was assessed by the mechanical and thermal thresholds. In the periaqueductal gray (PAG), the mRNA and protein levels of CB1R and hyperpolarization-activated cyclic nucleotide-gated cation channel 2 (HCN2) were measured by qRT-PCR and western blotting. After intraventricular injection of Noladin ether (NE) (a CB1R agonist), ZD 7288 (an HCN2 blocker), and AM 251 (a CB1R antagonist), the expression of tyrosine phosphorylation of N-methyl-D-aspartate receptor subtype 2B (pNR2B), calcium-calmodulin-dependent kinase II (CaMKII), and phosphorylated cAMP-responsive element binding protein (pCREB) was detected, and central sensitization was evaluated by the expression of calcitonin gene-related peptide (CGRP), c-Fos, and substance P (SP). Synaptic-associated protein (postsynaptic density protein 95 (PSD95) and synaptophysin (Syp)) and synaptic ultrastructure were detected to explore synaptic plasticity in central sensitization. RESULTS: We observed that the mRNA and protein levels of CB1R and HCN2 were both significantly increased in the PAG of CM rats. The application of NE or ZD 7288 ameliorated IS-induced hyperalgesia; repressed the pNR2B/CaMKII/pCREB pathway; reduced CGRP, c-Fos, SP, PSD95, and Syp expression; and inhibited synaptic transmission. Strikingly, the application of ZD 7288 relieved AM 251-evoked elevation of pNR2B, CGRP, and c-Fos expression. CONCLUSIONS: These data reveal that activation of CB1R alleviates central sensitization by regulating HCN2-pNR2B signaling in CM rats. The activation of CB1R might have a positive influence on the prevention of CM by mitigating central sensitization.

Systematic analysis of expression profiles and prognostic significance for MMDS-related iron-sulfur proteins in renal clear cell carcinoma.

Mitochondrial metabolism disorders play an important role in the occurrence and development of tumors, and iron-sulfur protein is an important molecule for maintaining the normal function of mitochondria. However, the relationship between the expression, prognostic value, and immune infiltration of MMDS-related iron-sulfur protein genes in kidney renal clear cell carcinoma (KIRC) remains unclear. Based on online databases bioinformatics analysis was performed to evaluate the expression differences, survival impacts, immune infiltration, and prognostic significance of multiple mitochondrial dysfunction syndrome (MMDS)-related iron-sulfur protein genes in KIRC patients. For example, the protein-protein interaction (PPI) network was constructed using STRING and GEPIA database; Survival impacts were constructed by TCGA database; Immune infiltration was analyzed using TIMER database. There were significant differences in the mRNA expression levels of ISCA1, ISCA2, C1ORF69 and NFU1 in KIRC among different tumor grades and individual cancer stages. Furthermore, KIRC with high transcription levels of ISCA1, ISCA2, C1ORF69 and NFU1 (p < 0.01) was significantly associated with long overall survival (OS) and disease-free survival (DFS). In addition, overexpression of four genes, NFU1, ISCA1, ISCA2, and C1ORF69 in KIRC indicated a better prognosis. Further studies showed that immune cells had a significantly positive correlation with iron-sulfur protein family genes, including CD8+ T cells, CD4+ T cells and B cells. More importantly, the results of immunohistochemistry showed that the expression of NFU1, ISCA1, ISCA2 and C1ORF69 in normal tissues was higher than that in renal clear cell carcinoma tissues. In this study, we systematically analyzed the expression and prognostic value of iron-sulfur protein family genes in KIRC. More importantly, NFU1, ISCA1, ISCA2, and C1ORF69 are expected to become potential therapeutic targets for KIRC, as well as potential prognostic markers for improving the survival rate and prognostic accuracy of KIRC.

Systematic analysis of expression profiles and prognostic significance of the FGF gene family in pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is a malignant tumor with one of the highest associated mortality rates worldwide, and a 5-year survival rate of <5%. Fibroblast growth factors (FGFs) serve important roles in numerous cellular functions, and dysregulation of FGFs contributes to various cancer types. However, there are few reports on the function of FGFs in PAAD. The Assistant for Clinical Bioinformatics database, Gene Expression Profiling Interactive Analysis, Kaplan-Meier plotter and Tumor Immune Estimation Resource were utilized to perform the protein-protein interaction network, functional enrichment, univariate Cox regression, least absolute shrinkage and selection operator (LASSO) Cox, differential expression, prognostic value and immune cell infiltration analyses of FGFs in patients with PAAD. Immunohistochemistry (IHC) was used to verify the predictive value of the model. A total of 22 FGF genes were identified. Based on the results of LASSO Cox regression analysis, a total of six genes, including FGF2, FGF8, FGF9, FGF13, FGF17 and FGF22, were selected for the establishment of the prognostic gene signature. High transcriptional levels of FGF17 and FGF22 were significantly associated with long overall survival. The expression of FGFs was associated with the infiltration of various immune cells. According to univariate and multivariate analyses, FGF2 and FGF8 may be useful independent prognostic biomarkers for the prognosis of patients with PAAD. IHC demonstrated that FGF2 and FGF8 were more highly expressed in PAAD tissues compared with that in normal tissues. The present findings offer a novel understanding for the selection of FGF prognostic biomarkers in PAAD.

Evaluation of the efficacy and safety of intradermal needle therapy on the sleep quality of patients following laparoscopic hysterectomy: study protocol for a randomized controlled trial.

Background: Sleep disorder is a commonly reported complication in patients who have undergone a hysterectomy, which increases perioperative complications and delays patient recovery. Several pharmacological and non-pharmacological approaches have been employed to improve the quality of sleep of patients during the postoperative period, but these strategies have certain limitations. Intradermal needle therapy is now among the most common treatments for insomnia in traditional Chinese medicine (TCM). The present study was developed to explore the effects of intradermal needle therapy (as an adjunct to physiotherapy-based treatments for postoperative sleep impairment) on the postoperative sleep quality of patients who have undergone a laparoscopic hysterectomy. Methods: This is a prospective, single-center, single-blind, randomized controlled trial. In total, 80 eligible patients will be randomly allocated to the control and experimental groups at a 1:1 ratio. Random numbers and grouping schemes will be generated using the SPSS 25.0 software package. Following the completion of the laparoscopic hysterectomy procedure, the patients will be returned to the medical ward and undergo authentic or sham intradermal needle therapy as appropriate. For patients in the experimental group, following sterilization, intradermal needles will be inserted into the bilaterally "Shenmen" (HT36) and "Sanyinjiao" (SP6) acupoints; the needles will be replaced after 24 h. False intradermal needles that exhibit similar surface characteristics but lack needles will be employed in the control group. Patients will undergo a single 3-day treatment course. The primary outcome is the Pittsburgh Sleep Quality Index. The secondary outcomes are the 10-Item Short-Form Identity-Consequence Fatigue Scale, the Hospital Anxiety and Depression Scale-Anxiety, and postoperative pain scores, which will be rated using a visual analog scale. Time to postoperative defecation and the duration of hospitalization will also be recorded. Discussion: The present study seeks to examine the efficacy of the intradermal needle as a therapeutic tool for improving the sleep quality of patients after surgery who have undergone a laparoscopic hysterectomy to provide a foundation for future large-scale clinical studies. Trial Registration: Chinese Clinical Trial Registry (identifier: ChiCTR2200056890).

Molecular mechanisms of platinum­based chemotherapy resistance in ovarian cancer (Review).

Cisplatin is one of the most effective chemotherapy drugs for ovarian cancer, but resistance is common. The initial response to platinum­based chemotherapy is as high as 80%, but in most advanced patients, final relapse and death are caused by acquired drug resistance. The development of resistance to therapy in ovarian cancer is a significant hindrance to therapeutic efficacy. The resistance of ovarian cancer cells to chemotherapeutic mechanisms is rather complex and includes multidrug resistance, DNA damage repair, cell metabolism, oxidative stress, cell cycle regulation, cancer stem cells, immunity, apoptotic pathways, autophagy and abnormal signaling pathways. The present review provided an update of recent developments in our understanding of the mechanisms of ovarian cancer platinum­based chemotherapy resistance, discussed current and emerging approaches for targeting these patients and presented challenges associated with these approaches, with a focus on development and overcoming resistance.

Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis.

Met tyrosine kinase, a receptor for a hepatocyte growth factor (HGF), plays a critical role in tumor growth, metastasis, and drug resistance. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network. Dysregulated mitochondrial dynamics are responsible for the progression and metastasis of many cancers. Here, using structured illumination microscopy (SIM) and high spatial and temporal resolution live cell imaging, we identified mitochondrial trafficking of receptor tyrosine kinase Met. The contacts between activated Met kinase and mitochondria formed dramatically, and an intact HGF/Met axis was necessary for dysregulated mitochondrial fission and cancer cell movements. Mechanically, we found that Met directly phosphorylated outer mitochondrial membrane protein Fis1 at Tyr38 (Fis1 pY38). Fis1 pY38 promoted mitochondrial fission by recruiting the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) to mitochondria. Fragmented mitochondria fueled actin filament remodeling and lamellipodia or invadopodia formation to facilitate cell metastasis in hepatocellular carcinoma (HCC) cells both in vitro and in vivo. These findings reveal a novel and noncanonical pathway of Met receptor tyrosine kinase in the regulation of mitochondrial activities, which may provide a therapeutic target for metastatic HCC.

Autophagy-mediated negative feedback attenuates the oncogenic activity of YAP in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy in humans, and new therapeutic targets are urgently needed. Yes-associated protein (YAP) plays a significant role in cancer progression. Autophagy is also closely associated with various human cancers. However, the interplay between YAP and autophagy in PDAC remains poorly understood. In this study, we found that YAP was upregulated and activated in PDAC. Further analysis revealed that there is a YAP-autophagy feedback loop in pancreatic cancer. Mechanistically, YAP activates autophagy by promoting Atg5 transcription via TEAD1-mediated binding, while autophagy negatively regulates YAP through autophagic degradation. The hyperactivation of YAP in PDAC unbalances the YAP-autophagy circuit and promotes cancer progression. Inhibition of autophagy enhances the oncogenic activity of YAP in PDAC. The autophagy activator rapamycin promotes the antitumor effect of verteporfin, a YAP inhibitor. Therefore, our study elucidated the interaction between YAP and autophagy in PDAC and our results suggest that targeting the YAP-autophagy circuit may be a new therapeutic strategy for pancreatic cancer.

FUT8-mediated aberrant N-glycosylation of B7H3 suppresses the immune response in triple-negative breast cancer.

Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC.

CUL3 (cullin 3)-mediated ubiquitination and degradation of BECN1 (beclin 1) inhibit autophagy and promote tumor progression.

Macroautophagy/autophagy plays an important role during the development of human cancer. BECN1 (beclin 1), a core player in autophagy regulation, is downregulated in many kinds of malignancy. The underlying mechanism, however, has not been fully illuminated. Here, we found that CUL3 (cullin 3), an E3 ubiquitin ligase, could interact with BECN1 and promote the K48-linked ubiquitination and degradation of this protein; In addition, CUL3 led to a decrease in autophagic activity through downregulating BECN1. We also found that KLHL38 was a substrate adaptor of the CUL3 E3 ligase complex-mediated ubiquitination and degradation of BECN1. In breast and ovarian cancer, CUL3 could promote the proliferation of tumor cells, and the expression of CUL3 was related to poor prognosis in patients. Our study reveals the underlying mechanism of BECN1 ubiquitination and degradation that affects autophagic activity and subsequently leads to tumor progression, providing a novel therapeutic strategy that regulates autophagy to combat cancer.Abbreviations: ATG: autophagy-related BECN1: beclin 1 CHX: cycloheximide CoIP: co-immunoprecipitation CUL3: cullin 3 IP: immunoprecipitation MS: mass spectrometry PtdIns3K: phosphatidylinositol 3-kinase UPS: ubiquitin-proteasome system.

c.3G>A mutation in the CRYAB gene that causes fatal infantile hypertonic myofibrillar myopathy in the Chinese population.

Infantile hypertonic myofibrillar myopathy is characterized by the rapid development of rigid muscles and respiratory insufficiency soon after birth, with very high mortality. It is extremely rare, and only a few cases having been reported until now. Here we report four Chinese infants with fatal neuromuscular disorders characterized by abdominal and trunk skeletal muscle stiffness and rapid respiratory insufficiency progression. Electromyograms showed increased insertion activities and profuse fibrillation potentials with complex repetitive discharges. Immunohistochemistry staining of muscle biopsies showed accumulations of desmin in the myocytes. Powdery Z-bands with dense granules across sarcomeres were observed in muscle fibers using electron microscopy. All patients carry a homozygous c.3G>A mutation in the CRYAB gene, which resulted in the loss of the initiating methionine and the absence of protein. This study's findings help further understand the disease and highlight a founder mutation in the Chinese population.

AKT-mediated regulation of chromatin ubiquitylation and tumorigenesis through Mel18 phosphorylation.

Polycomb repressor complex 1 (PRC1) is linked to the regulation of gene expression and histone ubiquitylation conformation, which contributes to carcinogenesis. However, the upstream regulators of PRC1 biogenesis machinery remain obscure. Here, we report that the polycomb group-related mammalian gene Mel18 is a target of the protein kinase AKT. AKT phosphorylates Mel18 at T334 to disrupt the interaction between Mel18 and other PRC1 members, leading to attenuated PRC1-dependent ubiquitylation of histone H2A at Lys119. As such, PRC1 target genes, many of which are known oncogenes, are derepressed upon T334-Mel18 phosphorylation, which promotes malignant behaviours, including cell proliferation, tumour formation, migration and invasion, bone and brain metastatic lesion formation. Notably, a positive correlation between AKT activity and pT334-Mel18 is observed, and prognostic models based on p-AKT and pT334-Mel18 that predicted overall survival and distant metastasis-free survival in breast cancer patients are established. These findings have implications for understanding the role of AKT and its associated proteins in chromatin ubiquitylation, and also indicate the AKT-Mel18-H2AK119ub axis as a novel prognostic biomarker and therapeutic target for cancer patients.

Occurrence and Transmission of blaNDM-Carrying Enterobacteriaceae from Geese and the Surrounding Environment on a Commercial Goose Farm.

We investigated the prevalence and transmission of NDM-producing Enterobacteriaceae in fecal samples of geese and environmental samples from a goose farm in southern China. The samples were cultivated on MacConkey agar plates supplemented with meropenem. Individual colonies were examined for blaNDM, and blaNDM-positive bacteria were characterized based on whole-genome sequencing (WGS) data from the Illumina and Oxford Nanopore Technologies (ONT) platforms. Of 117 samples analyzed, the carriage rates for New Delhi metallo-ß-lactamase (NDM)-positive Enterobacteriaceae were 47.1, 18, and 50% in geese, inanimate environments (sewage, soil, fodder, and dust), and mouse samples, respectively. Two variants (blaNDM-1 and blaNDM-5, in 4 and 40 isolates, respectively) were found among 44 blaNDM-positive Enterobacteriaceae; these variants belonged to eight species, and Escherichia coli was the most prevalent (50%). WGS analysis revealed that blaNDM coexisted with diverse antibiotic resistance genes (ARGs). Population structure analysis showed that most E. coli and Enterobacter sp. isolates were highly heterogeneous, while most Citrobacter sp. and P. stuartii isolates possessed extremely high genetic similarities. In addition, blaNDM-5-positive ST4358/ST48 E. coli isolates were found to be clonally spread between geese and the environment and were highly genetically similar to those reported from ducks, farm environments, and humans in China. Plasmid analysis indicated that IncX3 pHNYX644-1-like (n = 40) and untypeable pM2-1-like plasmids (n = 4) mediated blaNDM spread. pM2-1-like plasmids possessed diverse ARGs, including blaNDM-1, the arsenical and mercury resistance operons, and the maltose operon. Our findings revealed that the goose farm is a reservoir for NDM-positive Enterobacteriaceae The blaNDM contamination of wild mice and the novel pM2-1-like plasmid described here likely adds to the risk for dissemination of blaNDM and associated resistance genes.IMPORTANCE Carbapenem-resistant bacteria, in particular NDM-producing Enterobacteriaceae, have become a great threat to global public. These bacteria have been found not only in hospital and community environments but also among food animal production chains, which are recognized as reservoirs for NDM-producing Enterobacteriaceae However, the dissemination of NDM-producing bacteria in waterfowl farms has been less well explored. Our study demonstrates that the horizontal spread of blaNDM-carrying plasmids and the partial clonal spread of blaNDM-positive Enterobacteriaceae contribute to the widespread contamination of blaNDM in the goose farm ecosystem, including mice. Furthermore, we found a novel and transferable blaNDM-1-carrying multidrug resistance (MDR) plasmid that possessed multiple environmental adaptation-related genes. The outcomes of this study contribute to a better understanding of the prevalence and transmission of blaNDM-carrying Enterobacteriaceae among diverse niches in the farm ecosystem.

YAP in pancreatic cancer: oncogenic role and therapeutic strategy.

Pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), remains a fatal disease with few efficacious treatments. The Hippo signaling pathway, an evolutionarily conserved signaling module, plays critical roles in tissue homeostasis, organ size control and tumorigenesis. The transcriptional coactivator yes-associated protein (YAP), a major downstream effector of the Hippo pathway, is associated with various human cancers including PDAC. Considering its importance in cancer, YAP is emerging as a promising therapeutic target. In this review, we summarize the current understanding of the oncogenic role and regulatory mechanism of YAP in PDAC, and the potential therapeutic strategies targeting YAP.