Multilevel Regulation of NF-κB Signaling by NSD2 Suppresses Kras-Driven Pancreatic Tumorigenesis.

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer with a dismal overall prognosis. NSD2 is an H3K36-specific di-methyltransferase that has been reported to play a crucial role in promoting tumorigenesis. Here, the study demonstrates that NSD2 acts as a putative tumor suppressor in Kras-driven pancreatic tumorigenesis. NSD2 restrains the mice from inflammation and Kras-induced ductal metaplasia, while NSD2 loss facilitates pancreatic tumorigenesis. Mechanistically, NSD2-mediated H3K36me2 promotes the expression of IκBα, which inhibits the phosphorylation of p65 and NF-κB nuclear translocation. More importantly, NSD2 interacts with the DNA binding domain of p65, attenuating NF-κB transcriptional activity. Furthermore, inhibition of NF-κB signaling relieves the symptoms of Nsd2-deficient mice and sensitizes Nsd2-null PDAC to gemcitabine. Clinically, NSD2 expression decreased in PDAC patients and negatively correlated to nuclear p65 expression. Together, the study reveals the important tumor suppressor role of NSD2 and multiple mechanisms by which NSD2 suppresses both p65 phosphorylation and downstream transcriptional activity during pancreatic tumorigenesis. This study opens therapeutic opportunities for PDAC patients with NSD2 low/loss by combined treatment with gemcitabine and NF-κBi.

Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer.

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of cancer-associated fibroblasts (CAFs) as part of the host response to tumor cells. The origins and functions of transcriptionally diverse CAF populations in PDAC remain poorly understood. Tumor cell-intrinsic genetic mutations and epigenetic dysregulation may reshape the TME; however, their impacts on CAF heterogeneity remain elusive. SETD2, a histone H3K36 trimethyl-transferase, functions as a tumor suppressor. Through single-cell RNA sequencing, we identify a lipid-laden CAF subpopulation marked by ABCA8a in Setd2-deficient pancreatic tumors. Our findings reveal that tumor-intrinsic SETD2 loss unleashes BMP2 signaling via ectopic gain of H3K27Ac, leading to CAFs differentiation toward lipid-rich phenotype. Lipid-laden CAFs then enhance tumor progression by providing lipids for mitochondrial oxidative phosphorylation via ABCA8a transporter. Together, our study links CAF heterogeneity to epigenetic dysregulation in tumor cells, highlighting a previously unappreciated metabolic interaction between CAFs and pancreatic tumor cells.

Spatiotemporal role of SETD2-H3K36me3 in murine pancreatic organogenesis.

Pancreas development is tightly controlled by multilayer mechanisms. Despite years of effort, large gaps remain in understanding how histone modifications coordinate pancreas development. SETD2, a predominant histone methyltransferase of H3K36me3, plays a key role in embryonic stem cell differentiation, whose role in organogenesis remains elusive. Here, by combination of cleavage under targets and tagmentation (CUT&Tag), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and bulk RNA sequencing, we show a dramatic increase in the H3K36me3 level from the secondary transition phase and decipher the related transcriptional alteration. Using single-cell RNA sequencing, we define that pancreatic deletion of Setd2 results in abnormalities in both exocrine and endocrine lineages: hyperproliferative tip progenitor cells lead to abnormal differentiation; Ngn3+ endocrine progenitors decline due to the downregulation of Nkx2.2, leading to insufficient endocrine development. Thus, these data identify SETD2 as a crucial player in embryonic pancreas development, providing a clue to understanding the dysregulation of histone modifications in pancreatic disorders.

Oncogenic KRAS triggers metabolic reprogramming in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an extremely high lethality rate. Oncogenic KRAS activation has been proven to be a key driver of PDAC initiation and progression. There is increasing evidence that PDAC cells undergo extensive metabolic reprogramming to adapt to their extreme energy and biomass demands. Cell-intrinsic factors, such as KRAS mutations, are able to trigger metabolic rewriting. Here, we update recent advances in KRAS-driven metabolic reprogramming and the associated metabolic therapeutic potential in PDAC.

Premature aging of skeletal stem/progenitor cells rather than osteoblasts causes bone loss with decreased mechanosensation.

A distinct population of skeletal stem/progenitor cells (SSPCs) has been identified that is indispensable for the maintenance and remodeling of the adult skeleton. However, the cell types that are responsible for age-related bone loss and the characteristic changes in these cells during aging remain to be determined. Here, we established models of premature aging by conditional depletion of Zmpste24 (Z24) in mice and found that Prx1-dependent Z24 deletion, but not Osx-dependent Z24 deletion, caused significant bone loss. However, Acan-associated Z24 depletion caused only trabecular bone loss. Single-cell RNA sequencing (scRNA-seq) revealed that two populations of SSPCs, one that differentiates into trabecular bone cells and another that differentiates into cortical bone cells, were significantly decreased in Prx1-Cre; Z24f/f mice. Both premature SSPC populations exhibited apoptotic signaling pathway activation and decreased mechanosensation. Physical exercise reversed the effects of Z24 depletion on cellular apoptosis, extracellular matrix expression and bone mass. This study identified two populations of SSPCs that are responsible for premature aging-related bone loss. The impairment of mechanosensation in Z24-deficient SSPCs provides new insight into how physical exercise can be used to prevent bone aging.

Clinicopathologic Features and Prognosis of Melanoma in Northeast China: A Region-Based Cohort Study of 229 Consecutive Cases.

Melanoma has been reported in many parts of East Asia. However, there are no reports on the epidemiology of melanoma in Northeast China. In this study, we collected demographic, clinicopathologic, and treatment data of patients with melanoma treated at the First Hospital of Jilin University (Changchun, China). A total of 229 consecutive nonselective cases were analyzed for the incidence and clinicopathologic characteristics of melanoma. The median overall survival was 53.5 months. The 1-year, 3-year, and 5-year survival rates were 86.3, 66.4, and 44.8%, respectively. The median disease-free survival was 33.1 months, and the 1-year, 3-year, and 5-year disease-free survival rates were 75.0, 48.5, and 35.8%, respectively. Multivariate analysis showed that disease stage, Eastern Cooperative Oncology Group score, and lactic dehydrogenase were independent prognostic factors of overall survival. Pathologic subtype and stage were independent prognostic factors of disease-free survival. Furthermore, vascular invasion was a prognostic factor for overall survival in acral melanoma and a prognostic factor for disease-free survival in cutaneous melanoma. Compared with the Caucasian population, the population of Northeast China showed significant differences in disease location, pathologic subtype, gene status, and survival prognosis. In summary, our study showed that vascular invasion might be a prognostic factor in patients with acral and cutaneous melanoma.

Accelerated aging in articular cartilage by ZMPSTE24 deficiency leads to osteoarthritis with impaired metabolic signaling and epigenetic regulation.

Osteoarthritis (OA) is an age-related degenerative disease without disease-modifying therapy. The lack of aging-induced osteoarthritis models makes the discovery of therapeutic drugs more challenging. The deficiency of ZMPSTE24 could induce Hutchinson-Gilford progeria syndrome (HGPS), a genetic disorder of rapid aging. However, the relationship between HGPS and OA remains unclear. Our results found that the expression of Zmpste24 was decreased in the articular cartilage during the aging process. Zmpste24 knockout mice, Prx1-Cre; Zmpste24fl/fl mice and Col2-CreERT2; Zmpste24fl/fl mice displayed OA phenotype. Loss of Zmpste24 in articular cartilage could exacerbate the occurrence and development of osteoarthritis. Transcriptome sequencing revealed that deletion of Zmpste24 or accumulation of progerin affects chondrocyte metabolism, inhibits cell proliferation and promotes cell senescence. Using this animal model, we elucidate the upregulation of H3K27me3 during chondrocyte senescence and discover the molecular mechanism by which lamin A mutant stabilizes EZH2 expression. The construction of aging-induced osteoarthritis models and the elucidation of the signaling pathways and molecular mechanisms of articular chondrocyte senescence would benefit the discovery and development of new drugs for OA.

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.

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.

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.

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.

Ketogenesis acts as an endogenous protective programme to restrain inflammatory macrophage activation during acute pancreatitis.

BACKGROUND: Innate immunity and metabolites link to the pathogenesis and severity of acute pancreatitis (AP). However, liver metabolism and its role in immune response and AP progression remain elusive. We investigated the function of liver metabolism in the pathogenesis of AP. METHODS: Circulating ketone body ß-hydroxybutyrate (ßOHB) levels were determined in AP clinical cohorts and caerulein-induced AP (CER-AP) mouse models receiving seven (Cer*7) or twelve (Cer*12) injection regimens at hourly intervals. Liver transcriptomics and metabolomics were compared between CER-AP (Cer*7) and CER-AP (Cer*12). Inhibition of fatty acid ß-oxidation (FAO)-ketogenesis, or supplementation of ßOHB was performed in mouse models of AP. The effect and mechanism of ßOHB were examined in vitro. FINDINGS: Elevated circulating ßOHB was observed in patients with non-severe AP (SAP) but not SAP. These findings were replicated in CER-AP (Cer*7) and CER-AP (Cer*12), which manifested as limited and hyperactive immune responses, respectively. FAO-ketogenesis was activated in CER-AP (Cer*7), while impaired long-chain FAO and mitochondrial function were observed in the liver of CER-AP (Cer*12). Blockage of FAO-ketogenesis (Cpt1a antagonism or Hmgcs2 knockdown) worsened, while supplementation of ßOHB or its precursor 1,3-butanediol alleviated the severity of CER-AP. Mechanistically, ßOHB had a discernible effect on pancreatic acinar cell damage, instead, it greatly attenuated the activation of pancreatic and systemic proinflammatory macrophages via class I histone deacetylases. INTERPRETATION: Our findings reveal that hepatic ketogenesis is activated as an endogenous protective programme to restrain AP progression, indicating its potential therapeutic value. FUNDING: This work was supported by the National Natural Science Foundation of China, Shanghai Youth Talent Support Programme, and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant.

Smad4 Deficiency Promotes Pancreatic Cancer Immunogenicity by Activating the Cancer-Autonomous DNA-Sensing Signaling Axis.

Smad4, a key mediator of the transforming growth factor-ß signaling, is mutated or deleted in 20% of pancreatic ductal adenocarcinoma (PDAC) cancers and significantly affects cancer development. However, the effect of Smad4 loss on the immunogenicity and tumor immune microenvironment of PDAC is still unclear. Here, a surprising function of Smad4 in suppressing mouse PDAC tumor immunogenicity is identified. Although Smad4 deletion in tumor cells enhances proliferation in vitro, the in vivo growth of Smad4-deficient PDAC tumor is significantly inhibited on immunocompetent C57BL/6 (B6) mice, but not on immunodeficient mice or CD8+ cell-depleted B6 mice. Mechanistically, Smad4 deficiency significantly increases tumor cell immunogenicity by promoting spontaneous DNA damage and stimulating STING-mediated type I interferon signaling,which contributes to the activation of type 1 conventional dendritic cells (cDC1) and subsequent CD8+ T cells for tumor control. Furthermore, retarded tumor growth of Smad4-deficient PDAC cells on B6 mice is largely reversed when Sting is codeleted, or when the cells are implanted into interferon-alpha receptor-deficientmice or cDC1-deficientmice. Accordingly, Smad4 deficiency promotes PDAC immunogenicity by inducing tumor-intrinsic DNA damage-elicited type I interferon signaling.

Pediatric living donor left lateral segment liver transplantation for biliary atresia: Doppler ultrasound findings in early postoperative period.

PURPOSE: To analyze hepatic hemodynamic parameters detected by Doppler ultrasound (DU) of uncomplicated children with biliary atresia who underwent left lateral segment living donor liver transplantation (LLS-LDLT), explore its normal change trend over time and determine the normal reference interval. METHODS: We retrospectively involved the data from 227 biliary atresia patients (100 Males,127 Females). Hemodynamic parameters include peak systolic velocity (PSV), end-diastolic velocity (EDV), resistivity index (RI), and pulsation index (PI) of the hepatic artery (HA), portal vein velocity (PVV), portal vein flow (PVF) and hepatic vein velocity (HVV) during intra-operative and on the 1st, 3rd, 5th and 7th day after operation were collected. Repeated measures analysis of the variance and Friedman test were used to analyze the changing trend of hemodynamic parameters over time in the first week after the operation. RESULTS: PSVHA and EDVHA showed a similar changing tendency at one week after surgery, with an overall decrease-rise trend; RIHA and PIHA also changed similarly with an overall rise-decrease trend. The HVV and PVV at surgery were lower than at all time points after surgery. As for PVF, the value of POD5 was the highest and then decreased. Additionally, this study provided the normal reference interval of hemodynamic parameters for LLS-LDLT patients, which were PSVHA: 18.4-98.3 cm/s, EDVHA: 0-43.3 cm/s, RIHA: 0.41-1.0, PIHA: 0.51-2.0, PVV: 19.0-83.7 cm/s, HVV: 19.4-68.0 cm/s, and PVF:99.5-500.0 ml/min/100 g at intraoperation. Within the first postoperative week: PSVHA: 21.0-97.7 cm/s, EDVHA: 0-32.7 cm/s, RIHA: 0.47-1.0, PIHA: 0.62-2.0, PVV: 23.0-92.0 cm/s, HVV: 19.7-86.0 cm/s, and PVF: 100.0-513.0 ml/min/100 g. CONCLUSION: The hepatic hemodynamic of post-transplanted children detected by DU had specific changing trends and normal ranges, which provides valuable reference values for ultrasonologists and pediatric transplant clinicians.

Non-invasive Evaluation of Brain Death Caused by Traumatic Brain Injury by Ultrasound Imaging.

OBJECTIVES: To investigate the clinical value of non-invasive ultrasound imaging in the evaluation of brain death caused by traumatic brain injury. METHODS: Thirty-four patients with acute severe traumatic brain injury were admitted to hospital within 48 h after injury. All patients were monitored intracranial pressure, transcranial Doppler, echocardiography examination, collection intracranial pressure, MCA-Vs, MCA-Vd, MCA-Vm, EF, LVMPI, RVMPI and other indicators, and combined with clinical conditions and other related data for comparative study and statistical analysis. RESULTS: The blood flow spectrum was characterized by diastolic retrograde blood flow spectrum pattern and nail waveform spectrum shape when the patient had clinical brain death. For the parameters of transcranial Doppler, there were significant differences in MCA-Vm and PI between clinical brain death group and normal control group (P < 0.05). For the parameters of echocardiography, there were statistically significant differences in EF, LVMPI, and RVMPI between clinical brain death group and normal control group (P < 0.05). CONCLUSION: Non-invasive dynamic monitoring of cerebral hemodynamics and cardiac function parameters in patients with severe craniocerebral injury can provide a high accuracy and reliability for the preliminary diagnosis of brain death in patients with severe craniocerebral injury. It is helpful for early evaluation of prognosis and provides effective monitoring methods and guidance for clinical treatment.

Macrophage phenotypic switch orchestrates the inflammation and repair/regeneration following acute pancreatitis injury.

BACKGROUND: Impaired or hyperactive pancreas regeneration after injury would cause exocrine insufficiency or recurrent / chronic pancreatitis and potentially carcinogenesis. Macrophages are the most abundant immune cells in the regenerative pancreas, however their phenotype and role remain poorly defined. METHOD: Using caerulein-induced acute pancreatitis (AP) model, we examined the dynamic landscape of pancreatic macrophages throughout the acute inflammation to regeneration phases by flow cytometric and RNA-seq analyses. Liposome depletion of macrophages, Il4ra-/- mice as well as inhibitors were used to elucidate the role and regulatory mechanism of macrophages during pancreatic regeneration. FINDINGS: We found that M1 macrophages dominated in the pro-inflammatory phase of AP, while M2-like macrophages dominated during pancreas repair/regeneration. Depletion of macrophages at early or late regenerative stage dramatically blocked the acinar-ductal metaplasia (ADM) or delayed inflammation resolution, respectively. Moreover, alternative activation of macrophages was partially dependent on IL-4RA signaling, and ECM/AKT activation in pancreatic macrophages facilitated inflammation resolution during tissue regeneration. INTERPRETATION: Our findings illustrate a dynamic phenotype and function of macrophages during AP repair/regeneration, helping us better understand the mechanism of pancreatic regeneration and providing clues for novel therapeutic strategy.

Perineural Invasion Reprograms the Immune Microenvironment through Cholinergic Signaling in Pancreatic Ductal Adenocarcinoma.

Perineural invasion is a common feature of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the effect of perineural invasion on the microenvironment and how this affects PDAC progression. Transcriptome expression profiles of PDAC tissues with different perineural invasion status were compared, and the intratumoral T-cell density and levels of neurotransmitters in these tissues were assessed. Perineural invasion was associated with impaired immune responses characterized by decreased CD8+ T and Th1 cells, and increased Th2 cells. Acetylcholine levels were elevated in severe perineural invasion. Acetylcholine impaired the ability of PDAC cells to recruit CD8+ T cells via HDAC1-mediated suppression of CCL5. Moreover, acetylcholine directly inhibited IFNγ production by CD8+ T cells in a dose-dependent manner and favored Th2 over Th1 differentiation. Furthermore, hyperactivation of cholinergic signaling enhanced tumor growth by suppressing the intratumoral T-cell response in an orthotopic PDAC model. Conversely, blocking perineural invasion with bilateral subdiaphragmatic vagotomy in tumor-bearing mice was associated with an increase in CD8+ T cells, an elevated Th1/Th2 ratio, and improved survival. In conclusion, perineural invasion-triggered cholinergic signaling favors tumor growth by promoting an immune-suppressive microenvironment characterized by impaired CD8+ T-cell infiltration and a reduced Th1/Th2 ratio. SIGNIFICANCE: These findings provide a promising therapeutic strategy to modulate the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma with severe perineural invasion.

Loss of Setd2 promotes Kras-induced acinar-to-ductal metaplasia and epithelia-mesenchymal transition during pancreatic carcinogenesis.

OBJECTIVE: SETD2, the sole histone H3K36 trimethyltransferase, is frequently mutated or deleted in human cancer, including pancreatic ductal adenocarcinoma (PDAC). However, whether SETD2/H3K36me3 alteration results in PDAC remains largely unknown. DESIGN: TCGA(PAAD) public database and PDAC tissue array with SETD2/H3K36me3 staining were used to investigate the clinical relevance of SETD2 in PDAC. Furthermore, to define the role of SETD2 in the carcinogenesis of PDAC, we crossed conditional Setd2 knockout mice (PdxcreSetd2flox/flox) together with KrasG12D mice. Moreover, to examine the role of SETD2 after ductal metaplasia, Crisp/cas9 was used to deplete Setd2 in PDAC cells. RNA-seq and H3K36me3 ChIP-seq were performed to uncover the mechanism. RESULTS: SETD2 mutant/low expression was correlated with poor prognosis in patients with PDAC. Next, we found that Setd2 acted as a putative tumour suppressor in Kras-driven pancreatic carcinogenesis. Mechanistically, Setd2 loss in acinar cells facilitated Kras-induced acinar-to-ductal reprogramming, mainly through epigenetic dysregulation of Fbxw7. Moreover, Setd2 ablation in pancreatic cancer cells enhanced epithelia-mesenchymal transition (EMT) through impaired epigenetic regulation of Ctnna1. In addition, Setd2 deficiency led to sustained Akt activation via inherent extracellular matrix (ECM) production, which would favour their metastasis. CONCLUSION: Together, our findings highlight the function of SETD2 during pancreatic carcinogenesis, which would advance our understanding of epigenetic dysregulation in PDAC. Moreover, it may also pave the way for development of targeted, patients-tailored therapies for PDAC patients with SETD2 deficiency.

[Passive leg raising combined with echocardiography could evaluate volume responsiveness in patients with septic shock].

OBJECTIVE: To assess the value of passive leg raising (PLR) combined with echocardiography in predicting volume responsiveness in patients with septic shock. METHODS: Thirty septic shock patients with spontaneous respiration admitted to intensive care unit (ICU) of Tianjin First Center Hospital from July 2016 to August 2018 were enrolled. PLR and volume expansion (VE) were performed successively. The hemodynamic parameters including left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), stroke volume (SV) and left ventricular ejection fraction (LVEF) before PLR (baseline level), after PLR, immediately after VE were examined by echocardiography, and the central venous pressure (CVP) was monitored. The patients with increase in SV after VE (ΔSV) ≥ 15% were served as reaction group, while ΔSV < 15% were served as non-reaction group. The changes in LVEDV, LVESV, SV, LVEF and CVP at baseline level, after PLR and after VE were compared between the two groups. Pearson correlation method was used to analyze the correlation between ΔSV, increase in LVEF (ΔLVEF) after PLR and ΔSV, and ΔLVEF after VE. Receiver operating characteristic (ROC) curve was plotted to evaluate the predictive value of ΔSV and ΔLVEF after PLR for volume responsiveness. RESULTS: PLR and VE were successfully performed in 30 patients, of which 23 patients (76.7%) were enrolled in the reaction group, and 7 patients (23.3%) in the non-reaction group. Compared with baseline levels, LVEDV, SV, and LVEF in the reaction group were significantly increased after PLR [LVEDV (mL): 83.5±9.6 vs. 77.1±6.2, SV (mL): 48.5±5.6 vs. 43.2±4.9, LVEF: 0.58±0.04 vs. 0.56±0.06, all P < 0.05], and CVP was significantly increased after VE [cmH2O (1 cmH2O = 0.098 kPa): 7.4±3.3 vs. 4.6±0.7, P < 0.01], however, there was no significant change in LVESV. In the non-reaction group, SV and LVEF were significantly increased after PLR as compared with those at baseline levels [SV (mL): 42.7±3.7 vs. 40.6±3.1, LVEF: 0.52±0.05 vs. 0.50±0.05, both P < 0.05], while LVEDV and CVP were significantly increased after VE as compared with those at baseline levels [LVEDV (mL): 84.4±4.1 vs. 80.6±5.9, CVP (cmH2O): 10.6±3.5 vs. 7.6±0.5, both P < 0.05], however, there was no significant change in LVESV. Pearson correlation analysis showed that ΔSV and ΔLVEF after PLR were positively correlated with ΔSV and ΔLVEF after VE (r1 = 0.86, r2 = 0.65, both P < 0.01). ROC curve analysis showed that the area under ROC curve (AUC) of PLR-induced ΔSV and ΔLVEF for predicting volume responsiveness was 0.85 and 0.66 respectively. When the cut-off value of ΔSV after PLR was 10.6%, the sensitivity was 78.2%, the specificity was 82.3%; when the cut-off value of ΔLVEF after PLR was 3.6%, the sensitivity was 78.2%, and the specificity was 73.2%. CONCLUSIONS: ΔSV and ΔLVEF measured by PLR combined with echocardiography can be used to evaluate the volume responsiveness in patients with septic shock and can guide fluid therapy.

CD90 highly expressed population harbors a stemness signature and creates an immunosuppressive niche in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with no effective treatment. Cancer cells, especially cancer stem cells (CSCs), redirect immune cells to evade immune surveillance and even coopt these immune cells to support their growth and metastasis. However, the identification of CSCs and how CSCs interact with immune cells in PDAC remain uncharacterized. Here, we report that CD90 is expressed on both stromal and tumor cells and that high expression of CD90 is related to a poor prognosis in patients with PDAC. The CD90 highly expressed (CD90hi) population in PDAC cells harbors high stemness features and tumorigenicity. Notably, CD90 acts as an anchor for monocyte/macrophage adhesion, providing a physical interaction between CD90hi cells and monocytes/macrophages. In response, the crosstalk between CD90hi cells and monocytes/macrophages promotes immunosuppressive features of immune cells, which enhance the stemness and epithelial-mesenchymal transition (EMT) of PDAC cells. Moreover, PD-L1 is dominantly expressed in the CD90hi population, providing another strategy for these cells to evade immune surveillance. These findings provide an understanding of the biological significance of CD90 expression in PDAC cells and uncover a novel mechanism for how "stem-like" PDAC cells evade immune surveillance.