BZW1 Facilitates Glycolysis and Promotes Tumor Growth in Pancreatic Ductal Adenocarcinoma Through Potentiating eIF2α Phosphorylation.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by severe metabolic stress due to fibrosis and poor vascularization. BZW1 is an eIF5-mimic protein involved in tumorigenesis and progression. The aim of this study was to investigate the role of BZW1 in metabolic stress resistance in PDAC. METHODS: BZW1 expression was evaluated in human PDAC tissue microarray and PDAC cells. Glycolysis regulation of BZW1 and its correlation with glycolysis-related genes was analyzed. Tumor growth, cell proliferation, and apoptosis were evaluated in mice xenograft tumors and patient-derived organoids. RESULTS: The results of bioinformatic screening identified that BZW1 was 1 of the top 3 genes favorable for tumor progression in PDAC. The analysis of our cohort confirmed that BZW1 was overexpressed in human PDAC tissues compared with nontumor tissues, and its abnormal expression was correlated with large tumor size and poor prognosis. BZW1 promoted cell proliferation and inhibited apoptosis in both mouse xenograft models and PDAC-derived organoids via facilitating glycolysis in the oxygen-glucose-deprivation condition. Mechanically, BZW1 served as an adaptor for PKR-like endoplasmic reticulum (ER) kinase (PERK), facilitated the phosphorylation of eIF2α, promoted internal ribosome entry site-dependent translation of HIF1α and c-Myc, and thereby boosted the Warburg effect. In organoid-based xenografts with high BZW1 levels, both the PERK/eIF2α phosphorylation inhibitor GSK2606414 and ISRIB significantly suppressed tumor growth and prolonged animal survival. CONCLUSIONS: BZW1 is a key molecule in the internal ribosome entry site-dependent translation of HIF1α/c-Myc and plays crucial roles in the glycolysis of PDAC. BZW1 might serve as a therapeutic target for patients with pancreatic cancer.

An investigation of the relationships between suicidal ideation, psychache, and meaning in life using network analysis.

BACKGROUND: Previous studies have investigated the relationships between psychache or meaning in life and suicidal ideation based on sum score of corresponding scale. However, this practice has hampered the fine-grained understanding of their relationships. This network analysis study aimed to conduct a dimension-level analysis of these constructs and the relationships among them in a joint framework, and identify potential intervention targets to address suicidal ideation. METHODS: Suicidal ideation, psychache, and meaning in life were measured using self-rating scales among 738 adults. A network of suicidal ideation, psychache, and meaning in life was constructed to investigate the connections between dimensions and calculate the expected influence and bridge expected influence of each node. RESULTS: "Psychache" was positively linked to "sleep" and "despair", while "presence of meaning in life" had negative associations with "psychache", "despair", and "pessimism". The most important central nodes were "sleep" and "despair", and the critical bridge nodes were "presence of meaning in life" and "psychache". CONCLUSION: These preliminary findings uncover the pathological pathways underlying the relationships between psychache, meaning in life, and suicidal ideation. The central nodes and bridge nodes identified may be potential targets for effectively preventing and intervening against the development and maintenance of suicidal ideation.

ESE3/EHF, a promising target of rosiglitazone, suppresses pancreatic cancer stemness by downregulating CXCR4.

BACKGROUND AND AIMS: The crosstalk between cancer stem cells (CSCs) and their niche is required for the maintenance of stem cell-like phenotypes of CSCs. Here, we identified E26 transformation-specific homologous factor (EHF) as a key molecule in decreasing the sensitivity of pancreatic cancer (PC) cells to CSCs' niche stimulus. We also explored a therapeutic strategy to restore the expression of EHF. DESIGN: We used a LSL-KrasG12D/+mice, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse model and samples from patients with PC. Immunostaining, flow cytometry, sphere formation assays, anchorage-independent growth assay, in vivo tumourigenicity, reverse transcription PCR, chromatin immunoprecipitation (ChIP) and luciferase analyses were conducted in this study. RESULTS: CXCL12 derived from pancreatic stellate cells (PSCs) mediates the crosstalk between PC cells and PSCs to promote PC stemness. Tumorous EHF suppressed CSC stemness by decreasing the sensitivity of PC to CXCL12 stimulus and inhibiting the crosstalk between PC and CSC-supportive niches. Mechanically, EHF suppressed the transcription of the CXCL12 receptor CXCR4. EHF had a cell autonomous role in suppressing cancer stemness by inhibiting the transcription of Sox9, Sox2, Oct4 and Nanog. Rosiglitazone suppressed PC stemness and inhibited the crosstalk between PC and PSCs by upregulating EHF. Preclinical KPC mouse cohorts demonstrated that rosiglitazone sensitised PDAC to gemcitabine therapy. CONCLUSIONS: EHF decreased the sensitivity of PC to the stimulus from PSC-derived CSC-supportive niche by negatively regulating tumorous CXCR4. Rosiglitazone could be used to target PC stem cells and the crosstalk between CSCs and their niche by upregulating EHF.

ESE3-positive PSCs drive pancreatic cancer fibrosis, chemoresistance and poor prognosis via tumour-stromal IL-1ß/NF-κB/ESE3 signalling axis.

BACKGROUND: Desmoplastic stroma, a feature of pancreatic ductal adenocarcinoma (PDAC), contains abundant activated pancreatic stellate cells (PSCs). How PSCs promote PDAC progression remains incompletely understood. METHODS: Effect of epithelium-specific E-twenty six factor 3 (ESE3)-positive PSCs on PDAC fibrosis and chemoresistance was examined by western blot, RT-PCR, immunofluorescence, flow cytometry assay, chromatin immunoprecipitation, luciferase assay, immunohistochemistry and subcutaneous pancreatic cancer mouse model. RESULTS: ESE3 expression increased in PSCs in PDAC tissues compared with those in normal PSCs. Clinical data showed that ESE3 upregulation in PSCs was positively correlated with tumour size, pTNM stage, CA19-9, carcinoembryonic antigen and serum CA242 level. ESE3 overexpression in PSCs was an independent negative prognostic factor for disease-free survival and overall survival amongst patients with PDAC. Mechanistically, the conditional medium from the loss and gain of ESE3-expressing PSCs influenced PDAC chemoresistance and tumour growth. ESE3 directly induced the transcription of α-SMA, collagen-I and IL-1ß by binding to ESE3-binding sites on their promoters to activate PSCs. IL-1ß upregulated ESE3 in PSCs through NF-κB activation, and ESE3 was required for PSC activation by tumour cell-derived IL-1ß. CONCLUSION: Inhibiting the IL-1ß/ESE3 (PSCs)/IL-1ß-positive feedback loop is a promising therapeutic strategy to reduce tumour fibrosis and increase chemotherapeutic efficacy in PDAC.

The item network and domain network of burnout in Chinese nurses.

BACKGROUND: As a common social phenomenon, nurses' occupational burnout has a high incidence rate, which seriously affects their mental health and nursing level. The current assessment mostly uses the total score model and explores the influence of external factors on burnout, while the correlation between burnout items or dimensions is less explored. Ignoring the correlation between the items or dimensions may result in a limited understanding of nurse occupational burnout. This paper explores the item and dimension network structure of the Maslach Burnout Inventory-General Survey (MBI-GS) in Chinese nurses, so as to gain a deeper understanding of this psychological construct and identify potential targets for clinical intervention. METHODS: A total of 493 Chinese nurses were recruited by cluster sampling. All participants were invited to complete the survey on symptoms of burnout. Network analysis was used to investigate the item network of MBI-GS. In addition, community detection was used to explore the communities of MBI-GS, and then network analysis was used to investigate the dimension network of MBI-GS based on the results of community detection. Regularized partial correlation and non-regularized partial correlation were used to describe the association between different nodes of the item network and dimension network, respectively. Expected influence and predictability were used to describe the relative importance and the controllability of nodes in both the item and dimension networks. RESULTS: In the item network, most of the strongly correlated edges were in the same dimension of emotional exhaustion (E), cynicism (C) and reduced professional efficacy (R), respectively. E5 (Item 5 of emotional exhaustion, the same below) "I feel burned out from my work", C1 "I have become more callous toward work since I took this job", and R3 "In my opinion, I am good at my job" had the highest expected influence (z-scores = 0.99, 0.81 and 0.94, respectively), indicating theirs highest importance in the network. E1 "I feel emotionally drained from my work" and E5 had the highest predictability (E1 = 0.74, E5 = 0.74). It shows that these two nodes can be interpreted by their internal neighbors to the greatest extent and have the highest controllability in the network. The spinglass algorithm and walktrap algorithm obtained exactly the same three communities, which are consistent with the original dimensions of MBI-GS. In the dimension network, the emotional exhaustion dimension was closely related to the cynicism dimension (weight = 0.65). CONCLUSIONS: The network model is a useful tool to study burnout in Chinese nurses. This study explores the item and domain network structure of nurse burnout from the network perspective. By calculating the relevant indicators, we found that E5, C1, and R3 were the most central nodes in the item network and cynicism was the central node in the domain network, suggesting that interventions aimed at E5, C1, R3 and cynicism might decrease the overall burnout level of Chinese nurses to the greatest extent. This study provides potential targets and a new way of thinking for the intervention of nurse burnout, which can be explored and verified in clinical practice.

Interleukin 35 Expression Correlates With Microvessel Density in Pancreatic Ductal Adenocarcinoma, Recruits Monocytes, and Promotes Growth and Angiogenesis of Xenograft Tumors in Mice.

BACKGROUND & AIMS: Cells of the monocyte lineage contribute to tumor angiogenesis. Interleukin 35 (IL35) is a member of the IL12 family produced by regulatory, but not effector, T cells. IL35 is a dimer comprising the IL12 alpha and IL27 beta chains, encoded by IL12A and EBI3, respectively. Expression of IL35 is increased in pancreatic ductal adenocarcinomas (PDACs) compared with normal pancreatic tissues, and promotes metastasis. We investigated the role of IL35 in monocyte-induced angiogenesis of PDAC in mice. METHODS: We measured levels of IL35 protein, microvessel density, and numbers of monocytes in 123 sequential PDAC tissues from patients who underwent surgery in China in 2010. We performed studies with the human PDAC cell lines CFPAC-1, BxPC-3, Panc-1, MIA-PaCa-2, and mouse PDAC cell line Pan02. Monocyte subsets were isolated by flow cytometry from human peripheral blood mononuclear cells. Fused human or mouse IL12A and EBI3 genes were overexpressed in PDAC cells or knocked down using small hairpin RNAs. Cells were grown as xenograft tumors in SCID mice; some mice were given injections of an IL35-neutralizing antibody and tumor growth was monitored. We performed chemotaxis assays to measure the ability of IL35 to recruit monocytes. We analyzed mRNA sequences of 179 PDACs in the Cancer Genome Atlas to identify correlations between expression of IL12A and EBI3 and monocyte markers. Monocytes incubated with IL35 or PDAC cell supernatants were analyzed in tube formation and endothelial migration assays. RESULTS: In PDAC samples from patients, levels of IL35 mRNA and protein correlated with microvessel density and infiltration of monocyte lineage cells. In cells and mice with xenograft tumors, IL35 increased recruitment of monocytes into PDAC tumors, which required CCL5. Upon exposure to IL35, monocytes increased expression of genes whose products promote angiogenesis (CXCL1 and CXCL8). IL35 activated transcription of CCL5, CXCL1, and CXCL8 by inducing GP130 signaling, via IL12RB2 and phosphorylation of STAT1 and STAT4. A combination of a neutralizing antibody against IL35 and gemcitabine significantly decreased monocyte infiltration, microvessel density, and volume of xenograft tumors grown from PDAC cells in mice. CONCLUSIONS: PDAC cells produce IL35 to recruit monocytes via CCL5 and induce macrophage to promote angiogenesis via expression of CXCL1 and CXCL8. IL35 signaling promotes angiogenesis and growth of xenograft tumors from PDAC cells in mice. IL35 might serve as a therapeutic target for patients with pancreatic cancer.

Evaluation of serum D-dimer, fibrinogen, and CA19-9 for postoperative monitoring and survival prediction in resectable pancreatic carcinoma.

BACKGROUND: We sought to investigate the efficacy of serum D-dimer, fibrinogen, and CA19-9 for postoperative monitoring and prediction of survival in patients with resectable pancreatic carcinoma (PC). METHODS: One hundred and nineteen patients with resectable PC were enrolled. Serum D-dimer, fibrinogen, and CA19-9 values were analyzed before surgery and at the stages of relapse-free and progression disease. RESULTS: D-dimer, fibrinogen, and CA19-9 were significantly higher at the active stage of PC than those at the relapse-free stage [1059.2 (1690.1) ng/ml vs 485.18 (289.84) ng/ml, (3.71 ± 0.83) g/l vs (2.75 ± 0.52) g/l, 207.2 (681.8) U/ml vs 24.5 (30) U/ml, respectively, p < 0.01]. Patients with elevated preoperative D-dimer had significantly shorter overall survival (18.9 ± 1.9 months vs 29.2 ± 2.6 months, p < 0.01) and progression-free survival (10.6 ± 1.2 months vs 20.4 ± 2.4 months, p < 0.01) than did those with low D-dimer. The correlation between CA19-9 values and survival depended on the threshold value of CA19-9: when the threshold value was 37 U/ml, there was no correlation between CA19-9 and survival; when the threshold value was 253.8 U/ml (median CA19-9 for the enrolled patients), patients with elevated preoperative CA19-9 had significantly shorter overall survival (19.9 ± 2. 1 months vs 29.0 ± 2. 7 months) and progression-free survival (11.5 ± 1.5 months vs 21.0 ± 2. 6 months) than did the patients with low CA19-9 (p < 0.01); when the threshold value was 1000 U/ml, the overall survival was 15.5 ± 2.3 months vs 28.0 ± 2.0 months and the progression-free survival 8.9 ± 1.9 months vs 19.1 ± 1.9 months (p < 0.01). There was no correlation between fibrinogen and overall survival (25.8 ± 2.1 months vs 21.2 ± 2.9 months; p = 0.096) and progression-free survival (17.8 ± 2.1 months vs 12.7 ± 1.7 months; p = 0.168). CONCLUSIONS: For postoperative monitoring of patients with resectable PC, D-dimer, fibrinogen, and CA19-9 may be used as markers for monitoring disease relapse, but only preoperative D-dimer could predict survival.

Detection of Circulating Tumor Cells Using Negative Enrichment Immunofluorescence and an In Situ Hybridization System in Pancreatic Cancer.

Pancreatic cancer (PC) is the most lethal type of gastrointestinal cancer, and early detection and monitoring is an urgent problem. Circulating tumor cells (CTCs) are emerging as a non-invasive biomarker for tumor detection. However, the low sensitivity is a main problem in the traditional CellSearch System for detecting CTCs, especially in patients with PC. In this study, we used negative enrichment (NE), immunofluorescence and in situ hybridization (FISH) of chromosome 8 (NE-iFISH) to capture and identify CTCs in PC patients. We showed that the NE-iFISH system exhibited a dramatically high detection rate of CTCs in PC patients (90%). The diagnostic rate of PC reached 97.5% when combining CTCs ≥ 2 and carbohydrate antigen 19-9 (CA19-9) > 37 µmol/L. The 1-year survival in the group of CTCs < 3 was significantly higher than that of CTCs ≥ 3 (p = 0.043). In addition, we analyzed the role of chromosomal instability in CTCs detection. The group of triploid (three hybridization signals of chromosome 8) CTCs ≥ 3 showed a shorter 1-year survival (p = 0.0279) and overall survival (p = 0.0188) than the group with triploid CTCs < 3. Importantly, the triploid CTC number but not the overall CTC counts could be a predictor of chemo-sensitivity. Moreover, circulating tumor microembolus (CTMs) were found in stage IV patients, and were positively related to the poor response to chemotherapy. In conclusion, the NE-iFISH system significantly improved the positive detection rate of CTCs and triploid CTC could be used to predict prognosis or the response to the chemotherapy of PC patients. CTM is a potential indicator of the chemotherapeutic effect in advanced PC patients.

Α-Dendrotoxin-sensitive Kv1 channels contribute to conduction failure of polymodal nociceptive C-fibers from rat coccygeal nerve.

It is known that some patients with diabetic neuropathy are usually accompanied by abnormal painful sensations. Evidence has accumulated that diabetic neuropathic pain is associated with the hyperexcitability of peripheral nociceptors. Previously, we demonstrated that reduced conduction failure of polymodal nociceptive C-fibers and enhanced voltage-dependent sodium currents of small dorsal root ganglion (DRG) neurons contribute to diabetic hyperalgesia. To further investigate whether and how potassium channels are involved in the conduction failure, α-dendrotoxin (α-DTX), a selective blocker of the low-threshold sustained Kv1 channel, was chosen to examine its functional capability in modulating the conduction properties of polymodal nociceptive C-fibers and the excitability of sensory neurons. We found that α-DTX reduced the conduction failure of C-fibers from coccygeal nerve in vivo accompanied by an increased initial conduction velocity but a decreased activity-dependent slowing of conduction velocity. In addition, the number of APs evoked by step currents was significantly enhanced after the treatment with α-DTX in small-diameter sensory neurons. Further study of the mechanism indicates α-DTX-sensitive K(+) current significantly reduced and the activation of this current in peak and steady state shifted to depolarization for diabetic neurons. Expression of Kv channel subunits Kv1.2 and Kv1.6 was downregulated in both small dorsal root ganglion neurons and peripheral C-fibers. Taken together, these results suggest that α-DTX-sensitive Kv1 channels might play an important role in regulating the conduction properties of polymodal nociceptive C-fibers and firing properties of sensory neurons.

Curcumin promotes browning of white adipose tissue in a norepinephrine-dependent way.

Brown adipose tissue converts energy from food into heat via the mitochondrial uncoupling protein UCP1, defending against cold. In some conditions, inducible 'brown-like' adipocytes, also known as beige adipocytes, can develop within white adipose tissue (WAT). These beige adipocytes have characteristics similar to classical brown adipocytes and thus can burn lipids to produce heat. In the current study, we demonstrated that curcumin (50 or 100 mg/kg/day) decreased bodyweight and fat mass without affecting food intake in mice. We further demonstrated that curcumin improves cold tolerance in mice. This effect was possibly mediated by the emergence of beige adipocytes and the increase of thermogenic gene expression and mitochondrial biogenesis in inguinal WAT. In addition, curcumin promotes ß3AR gene expression in inguinal WAT and elevates the levels of plasma norepinephrine, a hormone that can induce WAT browning. Taken together, our data suggest that curcumin can potentially prevent obesity by inducing browning of inguinal WAT via the norepinephrine-ß3AR pathway.

Stem cell factor is a novel independent prognostic biomarker for hepatocellular carcinoma after curative resection.

Stem cell factor (SCF), a ligand of c-kit, is a hematopoietic growth factor. Uncontrolled activity of SCF/c-kit signaling pathway contributes to the formation of a variety of human malignancies. In this study, we determined whether SCF expression could risk-stratify patients with hepatocellular carcinoma (HCC) after curative resection. HCC tissues from 160 patients were collected during curative resection and stained with SCF and CD34, a marker for microvessel density (MVD), using immunohistochemistry. Two statistical analyses were performed: an independent continuous and a multivariate categorical analysis, with test/validation set-defined cut points, and Kaplan-Meier estimated outcome measures of overall survival (OS) and relapse-free survival (RFS). We found that higher levels of SCF confer worse OS (continuous P = 0.014; and categorical P = 0.009), and RFS (continuous P = 0.002; categorical P = 0.003) of patients with HCC. SCF varies independently from MVD-CD34, tumor node metastasis, histologic grade, age and gender, and retains prognostic significance when analysed as a categorical variable in a multivariate analysis . We confirmed that MVD-CD34 is also an independent prognostic marker for patients with HCC. The levels of SCF and CD34 showed a positive and significant correlation (P < 0.0001) and double low expression confers superior OS (median = 48 months) and RFS (median = 24 months), whereas double high expression confers shortest RFS (median = 10.5 months) compared with single measurements. The prognostic values of SCF and CD34 were independently determined in this study and we propose that both of them are independent prognostic markers for HCC.

The Relationship Between Negative Coping Styles, Psychological Resilience, and Positive Coping Styles in Military Personnel: A Cross-Lagged Analysis.

Background: Military personnel experience prolonged exposure to high-stress environments. Positive coping styles can assist in maintaining their mental and behavioral well-being, whereas negative coping styles cannot. Health behavior change theory specifies that an individual can transition from a negative to a positive coping style. The psychological resilience concept may prove vital in this transition. Methods: In a longitudinal study design, two questionnaires were administered to 233 military personnel twice, the first at T1 in April 2023 and the second at T2 in July 2023. The questionnaire measured individual negative coping style, positive coping style and psychological resilience. Results: The data showed that the negative coping style at T1 negatively predicted the level of psychological resilience at T2 (γ= - 0.26, p < 0.001) and the positive coping style at T2 (γ= - 0.16, p < 0.001). The level of psychological resilience at T1 positively predicted the positive coping style at T2 (γ= 0.22, p < 0.01). Psychological resilience played a mediating role between negative coping style and positive coping style. In addition, there was an interaction between psychological resilience and positive coping style in military personnel at the two time points. Conclusion: The negative coping styles that presently exist among military personnel have the potential to diminish their future positive coping styles by lowering their psychological resilience. This highlights the need to focus on the development and training of psychological resilience for military personnel, as it can effectively counteract negative coping styles and promote positive coping styles.

Affective norms for 501 Chinese words from three emotional dimensions rated by depressive disorder patients.

Introduction: Emotional words are often used as stimulus material to explore the cognitive and emotional characteristics of individuals with depressive disorder, while normal individuals mostly rate the scores of affective words. Given that individuals with depressive disorder exhibit a negative cognitive bias, it is possible that their depressive state could influence the ratings of affective words. To enhance the validity of the stimulus material, we specifically recruited patients with depression to provide these ratings. Methods: This study provided subjective ratings for 501 Chinese affective norms, incorporating 167 negative words selected from depressive disorder patients' Sino Weibo blogs, and 167 neutral words and 167 positive words selected from the Chinese Affective Word System. The norms are based on the assessments made by 91 patients with depressive disorder and 92 normal individuals, by using the paper-and-pencil quiz on a 9-point scale. Results: Regardless of the group, the results show high reliability and validity. We identified group differences in three dimensions: valence, arousal, and self-relevance: the depression group rated negative words higher, but positive and neutral words lower than the normal control group. Conclusion: The emotional perception affected the individual's perception of words, to some extent, this database expanded the ratings and provided a reference for exploring norms for individuals with different emotional states.

BICC1 drives pancreatic cancer stemness and chemoresistance by facilitating tryptophan metabolism.

Pancreatic adenocarcinoma is the fourth leading cause of malignancy-related deaths, with rapid development of drug resistance driven by pancreatic cancer stem cells. However, the mechanisms sustaining stemness and chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, we demonstrate that Bicaudal C homolog 1 (BICC1), an RNA binding protein regulating numerous cytoplasmic mRNAs, facilitates chemoresistance and stemness in PDAC. Mechanistically, BICC1 activated tryptophan catabolism in PDAC by up-regulating indoleamine 2,3-dioxygenase-1 (IDO1) expression, a tryptophan-catabolizing enzyme. Increased levels of tryptophan metabolites contribute to NAD+ synthesis and oxidative phosphorylation, leading to a stem cell-like phenotype. Blocking BICC1/IDO1/tryptophan metabolism signaling greatly improves the gemcitabine (GEM) efficacy in several PDAC models with high BICC1 level. These findings indicate that BICC1 is a critical tryptophan metabolism regulator that drives the stemness and chemoresistance of PDAC and thus a potential target for combinatorial therapeutic strategy against chemoresistance.

Tumor-derived interleukin 35 mediates the dissemination of gemcitabine resistance in pancreatic adenocarcinoma.

Rapid development of drug resistance after chemotherapy is a major cause of treatment failure in individuals with pancreatic ductal adenocarcinoma (PDAC). In this study, we illustrate that tumor-derived interleukin 35 (IL-35) mediates the accelerated resistance of PDAC to gemcitabine (GEM). We observe that GEM resistance can spread from GEM-resistant PDAC cells to GEM-sensitive cells, and that IL-35 is responsible for the propagation of chemoresistance, which is supported by sequencing and experimental data. Additionally, we discover that GEM-resistant cells have significantly higher levels of IL-35 expression. Mechanistically, aberrantly expressed IL-35 triggers transcriptional activation of SOD2 expression via GP130-STAT1 signaling, scavenging reactive oxygen species (ROS) and leading to GEM resistance. Furthermore, GEM treatment stimulates IL-35 expression through activation of the NF-κB pathway, resulting in acquired chemoresistance. In the mouse model, a neutralizing antibody against IL-35 enhances the tumor suppressive effect of GEM. Collectively, our data suggests that IL-35 is critical in mediating GEM resistance in pancreatic cancer, and therefore could be a valuable therapeutic target in overcoming PDAC chemoresistance.

Temporal colonization and metabolic regulation of the gut microbiome in neonatal oxen at single nucleotide resolution.

The colonization of microbes in the gut is key to establishing a healthy host-microbiome symbiosis for newborns. We longitudinally profiled the gut microbiome in a model consisting of 36 neonatal oxen from birth up to 2 months postpartum and carried out microbial transplantation to reshape their gut microbiome. Genomic reconstruction of deeply sequenced fecal samples resulted in a total of 3931 metagenomic-assembled genomes from 472 representative species, of which 184 were identified as new species when compared with existing databases of oxen. Single nucleotide level metagenomic profiling shows a rapid influx of microbes after birth, followed by dynamic shifts during the first few weeks of life. Microbial transplantation was found to reshape the genetic makeup of 33 metagenomic-assembled genomes (FDR < 0.05), mainly from Prevotella and Bacteroides species. We further linked over 20 million microbial single nucleotide variations to 736 plasma metabolites, which enabled us to characterize 24 study-wide significant associations (P < 4.4 × 10-9) that identify the potential microbial genetic regulation of host immune and neuro-related metabolites, including glutathione and L-dopa. Our integration analyses further revealed that microbial genetic variations may influence the health status and growth performance by modulating metabolites via structural regulation of their encoded proteins. For instance, we found that the albumin levels and total antioxidant capacity were correlated with L-dopa, which was determined by single nucleotide variations via structural regulations of metabolic enzymes. The current results indicate that temporal colonization and transplantation-driven strain replacement are crucial for newborn gut development, offering insights for enhancing newborn health and growth.

Gut microbial genomes with paired isolates from China illustrate probiotic and cardiometabolic effects.

The gut microbiome displays genetic differences among populations, and characterization of the genomic landscape of the gut microbiome in China remains limited. Here, we present the Chinese Gut Microbial Reference (CGMR) set, comprising 101,060 high-quality metagenomic assembled genomes (MAGs) of 3,707 nonredundant species from 3,234 fecal samples across primarily rural Chinese locations, 1,376 live isolates mainly from lactic acid bacteria, and 987 novel species relative to worldwide databases. We observed region-specific coexisting MAGs and MAGs with probiotic and cardiometabolic functionalities. Preliminary mouse experiments suggest a probiotic effect of two Faecalibacillus intestinalis isolates in alleviating constipation, cardiometabolic influences of three Bacteroides fragilis_A isolates in obesity, and isolates from the genera Parabacteroides and Lactobacillus in host lipid metabolism. Our study expands the current microbial genomes with paired isolates and demonstrates potential host effects, contributing to the mechanistic understanding of host-microbe interactions.

The CX3CL1/CX3CR1 reprograms glucose metabolism through HIF-1 pathway in pancreatic adenocarcinoma.

One of the hallmarks of cancer is revised glucose metabolism that promotes cell survival and proliferation. In pancreatic cancer, the regulatory mechanism of glucose metabolism remains to be elucidated. In this study, we found that CX3CR1 is expressed in pancreatic cancer cells lines. Exogenous or transfected CX3CL1 increased glucose uptake and lactate secretion. CX3CL1 stimulated HIF-1 expression through PI3K/Akt and MAPK pathways. Furthermore, knockdown of HIF-1 blocked CX3CL1-modified glucose metabolism in pancreatic adenocarcinoma cells. In conclusion, the CX3CL1/CX3CR1 reprograms glucose metabolism through HIF-1 pathway in pancreatic cancer cells.

Downregulation of microRNA-214 and overexpression of FGFR-1 contribute to hepatocellular carcinoma metastasis.

miR-214 is one of the most significantly downregulated microRNAs (miRNAs) in hepatocellular carcinoma (HCC). Fibroblast growth factor receptor 1 (FGFR-1) is a miR-214 target gene implicated in the progression of HCC. However, the roles of miR-214 and FGFR-1 in HCC are not fully understood. Here, we analyzed the expression of miR-214 and FGFR-1 in 65 cases of HCC and paired non-neoplastic tissue specimens using real-time PCR and Western blot (WB), respectively. Our data indicated that miR-214 was downregulated and FGFR-1 was overexpressed in HCC compared to the paired non-neoplastic tissues. The low miR-214 expression was correlated with portal vein invasion (p=0.016) and early recurrence (p=0.045) in HCC patients. Moreover, the low miR-214 expression was correlated with high positive rate of FGFR-1 in HCC cases (p=0.020). Our data further demonstrated that miR-214 overexpression in SK-HEP1 and HepG2 cells downregulated FGFR-1 expression and inhibited liver cancer cell invasion. The Luciferase assay results further demonstrated the targeted regulation of FGFR-1 by miR-214. In conclusion, our data indicate that the downregulation of miR-214 in HCC and the upregulation of its target gene FGFR-1 is associated with HCC progression. Therefore, miR-214 and FGFR-1 are potential prognostic markers and therapeutic targets in HCC.

Reduced conduction failure of the main axon of polymodal nociceptive C-fibres contributes to painful diabetic neuropathy in rats.

Painful diabetic neuropathy is a common complication of diabetes mellitus and can affect many aspects of life and severely limit patients' daily functions. Signals of painful diabetic neuropathy are believed to originate in the peripheral nervous system. However, its peripheral mechanism of hyperalgesia has remained elusive. Numerous studies have accumulated that polymodal nociceptive C-fibres play a crucial role in the generation and conduction of pain signals and sensitization of which following injury or inflammation leads to marked hyperalgesia. Traditionally, the number of nociceptive primary afferent firings is believed to be determined at the free nerve endings, while the extended main axon of unmyelinated C-fibres only involves the reliable and faithful propagation of firing series to the central terminals. We challenged this classic view by showing that conduction of action potential can fail to occur in response to repetitive activity when they travel down the main axon of polymodal nociceptive C-fibres. Quantitative analysis of conduction failure revealed that the degree of conduction failure displays a frequency-dependent manner. Local administration of low threshold, rapidly activating potassium current blocker, α-dendrotoxin (0.5 nM) and persistent sodium current blocker, low doses of tetrodotoxin (<100 nM) on the main axon of C-fibres can reciprocally regulate the degree of conduction failure, confirming that conduction failure did occur along the main axon of polymodal nociceptive C-fibres. Following streptozotocin-induced diabetes, a subset of polymodal nociceptive C-fibres exhibited high-firing-frequency to suprathreshold mechanical stimulation, which account for about one-third of the whole population of polymodal nociceptive C-fibres tested. These high-firing-frequency polymodal nociceptive C-fibres in rats with diabetes displayed a marked reduction of conduction failure. Delivery of low concentrations of tetrodotoxin and Nav1.8 selective blocker, A-803467 on the main axon of C-fibres was found to markedly enhance the conduction failure in a dose-dependent manner in diabetic rats. Upregulated expression of sodium channel subunits Nav1.7 and Nav1.8 in both small dorsal root ganglion neurons and peripheral C-fibres as well as enhanced transient and persistent sodium current and increased excitability in small dorsal root ganglion neurons from diabetic rats might underlie the reduced conduction failure in the diabetic high-firing-frequency polymodal nociceptive C-fibres. This study shed new light on the functional capability in the pain signals processing for the main axon of polymodal nociceptive C-fibres and revealed a novel mechanism underlying diabetic hyperalgesia.