Thermally stable C2-symmetric α-diimine nickel precatalysts for ethylene polymerization: semicrystalline to amorphous PE with high tensile and elastic properties.

In α-diimine nickel catalyst-mediated ethylene polymerization, adjusting catalytic parameters such as steric and electronic factors, as well as spectator ligands, offers an intriguing approach for tailoring the thermal and physical properties of the resulting products. This study explores two sets of C2-symmetric α-diimine nickel complexes-nickel bromide and nickel chloride-where ortho-steric and electronic substituents, as well as nickel halide, were varied to regulate simultaneously chain walking, chain transfer, and the properties of the polymers produced. These complexes were activated in situ with Et2AlCl, resulting in exceptionally high catalytic activities (in the level of 106-107 g (PE) mol-1 (Ni) h-1) under all reaction conditions. Nickel bromide complexes, with higher ortho-steric hindrance, exhibited superior catalytic activity compared to their less hindered counterparts, whereas the reverse was observed for complexes containing chloride. Increased steric hindrance in both sets of complexes facilitated higher polymer molecular weights and promoted chain walking reactions at lower reaction temperature (40 °C), while the effect became less pronounced at higher temperature (100 °C). However, the electron-withdrawing effect of ortho-substituents hindered the rate of monomer insertion, chain propagation, and chain walking reactions, leading to the synthesis of semi-crystalline polyethylene with an exceptionally high melt temperature of 134.6 °C and a high crystallinity of up to 31.9%. Most importantly, nickel bromide complexes demonstrated significantly higher activity compared to their chloride counterparts, while the latter yielded polymers with higher molecular weights and increased melt temperatures. These high molecular weights, coupled with controlled branching degrees, resulted in polyethylenes with excellent tensile strength (up to 13.9 MPa) and excellent elastic properties (up to 81%), making them suitable for a broad range of applications.

Interleukin-37 promotes DMBA/TPA skin cancer through SIGIRR-mediated inhibition of glycolysis in CD103+DC cells.

Interleukin 37 (IL-37), a member of the IL-1 family, is considered a suppressor of innate and adaptive immunity and, hence is a regulator of tumor immunity. However, the specific molecular mechanism and role of IL-37 in skin cancer remain unclear. Here, we report that IL-37b-transgenic mice (IL-37tg) treated with the carcinogenic 7,12-dimethylbenzoanthracene (DMBA)/12-o-tetradecylphorbol-13-acetate (TPA) exhibited enhanced skin cancer and increased tumor burden in the skin by inhibiting the function of CD103+ dendritic cells (DCs). Notably, IL-37 induced rapid phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and via single immunoglobulin IL-1-related receptor (SIGIRR), inhibited the long-term Akt activation. Specifically, by affecting the SIGIRR-AMPK-Akt signaling axis, which is related to the regulation of glycolysis in CD103+DCs, IL-37 inhibited their anti-tumor function. Our results show that a marked correlation between the CD103+DC signature (IRF8, FMS-like tyrosine kinase 3 ligand, CLEC9A, CLNK, XCR1, BATF3, and ZBTB46) and chemokines C-X-C motif chemokine ligand 9, CXCL10, and CD8A in a mouse model with DMBA/TPA-induced skin cancer. In a word, our results highlight that IL-37 as an inhibitor of tumor immune surveillance through modulating CD103+DCs and establishing an important link between metabolism and immunity as a therapeutic target for skin cancer.

Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction.

Interleukin-37b (hereafter called IL-37) was identified as fundamental inhibitor of natural and acquired immunity. The molecular mechanism and function of IL-37 in colorectal cancer (CRC) has been elusive. Here, we found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and suffered from dramatically increased tumor burdens in colon. Nevertheless, IL-37 is dispensable for intestinal mutagenesis, and CRC cell proliferation, apoptosis, and migration. Notably, IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models. CD8+ T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice, enabling tumor evasion of immune surveillance. The dysfunction led by IL-37 antagonizes IL-18-induced proliferation and effector function of CD8+ T cells, which was dependent on SIGIRR (single immunoglobulin interleukin-1 receptor-related protein). Finally, we observed that IL-37 levels were significantly increased in CRC patients, and positively correlated with serum CRC biomarker CEA levels, but negatively correlated with the CD8+ T cell infiltration in CRC patients. Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancer-immunity cycle as therapeutic targets in CRC.

EDIL3 deficiency ameliorates adverse cardiac remodelling by neutrophil extracellular traps (NET)-mediated macrophage polarization.

AIMS: After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils and monocytes/macrophages to myocardium, which in turn initiates inflammatory and reparative cascades, respectively. Either insufficient or excessive inflammation impairs cardiac healing. As an endogenous inhibitor of neutrophil adhesion, EDIL3 plays a crucial role in inflammatory regulation. However, the role of EDIL3 in MI remains obscure. We aimed to define the role of EDIL3 in cardiac remodelling after MI. METHODS AND RESULTS: Serum EDIL3 levels in MI patients were negatively associated with MI biomarkers. Consistently, WT mice after MI showed low levels of cardiac EDIL3. Compared with WT mice, Edil3-/- mice showed improvement of post-MI adverse remodelling, as they exhibited lower mortality, better cardiac function, shorter scar length, and smaller LV cavity. Accordingly, infarcted hearts of Edil3-/- mice contained fewer cellular debris and lower amounts of fibrosis content, with decreased collagen I/III expression and the percentage of α-smooth muscle actin myofibroblasts. Mechanistically, EDIL3 deficiency did not affect the recruitment of monocytes or T cells, but enhanced neutrophil recruitment and following expansion of pro-inflammatory Mertk-MHC-IIlo-int (myeloid-epithelial-reproductive tyrosine kinase/major histocompatibility complex II) macrophages. The injection of neutrophil-specific C-X-C motif chemokine receptor 2 antagonist eliminated the differences in macrophage polarization and cardiac function between WT and Edil3-/- mice after MI. Neutrophil extracellular traps (NETs), which were more abundant in the hearts of Edil3-/- mice, contributed to Mertk-MHC-IIlo-int polarization via Toll-like receptor 9 pathway. The inhibition of NET formation by treatment of neutrophil elastase inhibitor or DNase I impaired macrophage polarization, increased cellular debris and aggravated cardiac adverse remodelling, thus removed the differences of cardiac function between WT and Edil3-/- mice. Totally, EDIL3 plays an important role in NET-primed macrophage polarization and cardiac remodelling during MI. CONCLUSION: We not only reveal that EDIL3 deficiency ameliorates adverse cardiac healing via NET-mediated pro-inflammatory macrophage polarization but also discover a new crosstalk between neutrophil and macrophage after MI.

Autophagy-based unconventional secretion of HMGB1 by keratinocytes plays a pivotal role in psoriatic skin inflammation.

The precise mechanism through which macroautophagy/autophagy affects psoriasis is poorly understood. Here, we found that keratinocyte (KC) autophagy, which was positively correlated with psoriatic severity in patients and mouse models and could be inhibited by mitogen-activated protein kinase (MAPK) family inactivation. The impairment of autophagic flux alleviated psoriasisform inflammation. We also found that an autophagy-based unconventional secretory pathway (autosecretion) dependent on ATG5 (autophagy related 5) and GORASP2 (golgi reassembly stacking protein 2) promoted psoriasiform KC inflammation. Moreover, the alarmin HMGB1 (high mobility group box 1) was more effective than other autosecretory proteins in regulating psoriasiform cutaneous inflammation. HMGB1 neutralization in autophagy-efficient KCs eliminated the differences in psoriasiform inflammation between Krt14+/+-Atg5f/f KCs and Krt14Cre/+-atg5f/f KCs, and conversely, recombinant HMGB1 almost completely restored psoriasiform inflammation in Krt14Cre/+-atg5f/f KCs in vivo. These results suggest that HMGB1-associated autosecretion plays a pivotal role in cutaneous inflammation. Finally, we demonstrated that Krt14Cre/+-hmgb1f/f mice displayed attenuated psoriatic inflammation due to the essential crosstalk between KC-specific HMGB1-associated autosecretion and γδT cells. Thus, this study uncovered a novel autophagy mechanism in psoriasis pathogenesis, and the findings imply the clinical significance of investigating and treating psoriasis.Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; AGER: advanced glycosylation end-product specific receptor; Anti-HMGB1: anti-HMGB1 neutralizing antibody; Anti-IL18: anti-IL18 neutralizing antibody; Anti-IL1B: anti-IL1B neutralizing antibody; ATG5: autophagy related 5; BAF: bafilomycin A1; BECN1: beclin 1; CASP1: caspase 1; CCL: C-C motif chemokine ligand; CsA: cyclosporine A; ctrl shRNA: lentivirus harboring shRNA against control; CXCL: C-X-C motif chemokine ligand; DCs: dendritic cells; DMEM: dulbecco's modified Eagle's medium; ELISA: enzyme-linked immunosorbent assay; EM: electron microscopy; FBS: fetal bovine serum; GORASP2 shRNA: lentivirus harboring shRNA against GORASP2; GORASP2/GRASP55: golgi reassembly stacking protein 2; GR1: a composite epitope between LY6 (lymphocyte antigen 6 complex) locus C1 and LY6 locus G6D antigens; H&E: hematoxylin and eosin; HMGB1: high mobility group box 1; HMGB1 shRNA: lentivirus harboring shRNA against HMGB1; IFNG/IFN-γ: interferon gamma; IL17A: interleukin 17A; IL18: interleukin 18; IL1A/IL-1α: interleukin 1 alpha; IL1B/IL-1ß: interleukin 1 beta; IL22/IL-22: interleukin 22; IL23A: interleukin 23 subunit alpha; IL23R: interleukin 23 receptor; IMQ: imiquimod; ITGAM/CD11B: integrin subunit alpha M; ITGAX/CD11C: integrin subunit alpha X; IVL: involucrin; KC: keratinocyte; KD: knockdown; KO: knockout; Krt14+/+-Atg5f/f mice: mice bearing an Atg5 flox allele, in which exon 3 of the Atg5 gene is flanked by two loxP sites; Krt14+/+-Hmgb1f/f: mice bearing an Hmgb1 flox allele, in which exon 2 to 4 of the Hmgb1 gene is flanked by two loxP sites; Krt14Cre/+-atg5f/f mice: keratinocyte-specific atg5 knockout mice generated by mating Atg5-floxed mice with mice expressing Cre recombinase under the control of the promoter of Krt4; Krt14Cre/+-hmgb1f/f mice: keratinocyte-specific hmgb1 knockout mice generated by mating Hmgb1-floxed mice with mice expressing Cre recombinase under the control of the promoter of Krt14; Krt14-Vegfa mice: mice expressing 164-amino acid Vegfa splice variant recombinase under the control of promoter of Krt14; LAMP1: lysosomal associated membrane protein 1; LDH: lactate dehydrogenase; LORICRIN: loricrin cornified envelope precursor protein; M5: TNF, IL1A, IL17A, IL22 and OSM in combination; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MKI67: marker of proliferation Ki-67; MTT: thiazolyl blue tetrazolium bromide; NFKB/NF-κB: nuclear factor kappa B; NHEKs: primary normal human epidermal keratinocytes; NS: not significant; OSM: oncostatin M; PASI: psoriasis area and severity index; PtdIns3K: class III phosphatidylinositol 3-kinase; qRT-PCR: quantitative RT-PCR; RELA/p65: RELA proto-oncogene, NF-kB subunit; rHMGB1: recombinant HMGB1; rIL18: recombinant interleukin 18; rIL1B: recombinant interleukin 1 beta; S100A: S100 calcium binding protein A; SQSTM1/p62: sequestosome 1; T17: IL17A-producing T; TCR: T-cell receptor; tcrd KO mice: tcrd (T cell receptor delta chain) knockout mice, which show deficient receptor expression in all adult lymphoid and epithelial organs; TLR: toll-like receptor; TNF/TNF-α: tumor necrosis factor; WOR: wortmannin; WT: wild-type; γδT17 cells: IL17A-producing γδ T cells.

Merging three-dimensional CT with electroanatomic mapping facilitates ablation of ventricular arrhythmias originating from aortic root and great cardiac vein.

PURPOSE: In radiofrequency ablation near coronary arteries (CA), coronary angiography is traditionally recommended to estimate distance between catheter and CA. This study aimed to investigate the feasibility of an alternative approach for intuitively demonstrating spatial location of catheter and CA during ablation of ventricular arrhythmias (VAs) originating from aortic root (AR) and great cardiac vein (GCV). METHODS: During mapping and ablation, 3D-reconstructed cardiac CT and electroanatomic mapping were merged, and distance between CA and catheter was monitored. Coronary angiography, for distance verification, was used when the distance was less than 5 mm in image integration model (IIM). RESULTS: Twenty-three patients (52.26 ± 17.89 years, 12 men) with ablation originating in left cusp (LCC, n = 8), right cusp (n = 2), and left-right cusp junction (LCC-RCC, n = 12) and GCV (n = 1) were enrolled. In IIM, the distance between origin and CA was less than 5 mm in 2 VAs originating in LCC and one in GCV (3/23), whereas distance for ablation was always safe (12.3-22.3 mm) for VAs of LCC-RCC origin. IIM avoided angiography use in 20 patients, reducing radiation exposure by 80.6% (650.18 ± 624.31 vs 3356.97 ± 1529.46uGycm2, P = 0.088). VA termination failed in two cases of LCC origin due to proximity to CA, and was achieved in all other patients (91.3%). No CA damage occurred during the procedures. CONCLUSION: Mapping and ablation under IIM guidance of VAs of AR and GCV origin appears feasible and safe, while avoiding angiography use particularly in VAs of LCC-RCC origin.

Microstructure and Pitting Corrosion of Austenite Stainless Steel after Crack Arrest.

With synergy of plastic deformation near crack tip and pulse current treatment, complex phase transformation and recrystallization occur in the metallographic structure, with the austenite transforming to fine grain structure and deformation-induced martensite; but, without the plastic deformation, the phase transformation, and recrystallization it was difficult for the crack arrest process to take place only undergoing the pulse current treatment. The nano-indentation experiment showed that the phase transformation region contained the maximum residual compressive stress consisting of four parts: the plastic stress, the explosion stress, the thermal stress, and the transformation stress, which was beneficial to restrain the crack growth. However, the solidification structure and the deformation-induced martensite structure was vulnerable to pitting corrosion through scanning microelectrode technology (SMET) and pitting corrosion experiment, but the pitting corrosion resistance could be improved through the solution heat treatment.

NFATc1 is a tumor suppressor in hepatocellular carcinoma and induces tumor cell apoptosis by activating the FasL-mediated extrinsic signaling pathway.

Nuclear factor of activated T cells (NFAT) is a family of transcription factors that have important functions in many tumors. However, the expression level and functional role of NFAT in hepatocellular carcinoma (HCC) remain unclear. In this study, we showed that NFATc1 expression was decreased in both HCC tissues and cell lines. Low expression of NFATc1 was correlated with larger tumor size, advanced tumor-node-metastasis (TNM) stage, high serum AFP level, and liver cirrhosis. Furthermore, patients with low NFATc1 expression exhibited poor prognosis. Ectopic expression of NFATc1 in HCC cells inhibited proliferation and colony formation, leading to G1 arrest and induction of apoptosis. In addition, we demonstrated that NFATc1 increased Fas ligand (FasL) expression by directly binding to its promoter and activated the extrinsic apoptotic pathway. NFATc1 and FasL expression patterns and their prognostic value for patients with HCC were also evaluated in TCGA Liver Hepatocellular Carcinoma database. Knock-down of FasL expression by siRNA in HCC cell lines abolished NFATc1's antiproliferative and pro-apoptotic effects. In conclusion, NFATc1 is frequently inactivated in HCC and functions as a tumor suppressor in liver carcinogenesis. Ectopic expression of NFATc1 in HCC cells induces apoptosis by activating the FasL-mediated extrinsic signaling pathway.

Sox12 Is a Cancer Stem-Like Cell Marker in Hepatocellular Carcinoma.

Recent studies on molecular carcinogenesis suggest that the chemo-resistance of some cancers is largely due to presence of cancer stem cells (CSCs), which affect the chemotherapy outcome for hepatocellular carcinoma (HCC). However, currently no consensus on a CSC phenotype in HCC has been obtained. Here, we examined Sox12 as a novel CSC marker in HCC. Sox12+ versus Sox12- cells were purified from HCC cell lines. The Sox12+ cells were compared with Sox12- HCC cells for tumor sphere formation, chemo-resistance, tumor formation after serial adoptive transplantations in nude mice, and the frequency of developing distal metastasis. We found that compared to Sox12- HCC cells, Sox12+ HCC cells generated significantly more tumor spheres in culture, were more chemo-resistant to cisplatin, were detected in circulation more frequently, and formed distal tumor more frequently. Moreover, Sox12 appeared to functionally contribute to the stemness of HCC cells. Thus, we conclude that Sox12 may be a novel marker for enriching CSCs in HCC.

Giant mucinous adenocarcinoma of the appendix: a case report.

BACKGROUND: Appendiceal mucinous adenocarcinoma is an extremely rare disease in clinical practice. Here, we report a case of unprecedented size that occupied the entire abdomen of a man. CASE PRESENTATION: A 49-year-old Chinese Han man presented with symptoms of abdominal distension. During a computed tomography imaging examination, a cystic-solid mass that occupied his entire abdominal cavity was detected. During exploratory laparotomy, an appendiceal tumor in his abdominal-pelvic cavity measuring 27.6 × 14.2 cm was found, and he underwent tumor resection. The pathology of the tumor identified a well-differentiated appendiceal mucinous adenocarcinoma with mucin infiltrating into the soft tissue of the lump edge and omentum tissue. After surgery, our patient accepted intraperitoneal infusion chemotherapy. At present, he has had no recurrence for 15 months. CONCLUSIONS: To the best of our knowledge, the present case is the largest appendiceal mucinous adenocarcinoma reported. Surgical tumor resection is the preferred treatment for appendiceal mucinous adenocarcinoma. This is supplemented by chemotherapy which can further prolong survival.