Biogeographical and biodiversity patterns of planktonic microeukaryotes along the tropical western to eastern Pacific Ocean transect revealed by metabarcoding.

Microeukaryotic plankton (0.2-200 µm), which are morphologically and genetically highly diverse, play a crucial role in ocean productivity and carbon consumption. The Pacific Ocean (PO), one of the world's largest oligotrophic regions, remains largely unexplored in terms of the biogeography and biodiversity of microeukaryotes based on large-scale sampling. We investigated the horizontal distribution of microeukaryotes along a 16,000 km transect from the west to the east of the PO. The alpha diversity indices showed a distinct decreasing trend from west to east, which was highly correlated with water temperature. The microeukaryotic community, which was clustered into the western, central, and eastern PO groups, displayed a significant distance-decay relationship. Syndiniales, a lineage of parasitic dinoflagellates, was ubiquitously distributed along the transect and dominated the community in terms of both sequence and zero-radius operational taxonomic unit (ZOTU) proportions. The prevailing dominance of Syndiniales-affiliated ZOTUs and their close associations with dinoflagellates, diatoms, and radiolarians, as revealed by SparCC correlation analysis, suggested that parasitism may be an important trophic strategy in the surface waters of the PO. Geographical distance and temperature were the most important environmental factors that significantly correlated with community structure. Overall, our study sheds more light on the distribution pattern of both alpha and beta diversities of microeukaryotic communities and highlighted the importance of parasitisms by Syndiniales across the tropical PO.IMPORTANCEUnderstanding the biogeographical and biodiversity patterns of microeukaryotic communities is essential to comprehending their roles in biogeochemical cycling. In this study, planktonic microeukaryotes were collected along a west-to-east Pacific Ocean transect (ca. 16,000 km). Our study revealed that the alpha diversity indices were highly correlated with water temperature, and the microeukaryotic communities displayed a distinct geographical distance-driven pattern. The predominance of the parasitic dinoflagellate lineage Syndiniales and their close relationship with other microeukaryotic groups suggest that parasitism may be a crucial survival strategy for microeukaryotes in the surface waters of the Pacific Ocean. Our findings expand our understanding of the biodiversity and biogeographical pattern of microeukaryotes and highlight the significance of parasitic Syndiniales in the surface ocean.

Multi-omics analysis of adamantinomatous craniopharyngiomas reveals distinct molecular subgroups with prognostic and treatment response significance.

BACKGROUND: Adamantinomatous craniopharyngioma (ACP) is the commonest pediatric sellar tumor. No effective drug is available and interpatient heterogeneity is prominent. This study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles, imaging findings, and histological features, in order to predict the response to anti-inflammatory treatment and immunotherapies. METHODS: Totally 142 Chinese cases diagnosed with craniopharyngiomas were profiled, including 119 ACPs and 23 papillary craniopharyngiomas. Whole-exome sequencing (151 tumors, including recurrent ones), RNA sequencing (84 tumors), and DNA methylome profiling (95 tumors) were performed. Consensus clustering and non-negative matrix factorization were used for subgrouping, and Cox regression were utilized for prognostic evaluation, respectively. RESULTS: Three distinct molecular subgroups were identified: WNT, ImA, and ImB. The WNT subgroup showed higher Wnt/ß-catenin pathway activity, with a greater number of epithelial cells and more predominantly solid tumors. The ImA and ImB subgroups had activated inflammatory and interferon response pathways, with enhanced immune cell infiltration and more predominantly cystic tumors. Mitogen-activated protein kinases (MEK/MAPK) signaling was activated only in ImA samples, while IL-6 and epithelial-mesenchymal transition biomarkers were highly expressed in the ImB group, mostly consisting of children. The degree of astrogliosis was significantly elevated in the ImA group, with severe finger-like protrusions at the invasive front of the tumor. The molecular subgrouping was an independent prognostic factor, with the WNT group having longer event-free survival than ImB (Cox, P = 0.04). ImA/ImB cases were more likely to respond to immune checkpoint blockade (ICB) therapy than the WNT group ( P <0.01). In the preliminary screening of subtyping markers, CD38 was significantly downregulated in WNT compared with ImA and ImB ( P = 0.01). CONCLUSIONS: ACP comprises three molecular subtypes with distinct imaging and histological features. The prognosis of the WNT type is better than that of the ImB group, which is more likely to benefit from the ICB treatment.

Effects of Photobiomodulation Therapy on Hard Tissue Healing in Rat Tooth Extraction Sockets.

Objective: To investigate the effects of photobiomodulation therapy (PBMT) on hard tissue healing in rat maxillary first molar extraction sockets. Methods: A total of 20 male Wistar rats were used in the study. The right extraction sockets were irradiated with a Ga-Al-As laser (500 mW, 980 nm) for 51.7 J/cm2 every 24 h for 7 days, while the left sockets served as controls. Rats were sacrificed on days 3, 7, 14, and 28 after tooth extraction, and microcomputed tomography (CT) analysis, histopathological evaluation, and enzyme-linked immunosorbent assay (ELISA) were conducted at different time points. Results: Micro-CT analysis showed that the percentage of bone volume/tissue volume (TV) and bone mineral density were significantly higher in the experimental group compared to the control group on day 28 (p < 0.05). Histopathological evaluation revealed that PBMT promoted new bone formation and accelerated bone remodeling. ELISA demonstrated a significant increase in alkaline phosphatase expression in the laser sides on days 7 and 14 (p < 0.05). Conclusions: One application postextraction followed by seven consecutive daily applications of PBMT can effectively promote hard tissue healing in rat maxillary first molar extraction sockets.

A Clinical Observation Study for Transnasal Endoscopic Marsupialization in the Treatment of Maxillary Cyst.

The aim of this study was to investigate the feasibility and evaluate the clinical effects of transnasal marsupialization of maxillary cyst under nasal endoscope. Twenty patients with maxillary bone cysts were treated with endoscopic marsupialization. According to the location of the maxillary bone cyst, the opening window was selected in the nasal base or the inferior or middle nasal meatus. The cyst wall of the window was removed, and the fluid was drained out. The diameter of the opening window was more than 1 cm, so that the cyst and the maxillary sinus can be fused into a cavity. This ensured nasal drainage through the cyst cavity and nasal cavity or maxillary sinus. The patients were followed up for 6 to 18 months. No serious complications occurred. The cyst wall epithelialized 2 or 3 months after the operation, and the cyst cavity drained well with no recurrence. Intranasal marsupialization under a nasal endoscope is a feasible alternative for the treatment of maxillary cysts. It makes the procedure simple, safe, less traumatic, has definite clinical effects, and low recurrence rate. Especially suitable for maxillary cysts protruding into the nasal floor or maxillary sinus.

The diverse pancreatic tumor cell-intrinsic response to IFNγ is determined by epigenetic heterogeneity.

IFNγ signaling is mainly mediated through the activation of the canonical JAK-STAT signaling pathway, transcription factors, and epigenetic modifications. The activation of IFNγ signaling pathway may provide a novel option for tumor immunotherapy, but the outcomes remain controversial. In fact, recent studies suggest that the resistance to IFNγ-dependent immunotherapies is commonly derived from the tumor cell-intrinsic heterogeneity, the molecular mechanism of which remains elusive. Therefore, elucidating the tumor cell-intrinsic heterogeneity in response to IFNγ would be beneficial to improve the efficacy of immunotherapy. Here, we first delineated the epigenetic redistribution and transcriptome alteration in response to IFNγ stimulation, and demonstrated that ectopic gain of H3K4me3 and H3K27Ac at the promoter region mainly contributed to the enhancement of IFNγ-mediated transcriptional activity of interferon-stimulated genes (ISGs). Furthermore, we found that the cellular heterogeneity of PD-L1 expression in response to IFNγ was mainly attributed to cell-intrinsic H3K27me3 levels. Enhancement of H3K27me3 by GSK-J4 limited PD-L1hi tumor growth by salvaging the intratumoral cytotoxicity of CD8+ T cells, which may provide therapeutic strategies to overcome immune escape and resistance to IFNγ-based immunotherapies in pancreatic cancer.

Analysis of cuproptosis-related lncRNA signature for predicting prognosis and tumor immune microenvironment in pancreatic cancer.

Pancreatic cancer (PC) is a highly malignant digestive tract tumor, with a dismal 5-year survival rate. Recently, cuproptosis was found to be copper-dependent cell death. This work aims to establish a cuproptosis-related lncRNA signature which could predict the prognosis of PC patients and help clinical decision-making. Firstly, cuproptosis-related lncRNAs were identified in the TCGA-PAAD database. Next, a cuproptosis-related lncRNA signature based on five lncRNAs was established. Besides, the ICGC cohort and our samples from 30 PC patients served as external validation groups to verify the predictive power of the risk signature. Then, the expression of CASC8 was verified in PC samples, scRNA-seq dataset CRA001160, and PC cell lines. The correlation between CASC8 and cuproptosis-related genes was validated by Real-Time PCR. Additionally, the roles of CASC8 in PC progression and immune microenvironment characterization were explored by loss-of-function assay. As showed in the results, the prognosis of patients with higher risk scores was prominently worse than that with lower risk scores. Real-Time PCR and single cell analysis suggested that CASC8 was highly expressed in pancreatic cancer and related to cuproptosis. Additionally, gene inhibition of CASC8 impacted the proliferation, apoptosis and migration of PC cells. Furthermore, CASC8 was demonstrated to impact the expression of CD274 and several chemokines, and serve as a key indicator in tumor immune microenvironment characterization. In conclusion, the cuproptosis-related lncRNA signature could provide valuable indications for the prognosis of PC patients, and CASC8 was a candidate biomarker for not only predicting the progression of PC patients but also their antitumor immune responses.

RNA outperforms DNA-based metabarcoding in assessing the diversity and response of microeukaryotes to environmental variables in the Arctic Ocean.

The Arctic Ocean (AO) has a harsh environment characterized by low temperatures, extensive ice coverage, and periodic freezing and melting of sea ice, which has provided diverse habitats for microorganisms. Prior studies primarily focused on microeukaryote communities in the upper water or sea ice based on environmental DNA, leaving the composition of active microeukaryotes in the diverse AO environments largely unknown. This study provided a vertical assessment of microeukaryote communities in the AO from snow and ice to sea water at a depth of 1670 m using high-throughput sequencing of co-extracted DNA and RNA. RNA extracts depicted microeukaryote community structure and intergroup correlations more accurately and responded more sensitively to environmental conditions than those derived from DNA. Using RNA:DNA ratios as a proxy for relative activity of major taxonomic groups, the metabolic activities of major microeukaryote groups were determined along depth. Analysis of co-occurrence networks showed that parasitism between Syndiniales and dinoflagellates/ciliates in the deep ocean may be significant. This study increased our knowledge of the diversity of active microeukaryote communities and highlighted the importance of using RNA-based sequencing over DNA-based sequencing to examine the relationship between microeukaryote assemblages and the responses of microeukaryotes to environmental variables in the AO.

From the Sunlit to the Aphotic Zone: Assembly Mechanisms and Co-Occurrence Patterns of Protistan-Bacterial Microbiotas in the Western Pacific Ocean.

We know little about the assembly processes and association patterns of microbial communities below the photic zone. In marine pelagic systems, there are insufficient observational data regarding why and how the microbial assemblies and associations vary from photic to aphotic zones. In this study, we investigated size-fractionated oceanic microbiotas, specifically free-living (FL; 0.22 to 3 µm) and particle-associated (PA; >3 µm) bacteria and protists (0.22 to 200 µm) collected from the surface to 2,000 m in the western Pacific Ocean, to see how assembly mechanisms and association patterns changed from photic to aphotic zones. Taxonomic analysis revealed a distinct community composition between photic and aphotic zones that was largely driven by biotic associations rather than abiotic factors. Aphotic community co-occurrence was less widespread and robust than its photic counterparts, and biotic associations were crucial in microbial co-occurrence, having a higher influence on photic than aphotic co-occurrences. The decrease in biotic associations and the increase in dispersal limitation from the photic to the aphotic zone affect the deterministic-stochastic balance, leading to a more stochastic-process-driven community assembly for all three microbial groups in the aphotic zone. Our findings significantly contribute to our understanding of how and why microbial assembly and co-occurrence vary from photic to aphotic zones, offering insight into the dynamics of the protistan-bacterial microbiota in the western Pacific's photic and aphotic zones. IMPORTANCE We know little about the assembly processes and association patterns of microbial communities below the photic zone in marine pelagic systems. We discovered that community assembly processes differed between photic and aphotic zones, with all three microbial groups studied (protists and FL and PA bacteria) being more influenced by stochastic processes than in the photic zone. The decrease in organismic associations and the increase in dispersal limitation from the photic to the aphotic zone both have an impact on the deterministic-stochastic balance, resulting in a more stochastic process-driven community assembly for all three microbial groups in the aphotic zone. Our findings significantly contribute to the understanding of how and why microbial assembly and co-occurrence change between photic and aphotic zones, offering insight into the dynamics of the protist-bacteria microbiota in the western Pacific oceans.

Tumor Cell-Intrinsic SETD2 Deficiency Reprograms Neutrophils to Foster Immune Escape in Pancreatic Tumorigenesis.

Genetic and epigenetic alterations play central roles in shaping the immunosuppressive tumor microenvironment (TME) to evade immune surveillance. The previous study shows that SETD2-H3K36me3 loss promotes KRAS-induced pancreatic tumorigenesis. However, little is known about its role in remodeling the TME and immune evasion. Here, it is shown that SETD2 deficiency can reprogram neutrophils to an immunosuppressive phenotype, thereby promoting immune escape during pancreatic tumor progression. By comprehensive profiling of the intratumoral immune cells, neutrophils are identified as the subset with the most significant changes upon Setd2 loss. Setd2-deficient pancreatic tumor cells directly enhance neutrophil recruitment and reprogramming, thereby inhibiting the cytotoxicity of CD8+ T cells to foster tumor progression. Mechanistically, it is revealed that Setd2-H3K36me3 loss leads to ectopic gain of H3K27me3 to downregulate Cxadr expression, which boosts the PI3K-AKT pathway and excessive expression of CXCL1 and GM-CSF, thereby promoting neutrophil recruitment and reprogramming toward an immunosuppressive phenotype. The study provides mechanistic insights into how tumor cell-intrinsic Setd2 deficiency strengthens the immune escape during pancreatic tumorigenesis, which may offer potential therapeutic implications for pancreatic cancer patients with SETD2 deficiency.

ADAMTS12 promotes migration and epithelial-mesenchymal transition and predicts poor prognosis for pancreatic cancer.

BACKGROUND: ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs) family, a group of extracellular multifunctional enzymes, has been proven to play a pivotal role in the tumor. In pancreatic cancer, the role and mechanism of this family remain unclear. The present study aimed to figure out the hub gene of ADAMTSs and explore the exact roles in the prognosis and biological functions in pancreatic ductal adenocarcinoma (PDAC). METHODS: We used several databases to analyze the ADAMTS family and then screen out the hub genes. The expression of ADAMTS12 in 106 pairs of PDAC tumors and adjacent normal tissues was examined by immunohistochemistry, and its correlations with clinical parameters were further analyzed. The impacts of ADAMTS12 on the migration of PDAC cells were predicted by gene set enrichment analysis and confirmed by transwell assays. The potential impacts of ADAMTS12 on the epithelial-mesenchymal transition (EMT) were identified by database analysis and experimental proof of real-time quantitative polymerase chain reaction (qPCR) and Western blotting. RESULTS: Our study found that ADAMTS12 was a crucial gene in PDAC, and it was highly expressed in tumor tissues when compared to that in the adjacent tissues. ADATMS12 had predictive value of a poor prognosis for PDAC. The elevation of ADAMTS12 was parallel to the progression of PDAC. Inhibition of ADAMTS12 suppressed the migration of PDAC cells and interfered with the process of EMT. CONCLUSIONS: ADAMTS12 is a crucial member of ADAMTSs in PDAC and a predictor of poor prognosis. Additionally, based on its impacts on migration and metastasis in PDAC and the relationship with EMT, ADAMTS12 plays a role of an oncogene in PDAC and may be a promising target for treatment.

Identification of a novel cell cycle-related risk signature predicting prognosis in patients with pancreatic adenocarcinoma.

BACKGROUND: Growing evidence have indicated that cell cycle-related genes (CRGs) play an essential role in the progression of pancreatic adenocarcinoma (PAAD). Nevertheless, the application of CRGs in estimating the prognosis of PAAD patients is still lacking. This study aimed to establish a risk signature based on CRGs that can predict patients' overall survival for PAAD. METHODS: The expression and corresponding clinical data of PAAD patients from The Cancer Genome Atlas database and 200 cell cycle-related genes from the MSigDB were used for the generation and validation of the signature. LASSO Cox regression was applied to build the prediction model. The diagnostic value of signature was evaluated by receiver operating characteristic curves. Univariate and multivariate regression was used to construct the nomogram providing the clinicians a useful tool. RESULTS: A total of 103 CRGs were identified. Seven genes (RBM14, SMAD3, CENPA, KIF23, NUSAP1, INCENP, SMC4) with non-zero coefficients in LASSO analysis were used to construct the prognostic signature. The 7-gene signature significantly stratified patients into high- and low-risk groups in terms of overall survival, and the area under the receiver operating characteristic curve of 5-year survival reached 0.749. Multivariate analysis showed that the signature is an independent prognostic factor. We then mapped a nomogram to predict 1-, 3-, and 5-year survival for PAAD patients. The calibration curves indicated that the model was reliable. Finally, we discovered that TP53 and KRAS mutated most frequently in low and high-risk groups, respectively. CONCLUSION: Our findings suggested that the seven genes identified in this study are valuable prognostic predictors for patients with PAAD. These findings provided us with a novel insight that it is useful for understanding cell cycle mechanisms and for identifying patients with PAAD with poor prognosis.

Glycolysis addiction compensating for a defective pentose phosphate pathway confers gemcitabine sensitivity in SETD2-deficient pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy driven by genetic mutations and/or epigenetic dysregulation. Gemcitabine chemotherapy is the first-line regimen for pancreatic cancer but has limited efficacy. Our previous study revealed the role of SETD2-H3K36me3 loss in the initiation and metastasis of PDAC, but little is known about its role in tumor metabolism. Here, we found that SETD2-deficient PDAC enhanced glycolysis addiction via upregulation of glucose transporter 1 (GLUT1) to meet its large demand for glucose in progression. Moreover, SETD2 deficiency impaired nucleoside synthesis by directly downregulating the transcriptional level of transketolase (TKT) in the pentose phosphate pathway. The metabolic changes confer SETD2-deficient PDAC cells with increased sensitivity to gemcitabine under glycolysis restriction conditions. Collectively, our study provides mechanistic insights into how SETD2 deficiency reprograms glycolytic metabolism to compensate for insufficient nucleoside synthesis, suggesting that glycolysis restriction combined with gemcitabine might be a potential therapeutic strategy for PDAC patients with SETD2 deficiency.

HOXA10 promote pancreatic cancer progression via directly activating canonical NF-κB signaling pathway.

BACKGROUND: Although transcription factor homeobox A10 (HOXA10) plays an important role in regulating the development of the pancreas, a pathway of HOXA10 participates in pancreatic ductal adenocarcinoma (PDAC) progression has not been revealed. METHODS: Immunohistochemistry assays were applied to demonstrate the relationship between HOXA10 expression and PDAC progression. Functional assays were used to illustrate the oncogenic role of HOXA10 in PDAC progression. Regulatory mechanisms of HOXA10 induced IKKß gene transcription and the nuclear transcription factor kappa B (NF-κB) signal pathways activation were also investigated in PDAC cells. RESULTS: In the current study, we show that HOXA10 expression increased in PDAC with higher tumor stage and poor patient survival in public RNA-seq data suggesting HOXA10 is associated with PDAC progression. HOXA10 promotes PDAC cell proliferation, anchorage colony formation, and xenograft growth by activating canonical NF-κB signaling both in vitro and in vivo. Mechanically, HOXA10 up-regulates IKKß gene transcription directly and subsequently sustain the activation of NF-κB independent of tumor necrosis factor-alpha in PDAC cells. CONCLUSION: Collectively, up-regulation of HOXA10 gene expression promote cell growth and tumor progression through directly activating canonical NF-κB signaling in PDAC.

Screening of Hepatocellular Carcinoma Patients with High Risk of Early Recurrence After Radical Hepatectomy Using a Nomogram Model Based on the γ-Glutamyl Transpeptidase-to-Albumin Ratio.

BACKGROUND AND PURPOSE: The present study aimed to establish a γ-glutamyl transpeptidase-to-albumin ratio (GAR)-based nomogram model to predict early recurrence of hepatocellular carcinoma (HCC) after radical surgery. METHODS: Patients enrolled in this study were randomly allocated into a train and validation cohort in a ratio of 7:3. The Least Absolute Shrinkage and Selection Operator (LASSO) proportional hazards model and cox regression model were combined to identify independent risk factors related to HCC recurrence. Based on these risk factors, a predictive nomogram was constructed and validated in both inner and outer test cohorts. The performance of the nomogram was evaluated by C-index, the area under the receiver operating characteristic curve (AUC), the calibration curve and decision curve analysis. RESULTS: The tumor size, tumor number, BCLC stage, microvascular invasion (MVI) and GAR value were identified as independent risk factors related to HCC recurrence and used to construct the predictive nomogram. AUC of the nomogram showed satisfactory accuracy in predicting 1-, 3- and 5-year disease-free survival. The calibration curve showed agreement between the ideal and predicted values. The risk score more than 72 as calculated by the nomogram was related to early recurrence of HCC after radical surgery. DCA plots showed better clinical usability of the nomogram as compared with the BCLC staging system in all three included cohorts. CONCLUSION: The nomogram based on the GAR value may provide a new option for screening of the target HCC cohort of patients who need anti-recurrence therapy after surgery.

Spatial dynamics of active microeukaryotes along a latitudinal gradient: Diversity, assembly process, and co-occurrence relationships.

Recent global warming is profoundly and increasingly influencing the Arctic ecosystem. Understanding how microeukaryote communities respond to changes in the Arctic Ocean is crucial for understanding their roles in the biogeochemical cycles of nutrients and elements. Between July 22 and August 19, 2016, during cruise ARA07, seawater samples were collected along a latitudinal transect extending from the East Sea of Korea to the central Arctic Ocean. Environmental RNA was extracted and the V4 hypervariable regions of the reverse transcribed SSU rRNA were amplified. The sequences generated by high throughput sequencing were clustered into zero-radius OTUs (ZOTUs), and the taxonomic identities of each ZOTU were assigned using SINTAX against the PR2 database. Thus, the diversity, community composition, and co-occurrence networks of size fractionated microeukaryotes were revealed. The present study found: 1) the alpha diversity of pico- and nano-sized microeukaryotes showed a latitudinal diversity gradient; 2) three distinct communities were identified, i.e., the Leg-A, Leg-B surface, and Leg-B subsurface chlorophyll a maximum (SCM) groups; 3) distinct network structure and composition were found in the three groups; and 4) water temperature was identified as the primary factor driving both the alpha and beta diversities of microeukaryotes. This study conducted a comprehensive and systematic survey of active microeukaryotes along a latitudinal gradient, elucidated the diversity, community composition, co-occurrence relationships, and community assembly processes among major microeukaryote assemblages, and will help shed more light on our understanding of the responses of microeukaryote communities to the changing Arctic Ocean.

SULF2 enhances GDF15-SMAD axis to facilitate the initiation and progression of pancreatic cancer.

Owing to the lack of early diagnosis, pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal tumours. Because acinar-to-ductal metaplasia (ADM) is a critical process to pancreatic regeneration and PDAC initiation, we applied GSE65146, a dataset composed of transcripts at different time points in wild-type and KrasG12D mutant mice upon pancreatitis induction, to obtain regeneration- and tumour initiation-related genes. By overlapping with genes differentially expressed in human PDAC, we defined the initiation- and progression-related genes, and the most prognostic gene, SULF2, was selected for further verification. By using multiple PDAC genetically engineered murine models (GEMMs), we further verified that the expression of SULF2 was increased at the ADM and PDAC stages. Functionally, SULF2 was able to promote the dedifferentiation of acinar cells as well as the metastatic ability of PDAC. Additionally, our study revealed that SULF2 could enhance TGFß-SMAD signalling via GDF15. More importantly, serum SULF2 was elevated in patients with PDAC, and in combination with CA19-9, it provided a better method for PDAC diagnosis. Herein, our study screened out key genes for the initiation and progression of PDAC, providing potential indicators for the diagnosis of the disease.

IRAK2-NF-κB signaling promotes glycolysis-dependent tumor growth in pancreatic cancer.

BACKGROUND: Metabolic reprogramming has emerged as a core hallmark of cancer, and cancer metabolism has long been equated with aerobic glycolysis. Moreover, hypoxia and the hypovascular tumor microenvironment (TME) are major hallmarks of pancreatic ductal adenocarcinoma (PDAC), in which glycolysis is imperative for tumor cell survival and proliferation. Here, we explored the impact of interleukin 1 receptor-associated kinase 2 (IRAK2) on the biological behavior of PDAC and investigated the underlying mechanism. METHODS: The expression pattern and clinical relevance of IRAK2 was determined in GEO, TCGA and Ren Ji datasets. Loss-of-function and gain-of-function studies were employed to investigate the cellular functions of IRAK2 in vitro and in vivo. Gene set enrichment analysis, Seahorse metabolic analysis, immunohistochemistry and Western blot were applied to reveal the underlying molecular mechanisms. RESULTS: We found that IRAK2 is highly expressed in PDAC patient samples and is related to a poor prognosis. IRAK2 knockdown led to a significant impairment of PDAC cell proliferation via an aberrant Warburg effect. Opposite results were obtained after exogenous IRAK2 overexpression. Mechanistically, we found that IRAK2 is critical for sustaining the activation of transcription factors such as those of the nuclear factor-κB (NF-κB) family, which have increasingly been recognized as crucial players in many steps of cancer initiation and progression. Treatment with maslinic acid (MA), a NF-κB inhibitor, markedly attenuated the aberrant oncological behavior of PDAC cells caused by IRAK2 overexpression. CONCLUSIONS: Our data reveal a role of IRAK2 in PDAC metabolic reprogramming. In addition, we obtained novel insights into how immune-related pathways affect PDAC progression and suggest that targeting IRAK2 may serve as a novel therapeutic approach for PDAC.

Increased SPON1 promotes pancreatic ductal adenocarcinoma progression by enhancing IL-6 trans-signalling.

OBJECTIVES: This study investigated the specific molecular mechanism and the roles of extracellular matrix protein Spondin 1 (SPON1) in the development of pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: The expression pattern and clinical relevance of SPON1 was determined in GEO, Ren Ji and TCGA datasets, further validated by immunohistochemical staining and Kaplan-Meier analysis. Loss and gain of function experiments were employed to investigate the cellular function of SPON1 in vitro. Gene set enrichment analysis, luciferase assay, immunofluorescence and Western blot and immunoprecipitation were applied to reveal the underlying molecular mechanisms. Subcutaneous xenograft model was used to test the role of SPON1 in tumour growth and maintenance in vivo. RESULTS: SPON1 is significantly upregulated in PDAC tumour tissues and correlated with progression of PDAC. Loss and gain of function experiments showed that SPON1 promotes the growth and colony formation ability of pancreatic cancer cells. Combining bioinformatics assays and experimental signalling evidences, we found that SPON1 can enhance the IL-6/JAK/STAT3 signalling. Mechanistically, SPON1 exerts its oncogenic roles in pancreatic cancer by maintaining IL-6R trans-signalling through stabilizing the interaction of soluble IL-6R (sIL-6R) and glycoprotein-130 (gp130) in PDAC cells. Furthermore, SPON1 depletion greatly reduced the tumour burden, exerted positive effect with gemcitabine, prolonging PDAC mice overall survival. CONCLUSIONS: Our data indicate that SPON1 expression is dramatically increased in PDAC and that SPON1 promotes tumorigenicity by activating the sIL-6R/gp130/STAT3 axis. Collectively, our current work suggests SPON1 may be a potential therapy target for PDAC patient.

Biodegradation of Terrigenous Organic Matter in a Stratified Large-Volume Water Column: Implications of the Removal of Terrigenous Organic Matter in the Coastal Ocean.

Large amounts of terrigenous organic matter (TOM) are delivered to the ocean every year. However, removal processes of TOM in the ocean are still poorly constrained. Here, we report results from a 339-day dark incubation experiment with a unique system holding a vertically stratified freshwater-seawater column. The quality and quantity of dissolved organic matter (DOM), RNA-based size-fraction microbial communities, and environmental factors were high-frequency-monitored. Microbial processes impacted TOM composition, including an increased DOM photobleaching rate with incubation time. The mixed layer had changed the bacterial community structure, diversity, and higher oxygen consumption rate. A two-end member modeling analysis suggested that estimated nutrient concentrations and prokaryotic abundance were lower, and total dissolved organic carbon was higher than that of the measured values. These results imply that DOM biodegradation was stimulated during freshwater-seawater mixing. In the bottom layer, fluorescent DOM components increased with the incubation time and were significantly positively related to highly unsaturated, oxygenated, and presumably aromatic compound molecular formulas. These results suggest that surfaced-derived TOM sinking leads to increased DOM transformation and likely results in carbon storage in the bottom water. Overall, these results suggest that microbial transforming TOM plays more important biogeochemical roles in estuaries and coastal oceans than what we know before.

A novel and controllable SERS system for crystal violet and Rhodamine B detection based on copper nanonoodle substrates.

Copper nanostructures have attracted more and more attention due to low preparation cost, similar thermal conductivity and optical characteristics to silver nanostructures. A novel macroscopic dendritic copper nanonoodles with the length of 3-50 mm prepared by solid-state ionics method at 10 µA direct current electric field (DCEF) using fast ionic conductor RbCu4Cl3I2 films was reported. The surface-enhanced Raman scattering (SERS) performance of prepared copper nanonoodles was detected by crystal violet (CV) and rhodamine B (RB) aqueous solution as analyte molecules. The results present that the copper nanonoodles assembled by short-range order copper nanowires and the diameters of nanowires changed from 20 nm to 80 nm, many regularly arranged nanoparticles with the diameter from 5 to 10 nm existed on the prepared copper nanonoodles, which lead to the nanonoodles have high surface roughness. The copper nanonoodles contain only Cu element, no O element and the fractal dimension of copper nanonoodles is 1.355 because of macroscopic dendritic structures. The prepared copper nanonoodles composed of pure Cu have high surface roughness and the free electrons on the rough copper nanonoodles resonate with the atomic nuclei inside the copper nanonoodles to form a locally enhanced electromagnetic field under the excitation of incident light, so the limiting concentrations for CV and RB detected by the prepared copper nanonoodles are as low as 1 × 10-11 mol/L and 1 × 10-12 mol/L, respectively. The centimeter-scale copper nanonoodles with low limiting concentration of analyte molecules can be used to detect harmful food additives.