Fungi of the order Mucorales cause mucormycosis, a lethal infection with an incompletely understood pathogenesis. We now demonstrate that Mucorales fungi produce a toxin that plays a central role in virulence. Polyclonal antibodies against this toxin inhibit its ability to damage human cells in vitro, and prevent hypovolemic shock, organ necrosis, and death in mice with mucormycosis. RNAi inhibition of the toxin in Rhizopus delemar, compromises the ability of the fungus to damage host cells and attenuates virulence in mice. This 17 kDa toxin has structural and functional features of the plant toxin, ricin, including the ability to inhibit protein synthesis by its N-glycosylase activity, the existence of a motif that mediates vascular leak, and a lectin sequence. Antibodies against the toxin inhibit R. delemar-or toxin-mediated vascular permeability in vitro and cross-react with ricin. A monoclonal anti-ricin B chain antibody binds to the toxin and also inhibits its ability to cause vascular permeability. Therefore, we propose the name "mucoricin" for this toxin. Not only is mucoricin important in the pathogenesis of mucormycosis but our data suggest that a ricinlike toxin is produced by organisms beyond the plant and bacterial kingdoms. Importantly, mucoricin should be a promising therapeutic target.

Histopathological tumor regression grade (TRG) has been shown to be a prognostic factor in patients with esophageal cancer after neoadjuvant radiochemotherapy (RCT). The system introduced by Mandard to group TRG (Cancer 1994;73:2680-2686) has been used to analyse and discuss its prognostic significance on survival in a single institution retrospective analysis: TRG 1 (complete regression) - TRG 5 (absence of regressive changes). Sixty patients with locally advanced (T3/4 or N1) adenocarcinoma or squamous cell carcinoma received cisplatin-based RCT. Three to four weeks later operation for curative intent was performed. Median follow-up was 17.7 months. Histopathological tumor stages were stage 0 in 17%, stage I in 10%, stage II in 60%, stage III in 12% and stage IVA in 1%. The 5-year overall survival (OS) rate was 35%. In univariate analysis, ypN-status and TRG correlated significantly with OS (P = 0.004, P = 0.0008, respectively). While OS of TRG 1 differed significantly from all other groups, no differences in OS between the other TRG groups were seen. Patients with complete tumor regression after neoadjuvant RCT showed a much better survival than patients with tumors that responded less to induction therapy. Further qualitative subdivision of tumor regression could not identify patient groups with significant differences in prognosis. After comparing our data with the literature, it is reasonable to consider classifying all patients into 'Complete tumor regression' and 'Incomplete tumor regression'.

Tumor-associated macrophages can potentially kill tumor cells via the high concentrations of nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS); however , tumor-associated macrophages actually support tumor growth , as they are skewed toward M2 activation , which is characterized by low amounts of NO production and is proangiogenic. We show that the mouse renal cell carcinoma cell line, RENCA , which , on stimulation , expresses high levels of iNOS mRNA , loses its ability to express the iNOS protein. This effect is mediated by the microRNA miR146a , as inhibition of RENCA cells with anti-miR146a restores iNOS expression and NO production Tumor-associated macrophages (TAMs) typically infiltrate and accumulate in solid tumors, 1 and are equipped with efficient killing mechanisms, such as production of high cytotoxic amounts of nitric oxide (NO) by the enzyme inducible nitric oxide synthase (iNOS).2,3 High NO concentrations can either initiate tumor cell apoptosis (cytotoxic effects) or arrest cell cycle (cytostatic effects), as NO or its derivatives cause nitrosative stress that can release cytochrome c, increase nuclear accumulation of wild-type p53, and reduce Bcl-2.4 -6 However, the factors that determine whether the mechanism used would lead to cytotoxicity or cytostasis are still unknown.Expression of iNOS is up-regulated in many tumors, but immunohistochemistry reveals that it is mostly expressed in TAMs and only to a lesser degree in the tumor cells themselves. 7 However, TAMs are often ineffective in tumor killing and actually promote tumor growth. The paradox of strong iNOS expression that is correlated 8 with aggressiveness and high incidence of metastasis (eg, in breast, gastric, and colorectal carcinomas 7 ), is explained by the levels of NO that are, in fact, generated. While high levels of NO cause tumor-cell death, low amounts of NO actually promote tumor growth, angiogenesis, and metastasis by regulating blood flow, increasing vascular permeability, and up-regulating vascular endothelial growth factor and matrix metalloproteinases. -11Control over NO production is subject to the polarization of TAMs toward an alternative or M2 activation by anti-inflammatory mediators that are secreted by tumor cells; eg, interleukin-10, transforming growth factor ␤, and prostaglandin E 2 . These mediators can induce arginase-1, which competes with iNOS for the common substrate L-arginine, causing reduced NO generation.9 Hypoxia, characterizing solid tumors, can also reduce NO production by disrupting protein-protein interactions that are required for iNOS activity.

Key Points• Two novel transducer modules consisting of BTK in combination with either FLT3-ITD or TLR9 induce distinct oncogenic signaling programs.• This study suggests subtypespecific treatment strategies, including BTK/FLT3 inhibitor combinations, and shows how TLR9 affects AML biology.Acute myeloid leukemia (AML) is driven by niche-derived and cell-autonomous stimuli. Although many cell-autonomous disease drivers are known, niche-dependent signaling in the context of the genetic disease heterogeneity has been difficult to investigate. Here, we analyzed the role of Bruton tyrosine kinase (BTK) in AML. BTK was frequently expressed, and its inhibition strongly impaired the proliferation and survival of AML cells also in the presence of bone marrow stroma. By interactome analysis, (phospho)proteomics, and transcriptome sequencing, we characterized BTK signaling networks. We show that BTK-dependent signaling is highly context dependent. In Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-positive AML, BTK mediates FLT3-ITDdependent Myc and STAT5 activation, and combined targeting of FLT3-ITD and BTK showed additive effects. In Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-negative AML, BTK couples Toll-like receptor 9 (TLR9) activation to nuclear factor kΒ and STAT5. Both BTK-dependent transcriptional programs were relevant for cell cycle progression and apoptosis regulation. Thus, we identify context-dependent oncogenic driver events that may guide subtype-specific treatment strategies and, for the first time, point to a role of TLR9 in AML.

The aim of the present study was to evaluate the expression and localization of connexin (Cx) 26, -43 and -45 in a group of 35 patients with primary oral squamous cell carcinoma (OSCC) with the objective of making a more accurate disease prognosis. We analysed the expression of connexins in tissue samples of primary OSCC, matching oral mucosa free of dysplasia, and its associated lymph node metastases (LNM) by semi-quantitative immunohistochemistry of membrane, cytoplasmic and nuclear connexin expression. The levels of expression were correlated with the overall survival time (OS). Cx43 was overexpressed in tumour cells compared to epithelia in dysplasia-free mucosa. High membrane expression of Cx43 on tumour cells was the only statistically significant and independent prognostic factor of short OS (P=0.0088). Membrane expression of Cx43 in matching dysplasia-free mucosa acted similarly, but did not reach statistical significance (P=0.059). No correlation was found between the Cx26, Cx45 expression and OS. We conclude that Cx43 expression in dysplasia-free mucosa may indicate a very early stage of tumour promotion. Although overexpression of Cx43 is found in invasive tumours we only found membrane Cx43 expression to correlate with OS. This observation suggests that cytoplasmic Cx43 serves as storage and only membrane translocation may promote the formation of gap junctions and gap junctional intercellular communication (GJIC) with prognostic relevance.