These preclinical results indicate that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in PDAC.

Microsatellite instability (MSI) is a hallmark of mismatch repair (MMR) deficiency. High levels of MSI at mononucleotide and dinucleotide repeats in colorectal cancer (CRC) are attributed to inactivation of the MMR genes, hMLH1 and hMSH2. CRC with low levels of MSI (MSI-L) exists; however, its molecular basis is unclear. There is another type of MSIelevated microsatellite alterations at selected tetranucleotide repeats (EMAST)-where loci containing [AAAG] n or [ATAG] n repeats are unstable. EMAST is frequent in non-CRCs; however, the incidence of EMAST and its cause in CRC is not known. Here, we report that MutS homologue 3 (MSH3) knockdown or MSH3-deficient cells exhibit the EMAST phenotype and low levels of mutations at dinucleotide repeats. About 60% of 117 sporadic CRC cases exhibit EMAST. All of the cases defined as MSI-H (16 cases) exhibited high levels of EMAST. Among 101 non-MSI-H cases, all 19 cases of MSI-L and 35 of 82 cases of MSS exhibited EMAST. Although non-MSI-H CRC tissues contained MSH3-negative tumor cells ranging from 2% to 50% of the total tumor cell population, the tissues exhibiting EMAST contained more MSH3-negative cells (average, 31.5%) than did the tissues not exhibiting EMAST (8.4%). Taken together, our results support the concept that MSH3 deficiency causes EMAST or EMAST with low levels of MSI at loci with dinucleotide repeats in CRC. [Cancer Res 2008;68(20):8465-72]

Inhibitors of caspases-8, -6, or -3 partially inhibited taxolinduced apoptosis, whereas the caspase-10 inhibitor totally abrogated this process. Taxol-induced apoptosis was also associated with decreased mitochondrial membrane potential (⌬⌿m) and a significant increase in ROS generation. However, increased ROS production was not directly involved in taxol-triggered apoptosis. Therefore, these results demonstrate for the first time that taxol induces FADD-dependent apoptosis primarily through activation of caspase-10 but independently of death receptors.

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Non‐small‐cell lung cancer (NSCLC) is one of the most common and lethal malignant tumours worldwide with a poor 5‐year survival rate. Recent studies indicated that miRNAs have been involved in the tumorigenic driver pathways in NSCLC, but the relevant molecular mechanisms are not well‐understood. In this study, we investigated the biological functions and molecular mechanisms of miR‐138 in human NSCLC. The effects of miR‐138 on the NSCLC cell growth and epithelial‐mesenchymal transition (EMT) were first examined. Then the targeting connections of miR‐138 with G‐protein‐coupled receptor kinase‐interacting protein 1 (GIT1) and semaphorin 4C (SEMA4C) were confirmed by dual luciferase reporter assays. Finally, the effects of GIT1 and SEMA4C on the NSCLC cell growth and EMT were investigated respectively. We found that the ectopic expression of miR‐138 resulted in a significant inhibition of NSCLC growth and reversion of EMT. GIT1 and SEMA4C were identified as two novel targets of miR‐138. Furthermore, GIT1 and SEMA4C knockdown inhibited the cell growth and reversed EMT, just like the effects of miR‐138 overexpression on NSCLC cells, whereas ectopic expression of GIT1 and SEMA4C partly rescued the suppressive effects of miR‐138 in NSCLC cells. These data represent a crucial step towards the understanding of the novel roles and molecular mechanism of miR‐138, GIT1 and SEMA4C in NSCLC progression, which may provide some new targets or prognostic biomarkers for NSCLC treatment, thus having implications in translational oncology.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy partly due to frequent, severe cachexia. Serum activin correlates with cachexia and mortality, while exogenous activin causes cachexia in mice.MethodsIsoform‐specific activin expression and activities were queried in human and murine tumours and PDAC models. Activin inhibition was by administration of soluble activin type IIB receptor (ACVR2B/Fc) and by use of skeletal muscle specific dominant negative ACVR2B expressing transgenic mice. Feed‐forward activin expression and muscle wasting activity were tested in vivo and in vitro on myotubes.ResultsMurine PDAC tumour‐derived cell lines expressed activin‐βA but not activin‐βB. Cachexia severity increased with activin expression. Orthotopic PDAC tumours expressed activins, induced activin expression by distant organs, and produced elevated serum activins. Soluble factors from PDAC elicited activin because conditioned medium from PDAC cells induced activin expression, activation of p38 MAP kinase, and atrophy of myotubes. The activin trap ACVR2B/Fc reduced tumour growth, prevented weight loss and muscle wasting, and prolonged survival in mice with orthotopic tumours made from activin‐low cell lines. ACVR2B/Fc also reduced cachexia in mice with activin‐high tumours. Activin inhibition did not affect activin expression in organs. Hypermuscular mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not mortality when implanted with orthotopic tumours. Human tumours displayed staining for activin, and expression of the gene encoding activin‐βA (INHBA) correlated with mortality in patients with PDAC, while INHBB and other related factors did not.ConclusionsPancreatic adenocarcinoma tumours are a source of activin and elicit a systemic activin response in hosts. Human tumours express activins and related factors, while mortality correlates with tumour activin A expression. PDAC tumours also choreograph a systemic activin response that induces organ‐specific and gene‐specific expression of activin isoforms and muscle wasting. Systemic blockade of activin signalling could preserve muscle and prolong survival, while skeletal muscle‐specific activin blockade was only protective for weight loss. Our findings suggest the potential and need for gene‐specific and organ‐specific interventions. Finally, development of more effective cancer cachexia therapy might require identifying agents that effectively and/or selectively inhibit autocrine vs. paracrine activin signalling.

Introduction-Solid tumors, such as neuroblastoma (NB), are associated with a heterogeneous cell environment. Multicellular tumor spheroid (MCTS) cultures have been shown to better mimic growth characteristics of in vivo solid tumors. Because tumor spheroid growth patterns may be quite different from standard two-dimensional culture systems, we sought to compare the protein expression profiles of two-and three-dimensional in vitro NB cultures, i.e., monolayers and MCTS.

The development of efficient and low-cost hydrogen evolution reaction (HER) catalysts is critical for storing energy in hydrogen via water splitting but still presents great challenges. Herein, we report synthesis of three-dimensional (3-D) hierarchical nanoporous carbon (HNC) supported transition metal phosphides (TMPs) for the first time by in situ growth of CoP nanoparticles (NPs) in CaCO3 NP-templated Cinnamomum platyphyllum leaf extract-derived carbon. They were subsequently employed as a HER catalyst, showing an onset potential of 7 mV and an overpotential of 95.8 mV to achieve 10 mA cm(-2), a Tafel plot of 33 mV dec(-1), and an exchange current density of 0.1182 mA cm(-2), of which the onset overpotential and the Tafel plot are the lowest reported for non-noble-metal HER catalysts, and the overpotential to achieve 10 mA cm(-2) and the exchange current density also compare favorably to most reported HER catalysts. In addition, this catalyst exhibits excellent durability with negligible loss in current density after 2000 CV cycles ranging from +0.01 to -0.17 V vs RHE at a scan rate of 100 mV s(-1) or 22 h of chronoamperometric measurement at an overpotential of 96 mV and a high Faraday efficiency of close to 100%. This work not only creates a novel high-performance non-noble-metal HER electrocatalyst and demonstrates the great advantages of the in situ grown 3-D HNC supported TMP NPs for the electrocatalysis of HER but also offers scientific insight into the mechanism for the in situ growth of TMP and their precursor NPs, in which an ultralow reactant concentration and rich functional groups on the 3-D HNC support play critical roles.