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Systemic immune stimulation has been associated with increased risk of myeloid malignancies, but the pathogenic link is unknown. We demonstrate in animal models that experimental systemic immune activation alters the bone marrow stromal microenvironment, disarranging extracellular matrix (ECM) microarchitecture, with downregulation of secreted protein acidic and rich in cysteine (SPARC) and collagen-I and induction of complement activation. These changes were accompanied by a decrease in Treg frequency and by an increase in activated effector T cells. Under these conditions, hematopoietic precursors harboring nucleophosmin-1 (NPM1) mutation generated myeloid cells unfit for normal hematopoiesis but prone to immunogenic death, leading to neutrophil extracellular trap (NET) formation. NET fostered the progression of the indolent NPM1-driven myeloproliferation toward an exacerbated and proliferative dysplastic phenotype. Enrichment in NET structures was found in the bone marrow of patients with autoimmune disorders and in NPM1-mutated acute myelogenous leukemia (AML) patients. Genes involved in NET formation in the animal model were used to design a NET-related inflammatory gene signature for human myeloid malignancies. This signature identified two AML subsets with different genetic complexity and different enrichment in NPM1 mutation and predicted the response to immunomodulatory drugs. Our results indicate that stromal/ECM changes and priming of bone marrow NETosis by systemic inflammatory conditions can complement genetic and epigenetic events towards the development and progression of myeloid malignancy. [ABSTRACT FROM AUTHOR]

• An Object-Oriented modelling approach for dynamic simulation. • Development of the model for the DONES Parallel Kinematic Manipulator (PKM). • Simulation of the robots, including the main non-linear effects due to backlashes and static friction. • Development of a preliminary control strategy. This paper describes the modeling and simulation activities performed, within the EUROfusion framework, to support the engineering design and the development of the control system of the DONES Parallel Kinematic Manipulator (PKM), a 6-DoF parallel robot part of the Remote Handling System of the DONES facility. The main tasks of the PKM are the planned annual replacement of the Target Assembly and the High Flux Test Module, two of the crucial and most activated components of DONES. The PKM model, developed using the Modelica object-oriented language, is able to simulate the dynamics of the entire robots, including the main non-linear effects due to backlashes and static friction. The simulator is employed to support the preliminary design of the control system, based on an independent-joint approach with dual-loop cascade-PID logic. Simulations are then conducted to assess robot performances in terms of resolution, accuracy, repeatability and generated forces. [ABSTRACT FROM AUTHOR]

The matricellular protein osteopontin (OPN, Spp-1) is widely associated with cancer aggressiveness when produced by tumor cells, but its impact is uncertain when produced by leukocytes in the context of the tumor stroma. In a broad study using Spp1-/- mice along with gene silencing in tumor cells, we obtained evidence of distinct and common activities of OPN when produced by tumor or host cells in a spontaneously metastatic model of breast cancer. Different cellular localization of OPN is associated with its distinct activities, being mainly secreted in tumor cells while intracellular in myeloid cells. OPN produced by tumor cells supported their survival in the blood stream, whereas both tumor- and host-derived OPN, particularly from myeloid cells, rendered the metastatic site more immunosuppressive. Myeloid-derived suppressor cells (MDSC) expanded with tumor progression at both primary and lung metastatic sites. Of the expanded monocytic and granulocytic cell populations of MDSCs, the monocytic subset was the predominant source of OPN. In Spp1-/- mice, the inhibition of lung metastases correlated with the expansion of granulocyte-oriented MDSCs. Notably, monocytic MDSCs in Spp1-/- mice were less suppressive than their wild-type counterparts due to lower expression of arginase-1, IL6, and phospho-Stat3. Moreover, fewer regulatory T cells accumulated at the metastatic site in Spp1-/- mice. Our data find correlation with lung metastases of human mammary carcinomas that are associated with myeloid cells expressing OPN. Overall, our results unveiled novel functions for OPN in shaping local immunosuppression in the lung metastatic niche. [ABSTRACT FROM AUTHOR]

We have previously shown that C1q is expressed on endothelial cells (ECs) of newly formed decidual tissue. Here we demonstrate that C1q is deposited in wound-healing skin in the absence of C4 and C3 and that C1q mRNA is locally expressed as revealed by real-time PCR and in situ hybridization. C1q was found to induce permeability of the EC monolayer, to stimulate EC proliferation and migration, and to promote tube formation and sprouting of new vessels in a rat aortic ring assay. Using a murine model of wound healing we observed that vessel formation was defective in C1qa-/- mice and was restored to normal after local application of C1q. The mean vessel density of wound-healing tissue and the healed wound area were significantly increased in C1q-treated rats. On the basis of these results we suggest that C1q may represent a valuable therapeutic agent that can be used to treat chronic ulcers or other pathological conditions in which angiogenesis is impaired, such as myocardial ischemia. [ABSTRACT FROM AUTHOR]

In myeloid malignancies, the neoplastic clone outgrows normal hematopoietic cells toward BM failure. This event is also sustained by detrimental stromal changes, such as BM fibrosis and osteosclerosis, whose occurrence is harbinger of a dismal prognosis. We show that the matricellular protein SPARC contributes to the BM stromal response to myeloproliferation. The degree of SPARC expression in BM stromal elements, including CD146⁺ mesenchymal stromal cells, correlates with the degree of stromal changes, and the severity of BM failure characterizing the prototypical myeloproliferative neoplasm primary myelofibrosis. Using Sparc-/- mice and BM chimeras, we demonstrate that SPARC contributes to the development of significant stromal fibrosis in a model of thrombopoietin-induced myelofibrosis. We found that SPARC deficiency in the radioresistant BM stroma compartment impairs myelofibrosis but, at the same time, associates with an enhanced reactive myeloproliferative response to throm-bopoietin. The link betwen SPARC stromal deficiency and enhanced myeloid cell expansion under a myeloproliferative spur is also supported by the myeloproliferative phenotype resulting from the transplantation of defective Apemin mutant hematopoietic cells into Sparc-/- but not WT recipient BM stroma. Our results high-light a complex Influence of SPARC over the stromal and hematopoietic BM response in myeloproliferative conditions. [ABSTRACT FROM AUTHOR]

Antineutrophil cytoplasmic antibodies (ANCAs) target proteins normally re-tained within neutrophils, indicating that cell death is involved in the autoimmunity process. Still, ANCA pathogenesis re-mains obscure. ANCAs activate neutro-phils Inducing their respiratory burst and a peculiar form of cell death, named NETo-sis, characterized by formation of neutro-phil extracellular traps (NETs), decon-densed chromatin threads decorated with cytoplasmic proteins endorsed with anti-microbial activity. NETs have been consis-tently detected in ANCA-associated small-vessel vasculitis, and this association prompted us to test whether the peculiar structure of NET favors neutrophil pro-teins uploading into myeloid dendritic cells and the induction of ANCAs and associated autoimmunity. Here we show that myeloid DCs uploaded with and acti-vated by NET components induce ANCA and autoimmunity when injected into na-ive mice. DC uploading and autoimmunity induction are prevented by NET treatment with DNAse, indicating that NET struc-tural Integrity is needed to maintain the antigenicity of cytoplasmic proteins. We found NET intermingling with myeloid dendritic cells also positive for neutrophil myeloperoxidase in myeloperoxidase-ANCA-associated microscopic poliangi-itis providing a potential correlative pic-ture In human pathology. These data provide the first demonstration that NET structures are highly immunogenic such to trigger adaptive Immune response relevant for autoimmunity. [ABSTRACT FROM AUTHOR]

Mast cells (MC) are c-Kit--expressing cells, best known for their primary involvement in allergic reactions, but recently reappraised as important players in either cancer promotion or inhibition. Here, we assessed the role of MCs in prostate tumor development. In prostate tumors from both tumor-prone transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and human patients, MCs are specifically enriched and degranulated in areas of well-differentiated (WD) adenocarcinoma but not around poorly differentiated (PD) foci that coexist in the same tumors. We derived novel TRAMP tumor cell lines, representative of WD and PD variants, and through pharmacologic stabilization or genetic ablation of MCs in recipients mice, we showed that MCs promote WD adenocarcinoma growth but are dispensable for PD tumors. WD tumors rely on MCs for matrix metalloprotease 9 (MMP-9) provision, as reconstitution of MC-deficient mice with wild-type but not MMP-9-/- MCs was sufficient to promote their growth. In contrast, PD tumors are MMP-9 self-competent, consistently with epithelial-to-mesenchymal transition. Such a dual source of MMP-9 was confirmed in human tumors, suggesting that MCs could be a good target for early-stage prostate cancer. Interestingly, in testing whether MC targeting could block or delay tumorigenesis in tumor-prone TRAMP mice, we observed a high incidence of early and aggressive tumors, characterized by a neuroendocrine (NE) signature and c-Kit expression. Taken together, these data underscore the contribution of MCs in tumor progression and uncover a new, opposite role of MCs in protecting against the occurrence of aggressive NE variants in prostate cancer. [ABSTRACT FROM AUTHOR]

Franco V, Tripodo C, Rizzo A, Stella M, Florena AM. Bone marrow biopsy in Hodgkin's lymphoma. Eur J Haematol 2004: 73: 149–155. © Blackwell Munksgaard 2004. In the study of patients with Hodgkin's lymphoma (HL) the evaluation of bone marrow biopsy (BMB) can be difficult. In this review we analyze the main diagnostic features and the clinical risk factors of BM involvement. Although the role of BMB is criticized by some authors, its value is irreplaceable in the staging of HL and in the diagnosis of primary medullary HL. The Ann Arbor staging committee criteria should be revised and updated in the light of the current immunohistochemical studies that give a fundamental help in the diagnostic process. A single BMB should be adequate for diagnosis in most instances. In cases of suspicious involvement a controlateral BMB could be performed. [ABSTRACT FROM AUTHOR]

• Control strategies for the full-power mode operation of the MSFR are identified, developed, and tested. • Selection of input/output variables through Relative Gain Array and free-dynamics outcomes. • Four different decentralized-feedback control strategies are implemented by employing PID controllers. • The control strategies are tested on a power plant simulator in two typical controlled operational transients. • Load following capabilities turns out to be promising and compatible with operational constraints. In this paper, different control strategies for the full-power mode operation (i.e. from 50% to 100% of reactor rated power) of the MSFR are identified, developed, and their performances tested, starting from the results of a MSFR power plant simulator. In order to support the qualitative results gained from the free-dynamics outcomes, a technique known as Relative Gain Array is employed to obtain a quantitative measure of the degree of interaction between the various input and output variables, and to identify the most favorable couplings. In the development of control strategies, particular attention is placed on several specific aspects, in particular the load-following capabilities of the power plant, the need to keep the molten salts temperatures within a rather narrow window to avoid boiling or freezing risks during operational transients, and the need to maintain the operating conditions of the energy conversion system as constant as possible. Four different decentralized-feedback control strategies are implemented – with different number of controlled outputs – by employing conventional PID controllers, which are designed and tuned with appropriate phase and gain margins to account for modeling uncertainties. The different control strategies are then tested on the power plant simulator in two typical controlled operational transients, highlighting the very promising behavior of the MSFR in terms of load-following capabilities. The results of the present work will also provide valuable insights in support to the optimization and finalization of the MSFR power plant design. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is the commonest form of lymphoid malignancy, with a prevalence of about 40% worldwide. Its classification encompasses a common form, also termed as "not otherwise specified" (NOS), and a series of variants, which are rare and at least in part related to viral agents. Over the last two decades, DLBCL-NOS, which accounts for more than 80% of the neoplasms included in the DLBCL chapter, has been the object of an increasing number of molecular studies which have led to the identification of prognostic/predictive factors that are increasingly entering daily practice. In this review, the main achievements obtained by gene expression profiling (with respect to both neoplastic cells and the microenvironment) and next-generation sequencing will be discussed and compared. Only the amalgamation of molecular attributes will lead to the achievement of the long-term goal of using tailored therapies and possibly chemotherapy-free protocols capable of curing most (if not all) patients with minimal or no toxic effects. [ABSTRACT FROM AUTHOR]

The article focuses on cyclooxygenase, the enzyme catalyzing the conversion of arachidonic acid into prostaglandin H2. The functional roles of the inducible form of cyclooxygenase, COX-2, which have been studied include cell growth, cell death and development of neoplasia. Growth factors such as cytokines and tumour promoters have stimulated COX-2 expression in most cells and tissue and a substantial body of evidence supports its role in resistance to apoptosis in several human haematological malignancies.

Immune cell-derived extracellular vesicles (EV) affect tumor progression and hold promise for therapeutic applications. Eosinophils are major effectors in Th2-related pathologies recently implied in cancer. Here, we evaluated the anti-tumor activities of eosinophil-derived EV following activation with the alarmin IL-33. We demonstrate that IL-33-activated mouse and human eosinophils produce higher quantities of EV with respect to eosinophils stimulated with IL-5. Following incorporation of EV from IL-33-activated eosinophils (Eo33-EV), but not EV from IL-5-treated eosinophils (Eo5-EV), mouse and human tumor cells increased the expression of cyclin-dependent kinase inhibitor (CDKI)-related genes resulting in cell cycle arrest in G0/G1, reduced proliferation and inhibited tumor spheroid formation. Moreover, tumor cells incorporating Eo33-EV acquired an epithelial-like phenotype characterized by E-Cadherin up-regulation, N-Cadherin downregulation, reduced cell elongation and migratory extent in vitro, and impaired capacity to metastasize to lungs when injected in syngeneic mice. RNA sequencing revealed distinct mRNA signatures in Eo33-EV and Eo5-EV with increased presence of tumor suppressor genes and enrichment in pathways related to epithelial phenotypes and negative regulation of cellular processes in Eo33-EV compared to Eo5-EV. Our studies underscore novel IL-33-stimulated anticancer activities of eosinophils through EV-mediated reprogramming of tumor cells opening perspectives on the use of eosinophil-derived EV in cancer therapy. [ABSTRACT FROM AUTHOR]

Confined cell migration hampers genome integrity and activates the ATR and ATM mechano-transduction pathways. We investigated whether the mechanical stress generated by metastatic interstitial migration contributes to the enhanced chromosomal instability observed in metastatic tumor cells. We employed live cell imaging, micro-fluidic approaches, and scRNA-seq to follow the fate of tumor cells experiencing confined migration. We found that, despite functional ATR, ATM, and spindle assembly checkpoint (SAC) pathways, tumor cells dividing across constriction frequently exhibited altered spindle pole organization, chromosome mis-segregations, micronuclei formation, chromosome fragility, high gene copy number variation, and transcriptional de-regulation and up-regulation of c-MYC oncogenic transcriptional signature via c-MYC locus amplifications. In vivo tumor settings showed that malignant cells populating metastatic foci or infiltrating the interstitial stroma gave rise to cells expressing high levels of c-MYC. Altogether, our data suggest that mechanical stress during metastatic migration contributes to override the checkpoint controls and boosts genotoxic and oncogenic events. Our findings may explain why cancer aneuploidy often does not correlate with mutations in SAC genes and why c-MYC amplification is strongly linked to metastatic tumors. [ABSTRACT FROM AUTHOR]

Lung is a specialized tissue where metastases from primary lung tumors takeoff and those originating from extra-pulmonary sites land. One commonality characterizing these processes is the supportive role exerted by myeloid cells, particularly neutrophils, whose recruitment is facilitated in this tissue microenvironment. Indeed, neutrophils have important part in the pathophysiology of this organ and the key mechanisms regulating neutrophil expansion and recruitment during infection can be co-opted by tumor cells to promote growth and metastasis. Although neutrophils dominate the myeloid landscape of lung cancer other populations including macrophages, dendritic cells, mast cells, basophils and eosinophils contribute to the complexity of lung cancer TME. In this review, we discuss the origin and significance of myeloid cells heterogeneity in lung cancer, which translates not only in a different frequency of immune populations but it encompasses state of activation, morphology, localization and mutual interactions. The relevance of such heterogeneity is considered in the context of tumor growth and response to immunotherapy. [ABSTRACT FROM AUTHOR]

The development and progression of Chronic Lymphocytic Leukemia (CLL) require co-operation of both microenvironment and cytokines. Investigating the IL-23R/IL-23 axis we found that circulating cells of early-stage CLL patients with shorter time-to-treatment (but not of those with a more benign course) expressed a defective form of the IL-23R complex lacking the IL-12Rß1 chain. However, the cells from both patient groups expressed the com-plete IL-23R complex in tissue infiltrates and could be induced to express it when co-cultured with activated T cells or other CD40L-bearing cells. IL-23 production by CLL cells activated in vitro in this fashion and in lymphoid tissues was observed suggesting the exist-ence of an autocrine/ paracrine loop causing CLL cell proliferation. Culture of CLL cells with stromal cells, nurse like cells and stimulation with anti IgM antibodies and IL-4 failed to activate this loop. Interference with the IL-23R/IL-23 axis using an anti-IL-23p19 anti-body proved effective in controlling disease onset/expansion in xenografted mice, suggesting potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Summary: Surface expression of a functional B cell antigen receptor (BCR) is essential for the survival and proliferation of mature B cells. Most types of B‐cell lymphoproliferative disorders retain surface BCR expression, including B‐cell non‐Hodgkin lymphomas (B‐NHL) and chronic lymphocytic leukemia (CLL). Targeting BCR effectors in B‐NHL cell lines in vitro has indicated that this signaling axis is crucial for malignant B cell growth. This has led to the development of inhibitors of BCR signaling, which are currently used for the treatment of CLL and several B‐NHL subtypes. Recent studies based on conditional BCR inactivation in a MYC‐driven mouse B‐cell lymphoma model have revisited the role of the BCR in MYC‐expressing tumor B cells. Indeed, lymphoma cells losing BCR expression continue to grow unless subjected to competition with their BCR‐expressing counterparts, which causes their elimination. Here, we discuss the molecular nature of the fitness signal delivered by the BCR to MYC‐expressing malignant B cells, ensuring their preferential persistence within a rapidly expanding tumor population. We also review growing evidence of Ig‐negative cases belonging to several B‐NHL subtypes and CLL, and discuss the clinical implications of these findings in relation to an emerging picture of clinical resistances to anti‐BCR therapies. [ABSTRACT FROM AUTHOR]

A letter to the editor on a study which examined if in addition to monocyte/macrophages, other cell types could be recruited by chronic lymphocytic leukaemia (CLL) derived C-C motif chemokine 3 (CCL3)/ C-C motif chemokine 4 (CCL4) in CLL-involved bone marrow microenvironment, is presented.

Within the EUROfusion roadmap for the technological development of the European-DEMOnstration (EU-DEMO) reactor, a key point has been identified in the discontinuous operation (pulse-dwell-pulse) of the machine. Water Cooled Lithium Lead (WCLL) Breeding Blanket (BB) Primary Heat Transfer Systems (PHTSs) adopt technology and components commonly used in nuclear fission power plants, whose performances could be negatively affected by the above mentioned pulsation, as well as by low-load operation in the dwell phase. This makes mandatory a full assessment of the functional feasibility of such components through accurate design and validation. For this purpose, ENEA Experimental Engineering Division at Brasimone R.C. aims at realizing STEAM, a water operated facility forming part of the multipurpose experimental infrastructure Water cooled lithium lead -thermal-HYDRAulic (W-HYDRA), conceived to investigate the water technologies applied to the DEMO BB and Balance of Plant systems and components. The experimental validation has the two main objectives of reproducing the DEMO operational phases by means of steady-state and transient tests, as well as performing dedicated tests on the steam generator aiming at demonstrating its ability to perform as intended during the power phases of the machine. STEAM is mainly composed of primary and secondary water systems reproducing the thermodynamic conditions of the DEMO WCLL BB PHTS and power conversion system, respectively. The significance of the STEAM facility resides in its capacity to amass experimental data relevant for the advancement of fusion-related technologies. This capability is attributable to the comprehensive array of instruments with which the facility will be equipped and whose strategic location is described in this work. The operational phases of the STEAM facility at different power levels are presented, according to the requirements of the experiments. Furthermore, a preliminary analysis for the definition of the control strategy for the OTSG mock-up was performed. In particular, two different control strategies were identified and tested, both keeping the primary mass flow constant and regulating the feedwater mass flow to follow a temperature set-point in the primary loop. The obtained numerical results yielded preliminary feedback on the regulation capability of the DEMO steam generator mock-up during pulsed operation, showing that no relevant overtemperature jeopardized the facility integrity, thanks to the high system responsivity to rapid load variations. [ABSTRACT FROM AUTHOR]

Neoplastic B-cell clones commonly arise within secondary lymphoid organs (SLO). However, during disease progression, lymphomatous cells may also colonize the bone marrow (BM), where they localize within specialized stromal niches, namely the osteoblastic and the vascular niche, according to their germinal center- or extra-follicular-derivation, respectively. We hypothesized the existence of common stromal motifs in BM and SLO B-cell lymphoid niches involved in licensing normal B-cell development as well as in fostering transformed B lymphoid cells. Thus, we tested the expression of prototypical mesenchymal stromal cell (MSC) markers and regulatory matricellular proteins in human BM and SLO under physiologically unperturbed conditions and during B-cell lymphoma occurrence. We identified common stromal features in the BM osteoblastic niche and SLO germinal center (GC) microenvironments, traits that were also enriched within BM infiltrates of GC-associated B-cell lymphomas, suggesting that stromal programs involved in central and peripheral B-cell lymphopoiesis are also involved in malignant B-cell nurturing. Among factors co-expressed by stromal elements within these different specialized niches, we identified the pleiotropic matricellular protein secreted protein acidic and rich in cysteine (SPARC). The actual role of stromal SPARC in normal B-cell lymphopoiesis, investigated inSparc?/?mice and BM chimeras retaining theSparc?/?genotype in host stroma, demonstrated defective BM and splenic B-cell lymphopoiesis. Moreover, in theTrp53knockout (KO) lymphoma model,p53?/?/Sparc?/?double-KO mice displayed impaired spontaneous splenic B-cell lymphomagenesis and reduced neoplastic clone BM infiltration in comparison with theirp53?/?/Sparc+/+counterparts. Our results are among the first to demonstrate the existence of common stromal programs regulating both the BM osteoblastic niche and the SLO GC lymphopoietic functions potentially fostering the genesis and progression of B-cell malignancies. [ABSTRACT FROM PUBLISHER]

Simple Summary: The present study aimed to investigate the salivary microbiota composition employing for the first time in the literature the Oxford Nanopore Technology in patients affected by oral squamous cell carcinoma (OSCC). Unstimulated saliva samples from 24 patients affected by OSCC and 7 patients free from OSCC were collected and analyzed. In the OSCC group, 13 patients were males and 11 females with a mean age of 65.5 ± 13.9 years; in the control group, 5 patients were males and 2 females with a mean age of 51.4 ± 19.2 years. Regarding the salivary microbiota composition, Prevotella, Chlamydia, Tissierellia, Calothrix, Leotiomycetes, Firmicutes and Zetaproteobacteria were the most abundant microorganisms detected in OSCC patients. If the association between the alteration of salivary microbiota composition and OSCC onset was confirmed, it could have significant implications in the prevention strategy and in follow-up visits. Background: Advancements in DNA sequencing technology have facilitated the assessment of the connection between the oral microbiome and various diseases. The aim of the present study was to investigate the salivary microbiota composition employing for the first time in the literature the Oxford Nanopore Technology in patients affected by oral squamous cell carcinoma (OSCC). Methods: Unstimulated saliva samples of 31 patients were collected (24 OSCC patients and 7 controls). DNA was extracted using the QIAamp DNA Blood Kit and metagenomic long sequencing reads were performed using the MinION device. Results: In the OSCC group, 13 were males and 11 were females, with a mean age of 65.5 ± 13.9 years; in the control group, 5 were males and 2 were females, with a mean age of 51.4 ± 19.2 years. The border of the tongue was the most affected OSCC site. The microorganisms predominantly detected in OSCC patients were Prevotella, Chlamydia, Tissierellia, Calothrix, Leotiomycetes, Firmicutes and Zetaproteobacteria. Conclusions: This study confirmed the predominance of periodontopathic bacteria in the salivary microbiome in the OSCC group. If a direct correlation between oral dysbiosis and OSCC onset was proven, it could lead to new prevention strategies and early diagnostic tools. [ABSTRACT FROM AUTHOR]

Mast cells are evolutionarily ancient cells, endowed with a unique developmental, phenotypic, and functional plasticity. They are resident cells that participate in tissue homeostasis by constantly sampling the microenvironment. As a result of their large repertoire of receptors, they can respond to multiple stimuli and selectively release different types and amounts of mediator. Here, we present and discuss the recent mast cell literature, focusing on studies that demonstrate that mast cells are more than a switch that is turned ‘off’ when in the resting state and ‘on’ when in the degranulating state. We propose a new vision of mast cells in which, by operating in a ‘rheostatic’ manner, these cells finely modulate not only immune responses, but also the pathogenesis of several inflammatory disorders, including infection, autoimmunity, and cancer. [ABSTRACT FROM AUTHOR]

The maintenance of tissue homeostasis requires extracellular matrix (ECM) remodeling. Immune cells actively participate in regenerating damaged tissues contributing to ECM deposition and shaping. Dysregulated ECM deposition characterizes fibrotic diseases and cancer stromatogenesis, where a chronic inflammatory state sustains the ECM increase. In cancer, the ECM fosters several steps of tumor progression, providing pro-survival and proliferative signals, promoting tumor cell dissemination via collagen fibers or acting as a barrier to impede drug diffusion. Interfering with processes leading to chronic ECM deposition, as occurring in cancer, might allow the simultaneous targeting of both primary tumors and metastatic lesions. However, a note of caution comes from data showing that defective ECM deposition is associated with an exacerbated inflammatory and autoimmune phenotype and to lymphomagenesis. Immune cells display ITIM-inhibitory receptors recognizing collagens as counter ligands, which negatively regulate the immune response. This is in line with the idea that ECM components can provide homeostatic signals to immune cells to regulate and prevent unwanted activation, a concept particularly relevant in cancer where these mechanisms could be in place to keep infiltrating immune cells in a suppressive pro-tumoral state. In this context, the pharmacological targeting of myeloid cells, for which both direct and indirect roles in ECM deposition have been shown, can be a relevant option to this purpose. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma (OS) is the most common primary bone tumor in children and adolescent. Surgery and multidrug chemotherapy are the standard of treatment achieving 60–70% of event-free survival for localized disease at diagnosis. However, for metastatic disease, the prognosis is dismal. Exploiting immune system activation in the setting of such unfavorable mesenchymal tumors represents a new therapeutic challenge. Methods: In immune competent OS mouse models bearing two contralateral lesions, we tested the efficacy of intralesional administration of a TLR9 agonist against the treated and not treated contralateral lesion evaluating abscopal effect. Multiparametric flow cytometry was used to evaluate changes of the tumor immune microenviroment. Experiments in immune-deficient mice allowed the investigation of the role of adaptive T cells in TLR9 agonist effects, while T cell receptor sequencing was used to assess the expansion of specific T cell clones. Results: TLR9 agonist strongly impaired the growth of locally-treated tumors and its therapeutic effect also extended to the contralateral, untreated lesion. Multiparametric flow cytometry showed conspicuous changes in the immune landscape of the OS immune microenvironment upon TLR9 engagement, involving a reduction in M2-like macrophages, paralleled by increased infiltration of dendritic cells and activated CD8 T cells in both lesions. Remarkably, CD8 T cells were needed for the induction of the abscopal effect, whereas they were not strictly necessary for halting the growth of the treated lesion. T cell receptor (TCR) sequencing of tumor infiltrating CD8 T cells showed the expansion of specific TCR clones in the treated tumors and, remarkably, their selected representation in the contralateral untreated lesions, providing the first evidence of the rewiring of tumor-associated T cell clonal architectures. Conclusions: Overall these data indicate that the TLR9 agonist acts as an in situ anti-tumor vaccine, activating an innate immune response sufficient to suppress local tumor growth while inducing a systemic adaptive immunity with selective expansion of CD8 T cell clones, which are needed for the abscopal effect. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Intrasinusoidal bone marrow infiltration and splenic marginal zone lymphoma: a quantitative study," by Achille Pich in the 2006 issue.

In the framework of the EUROfusion Horizon Europe Programme, ENEA and its linked third parties are in charge of the conceptual design of the steam generators belonging to EU DEMO WCLL Breeding Blanket Primary Heat Transfer Systems (BB PHTSs). In particular, in 2021, design activities and supporting numerical simulations were carried out in order to achieve a feasible and robust preliminary concept design of the Once Through Steam Generators (OTSGs), selected as reference technology for the DEMO Balance of Plant at the end of the Horizon 2020 Programme. The design of these components is very challenging. In fact, the steam generators have to deliver the thermal power removed from the two principal blanket subsystems, i.e., the First Wall (FW) and the Breeding Zone (BZ), to the Power Conversion System (PCS) for its conversion into electricity, operating under plasma pulsed regime and staying in dwell period at a very low power level (decay power). Consequently, the OTSG stability and control represent a key point for these systems' operability and the success of a DEMO BoP configuration with direct coupling between the BB PHTS and the PCS. In this paper, the authors reported and critically discussed the FW and BZ steam generators' thermal-hydraulic and mechanical design, the developed 3D CAD models, as well as the main results of the stability analyses and the control strategy to be adopted. [ABSTRACT FROM AUTHOR]

Hepatoid thymic carcinoma (HTC) is an extremely rare variant of primary epithelial tumor of the thymus morphologically resembling hepatocellular carcinoma Herein, we report an additional case of HTC diagnosed in a 40-years-old man affected by polycythemia vera and treated with ropeginterferon alfa 2-b, for the first time deeply analyzing the molecular profile of this distinctive thymic malignancy. By immunohistochemistry, tumor cells were positive for cytokeratin 7–19, GLUT1, and Hep-Par-1, whereas AFP tested negative. Whole exome sequencing revealed loss of function mutations in TP53 , STK11, PBRM1, SMAD3 , FN1 , NTRK1, and FANCD2 , as well as gain of function mutations in MTOR , BCL11A and COL1A1 , along with amplification of CCND3 and MDM2. This mutational landscape halfway between thymic carcinoma (TP53 , PBRM1) and hepatoid variant carcinoma of other sites (STK11) suggests that, at some point during carcinogenesis, a switch occurred from an epithelial thymic phenotype to a hepatoid-like one. [ABSTRACT FROM AUTHOR]

Background: Autoimmune disorders, including Systemic Lupus Erythematosus (SLE), are associated with increased incidence of hematological malignancies. The matricellular protein osteopontin (OPN) has been linked to SLE pathogenesis, as SLE patients show increased serum levels of OPN and often polymorphisms in its gene. Although widely studied for its pro-tumorigenic role in different solid tumours, the role of OPN in autoimmunity-driven lymphomagenesis has not been investigated yet. Methods: To test the role of OPN in the SLE-associated lymphomagenesis, the SLE-like prone Faslpr/lpr mutation was transferred onto an OPN-deficient background. Spleen from Faslpr/lpr and OPN-/-Faslpr/lpr mice, as well as purified B cells, were analysed by histopathology, flow cytometry, Western Blot, immunohistochemistry, immunofluorescence and gene expression profile to define lymphoma characteristics and investigate the molecular mechanisms behind the observed phenotype. OPN cellular localization in primary splenic B cells and mouse and human DLBCL cell lines was assessed by confocal microscopy. Finally, gain of function experiments, by stable over-expression of the secreted (sOPN) and intracellular OPN (iOPN) in OPN-/-Faslpr/lpr -derived DLBCL cell lines, were performed for further validation experiments. Results: Despite reduced autoimmunity signs, OPN-/-Faslpr/lpr mice developed splenic lymphomas with higher incidence than Faslpr/lpr counterparts. In situ and ex vivo analysis featured such tumours as activated type of diffuse large B cell lymphoma (ABC-DLBCL), expressing BCL2 and c-MYC, but not BCL6, with activated STAT3 signaling. OPN-/-Faslpr/lpr B lymphocytes showed an enhanced TLR9-MYD88 signaling pathway, either at baseline or after stimulation with CpG oligonucleotides, which mimic dsDNA circulating in autoimmune conditions. B cells from Faslpr/lpr mice were found to express the intracellular form of OPN. Accordingly, gene transfer-mediated re-expression of iOPN, but not of its secreted isoform, into ABC-DLBCL cell lines established from OPN-/-Faslpr/lpr mice, prevented CpG-mediated activation of STAT3, suggesting that the intracellular form of OPN may represent a brake to TLR9 signaling pathway activation. Conclusion: These data indicate that, in the setting of SLE-like syndrome in which double strand-DNA chronically circulates and activates TLRs, B cell intracellular OPN exerts a protective role in autoimmunity-driven DLBCL development, mainly acting as a brake in the TLR9-MYD88-STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Simple Summary: This review aimed to analyse the current knowledge regarding the composition of salivary microbiota of patients with oral squamous cell carcinoma (OSCC). The protocol for this study was designed following the PRISMA guidelines. Observational studies, in human subjects with histological diagnosis of OSCC, concerning the analysis of salivary microbiota, were selected. Eleven papers were included. The salivary microbiomes of 1335 patients were analysed. Periodontal pathogens were the most frequent bacteria detected in patients with OSCC. We have found that although there are evident alterations in the composition of the salivary microbiota in OSCC patients, due to the great heterogeneity of the studies, it is still a challenge to identify a specific microbiota pattern. If the associations between alterations in the salivary microbiome and OSCC are confirmed, microbiome analysis could represent a useful tool for the screening and follow-up of patients affected by OSCC. Background: Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers worldwide. Despite recent advances in diagnosis and treatment, in recent years, an increase in the incidence of OSCC has been registered, and the mortality rate is still high. This systematic review aims to identify a potential association between the composition of salivary microbiota and OSCC. Materials and Methods: The protocol for this study was designed following the PRISMA guidelines. Records were identified using different search engines (e.g., Medline/PubMed). Observational studies, in human subjects with histological diagnosis of OSCC, concerning the analysis of salivary microbiota, were selected. Results: Eleven papers were included. The salivary microbiomes of 1335 patients were analysed (n.687 OSCC and n.648 controls). Due to the great heterogeneity of the studies, it was not possible to profile a specific microbiota associated with OSCC. However, periodontal pathogens were the most common bacteria detected in patients with OSCC (i.e., Fusobacterium, Prevotella). Conclusions: Although there are evident alterations in the salivary microbiota composition in OSCC patients, it is still a challenge to identify a specific microbiota pattern in OSCC patients. If the associations between specific salivary microorganisms and OSCC are confirmed, microbiome analysis could be a useful tool for the screening and follow-up of patients affected by OSCC. [ABSTRACT FROM AUTHOR]

Rituximab®provides high response rates and effective disease palliation in patients with splenic marginal zone lymphoma (SMZL). We conducted a phase II trial in patients with SMZL who were either untreated or were splenectomized but had shown disease progression within 1 year after splenectomy. Treatment consisted of six courses of Rituximab with cyclophosphamide, vincristine, non-pegylated liposomal doxorubicin and prednisone (R-COMP). Fifty-one patients were eligible for the analysis. The overall response rate was 84%. The 6-year progression-free survival and overall survival were 54% and 72%, respectively. Toxicity was substantial (grade ≥ 3 neutropenia: 26%; grade ≥ 3 infections: 8%). Of the 15 deaths, two occurred on treatment (one sepsis and one pneumonia). Six deaths were due to lymphoma progression, four to secondary neoplasia, one to sepsis, one to pneumonia and one to splenectomy complications. R-COMP should be restricted to patients with bulky disease associated with symptoms or to patients with possible histological transformation. [ABSTRACT FROM AUTHOR]

Abstract: Lymphnode swelling during immune responses is a transient, finely regulated tissue rearrangement, accomplished with the participation of the extracellular matrix. Here we show that murine and human reactive lymph nodes express SPARC in the germinal centres. Defective follicular dendritic cell networking in SPARC-deficient mice is accompanied by a severe delay in the arrangement of germinal centres and development of humoral autoimmunity, events that are linked to Th17 development. SPARC is required for the optimal and rapid differentiation of Th17 cells, accordingly we show delayed development of experimental autoimmune encephalomyelitis whose pathogenesis involves Th17. Not only host radioresistant cells, namely follicular dendritic cells, but also CD4+ cells are the relevant sources of SPARC, in vivo. Th17 differentiation and germinal centre formation mutually depend on SPARC for a proper functional crosstalk. Indeed, Th17 cells can enter the germinal centres in SPARC-competent, but not SPARC-deficient, mice. In summary, SPARC optimizes the changes occurring in lymphoid extracellular matrix harboring complex interactions between follicular dendritic cells, B cells and Th17 cells. [Copyright &y& Elsevier]

Background: Although multimodality treatment can induce high rate of remission in many subtypes of non-Hodgkin's lymphoma (NHL), significant proportions of patients relapse with incurable disease. The effect of human bone marrow (BM) mesenchymal stem cells (MSC) on tumor cell growth is controversial, and no specific information is available on the effect of BM-MSC on NHL. Methodology/Principal Findings: The effect of BM-MSC was analyzed in two in vivo models of disseminated non-Hodgkin's lymphomas with an indolent (EBV2 Burkitt-type BJAB, median survival = 46 days) and an aggressive (EBV+ B lymphoblastoid SKW6.4, median survival = 27 days) behavior in nude-SCID mice. Intra-peritoneal (i.p.) injection of MSC (4 days after i.p. injection of lymphoma cells) significantly increased the overall survival at an optimal MSC:lymphoma ratio of 1:10 in both xenograft models (BJAB+MSC, median survival = 58.5 days; SKW6.4+MSC, median survival = 40 days). Upon MSC injection, i.p. tumor masses developed more slowly and, at the histopathological observation, exhibited a massive stromal infiltration coupled to extensive intra-tumor necrosis. In in vitro experiments, we found that: i) MSC/lymphoma co-cultures modestly affected lymphoma cell survival and were characterized by increased release of pro-angiogenic cytokines with respect to the MSC, or lymphoma, cultures; ii) MSC induce the migration of endothelial cells in transwell assays, but promoted endothelial cell apoptosis in direct MSC/endothelial cell co-cultures. Conclusions/Significance: Our data demonstrate that BM-MSC exhibit anti-lymphoma activity in two distinct xenograft SCID mouse models of disseminated NHL. [ABSTRACT FROM AUTHOR]

Regulatory cells can mould the fate of the immune response by direct suppression of specific subsets of effector cells, or by redirecting effectors against invading pathogens and infected or neoplastic cells. These functions have been classically, although not exclusively, ascribed to different subsets of T cells. Recently, mast cells have been shown to regulate physiological and pathological immune responses, and thus to act at the interface between innate and adaptive immunity assuming different functions and behaviors at discrete stages of the immune response. Here, we focus on these poorly defined, and sometimes apparently conflicting, functions of mast cells. [Copyright &y& Elsevier]

Aims: Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that, in some instances, may show a granulomatous reaction associated with a favourable prognosis and occasional spontaneous regression. In the present study, we aimed to define the tumour microenvironment (TME) in four such cases, two of which regressed spontaneously. Methods and results: All cases showed aggregates of tumour cells with the typical morphology, molecular cytogenetics and immunophenotype of BL surrounded by a florid epithelioid granulomatous reaction. All four cases were Epstein-Barr virus (EBV)-positive with type I latency. Investigation of the TME showed similar features in all four cases. The analysis revealed a proinflammatory response triggered by Th1 lymphocytes and M1 polarised macrophages encircling the neoplastic cells with a peculiar topographic distribution. Conclusions: Our data provide an in-vivo picture of the role that specific immune cell subsets might play during the early phase of BL, which may be capable of maintaining the tumour in a self-limited state or inducing its regression. These novel results may provide insights into new potential therapeutic avenues in EBV-positive BL patients in the era of cellular immunotherapy. [ABSTRACT FROM AUTHOR]

Aims: Burkitt lymphoma (BL) is an aggressive B‐cell lymphoma that, in some instances, may show a granulomatous reaction associated with a favourable prognosis and occasional spontaneous regression. In the present study, we aimed to define the tumour microenvironment (TME) in four such cases, two of which regressed spontaneously. Methods and results: All cases showed aggregates of tumour cells with the typical morphology, molecular cytogenetics and immunophenotype of BL surrounded by a florid epithelioid granulomatous reaction. All four cases were Epstein–Barr virus (EBV)‐positive with type I latency. Investigation of the TME showed similar features in all four cases. The analysis revealed a proinflammatory response triggered by Th1 lymphocytes and M1 polarised macrophages encircling the neoplastic cells with a peculiar topographic distribution. Conclusions: Our data provide an in‐vivo picture of the role that specific immune cell subsets might play during the early phase of BL, which may be capable of maintaining the tumour in a self‐limited state or inducing its regression. These novel results may provide insights into new potential therapeutic avenues in EBV‐positive BL patients in the era of cellular immunotherapy. [ABSTRACT FROM AUTHOR]

Primary hepatic lymphoma is a rare but well-defined lymphoma entity that often pursues an aggressive clinical course. Most cases have been described in hepatitis C virus (HCV)-related chronic liver disease patients. Although anthracycline-based chemotherapy has been reported to be highly effective, the best therapeutic strategy has not been defined yet. The prognosis is dismal especially in patients treated with chemotherapy alone or when an advanced liver disease is present. Herein, we describe a case of primary hepatic large B-cell non-Hodgkin's lymphoma, in a patient with HCV chronic infection. After a minor response with eight cycles of CHOP chemotherapy, a complete and sustained remission was obtained witha-interferon at the daily dose of 3?MU. HCV-RNA clearance pace from the blood almost paralleled the response of the lymphoma and both diseases went in remission within 1 year of therapy. The possible place ofa-Interferon in the treatment of primary hepatic lymphoma is discussed.The Hematology Journal (2004) 5, 530-533. doi:10.1038/sj.thj.6200408 [ABSTRACT FROM AUTHOR]

GLO:F2H7/01nov21:ctm2580-fig-0002.jpg PHOTO (COLOR): 2 Gemcitabine and/or probiotic treatment shape gut microbiota richness and composition. To get more insight into the role of the single probiotic strains included in our blend on PC and gemcitabine effect, BxPC-3 cells were cultured with probiotic cell-free supernatants (CFSs), with or without gemcitabine. An increased belief of the therapeutic effect of probiotics has recently risen, since their consumption, by restoring a healthy gut environment, prevents cancer onset and progression and also boosts anticancer therapies' efficacy while reducing their toxicity.1 We previously uncovered that gemcitabine deeply modifies the intestinal microbiota in a mouse model of pancreatic cancer (PC), shifting it toward an inflammation-related profile.2 Based on this observation, we formulated a probiotic blend (composed as in Table S1), which was tested in the current study to investigate whether restoring a balanced microbiota could reduce gemcitabine-induced side effects. Tuning gut microbiota through a probiotic blend in gemcitabine-treated pancreatic cancer xenografted mice. [Extracted from the article]

We observed ten children with a papular eruption with purpuric features during the SARS‐CoV‐2 pandemic in Northern Italy (May‐December 2020). Histological examination showed signs of SARS‐CoV‐2‐related dermatosis. Evidence of nucleocapsid viral proteins using SARS‐CoV‐2 (2019‐nCoV) nucleocapsid antibody revealed cuticular staining of the deep portion of the eccrine glands in all cases. [ABSTRACT FROM AUTHOR]

Background: Eribulin mesylate (E) is indicated for metastatic breast cancer patients previously treated with anthracycline and taxane. We argued that E could also benefit patients eligible for neoadjuvant chemotherapy. Methods: Patients with primary triple negative breast cancer ≥2 cm received doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 x 4 cycles (AT) followed by E 1.4 mg/m2 x 4 cycles. Primary endpoint was pathological complete response (pCR) rate; secondary and explorative endpoints included clinical/metabolic response rates and safety, and biomarker analysis, respectively. Using a two-stage Simon design, 43 patients were to be included provided that 4 of 13 patients had achieved pCR in the first stage of the study. Results: In stage I of the study 13 women were enrolled, median age 43 years, tumor size 2–5 cm in 9/13 (69%), positive nodal status in 8/13 (61%). Main grade 3 adverse event was neutropenia (related to AT and E in 4 and 2 cases, respectively). AT followed by E induced clinical complete + partial responses in 11/13 patients (85%), pCR in 3/13 (23%). Median measurements of maximum standardized uptake value (SUVmax) resulted 13, 3, and 1.9 at baseline, after AT and E, respectively. Complete metabolic response (CMR) occurred after AT and after E in 2 and 3 cases, respectively. Notably, 2 of the 5 (40%) patients with CMR achieved pCR at surgery. Immunostaining of paired pre-/post-treatment tumor specimens showed a reduction of β-catenin, CyclinD1, Zeb-1, and c-myc expression, in the absence of N-cadherin modulation. The study was interrupted at stage I due to the lack of the required patients with pCR. Conclusions: Despite the early study closure, preoperative E following AT showed clinical and biological activity in triple negative breast cancer patients. Furthermore, the modulation of β-catenin pathway core proteins, supposedly outside the domain of epithelial–mesenchymal transition, claims for further investigation. Trial registration: EU Clinical Trial Register, EudraCT number . [ABSTRACT FROM AUTHOR]

Summary: Splenectomy in addition to immunotherapy with rituximab can provide quick and sometimes durable disease control in patients with splenic marginal zone lymphoma (SMZL). However, systemic chemotherapy is ultimately required in many cases. The BRISMA (Bendamustine‐rituximab as first‐line treatment of splenic marginal zone lymphoma)/IELSG (International Extranodal Lymphoma Study Group)36 trial is an open‐label, single arm phase II study designed by the IELSG in cooperation with the Fondazione Italiana Linfomi and the lymphoma Study Association according to Simon's two‐stage method. The primary endpoint was complete response rate. Fifty‐six patients with SMZL diagnosis confirmed on central revision were treated with bendamustine (90 mg/m2 days 1, 2) and rituximab (375 mg/m2 day 1) every 28 days for six cycles (B‐R). The overall response and CR rates were 91% and 73%, respectively. Duration of response, progression‐free survival and overall survival at 3 years were 93% (95% confidence interval [CI] 81–98), 90% (95% CI 77–96) and 96% (95% CI 84–98), respectively. Toxicity was mostly haematological. Neutropenia grade ≥3 was recorded in 43% of patients; infections and febrile neutropenia in 5·4% and 3·6%. Overall, 14 patients (25%) experienced serious adverse events. Five patients (9%) went off‐study because of toxicity and one patient died from infection. In conclusion, B‐R resulted in a very effective first‐line regimen for SMZL. Based on the results achieved in the BRISMA trial, B‐R should be considered when a chemotherapy combination with rituximab is deemed necessary for symptomatic SMZL patients. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-25, a member of the IL-17 cytokine superfamily, is produced by immune and non-immune cells and exerts type 2 pro-inflammatory effects in vitro and in vivo. The IL-25 receptor(R) is composed of the IL-17RA/IL-17RB subunits. Previous work showed that germinal centre (GC)-derived B-cell non Hodgkin lymphomas (B-NHL) expressed IL-17AR, formed by IL-17RA and IL-17RC subunits, and IL-17A/IL-17AR axis promoted B-NHL growth by stimulating neoangiogenesis. Here, we have investigated expression and function of IL-25/IL-25R axis in lymph nodes from human GC-derived B-NHL, i.e. Follicular Lymphoma (FL,10 cases), Diffuse Large B Cell Lymphoma (6 cases) and Burkitt Lymphoma (3 cases). Tumor cells expressed IL-25R and IL-25 that was detected also in non-malignant cells by flow cytometry. Immunohistochemical studies confirmed expression of IL-25R and IL-25 in FL cells, and highlighted IL-25 expression in bystander elements of the FL microenvironment. IL-25 i) up-regulated phosphorylation of NFkBp65, STAT-1 and JNK in B-NHL cells; ii) inhibited in vitro proliferation of the latter cells; iii) exerted antitumor activity in two in vivo B-NHL models by dampening expression of pro-angiogenic molecules as VEGF-C, CXCL6 and ANGPT3. In conclusion, IL-25, that is intrinsically pro-angiogenic, inhibits B-NHL growth by reprogramming the angiogenic phenotype of B-NHL cells. [ABSTRACT FROM AUTHOR]

JMJD6 is known to localize in the nucleus, exerting histone arginine demethylase and lysyl hydroxylase activities. A novel localization of JMJD6 in the extracellular matrix, resulting from its secretion as a soluble protein, was unveiled by a new anti-JMJD6 mAb called P4E11, which was developed to identify new targets in the stroma. Recombinant JMJD6 binds with collagen type I (Coll-I), and distinct JMJD6 peptides interfere with collagen fibrillogenesis, collagen-fibronectin interaction, and adhesion of human tumor cells to the collagen substrate. P4E11 and collagen binding to JMJD6 are mutually exclusive because the amino acid sequences of JMJD6 necessary for the interaction with Coll-I are part of the conformational epitope recognized by P4E11. In mice injected with mouse 4T1 breast carcinoma cells, treatment with P4E11 reduced fibrosis at the primary tumor and prevented lung metastases. Reduction of fibrosis has also been documented in human breast and ovarian tumors (MDA-MB-231 and IGROV1, respectively) xenotransplanted into immunodeficient mice treated with P4E11. In summary, this study uncovers a new localization and function for JMJD6 that is most likely independent from its canonical enzymatic activities, and demonstrates that JMJD6 can functionally interact with Coll-I. P4E11 mAb, inhibiting JMJD6/Coll-I interaction, represents a new opportunity to target fibrotic and tumor diseases. [ABSTRACT FROM AUTHOR]

Thyroid carcinoma is generally associated with good prognosis, but no effective treatments are currently available for aggressive forms not cured by standard therapy. To find novel therapeutic targets for this tumor type, we had previously performed a siRNA-based functional screening to identify genes essential for sustaining the oncogenic phenotype of thyroid tumor cells, but not required to the same extent for the viability of normal cells (non-oncogene addiction paradigm). Among those, we found the coatomer protein complex ζ1 (COPZ1) gene, which is involved in intracellular traffic, autophagy and lipid homeostasis. In this paper, we investigated the mechanisms through which COPZ1 depletion leads to thyroid tumor cell death. We showed that siRNA-mediated COPZ1 depletion causes abortive autophagy, endoplasmic reticulum stress, unfolded protein response and apoptosis. Interestingly, we observed that mouse tumor xenografts, locally treated with siRNA targeting COPZ1, showed a significant reduction of tumor growth. On the whole, we demonstrated for the first time the crucial role of COPZ1 in the viability of thyroid tumor cells, suggesting that it may be considered an attractive target for novel therapeutic approaches for thyroid cancer. [ABSTRACT FROM AUTHOR]

The complex interaction between cells undergoing transformation and the various stromal and immunological cell components of the tumor microenvironment (TME) crucially influences cancer progression and diversification, as well as endowing clinical and prognostic significance. The immunosuppression characterizing the TME depends on the recruitment and activation of different cell types including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Less considered is the non-cellular component of the TME. Here, we focus on the extracellular matrix (ECM) regulatory activities that, within the TME, actively contribute to many aspects of tumor progression, acting on both tumor and immune cells. Particularly, ECM-mediated regulation of tumor-associated immunosuppression occurs through the modulation of myeloid cell expansion, localization, and functional activities. Such regulation is not limited to the TME but occurs also within the bone marrow, wherein matricellular proteins contribute to the maintenance of specialized hematopoietic stem cell niches thereby regulating their homeostasis as well as the generation and expansion of myeloid cells under both physiological and pathological conditions. Highlighting the commonalities among ECM-myeloid cell interactions in bone marrow and TME, in this review we present a picture in which myeloid cells might sense and respond to ECM modifications, providing different ECM-myeloid cell interfaces that may be useful to define prognostic groups and to tailor therapeutic interventions. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia ( CLL) is the most common leukemia in adults. Its clinical course is typically indolent; however, based on a series of pathobiological, clinical, genetic, and phenotypic parameters, patient survival varies from less than 5 to more than 20 years. In this paper, we show for the first time that the expression of the interferon-inducible DNA sensor IFI16, a member of the PYHIN protein family involved in proliferation inhibition and apoptosis regulation, is associated with the clinical outcome in CLL. We studied 99 CLLs cases by immunohistochemistry and 10 CLLs cases by gene expression profiling. We found quite variable degrees of IFI16 expression among CLLs cases. Noteworthy, we observed that a reduced IFI16 expression was associated with a very poor survival, but only in cases with ZAP70/ CD38 expression. Furthermore, we found that IFI16 expression was associated with a specific gene expression signature. As IFI16 can be easily detected by immunohistochemistry or flow cytometry, it may become a part of phenotypic screening in CLL patients if its prognostic role is confirmed in independent series. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) are innate immune cells that exert positive and negative immune modulatory functions capable to enhance or limit the intensity and/or duration of adaptive immune responses. Although MCs are crucial to regulate T cell immunity, their action in the pathogenesis of autoimmune diseases is still debated. Here we demonstrate that MCs play a crucial role in T1D pathogenesis so that their selective depletion in conditional MC knockout NOD mice protects them from the disease. MCs of diabetic NOD mice are overly inflammatory and secrete large amounts of IL-6 that favors differentiation of IL-17-secreting T cells at the site of autoimmunity. Moreover, while MCs of control mice acquire an IL-10 + phenotype upon interaction with FoxP3 + Treg cells, MCs of NOD mice do not undergo this tolerogenic differentiation. Our data indicate that overly inflammatory MCs unable to acquire a tolerogenic IL-10 + phenotype contribute to the pathogenesis of autoimmune T1D. [ABSTRACT FROM AUTHOR]

Patients affected by colorectal cancer (CRC) with DNA mismatch repair deficiency (MMRd), often respond to immune checkpoint blockade therapies, while those with mismatch repair-proficient (MMRp) tumors generally do not. Interestingly, a subset of MMRp CRCs contains variable fractions of MMRd cells, but it is unknown how their presence impacts immune surveillance. We asked whether modulation of the MMRd fraction in MMR heterogeneous tumors acts as an endogenous cancer vaccine by promoting immune surveillance. To test this hypothesis, we use isogenic MMRp (Mlh1 +/+ ) and MMRd (Mlh1 −/− ) mouse CRC cells. MMRp/MMRd cells mixed at different ratios are injected in immunocompetent mice and tumor rejection is observed when at least 50% of cells are MMRd. To enrich the MMRd fraction, MMRp/MMRd tumors are treated with 6-thioguanine, which leads to tumor rejection. These results suggest that genetic and pharmacological modulation of the DNA mismatch repair machinery potentiate the immunogenicity of MMR heterogeneous tumors. [Display omitted] • MMR heterogeneity affects immune surveillance in mouse CRC • In vivo 6TG treatment increases the MMRd fraction of MMR heterogeneous tumors • Pharmacological selection of MMRd cells improves immune surveillance in MMR tumors The impact of MMR heterogeneity on immune surveillance of colon cancers is largely unexplored. This proof-of-concept study by Amodio et al. suggests that MMR heterogeneity can be exploited through an endogenous vaccination approach based on pharmacological modulation of the DNA MMR, which potentiates cancer immunogenicity. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to several articles on the use of intrapleural bortezomib in myelomatous pleural effusion, published in previous issues.