SUMMARY Here, we report that kinase-dead IKKα knock-in mice develop spontaneous lung squamous cell carcinomas (SCCs) associated with IKKα downregulation and marked pulmonary inflammation. IKKα reduction upregulated the expression of p63, Trim29, and keratin 5 (K5), which serve as diagnostic markers for human lung SCCs. IKKαlowK5+p63hi cell expansion and SCC formation were accompanied by inflammation-associated deregulation of oncogenes, tumor suppressors, and stem cell regulators. Reintroducing transgenic K5.IKKα, depleting macrophages, and reconstituting irradiated mutant animals with WT bone marrow (BM) prevented SCC development, suggesting that BM-derived IKKα-mutant macrophages promote the transition of IKKαlowK5+p63hi cells to tumor cells. This mouse model resembles human lung SCCs, sheds light on the mechanisms underlying lung malignancy development, and identifies targets for therapy of lung SCCs.

Sustained hepatic inflammation, driven by factors such as alcohol consumption, non-alcoholic fatty liver disease (NAFLD) and/or chronic viral hepatitis (Hepatitis B and C), results in damage to parenchyma, oxidative stress, and compensatory regeneration/proliferation. There is substantial evidence linking these inflammation-associated events with the increased incidence of hepatocellular carcinogenesis. While acute liver inflammation can play a vital and beneficial role in response to liver damage or acute infection, the effects of chronic liver inflammation, including liver fibrosis and cirrhosis, are sufficient in a fraction of individuals to initiate the process of transformation and the development of hepatocellular carcinoma (HCC). This review highlights immune-dependent mechanisms that may be associated with hepatocellular oncogenesis, including critical transformative events/pathways in the context of chronic inflammation and subverted tolerogenesis.

Mammalian target of rapamycin (mTOR) is a central mediator of cancer cell growth, but it also directs immune cell differentiation and function. On this basis, we have explored the hypothesis that mTOR inhibition can enhance cancer immunotherapy. Here we report that a combination of αCD40 agonistic antibody and the ATP-competitive mTOR kinase inhibitory drug AZD8055 elicited synergistic anti-tumor responses in a model of metastatic renal cell carcinoma. In contrast to the well-established mTOR inhibitor rapamycin, AZD8055 increased the infiltration, activation and proliferation of CD8+ T cells and NK cells in liver metastatic foci when combined with the CD40 agonist. AZD8055/ αCD40-treated mice also display an increased incidence of matured macrophages and dendritic cells compared to that achieved in mice by αCD40 or AZD8055 treatment alone. We found that the combination treatment also increased macrophage production of TNFα; which played an indispensable role in activation of the observed anti-tumor immune response. Levels of Th1 cytokines, including IL-12, IFN-γ, TNFα, and the Th1-associated chemokines RANTES, MIG and IP-10 were each elevated significantly in the livers of mice treated with the combinatorial therapy versus individual treatments. Notably, the AZD8055/αCD40-induced anti-tumor response was abolished in IFN-γ −/− and CD40 −/− mice, establishing the reliance of the combination therapy on host IFN-γ and CD40 expression. Our findings offer a preclinical proof of concept that, unlike rapamycin, the ATP-competitive mTOR kinase inhibitor AZD8055 can contribute with αCD40 treatment to trigger a restructuring of the tumor immune microenvironment to trigger regressions of an established metastatic cancer.

Aeromonas veronii is a kind of opportunistic pathogen to fish and humans, significantly impending aquaculture production. Recently, we isolated two A. veronii strains, named GYC1 and GYC2, from diseased Gibel carp (Carassius gibelio) in China. Based on gyrB (DNA gyrase B subunit) genes of GYC1 and GYC2, the constructed phylogenetic tree showed that the two strains were clustered with A. veronii. Sixteen virulence genes related to the pathogenicity of Aeromonas spp. were subjected to PCR assay. The genes of ompAI, ompAII, lafA, act, aer, fla, gcaT and acg were detected in the two strains, while genes of hly, ahp, lip, ast and alt were not detected. Additionally, genes eprCAI, ela and exu were only detected in the strain GYC1. Furthermore, the results of extracellular enzyme analysis revealed that the two isolates can produce hemolysin, caseinase, esterase, amylase and lecithinase, which were closely related to the pathogenicity of the two strains. However, the results showed that there was no gelatinase activity in either strain. According to the antibiotic resistant assay, the two strains were sensitive to cephalosporins and aminoglycosides, while they were resistant to penicillins and quinolones. Through this study, the virulence characteristics, including virulence genes and extracellular enzymes, the pathogenicity of A. veronii was clarified, enhancing the understanding about this pathogenic bacterium and providing the theoretical basis in disease control.

Introduction: BRCA1-associated protein-1 (BAP1), a nuclear deubiquitinase thought to be involved in DNA doublestrand break repair, is frequently mutated in mesothelioma. Because poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPIs) induce synthetic lethality in BRCA1/2 mutant cancers, we evaluated whether BAP1 inactivating mutations confer sensitivity to PARPIs in mesothelioma and if combination therapy with temozolomide (TMZ) would be beneficial.Methods: A total of 10 patient-derived mesothelioma cell lines were generated and characterized for BAP1 mutation status, protein expression, nuclear localization, and sensitivity to the PARPIs, olaparib, and talazoparib, alone or in combination with TMZ. BAP1 deubiquitinase (DUB) activity was evaluated by ubiquitin with 7-amido-4methylcoumarin assay. BAP1 knockout mesothelioma cell lines were generated by CRISPR-Cas9. Because Schlafen 11 (SLFN11) and O 6 -methylguanine-DNA methyltransferase also drive response to TMZ and PARPIs, we tested their expression and relationship with drug response.Results: BAP1 mutations or copy-number alterations, or both were present in all 10 cell lines. Nonetheless, four cell lines exhibited intact DUB activity and two had nuclear BAP1 localization. Half maximal-inhibitory concentrations of olaparib and talazoparib ranged from 4.8 mM to greater than 50 mM and 0.039 mM to greater than 5 mM, respectively, classifying them into sensitive (two) or resistant (seven) cells, independent of their BAP1 status. Cell lines with BAP1 knockout resulted in the loss of BAP1 DUB activity but did not increase sensitivity to talazoparib. Response to PARPI tended to be associated with high SLFN11 expression, and combination with temozolomide increased sensitivity of cells with low or no MGMT expression.

We investigate the propagation of the spatial soliton in cylindrical strongly nonlocal media by a novel method of image beam of light. The effect of the boundary on the soliton acting as the dynamic force for the soliton steering is equivalent to the force between the soliton beam and the image beam. The trajectory of the soliton is analytically studied which is in good agreement with the experimental results.

NKT cells are a heterogeneous subset of specialized, self-reactive T cells, with innate and adaptive immune properties, which allow them to bridge innate and adaptive immunity and profoundly influence autoimmune and malignant disease outcomes. NKT cells mediate these activities through their ability to rapidly express pro- and anti-inflammatory cytokines that influence the type and magnitude of the immune response. Not only do NKT cells regulate the functions of other cell types, but experimental evidence has found NKT cell subsets can modulate the functions of other NKT subsets. Depending on underlying mechanisms, NKT cells can inhibit or exacerbate autoimmunity and malignancy, making them potential targets for disease intervention. NKT cells can respond to foreign and endogenous antigenic glycolipid signals that are expressed during pathogenic invasion or ongoing inflammation, respectively, allowing them to rapidly react to and influence a broad array of diseases. In this article we review the unique development and activation pathways of NKT cells and focus on how these attributes augment or exacerbate autoimmune disorders and malignancy. We also examine the growing evidence that NKT cells are involved in liver inflammatory conditions that can contribute to the development of malignancy.

LMB-100 is an immunotoxin targeting the cell surface protein mesothelin, which is highly expressed in many cancers including mesothelioma. Having observed that patients receiving pembrolizumab off protocol after LMB-100 treatment had increased tumor responses; we characterized these responses and developed animal models to study whether LMB-100 made tumors more responsive to antibodies blocking programmed cell death protein 1 (PD-1). The overall objective tumor response in the 10 patients who received PD-1 inhibitor (pembrolizumab, 9; nivolumab, 1) after progression on LMB-100 was 40%, and the median overall survival was 11.9 months. Of the seven evaluable patients, four had objective tumor responses, including one complete response and three partial responses, and the overall survival for these patients was 39.0+, 27.7, 32.6+, and 13.8 months. When stratified with regard to programmed death ligand 1 (PD-L1) expression, four of five patients with tumor PD-L1 expression had objective tumor response. Patients with positive tumor PD-L1 expression also had increased progression-free survival (11.3 versus 2.1 months, P = 0.0018) compared with those lacking PD-L1 expression. There was no statistically significant difference in overall survival (27.7 versus 6.8 months, P = 0.1). LMB-100 caused a systemic inflammatory response and recruitment of CD8+ T cells in patients’ tumors. The enhanced antitumor effects with LMB-100 plus anti–PD-1 antibody were also observed in a human peripheral blood mononuclear cell–engrafted mesothelioma mouse model and a human mesothelin–expressing syngeneic lung adenocarcinoma mouse model. LMB-100 plus pembrolizumab is now being evaluated in a prospective clinical trial for patients with mesothelioma.