Predicting histologic grades for pancreatic neuroendocrine tumors by radiologic image-based artificial intelligence: a systematic review and meta-analysis.

Background: Accurate detection of the histological grade of pancreatic neuroendocrine tumors (PNETs) is important for patients' prognoses and treatment. Here, we investigated the performance of radiological image-based artificial intelligence (AI) models in predicting histological grades using meta-analysis. Method: A systematic literature search was performed for studies published before September 2023. Study characteristics and diagnostic measures were extracted. Estimates were pooled using random-effects meta-analysis. Evaluation of risk of bias was performed by the QUADAS-2 tool. Results: A total of 26 studies were included, 20 of which met the meta-analysis criteria. We found that the AI-based models had high area under the curve (AUC) values and showed moderate predictive value. The pooled distinguishing abilities between different grades of PNETs were 0.89 [0.84-0.90]. By performing subgroup analysis, we found that the radiomics feature-only models had a predictive value of 0.90 [0.87-0.92] with I2 = 89.91%, while the pooled AUC value of the combined group was 0.81 [0.77-0.84] with I2 = 41.54%. The validation group had a pooled AUC of 0.84 [0.81-0.87] without heterogenicity, whereas the validation-free group had high heterogenicity (I2 = 91.65%, P=0.000). The machine learning group had a pooled AUC of 0.83 [0.80-0.86] with I2 = 82.28%. Conclusion: AI can be considered as a potential tool to detect histological PNETs grades. Sample diversity, lack of external validation, imaging modalities, inconsistent radiomics feature extraction across platforms, different modeling algorithms and software choices were sources of heterogeneity. Standardized imaging, transparent statistical methodologies for feature selection and model development are still needed in the future to achieve the transformation of radiomics results into clinical applications. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022341852.

LINC00909 up-regulates pluripotency factors and promotes cancer stemness and metastasis in pancreatic ductal adenocarcinoma by targeting SMAD4.

BACKGROUND: Pancreatic cancer stem cells are crucial for tumorigenesis and cancer metastasis. Presently, long non-coding RNAs were found to be associated with Pancreatic Ductal Adenocarcinoma stemness characteristics but the underlying mechanism is largely known. Here, we aim to explore the function of LINC00909 in regulating pancreatic cancer stemness and cancer metastasis. METHODS: The expression level and clinical characteristics of LINC00909 were verified in 80-paired normal pancreas and Pancreatic Ductal Adenocarcinoma tissues from Guangdong Provincial People's Hospital cohort by in situ hybridization. RNA sequencing of PANC-1 cells with empty vector or vector encoding LINC00909 was experimented for subsequent bioinformatics analysis. The effect of LINC00909 in cancer stemness and metastasis was examined by in vitro and in vivo experiments. The interaction between LINC00909 with SMAD4 and the pluripotency factors were studied. RESULTS: LINC00909 was generally upregulated in pancreatic cancer tissues and was associated with inferior clinicopathologic features and outcome. Over-expression of LINC00909 enhanced the expression of pluripotency factors and cancer stem cells phenotype, while knock-down of LINC00909 decreased the expression of pluripotency factors and cancer stem cells phenotype. Moreover, LINC00909 inversely regulated SMAD4 expression, knock-down of SMAD4 rescued the effect of LINC00909-deletion inhibition on pluripotency factors and cancer stem cells phenotype. These indicated the effect of LINC00909 on pluripotency factors and CSC phenotype was dependent on SMAD4 and MAPK/JNK signaling pathway, another downstream pathway of SMAD4 was also activated by LINC00909. Specifically, LINC00909 was localized in the cytoplasm in pancreatic cancer cells and decreased the stability the SMAD4 mRNA. Finally, we found over-expression of LINC00909 not only accelerated tumor growth in subcutaneous mice models, but also facilitated tumorigenicity and spleen metastasis in orthotopic mice models. CONCLUSION: We demonstrate LINC00909 inhibits SMAD4 expression at the post-transcriptional level, which up-regulates the expression of pluripotency factors and activates the MAPK/JNK signaling pathway, leading to enrichment of cancer stem cells and cancer metastasis in pancreatic cancer.

Effect of faba bean Vicia faba L. water/alcohol extract on growth performance, antioxidant capacity, textural properties, and collagen deposition in the swim bladder of juvenile Nibea coibor.

Faba bean has gained attention as a cost-effective protein source with the potential to enhance product quality (texture properties, collagen content, etc.) in fish. However, its anti-nutrition factor, high feed conversion ratio, poor growth performance, etc. limit the widely application as a dietary source, especially in carnivorous fish. The water or alcohol extract of faba bean might resolve the problem. In this study, the juvenile Nibea coibor, known for their high-protein, large-sized, and high-grade swim bladder, were fed with seven isoproteic and isolipid experimental diets with the additive of faba bean water extract (1.25%, 2.5%, and 5%) or faba bean alcohol extract (0.9%, 1.8%, and 3.6%), with a control group without faba bean extract. After the 10-week feeding trail, the growth, antioxidant capacity, textural properties, and collagen deposition of the swim bladder were analyzed. Results showed that the 1.25% faba bean water extract group could significantly promote growth, textural quality of the swim bladder, and have beneficial effects on antioxidant response of fish. Conversely, dietary supplementation of faba bean alcohol extract resulted in reduced growth performance in a dose-dependent manner. Furthermore, fish fed diet with 1.25% faba bean water extract exhibited increased collagen content and upregulated collagen-related gene expression in the swim bladder, which was consistent with the Masson stain analysis for collagen fiber. Our results suggested that the anti-nutrient factor and bioactive component of faba bean may mainly be enriched in alcohol extract and water extract of faba bean, respectively. Besides, the appropriate addition of water extract of faba bean may improve the texture quality of the swim bladder by promoting collagen deposition. This study would provide a theoretical basis for the formulated diets with faba bean extract to promote product quality of marine fish.

A hierarchical prognostic model for Co-diabetes pancreatic adenocarcinoma.

Background: Co-diabetes pancreatic adenocarcinoma has a poorer prognosis than pancreatic adenocarcinoma without diabetes. This study aimed to develop a reliable prognostic model for patients with co-diabetes pancreatic adenocarcinoma. Method: Overall, 169 patients with co-diabetes pancreatic adenocarcinoma were included in our study. First, the independent risk factors affecting the prognosis of patients with co-diabetes pancreatic adenocarcinoma were determined by univariate and multivariate Cox regression analyses. Based on these identified risk factors, we developed a nomogram and evaluated its predictive ability using the concordance index, receiver operating characteristic curve, calibration plot, decision curve, and net reclassification index. Results: In this study, prealbumin, transferrin, carcinoembryonic antigen, distant metastasis, tumor differentiation neutrophil count, lymphocyte count and fasting blood glucose were confirmed as significant prognostic factors. Based on these predictors, a new nomogram was developed. Compared with the American Joint Committee on Cancer 8 staging system and other models, the nomogram achieved a higher concordance index in the training (0.795) and validation (0.729) queues. The area under the nomogram's curve for predicting patient survival at 0.5, 1, and 1.5 years in the training queue was >0.8. Patients were risk-stratified using the nomogram, and Kaplan-Meier survival curves of subgroups were plotted. The Kaplan-Meier curve also showed better separation than the American Joint Committee on Cancer 8 staging system, indicating that our model has a better risk hierarchical ability. Conclusions: Compared to the American Joint Committee on Cancer 8 staging system and other predictive models, our model showed better predictive ability for patients with co-diabetes pancreatic adenocarcinoma. Our model will help in patients' risk stratification and improves their prognosis.

Effects of Ammonia and Salinity Stress on Non-Volatile and Volatile Compounds of Ivory Shell (Babylonia areolata).

In this study, the flavor compounds of ivory shell (Babylonia areolata) and their changes caused by ammonia and salinity stresses were studied. Ammonia stress improved the contents of free amino acids (FAAs), 5'-adenosine monophosphate (AMP), citric acid, and some mineral ions such as Na+, PO43-, and Cl-. The FAA contents decreased with increasing salinity, while the opposite results were observed in most inorganic ions (e.g., K+, Na+, Mg2+, Mn2+, PO43-, and Cl-). Hyposaline and hypersaline stresses increased the AMP and citric acid contents compared to the control group. The equivalent umami concentration (EUC) values were 3.53-5.14 g monosodium glutamate (MSG)/100 g of wet weight, and the differences in EUC values among treatments were mainly caused by AMP. Hexanal, butanoic acid, and 4-(dimethylamino)-3-hydroxy- and (E, E)-3,5-octadien-2-one were the top three volatile compounds, and their profiles were significantly affected when ivory shells were cultured under different ammonia and salinity conditions.

Antibacterial Activity and Mechanisms of TroHepc2-22, a Derived Peptide of Hepcidin2 from Golden Pompano (Trachinotus ovatus).

Hepcidin, a cysteine-rich antimicrobial peptide, has a highly conserved gene structure in teleosts, and it plays an essential role in host immune response against various pathogenic bacteria. Nonetheless, few studies on the antibacterial mechanism of hepcidin in golden pompano (Trachinotus ovatus) have been reported. In this study, we synthesized a derived peptide, TroHepc2-22, from the mature peptide of T. ovatus hepcidin2. Our results showed that TroHepc2-22 has superior antibacterial abilities against both Gram-negative (Vibrio harveyi and Edwardsiella piscicida) and Gram-positive (Staphylococcus aureus and Streptococcus agalactiae) bacteria. Based on the results of a bacterial membrane depolarization assay and propidium iodide (PI) staining assay in vitro, TroHepc2-22 displayed antimicrobial activity by inducing the bacterial membrane depolarization and changing the bacterial membrane permeability. Scanning electron microscopy (SEM) visualization illustrated that TroHepc2-22 brought about membrane rupturing and the leakage of the cytoplasm for the bacteria. In addition, TroHepc2-22 was verified to have hydrolytic activity on bacterial genomic DNA in view of the results of the gel retardation assay. In terms of the in vivo assay, the bacterial loads of V. harveyi in the tested immune tissues (liver, spleen, and head kidney) were significantly reduced in T. ovatus, revealing that TroHepc2-22 significantly enhanced the resistance against V. harveyi infection. Furthermore, the expressions of immune-related genes, including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin 1-ß (IL-1ß), IL-6, Toll-like receptor 1 (TLR1), and myeloid differentiation factor 88 (MyD88) were significantly increased, indicating that TroHepc2-22 might regulate inflammatory cytokines and activate immune-related signaling pathways. To summarize, TroHepc2-22 possesses appreciable antimicrobial activity and plays a vital role in resisting bacterial infection. The observation of our present study unveils the excellent application prospect of hepcidin as a substitute for antibiotics to resist pathogenic microorganisms in teleosts.

Clinical values of serum Semaphorin 4D (Sema4D) in medication­related osteonecrosis of the jaw.

BACKGROUND: Bisphosphonates (BPs) are widely used in clinical practice to prevent and treat bone metabolism-related diseases. Medication-related osteonecrosis of the jaw (MRONJ) is one of the major sequelae of BPs use. Early prediction and intervention of MRONJ are of great significance. METHODS: Ninety-seven patients currently on treatment with BPs or with a history of BPs usage and 45 healthy volunteers undergoing dentoalveolar surgery were included in this study. Participants' serum Semaphorin 4D (Sema4D) levels were measured and analyzed before participants underwent surgery (T0) and after a 12-month follow-up (T1). Kruskal-Wallis test and ROC analysis were used to examine the predictive effect of Sema4D on MRONJ. RESULTS: Sema4D levels in serum of patients corresponding to confirmed MRONJ were significantly lower at both T0 and T1 time points compared to non-MRONJ and healthy controls. Sema4D has a statistically predictive effect on the occurrence and diagnosis of MRONJ. Serum Sema4D levels were significantly reduced in MRONJ class 3 patients. MRONJ patients who received intravenous BPs had significantly lower Sema4D levels than those who received oral BPs. CONCLUSION: Serum Sema4D level has predictive value for the onset of MRONJ in BPs users within 12 weeks after dentoalveolar surgery.

Ustiloxin A inhibits proliferation of renal tubular epithelial cells in vitro and induces renal injury in mice by disrupting structure and respiratory function of mitochondria.

Recently, we found that Ustiloxin A (UA, a mycotoxin) was widely detected in paddy environment and rice samples from several countries, and was also detected in human urine samples from China. However, the current knowledge about the health risks of UA are limited. In this research, the cytotoxicity of UA in mice renal tubular epithelial cells (mRTECs) was evaluated, and the results indicated that UA arrested cell cycle in G2/M phase via altering cellular morphology and microtubule, and inhibited the proliferation and division of mRTECs. Furthermore, UA could inhibit mitochondrial respiration via binding to the CoQ-binding site in dihydro-orotate dehydrogenase (DHODH) protein, and resulted in mitochondrial damage. These adverse effects of UA on mitochondria might be responsible for the cytotoxicity observed in vitro. In vivo, UA at concentrations that were comparable to the realistic concentrations of human exposure induced renal insufficiency in mice, and this might be associated with the renal mitochondrial damage in mice. However, exposure to UA at those realistic concentrations did not promote the progression from renal insufficiency to renal fibrosis and chronic kidney disease was not observed in mice.

TroTNFSF6, a tumor necrosis factor ligand superfamily member, promotes antibacterial immune response of golden pompano, Trachinotus ovatus.

Tumor necrosis factor ligand superfamily member 6 (TNFSF6), also known as FasL/CD95L, is essential for maintaining the body's immune homeostasis. However, the current reports on TNFSF6 in fish are relatively scarce. In the present study, we conducted functional analyses of a TNFSF6 (TroTNFSF6) from the teleost fish golden pompano (Trachinotus ovatus). TroTNFSF6 is composed of 228 amino acids and has a low similarity with other species (9.65%-58.79%). TroTNFSF6 was expressed in the 11 tissues tested and was significantly up-regulated after Edwardsiella tarda infection. In vivo, overexpression of TroTNFSF6 effectively stimulated the AKP and ACP activities, and reduced bacterial infection in fish tissues. Correspondingly, knockdown of TroTNFSF6 expression resulted in increasing bacterial dissemination and colonization in fish tissues. In vitro, recombinant TroTNFSF6 protein promoted the proliferation of T. ovatus head kidney lymphocytes (HKLs), and promoted the apoptosis of murine liver cancer cells (Hepa1-6). The results indicated that TroTNFSF6 plays an important role in the T. ovatus antibacterial immunity. These observations will facilitate the future in-depth study of teleost TNFSF6.

Identification by genetic algorithm optimized back propagation artificial neural network and validation of a four-gene signature for diagnosis and prognosis of pancreatic cancer.

Background: Although some improvements in the management of pancreatic cancer (PC) have been made, no major breakthroughs in terms of biomarker discovery or effective treatment have emerged. Here, we applied artificial intelligence (AI)-based methods to develop a model to diagnose PC and predict survival outcome. Methods: Multiple bioinformatics methods, including Limma Package, were performed to identify differentially expressed genes (DEGs) in PC. A Back Propagation (BP) model was constructed, followed by Genetic Algorithm (GA) filtering and verification of its prognosis capacity in the TCGA cohort. Furthermore, we validated the protein expression of the selected DEGs in 92 clinical PC tissues using immunohistochemistry. Finally, intro studies were performed to assess the function of SLC6A14 and SPOCK1 on pancreatic ductal adenocarcinoma (PDAC) cells proliferation and apoptosis. Results: Four candidate genes (LCN2, SLC6A14, SPOCK1, and VCAN) were selected to establish a four-gene signature for PC. The gene signature was validated in the TCGA PC cohort, and found to show satisfactory discrimination and prognostic power. Areas under the curve (AUC) values of overall survival were both greater than 0.60 in the TCGA training cohort, test cohort, and the entire cohort. Kaplan-Meier analyses showed that high-risk group had a significantly shorter overall survival and disease-free survival than the low-risk group. Further, the elevated expression of SLC6A14 and SPOCK1 in PC tissues was validated in the TCGA + GETx datasets and 92 clinical PC tissues, and was significantly associated with poor survival in PC. In PDAC cell line, SLC6A14 or SPOCK1 knockdown inhibited cells proliferation, migration and promoted cells apoptosis. Conclusions: Using Limma Package and GA-ANN, we developed and validated a diagnostic and prognostic gene signature that yielded excellent predictive capacity for PC patients' survival. In vitro studies were further conducted to verify the functions of SLC6A14 and SPOCK1 in PC progression.

Promotion effect on liver tumor progression of microcystin-LR at environmentally relevant levels in female krasV12 transgenic zebrafish.

Microcystin-LR (MC-LR) is a kind of natural toxin which exists widely in aquatic environments and has been reported to be hepatotoxic and carcinogenic. At present, the promoting mechanism of MC-LR on hepatocellular carcinoma (HCC) remains largely unexplored. In this study, the hepatocellular promoting effect of MC-LR was described in KrasV12 transgenic zebrafish, a doxycycline (DOX) inducible HCC model. Our results showed that MC-LR could aggravate the progression of HCC at an environmentally relevant concentration (3 µg/L), which was accompanied by the decreased activity and down-regulated transcription level of serine/threonine phosphatase 2A (PP2A). Using TMT labeling quantitative phosphoproteomics, we found that the 1049 phosphopeptides were significantly changed (508 up-regulated and 541 down-regulated) in liver from combined exposure to DOX and 3 µg/L MC-LR group compared to the DOX group. Enriched pathways by KEGG analysis suggested that differentially phosphorylated proteins were mainly related to Wnt signaling pathway. Furthermore, the mRNA expression and protein abundance of ß-Catenin in Wnt signaling pathway were significantly up-regulated following exposure to MC-LR. In short, our results suggested that MC-LR significantly inhibited the activity of PP2A, which in turn activated Wnt signaling, eventually resulting in progression of liver tumor in transgenic zebrafish.

Application of agricultural pesticides in a peak period induces an abundance decline of metazoan zooplankton in a lake ecosystem.

The contamination of pesticides has been recognized as a major stressor in fresh water ecosystems in terms of the losses of services and population declines and extinctions. However, information on the adverse effects of pesticides on zooplankton communities under natural field conditions are still lacking, although zooplankton is quite sensitive to most of pesticides in laboratory studies. In this study, a natural lake ecosystem (Liangzi Lake) was used to determine the relationship between pesticide contamination and abundance decline of metazoan zooplankton. In August 2020, the comprehensive trophic level indexes and the abundance of phytoplankton in the 14 sampling sites of Liangzi Lake were comparable, but the abundance of metazoan zooplankton showed significant variations across two orders of magnitude. These results suggested that other factors, such as pesticide contamination, might be responsible for the variations of metazoan zooplankton community. Furthermore, the responsible pesticides were screened, and totally 29 pesticides were obtained. Finally, five pesticides were identified to provide more than 99.4% toxic contributions and chlorpyrifos and cypermethrin were two main causal agents. These results were further supported by laboratory exposure experiments using D. magna and field study in November 2020, where the concentrations of the 29 pesticides were strongly decreased and the abundance of metazoan zooplankton was comparable across the 14 sites of Liangzi Lake. Taken together, this work provided an evidence that the contamination of pesticides might be responsible for the abundance decline of metazoan zooplankton in a natural freshwater ecosystem.

Effects of High Hydrostatic Pressure and Storage Temperature on Fatty Acids and Non-Volatile Taste Active Compounds in Red Claw Crayfish (Cherax quadricarinatus).

The effects of high hydrostatic pressure (treated with 200, 400 and 600 MPa) and storage temperatures (4 °C and −20 °C) on the fatty acids and flavor compounds of red claw crayfish were studied. HHP decreased the PUFA, GMP, IMP and AMP, citric and lactic acids, and PO43− contents, but the FAA, Ca2+ and Cl− contents increased in HHP-treated crayfish compared to untreated crayfish at 0 d. Storage at −20 °C could restrain the fatty acids and flavor contents compared to those stored at 4 °C. The GMP, AMP, citric acid and PO43− contents decreased, and Ca2+ and Cl− contents increased after storage at 4 °C for 15 d (p < 0.05). HHP at 200 and 400 MPa increased EUC on 0 d. No significant changes in EUC were observed after storage at −20 °C for 15 d, significant decreases were noted at 4 °C than the crayfish stored for 0 d (p < 0.05), except for the untreated group. Generally, HHP at 200 or 400 MPa, and storage at −20 °C is beneficial according to the shelling rates and EUC of crayfish.

Microbial degradation of aristolochic acid I by endophytic fungus A.h-Fs-1 of Asarum heterotropoides.

Asari Radix et Rhizoma is commonly used in classic prescriptions of herbal medicine in several Asian countries for resuscitation, pain relief, and sore treatment, and Asarum heterotropoides (A. heterotropoides) is an important source material of Asari Radix et Rhizoma. However, the plants of the Asari Radix et Rhizoma and some plants in Asarum spp. contain aristolochic acid I (AAI), which is considered as a carcinogen. The objective of the current study is to detoxify Asarum spp. through microbial degradation of AAI in order to ensure drug safety. Based on the observation of the close correlation between endophytic fungi of A. heterotropoides and AAI, we identified an AAI-degrading fungus and screened for candidate genes involved in AAI degradation. Full-length O-demethylase genes (ODMs) were cloned including A.h-ODM-5, Fs-ODM-4, and Fs-ODM-1, and their ability to degrade AAI was tested in vitro. The results showed that the AAI-degrading fungus was identified as Neocosmospora solani (A.h-Fs-1, endophytic fungi of A. heterotropoides), and verified the capability of specific O-demethylation to modify the structure of AAI. We further identified the functional ODMs in A.h-Fs-1 capable of degrading AAI and uncovered the AAI degradation mechanism of A.h-Fs-1. The microbial degradation of AAI demonstrated in the present study offers a new method to detoxify plant materials used for herbal medicine, and would enhance the regulation of toxic ingredients content in herbal medicine source materials.

Macrophage migration inhibitory factor (MIF) of golden pompano (Trachinotus ovatus) is involved in the antibacterial immune response.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with a unique structure involved in immune regulation and inflammation. In the present study, we identified a MIF from Trachinotus ovatus (golden pompano) and analyzed its function. TroMIF shares high homology (58.26%-94.78%) with the other known MIF sequences of vertebrates. TroMIF is most closely related to large yellow croaker (Larimichthys crocea). The expression of TroMIF was most abundant in the liver and head kidney, and was significantly up-regulated after Edwardsiella tarda infection. The subcellular localization of TroMIF was mostly distributed in the cytoplasm. In vitro results revealed that the recombinant protein rTroMIF could inhibit the migration of head kidney lymphocytes (HKLs) and macrophages (HKMs) and enhance the phagocytic activity of HKMs. As a pro-inflammatory cytokine, rTroMIF could increase the expression levels of some pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1ß), IL-6, IL-8, and interferon-gamma (IFN-γ) and decrease the expression of IL-10. The rTroMIF was proved to have enzymatic redox activity in vitro. Furthermore, overexpression of TroMIF in the head kidney cell line of golden pompano could significantly enhance its ability to resist E. tarda infection from 1 h to 4 h. The knockdown of TroMIF expression induced a significant increase in the number of bacteria after E. tarda infection at 1, 2, and 4 hpi. Our results suggest that TroMIF is an essential effector of the innate immune system and plays a pivotal role in antibacterial immunity.

ZMAT1 acts as a tumor suppressor in pancreatic ductal adenocarcinoma by inducing SIRT3/p53 signaling pathway.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancer due to its highly aggressive phenotype and lack of effective biomarkers or treatment strategies. ZMAT1 belongs to the C2H2 type zinc finger family, but its biological function is rarely investigated, as well as its role in cancer development. METHODS: Multiple bioinformatics analyses were used to evaluate ZMAT1 expression and potential role in PDAC. Intro and vivo studies were performed to assess the effects of ZMAT1 on PDAC cells growth. Furthermore, CHIP-seq and luciferase reporter assay was conducted to identify its specific regulatory mechanism in PDAC. RESULTS: The current study identified the down-regulation of ZMAT1 and its associations with unfavorable clinicopathological characteristics and poor survival of PDAC. Further, we found overexpression of ZMAT1 inhibited pancreatic cancer cell proliferation by inducing p21, leading to impaired S/G2 cell cycle progression. Besides, over-expression of ZMAT1 led to decreased pancreatic cancer cell apoptosis. Mechanistically, ZMAT1 up-regulated p53 expression and inhibition of p53 abrogated the effect of ZMAT1 over-expression on pancreatic cancer cell, indicating the role of ZMAT1 in PDAC was dependent on p53. By performing CHIP-seq assay, we found ZMAT1 did not bind to P53 but bound to the promoter region of SIRT3, an upstream regulator for p53. Luciferase reporter assay showed transfection of ZMAT1 induced SIRT3 transcription, suggesting ZMAT1 was a transcriptional activator for SIRT3. CONCLUSION: Our findings indicated the role of ZMAT1-SIRT3-p53 signaling pathway during tumor growth, highlighting that ZMAT1 is a tumor suppressor and novel biomarker of PDAC.

Microvascular Invasion in Hepatocellular Carcinoma: A Review of Its Definition, Clinical Significance, and Comprehensive Management.

Hepatocellular carcinoma (HCC) is one of the most common types of malignancies in the world, and most HCC patients undergoing liver resection relapse within five years. Microvascular invasion (MVI) is an independent factor for both the disease-free survival and overall survival of HCC patients. At present, the definition of MVI is still controversial, and a global consensus on how to evaluate MVI precisely is needed. Moreover, this review summarizes the current knowledge and clinical significance of MVI for HCC patients. In terms of management, antiviral therapy, wide surgical margins, and postoperative transcatheter arterial chemoembolization (TACE) could effectively reduce the incidence of MVI or improve the disease-free survival and overall survival of HCC patients with MVI. However, other perioperative management practices, such as anatomical resection, radiotherapy, targeted therapy and immune therapy, should be clarified in future investigations.

Protein Engineering of PhUGT, a Donor Promiscuous Glycosyltransferase, for the Improved Enzymatic Synthesis of Antioxidant Quercetin 3-O-N-Acetylgalactosamine.

Quercetin 3-O-N-acetylgalactosamine (Q3GalNAc), a derivative of dietary hyperoside, had never been enzymatically synthesized due to the lack of well-identified N-acetylgalactosamine-transferase (GalNAc-T). Herein, PhUGT, an identified flavonoid 3-O-galactosyltransferase from Petunia hybrida, was demonstrated to display quercetin GalNAc-T activity, transferring a N-acetylgalactosamine (GalNAc) from UDP-N-acetylgalactosamine (UDP-GalNAc) to the 3-OH of quercetin to form Q3GalNAc with a low conversion of 11.7% at 40 °C for 2 h. Protein engineering was thus performed, and the resultant PhUGT variant F368T got an enhanced conversion of 75.5% toward UDP-GalNAc. The enzymatically synthesized Q3GalNAc exhibited a comparable antioxidant activity with other quercetin 3-O-glycosides. Further studies revealed that PhUGT was a donor promiscuous glycosyltransferase (GT), recognizing seven sugar donors. This finding overturned a previous notion that PhUGT exclusively recognized UDP-galactose (UDP-Gal). The reason why PhUGT was mistaken for a UDP-Gal-specific GT was demonstrated to be a shorter reaction time, in which many quercetin 3-O-glycosides, except hyperoside, could not be effectively synthesized. The fact that the microbial cell factory expressing PhUGT could yield an array of Q3Gs further confirmed the donor promiscuity of PhUGT. This study laid a foundation for the scale production of Q3GalNAc and provided a potent biocatalyst capable of glycodiversifying quercetin as well.

An injectable thermosensitive hydrogel loaded with a theranostic nanoprobe for synergistic chemo-photothermal therapy for multidrug-resistant hepatocellular carcinoma.

Multi-drug resistance (MDR) is a complicated cellular defense mechanism for tumor cells to resist chemotherapy drugs, which is also the main cause of chemotherapy failure. In this study, a local injectable hydrogel delivery system was used to construct an on-demand sustained-release platform with the advantages of chemotherapy, photothermal therapy (PTT), and magnetic resonance imaging (MRI). It could achieve synergistic chemo-photothermal therapy and real-time evaluation of the therapeutic effects (via MRI) for MDR hepatocellular carcinoma (HCC). Furthermore, after a single administration, the prepared hydrogel with a theranostic nanoprobe could release the therapeutic agents on demand for up to 14 d. Firstly, doxorubicin (DOX) and gold-manganese oxide (Au-MnO) nanoparticles (NPs) were incorporated into liposome-based self-assembled micelles, then loaded into the thermosensitive hydrogel (F127) to form DOX@Au-MnO-L NPs/F127 hydrogel (DAML/H). The prepared NP complex showed a spherical morphology with a narrow size distribution. The prepared hydrogel drug delivery system had injectable properties and stable photothermal conversion. Both the DOX@Au-MnO-L NPs and DAML/H showed controlled drug release under near infrared (NIR) laser irradiation. The in vitro MRI studies indicated that the prepared DAML/H had a high relaxation rate (14.38 mM-1 s-1) and good MRI scanning sensitivity conditions. The in vitro and in vivo results suggested the synergistic chemo-photothermal therapy of DAML/H with NIR irradiation (808 nm, 1 W cm-2, 10 min) improved the antitumor efficacy for MDR HCC. The in vivo retention experiment of Au in tumors indicated that the prepared hydrogel drug delivery system (DAML/H) had a good ability to retain Au in the tumor for a long time (at least 14 d). The western blotting results revealed that DAML/H with laser treatment could effectively downregulate P-glycoprotein (P-gp), p53 and antiapoptotic protein (Bcl-2), whereas the expression level of proapoptotic protein (Bax) and caspase-3 were increased. Therefore, DAML/H could serve as a promising synergistic chemo-photothermal therapy for MDR HCC, and a single administration might achieve long-term (14 d), on-demand, sustained-release treatment of tumors.

A high-throughput screening assay for identification of chemicals with liver tumor promoting potential using a transgenic zebrafish line.

Traditional high-throughput methods for identification of chemicals with liver tumor promotion potentials are based on established cancer cell lines, and rapid and cost-effective high-throughput screening assays in whole organisms are presently lacking. In this study, a transgenic zebrafish liver cancer model was employed to develop a method that could be used to identify chemicals with liver tumor promotion effect quickly and accurately. The method consisted of three parts, including exposure preparation, exposure process and image acquisition. In brief, after chemical exposure for 7 days, 96-well plate exposure system for zebrafish larvae was assessed by microplate reader. Then, the liver cancer promoting potential chemicals were evaluated by field area and field average intensity of fluorescence. The results were further validated by conducting histopathological examination. Our data demonstrated that the high-throughput screening assay developed in this study was reproducible and could be used to rapidly screen chemicals with liver tumor promoting potentials by using tris-(2-chloropropyl)-phosphate (TDCIPP) as a positive control. Furthermore, some other positive chemicals found in previous studies and environmental compounds were assessed using the established method. Results indicated that 86.7% of the positive chemicals and five environmental compounds out of seventeen compounds could enhance liver tumor progression.