Targeting ACYP1-mediated glycolysis reverses lenvatinib resistance and restricts hepatocellular carcinoma progression.

Acylphosphatase 1 (ACYP1), a protein located in the mammalian cell cytoplasm, has been shown to be associated with tumor initiation and progression by functioning as a metabolism-related gene. Here we explored the potential mechanisms by which ACYP1 regulates the development of HCC and participates in the resistance to lenvatinib. ACYP1 can promote the proliferation, invasion, and migration capacities of HCC cells in vitro and in vivo. RNA sequencing reveals that ACYP1 markedly enhances the expression of genes related to aerobic glycolysis, and LDHA is identified as the downstream gene of ACYP1. Overexpression of ACYP1 upregulates LDHA levels, which then increases the malignancy potential of HCC cells. GSEA data analysis reveals the enrichment of differentially expressed genes in the MYC pathway, indicating a positive correlation between MYC and ACYP1 levels. Mechanistically, ACYP1 exerts its tumor-promoting roles by regulating the Warburg effect through activating the MYC/LDHA axis. Mass spectrometry analysis and Co-IP assays confirm that ACYP1 can bind to HSP90. The regulation of c-Myc protein expression and stability by ACYP1 is HSP90 dependent. Importantly, lenvatinib resistance is associated with ACYP1, and targeting ACYP1 remarkably decreases lenvatinib resistance and inhibits progression of HCC tumors with high ACYP1 expression when combined with lenvatinib in vitro and in vivo. These results illustrate that ACYP1 has a direct regulatory role in glycolysis and drives lenvatinib resistance and HCC progression via the ACYP1/HSP90/MYC/LDHA axis. Targeting ACYP1 could synergize with lenvatinib to treat HCC more effectively.

Vaccarin improves insulin sensitivity and glucose uptake in diet-induced obese mice via activation of GPR120-PI3K/AKT/GLUT4 pathway.

Insulin resistance is a risk factor for type 2 diabetes and is often associated with obesity. Vaccarin, a flavonoid found in vaccaria seeds, is commonly used in traditional Chinese medicine for activating blood circulation. Here, we showed that vaccarin ameliorates high-fat diet-induced obesity and insulin resistance in mice by reducing fat accumulation and improving insulin sensitivity in white adipose tissue. Further hyperinsulinemic-euglycemic clamp test revealed enhanced glucose uptake in vaccarin-treated WAT and skeletal muscle, consistent with activated insulin signaling pathway in these tissues. Mechanistically, vaccarin activates adipose tissue GPR120 and subsequently activating the PI3K/AKT/GLUT4 signaling pathway in 3T3-L1 cells. Together, these results reveal an undiscovered function of vaccarin in preventing obesity-related insulin resistance and advocates that vaccarin holds promise for further development as an innovative agent for the prevention of metabolic disorders.

The use of distress thermometer in advanced cancer inpatients with pain.

OBJECTIVE: This study aimed to provide support for the extensive application of Distress Thermometer (DT) in advanced cancer inpatients with pain and explored factors associated with high DT scores among this population. METHODS: Advanced cancer patients with pain were recruited from Department of Pain Relief in Tianjin Cancer Hospital and Institute, China. They completed the DT with problems list and HADS within 48 h after admission. The cutoff score of DT was evaluated against Hospital Anxiety and Depression Scale (HADS) for its sensitivity and specificity by using receiver operating characteristic (ROC) curves. Multiple logistic regression model analysis was performed to investigate correlates of DT scores. RESULTS: Four hundred forty one inpatients with mixed diagnoses were recruited. Referring to the cutoff of 15 on HADS, DT cutoff score of 5 yielded AUC of 0.757, with an optimal sensitivity of 0.861 and specificity of 0.531. Using the cutoff scores of greater than or equal to 5, 70.5% of the patients were distressed. Logistic regression analysis of DT found that the breakthrough pain, poorer KPS, higher pain degree, and emotional problems were the predictive factor for current distress. CONCLUSION: DT is efficacious in screening for psychological distress in advanced cancer inpatients with pain. Psychological distress is prevalent with a cutoff score of greater than or equal to five. To better identify the distressed cancer patients with pain, pain degree, performance status, and emotional problems should be considered together.

The impact of positive nodal chain ratio on individualized multimodality therapy in non-small-cell lung cancer.

This study aimed to analyze the prognostic significance of the positive nodal chain ratio (NCR) in non-small-cell lung cancer (NSCLC). A total of 208 pIIIa-N2 NSCLC patients who underwent complete surgical resections with a systematic nodal dissection were enrolled. The median values of NCR and the positive lymph node ratio (LNR) were used to grouping patients. The differences of overall survival (OS) and disease-free survival (DFS) between the different groups were compared. The median values of NCR and LNR were 0.31 and 0.45, respectively. The patients were separated into group A (NCR ≤0.45 and LNR ≤0.31; 91 cases), group B (NCR ≤0.45 and LNR >0.31 or NCR >0.45 and LNR ≤0.31; 51 cases), and group C (NCR >0.45 and LNR >0.31; 66 cases) according to their combined LCR and LNR values. Groups A, B, and C exhibited significantly different prognoses (5-year OS: 43.7, 25.2, and 12.3 %, respectively, p < 0.0001; 5-year DFS: 30.4, 23.3, and 8.6 %, respectively, p < 0.0001). Multivariate analyses revealed that this novel grouping method based on the combination of NCR and LNR was an independent prognostic factor for 5-year OS and 5-year DFS in pIIIa-N2 NSCLC. In group C, patients who received no postoperative treatment, adjuvant chemotherapy alone, or chemoradiotherapy exhibited different 5-year OS rates (0.0, 11.6, and 37.5 %, respectively, p = 0.003) and 5-year DFS rates (0.0, 7.5, and 25.0 %, respectively, p = 0.009). Therefore, postoperative chemoradiotherapy may significantly improve the prognosis of patients displaying NCR >0.45 and LNR >0.31. NCR combined with LNR may be more effective to guide individualized multimodality therapy including postoperative chemoradiotherapy for pIIIa-N2 NSCLC.

Ultrasensitive electrochemiluminescence biosensor based on polymethylene blue nanoparticles and DNA network for Staphylococcus aureus detection.

A novel bipolar electrode (BPE)-electrochemiluminescence (ECL) device was constructed for the ultra-sensitive detection of Staphylococcus aureus (S. aureus) by combining polymerase chain reaction (PCR) amplification and DNA network-loaded polymethylene blue nanoparticles (pMB NPs). The presence of target triggered the dissociation of double-stranded DNA on Fe3O4 NPs and the release of T strand, which initiated the PCR. The PCR product contains two protruding single-stranded DNA fragments that serve as bridges to connect Au NPs labeled probes. The PCR-Au products were captured by the probes on cathode of BPE to form three-dimensional DNA networks, which offer multiple adsorption sites for pMB NPs, leading to the remarkable enhancement of ECL intensity. Under optimal circumstances, a wide linear range from 10 to 108 CFU/mL and a low detection limit of 0.78 CFU/mL were achieved. This research opens new horizons for the application of PCR-based biosensors for the accurate and sensitive measurement of pathogenic bacteria.

A prognostic metabolism-related gene signature associated with the tumor immune microenvironment in neuroblastoma.

Neuroblastoma (NB) is the most prevalent malignant solid tumor in children. Tumor metabolism, including lipid, amino acid, and glucose metabolism, is intricately linked to the genesis and progression of tumors. This study aimed to establish a prognostic gene signature for NB patients, based on metabolism-related genes, and to investigate a treatment approach that could enhance the survival rate of high-risk NB patients. From the NB dataset GSE49710, we identified metabolism-related gene markers utilizing the "limma" R package and univariate Cox analysis combined with least absolute shrinkage and selection operator (LASSO) regression analysis. We explored the correlation between these gene markers and the overall survival of NB patients. Gene set enrichment analysis (GSEA) and single-sample GSEA algorithms were used to assess the differences in metabolism and immune status. Furthermore, we examined the association between metabolic subgroups and drug responsiveness. Concurrently, data downloaded from TARGET and MTAB were used for external verification. Using multicolor immunofluorescence and immunohistochemistry, we investigated the relationship between the lipid metabolism-related gene ELOVL6 with both the International Neuroblastoma Staging System classification of NB and survival rate. Finally, we explored the effect of high ELOVL6 expression on the immune microenvironment in NB using flow cytometry. We identified an eight-gene signature comprising metabolism-related genes in NB: ELOVL6, OSBPL9, RPL27A, HSD17B3, ACHE, AKR1C1, PIK3R1, and EPHX2. This panel effectively predicted disease-free survival, and was validated using an internal dataset from GSE49710 and two external datasets from the TARGET and MTAB databases. Moreover, our findings confirmed that ELOVL6 fosters an immunosuppressive microenvironment and contributes to the malignant progression in NB. The eight-gene signature is significant in predicting the prognosis of NB, effectively classifying patients into high- and low-risk groups. This classification may guide the development of innovative treatment strategies for these patients. Notably, the signature gene ELOVL6 markedly encourages an immunosuppressive microenvironment and malignant progression in NB.

Expression pattern of Boule in dairy goat testis and its function in promoting the meiosis in male germline stem cells (mGSCs).

Boule is a conserved gene in meiosis, which encodes RNA binding protein required for spermatocyte meiosis. Deletion of Boule was found to block meiosis in spermatogenesis, which contributes to infertility. Up to date, the expression and function of Boule in the goat testis are not known. The objectives of this study were to investigate the expression pattern of Boule in dairy goat testis and their function in male germline stem cells (mGSCs). The results first revealed that the expression level of Boule in adult testes was significantly higher than younger and immature goats, and azoospermia and male intersex testis. Over-expression of Boule promoted the expression of meiosis-related genes in dairy goat mGSCs. The expression of Stra8 was up-regulated by over-expression of Boule analyzed by Western blotting and Luciferase reporter assay. While, Cdc25a, the downstream regulator of Boule, was found not to affect the expression of Stra8, and our data illustrated that Cdc25a did not regulate meiosis via Stra8. The expression of Stra8 and Boule was up-regulated by RA induction. Taken together, results suggest the Boule plays an important role in dairy goat spermatogenesis and that over-expression of Boule may promote spermatogenesis and meiosis in dairy goat.

Reconstruction of damaged corneal epithelium using Venus-labeled limbal epithelial stem cells and tracking of surviving donor cells.

Limbal epithelial stem cells are responsible for the self-renewal and replenishment of the corneal epithelium. Although it is possible to repair the ocular surface using limbal stem cell transplantation, the mechanisms behind this therapy are unclear. To investigate the distribution of surviving donor cells in a reconstructed corneal epithelium, we screened a Venus-labeled limbal stem cell strain in goats. Cells were cultivated on denuded human amniotic membrane for 21 days to produce Venus-labeled corneal epithelial sheets. The Venus-labeled corneal epithelial sheets were transplanted to goat models of limbal stem cell deficiency. At 3 months post-surgery, the damaged corneal epithelia were obviously improved in the transplanted group compared with the non-transplanted control, with the donor cells still residing in the reconstructed ocular surface epithelium. Using Venus as a marker, our results indicated that the location and survival of donor cells varied, depending on the corneal epithelial region. Additionally, immunofluorescent staining of the reconstructed corneal epithelium demonstrated that many P63(+) cells were unevenly distributed among basal and suprabasal epithelial layers. Our study provides a new model, and reveals some of the mechanisms involved in corneal epithelial cell regeneration research.

Gender depended potentiality of differentiation of human umbilical cord mesenchymal stem cells into oocyte-Like cells in vitro.

Recent studies have demonstrated that germ-like cells could be differentiated from human umbilical cord mesenchymal stem cells (hUC-MSCs) in vitro. Whether the sexuality of hUC-MSCs affects the formation efficiency of germ-like cells derived from hUC-MSCs is still unclear. To clearly test the formation efficiency of oocyte-like cells from male and female hUC-MSCs, obtained hUC-MSCs were induced by 20% follicular fluid (FF) according to the method that has been proved by our previous studies. Results showed that hUC-MSCs differentiated into oocyte-like structures and expressed germ cell makers. It was noted that the presence of advanced oocyte-like cells in male hUC-MSCs (m-hUC-MSCs) was similar as that in female hUC-MSCs (f-hUC-MSCs); however, the expression of germ cell's specific markers in m-hUC-MSCs was delayed compared with that in f-hUC-MSCs. In addition, immunofluorescence analysis demonstrated that germ cell-specific markers, Oct4, Vasa, Dazl, ZP2, ZP3 and Stra8, were expressed on the 14th day after induction in both f-hUC-MSCs and m-hUC-MSCs. However, the size of oocyte-like cells from f-hUC-MSCs was larger than that in m-hUC-MSCs. The level of secreted oestradiol was significantly higher in f-hUC-MSCs than m-hUC-MSCs. We sought to determine whether critical germ cell's transcription factor-Figlα will promote the development of oocyte-like cells. Some germ cell-specific markers were increased when exogenous Figlα was transfected into hUC-MSCs. This process implied that germ-like cells might be produced by over-expression of exogenous germ cell-specific gene, and this process was similar as that in production of germ cells in induced pluripotent stem cells (iPSCs). Finally, to verify the feasibility that hUC-MSCs differentiate into germ cells, hUC-MSCs were transplanted into seminiferous tubules and kidney capsule of mouse, respectively, and we found the transplanted cells differentiated into germ-like cells in recipient's seminiferous tubules and kidney capsule. This study will provide a simple model to study mammalian germ cell specification using hUC-MSCs in vitro.

Novel electrochemiluminescence biosensor of fumonisin B1 detection using MWCNTs-PDMS flexible bipolar electrode.

A novel portable and disposable bipolar electrode (BPE)-electrochemiluminescence (ECL) device was fabricated for fumonisin B1 (FB1) detection. BPE was fabricated by using MWCNTs and polydimethylsiloxane (PDMS) due to their excellent electrical conductivity and good mechanical stiffness. After the deposition of Au NPs on the cathode of BPE, the ECL signal could be improved 89-fold. Then a specific aptamer-based sensing strategy was constructed by grafting capture DNA on Au surface, followed by hybridizing with aptamer. Meanwhile, an excellent catalyst, Ag NPs was labeled on aptamer to activate oxygen reduction reaction, leading to a 13.8-fold enhancement in ECL signal at the anode of BPE. Under the optimal conditions, the biosensor exhibited a wide linear range of 0.10 pg/mL to 10 ng/mL for FB1 detection. Meanwhile, it demonstrated satisfactory recoveries for real sample detection with good selectivity, making it to be a convenient and sensitive device for mycotoxin assay.

Recent Advances in Electrochemiluminescence Biosensors for Mycotoxin Assay.

Rapid and efficient detection of mycotoxins is of great significance in the field of food safety. In this review, several traditional and commercial detection methods are introduced, such as high-performance liquid chromatography (HPLC), liquid chromatography/mass spectrometry (LC/MS), enzyme-linked immunosorbent assay (ELISA), test strips, etc. Electrochemiluminescence (ECL) biosensors have the advantages of high sensitivity and specificity. The use of ECL biosensors for mycotoxins detection has attracted great attention. According to the recognition mechanisms, ECL biosensors are mainly divided into antibody-based, aptamer-based, and molecular imprinting techniques. In this review, we focus on the recent effects towards the designation of diverse ECL biosensors in mycotoxins assay, mainly including their amplification strategies and working mechanism.

CD73/NT5E is a Potential Biomarker for Cancer Prognosis and Immunotherapy for Multiple Types of Cancers.

Cluster of Differentiations 73 (CD73)/ecto-5'-nucleotidase (NT5E) is a novel type of immune molecular marker expressed on many tumor cells and involved in regulating the essential immune functions and affecting the prognosis of cancer patients. However, it is not clear how the NT5E is linked to the infiltration levels of the immune cells in pan-cancer patients and their final prognosis. This study explores the role of NT5E in 33 tumor types using GEPIA, TIMER, Oncomine, BioGPS databases, and several bioinformatic tools. The findings reveal that the NT5E is abnormally expressed in a majority of the types of cancers and can be used for determining the prognosis prediction ability of different cancers. Moreover, NT5E is significantly related to the infiltration status of numerous immune cells, immune-activated pathways, and immunoregulator expressions. Last, specific inhibitor molecules, like NORNICOTINE, AS-703026, and FOSTAMATINIB, which inhibit the expression of NT5E in various types of cancers, are screened with the CMap. Thus, it is proposed that NT5E can be utilized as a potential biomarker for predicting the prognosis of cancer patients and determining the infiltration of various immune cells in different types of cancers.

CD73, a Promising Therapeutic Target of Diclofenac, Promotes Metastasis of Pancreatic Cancer through a Nucleotidase Independent Mechanism.

CD73, a cell surface-bound nucleotidase, facilitates extracellular adenosine formation by hydrolyzing 5'-AMP to adenosine. Several studies have shown that CD73 plays an essential role in immune escape, cell proliferation and tumor angiogenesis, making it an attractive target for cancer therapies. However, there are limited clinical benefits associated with the mainstream enzymatic inhibitors of CD73, suggesting that the mechanism underlying the role of CD73 in tumor progression is more complex than anticipated, and further investigation is necessary. In this study, CD73 is found to overexpress in the cytoplasm of pancreatic ductal adenocarcinoma (PDAC) cells and promotes metastasis in a nucleotidase-independent manner, which cannot be restrained by the CD73 monoclonal antibodies or small-molecule enzymatic inhibitors. Furthermore, CD73 promotes the metastasis of PDAC by binding to the E3 ligase TRIM21, competing with the Snail for its binding site. Additionally, a CD73 transcriptional inhibitor, diclofenac, a non-steroidal anti-inflammatory drug, is more effective than the CD73 blocking antibody for the treatment of PDAC metastasis. Diclofenac also enhances the therapeutic efficacy of gemcitabine in the spontaneous KPC (LSL-KrasG12D/+ , LSL-Trp53R172H/+ , and Pdx-1-Cre) pancreatic cancer model. Therefore, diclofenac may be an effective anti-CD73 therapy, when used alone or in combination with gemcitabine-based chemotherapy regimen, for metastatic PDAC.

Combination of RUNX1 inhibitor and gemcitabine mitigates chemo-resistance in pancreatic ductal adenocarcinoma by modulating BiP/PERK/eIF2α-axis-mediated endoplasmic reticulum stress.

BACKGROUND: Gemcitabine (GEM)-based chemotherapy is the first-line option for pancreatic ductal adenocarcinoma (PDAC). However, the development of drug resistance limits its efficacy, and the specific mechanisms remain largely unknown. RUNX1, a key transcription factor in hematopoiesis, also involved in the malignant progression of PDAC, but was unclear in the chemoresistance of PDAC. METHODS: Comparative analysis was performed to screen GEM-resistance related genes using our single-cell RNA sequencing(scRNA-seq) data and two public RNA-sequencing datasets (GSE223463, GSE183795) for PDAC. The expression of RUNX1 in PDAC tissues was detected by qRT-PCR, immunohistochemistry (IHC) and western blot. The clinical significance of RUNX1 in PDAC was determined by single-or multivariate analysis and survival analysis. We constructed the stably expressing cell lines with shRUNX1 and RUNX1, and successfully established GEM-resistant cell line. The role of RUNX1 in GEM resistance was determined by CCK8 assay, plate colony formation assay and apoptosis analysis in vitro and in vivo. To explore the mechanism, we performed bioinformatic analysis using the scRNA-seq data to screen for the endoplasm reticulum (ER) stress signaling that was indispensable for RUNX1 in GEM resistance. We observed the cell morphology in ER stress by transmission electron microscopy and validated RUNX1 in gemcitabine resistance depended on the BiP/PERK/eIF2α pathway by in vitro and in vivo oncogenic experiments, using ER stress inhibitor(4-PBA) and PERK inhibitor (GSK2606414). The correlation between RUNX1 and BiP expression was assessed using the scRNA-seq data and TCGA dataset, and validated by RT-PCR, immunostaining and western blot. The mechanism of RUNX1 regulation of BiP was confirmed by ChIP-PCR and dual luciferase assay. Finally, the effect of RUNX1 inhibitor on PDAC was conducted in vivo mouse models, including subcutaneous xenograft and patient-derived xenograft (PDX) mouse models. RESULTS: RUNX1 was aberrant high expressed in PDAC and closely associated with GEM resistance. Silencing of RUNX1 could attenuate resistance in GEM-resistant cell line, and its inhibitor Ro5-3335 displayed an enhanced effect in inhibiting tumor growth, combined with GEM treatment, in PDX mouse models and GEM-resistant xenografts. In detail, forced expression of RUNX1 in PDAC cells suppressed apoptosis induced by GEM exposure, which was reversed by the ER stress inhibitor 4-PBA and PERK phosphorylation inhibitor GSK2606414. RUNX1 modulation of ER stress signaling mediated GEM resistance was supported by the analysis of scRNA-seq data. Consistently, silencing of RUNX1 strongly inhibited the GEM-induced activation of BiP and PERK/eIF2α signaling, one of the major pathways involved in ER stress. It was identified that RUNX1 directly bound to the promoter region of BiP, a primary ER stress sensor, and stimulated BiP expression to enhance the reserve capacity for cell adaptation, which in turn facilitated GEM resistance in PDAC cells. CONCLUSIONS: This study identifies RUNX1 as a predictive biomarker for response to GEM-based chemotherapy. RUNX1 inhibition may represent an effective strategy for overcoming GEM resistance in PDAC cells.

Prognostic Implications of an Autophagy-related Gene Signature in Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is difficult to diagnose and resistant to therapy and has a poor prognosis. Autophagy plays a vital role in PDAC development and progression. This study aimed to establish an autophagy-related gene (ARG) signature to predict the prognosis of patients with PDAC. MATERIALS AND METHODS: The expression profiles of PDAC and healthy pancreatic tissues were obtained from The Cancer Genome of Atlas (TCGA) and GTEx (Genotype-Tissue Expression) databases, respectively. Univariate and multivariate Cox regression analyses were performed on differentially expressed ARGs to identify the optimal prognosis-related genes. RESULTS: A total of 73 ARGs demonstrated significant differences in expression levels between PDAC and healthy pancreatic tissues. Several pathways that play crucial roles in biological processes were identified via enrichment analyses. Furthermore, an ARG signature was established based on overall survival-related ARGs (CASP4, BAK1, PIK3R4, CASP8, BIRC5, RPTOR, and CAPN1) using least absolute shrinkage and selection operator (LASSO) regression. Cox regression analysis confirmed that the 7-gene signature was an independent prognostic factor for patients with PDAC (P<0.001). In addition, the GSE21501 and GSE28735 datasets were used to validate the predictive value of the prognostic model for PDAC. We also constructed a clinical nomogram with a concordance index of 0.712 to predict the overall survival of patients by integrating clinical characteristics and the ARG signature. Calibration curves substantiated fine concordance between nomogram prediction and actual observation. CONCLUSION: We constructed a new ARG-related prognostic model, which can be a prognostic biomarker and offers insights into identifying potential therapeutic targets for PDAC.

Rapid degradation of organic pollutants by Fe3O4@PDA/Ag catalyst in advanced oxidation process.

Over the past decades, the development of novel catalysts on the degradation of organic pollutants has attracted increasing attention. In this work, we synthesized silver decorated magnetic nanoparticles (Fe3O4@PDA/Ag NPs) to activate H2O2 for organic pollutants removal via advanced oxidation processes (AOPs). The catalyst was prepared through in-situ reduction of AgNO3 by the polydopamine (PDA) layer on Fe3O4 NPs. Chemiluminescence results obtained from luminol/H2O2 system revealed that the catalyst exhibited excellent catalytic effect on the decomposition of H2O2 into reactive oxygen species (ROS) and superoxide radical (O2-) was mainly responsible for the oxidative degradation. Importantly, the fast evolution frequency of oxygen gas bubbles produced in the reaction of Ag NPs and H2O2 could generate vigorous fluid convection and autonomous motion of catalyst when H2O2 concentration reached 1%. Additionally, the catalyst can suspend in solution for several minutes. Therefore, by coupling the vigorous motion with slow sedimentation velocity, the catalyst can realize rapid degradation of organic pollutants without external mixing force. The Fe3O4@PDA/Ag NPs catalysts not only showed a high removal efficiency of malachite green, but also can be applied for the degradation of other dyes, making it to be a promise candidate for environmental remediation. With the merits of excellent catalytic effect, fast degradation speed, and simplicity of operation, the prepared catalysts exhibits great potential in the practical field.

Perioperative Serum Scoring Systems Predict Early Recurrence and Poor Prognosis of Resectable Pancreatic Cancer.

Objective: Some patients with pancreatic ductal adenocarcinoma (PDAC) are prone to rapid recurrence or metastasis after radical resection. However, evaluation methods for effectively identifying these patients are lacking. In this study, we established perioperative serum scoring systems to screen patients with early recurrence and poor prognosis. Methods: We systematically analysed 44 perioperative serum parameters, including systemic inflammatory parameters, coagulation system parameters, tumor markers, and 18 clinicopathological characteristics of 218 patients with radical resection in our centre. Univariate Cox regression and LASSO regression models were used to screen variables. Kaplan-Meier survival analysis was used to compare relapse-free survival and overall survival. Multivariate Cox regression was used to evaluate the independent risk variables. AUC and C-index were used to reveal the effectiveness of the models. In addition, the effectiveness was also verified in an independent cohort of 109 patients. Results: Preoperative systemic immune coagulation cascade (SICC) (including increased neutrophil to lymphocyte ratio, decreased lymphocyte to monocyte ratio, increased platelet and fibrinogen) and increased postoperative tumor markers (TMs) (CA199, CEA and CA242) were independent risk factors for early recurrence of resectable pancreatic cancer. On this basis, we established the preoperative SICC score and postoperative TMs score models. The patients with higher preoperative SICC or postoperative TMs score were more likely to have early relapse and worse prognosis. The nomogram based on preoperative SICC, postoperative TMs, CACI, smoking index, vascular cancer embolus and adjuvant chemotherapy can effectively evaluate the recurrence rate (AUC1 year: 0.763, AUC2 year: 0.679, AUC3 year: 0.657) and overall survival rate (AUC1 year: 0.770, AUC3 year: 0.804, AUC5 year: 0.763). Conclusion: Preoperative SICC and postoperative TMs can help identify resectable PDAC patients with early recurrence and poor prognosis.

Identification of Ferroptosis-Related Genes Signature Predicting the Efficiency of Invasion and Metastasis Ability in Colon Adenocarcinoma.

Background: Colon adenocarcinoma (COAD) is one of the most prevalent cancers worldwide and has become a leading cause of cancer death. Although many potential biomarkers of COAD have been screened with the bioinformatics method, it is necessary to explore novel markers for the diagnosis and appropriate individual treatments for COAD patients due to the high heterogeneity of this disease. Epithelial-to-mesenchymal transition (EMT)-mediated tumor metastasis suggests poor prognosis of cancers. Ferroptosis is involved in tumor development. EMT signaling can increase the cellular sensitivity to ferroptosis in tumors. The aim of our study is finding novel prognostic biomarkers to determine COAD patients for predicting efficiency of metastasis status and targeting precise ferroptosis-related therapy. Methods: A novel gene signature related to metastasis and ferroptosis was identified combing with risk model and WGCNA analysis with R software. The biological functions and predictive ability of the signature in COAD were explored through bioinformatics analysis. Results: We established a four-gene prognostic signature (MMP7, YAP1, PCOLCE, and HOXC11) based on EMT and ferroptosis related genes and validated the reliability and effectiveness of this model in COAD. This four-gene prognostic signature was closely connected with metastasis and ferroptosis sensitivity of COAD. Moreover, WGCNA analysis further confirmed the correlation between PCOLCE, HOXC11, and liver and lymphatic invasion of COAD. Conclusion: The four genes may become potential prognostic biomarkers to identify COAD patients with metastasis. Moreover, this four-gene signature may be able to determine the COAD suitable with ferroptosis induction therapy. Finally, PCOLCE2 and HOXC11 were selected individually because of their novelties and precise prediction ability. Overall, this signature provided novel possibilities for better prognostic evaluation of COAD patients and may be of great guiding significance for individualized treatment and clinical decision.

CD73 induces gemcitabine resistance in pancreatic ductal adenocarcinoma: A promising target with non-canonical mechanisms.

CD73, a cell surface-localized ecto-5'-nucleotidase, is the major enzymatic source of extracellular adenosine. Canonically, it plays multiple roles in cancer-related processes via its metabolite. As a druggable target, clinical trials targeting CD73 in various malignant diseases are currently ongoing. Here, we report the ecto-5'-nucleotidase-independent functions of CD73 in pancreatic ductal adenocarcinoma (PDAC). Our findings support that the elevated expression of CD73 in PDAC cells promotes gemcitabine (GEM) resistance by activating AKT. We discovered that a large amount of intracellular CD73 are localized in the endoplasmic reticulum membrane. Intracellular CD73 physically interacts with major vault protein to activate the SRC-AKT circuit. Troglitazone (TGZ) is a peroxisome proliferator-activated receptor gamma agonist that could inhibit the expression of CD73. The administration of TGZ markedly enhances sensitivity to GEM via downregulating CD73 in PDAC. Our findings support that CD73 could be targeted to overcome chemoresistance in PDAC.

Dmrt1 regulates the immune response by repressing the TLR4 signaling pathway in goat male germline stem cells.

Double sex and mab-3-related transcription factor 1 (Dmrt1), which is expressed in goat male germline stem cells (mGSCs) and Sertoli cells, is one of the most conserved transcription factors involved in sex determination. In this study, we highlighted the role of Dmrt1 in balancing the innate immune response in goat mGSCs. Dmrt1 recruited promyelocytic leukemia zinc finger (Plzf), also known as zinc finger and BTB domain-containing protein 16 (Zbtb16), to repress the Toll-like receptor 4 (TLR4)-dependent inflammatory signaling pathway and nuclear factor (NF)-κB. Knockdown of Dmrt1 in seminiferous tubules resulted in widespread degeneration of germ and somatic cells, while the expression of proinflammatory factors were significantly enhanced. We also demonstrated that Dmrt1 stimulated proliferation of mGSCs, but repressed apoptosis caused by the immune response. Thus, Dmrt1 is sufficient to reduce inflammation in the testes, thereby establishing the stability of spermatogenesis and the testicular microenvironment.