From pain to tumor immunity: influence of peripheral sensory neurons in cancer

The nervous and immune systems are the primary sensory interfaces of the body, allowing it to recognize, process, and respond to various stimuli from both the external and internal environment. These systems work in concert through various mechanisms of neuro-immune crosstalk to detect threats, provide defense against pathogens, and maintain or restore homeostasis, but can also contribute to the development of diseases. Among peripheral sensory neurons (PSNs), nociceptive PSNs are of particular interest. They possess a remarkable capability to detect noxious stimuli in the periphery and transmit this information to the brain, resulting in the perception of pain and the activation of adaptive responses. Pain is an early symptom of cancer, often leading to its diagnosis, but it is also a major source of distress for patients as the disease progresses. In this review, we aim to provide an overview of the mechanisms within tumors that are likely to induce cancer pain, exploring a range of factors from etiological elements to cellular and molecular mediators. In addition to transmitting sensory information to the central nervous system, PSNs are also capable, when activated, to produce and release neuropeptides (e.g., CGRP and SP) from their peripheral terminals. These neuropeptides have been shown to modulate immunity in cases of inflammation, infection, and cancer. PSNs, often found within solid tumors, are likely to play a significant role in the tumor microenvironment, potentially influencing both tumor growth and anti-tumor immune responses. In this review, we discuss the current state of knowledge about the degree of sensory innervation in tumors. We also seek to understand whether and how PSNs may influence the tumor growth and associated anti-tumor immunity in different mouse models of cancer. Finally, we discuss the extent to which the tumor is able to influence the development and functions of the PSNs that innervate it

The epigenetic regulator RINF (CXXC5) maintains SMAD7 expression in human immature erythroid cells and sustains red blood cells expansion

The gene CXXC5, encoding a Retinoid-Inducible Nuclear Factor (RINF), is located within a region at 5q31.2 commonly deleted in myelodysplastic syndrome (MDS) and adult acute myeloid leukemia (AML). RINF may act as an epigenetic regulator and has been proposed as a tumor suppressor in hematopoietic malignancies. However, functional studies in normal hematopoiesis are lacking, and its mechanism of action is unknow. Here, we evaluated the consequences of RINF silencing on cytokineinduced erythroid differentiation of human primary CD34+ progenitors. We found that RINF is expressed in immature erythroid cells and that RINF-knockdown accelerated erythropoietin-driven maturation, leading to a significant reduction (~45%) in the number of red blood cells (RBCs), without affecting cell viability. The phenotype induced by RINF-silencing was TGFβ-dependent and mediated by SMAD7, a TGFβ- signaling inhibitor. RINF upregulates SMAD7 expression by direct binding to its promoter and we found a close correlation between RINF and SMAD7 mRNA levels both in CD34+ cells isolated from bone marrow of healthy donors and MDS patients with del(5q). Importantly, RINF knockdown attenuated SMAD7 expression in primary cells and ectopic SMAD7 expression was sufficient to prevent the RINF knockdowndependent erythroid phenotype. Finally, RINF silencing affects 5’-hydroxymethylation of human erythroblasts, in agreement with its recently described role as a Tet2- anchoring platform in mouse. Altogether, our data bring insight into how the epigenetic factor RINF, as a transcriptional regulator of SMAD7, may fine-tune cell sensitivity to TGFβ superfamily cytokines and thus play an important role in both normal and pathological erythropoiesis

Transdifferentiation of Human Circulating Monocytes Into Neuronal-Like Cells in 20 Days and Without Reprograming

Despite progress, our understanding of psychiatric and neurological illnesses remains poor, at least in part due to the inability to access neurons directly from patients. Currently, there are in vitro models available but significant work remains, including the search for a less invasive, inexpensive and rapid method to obtain neuronal-like cells with the capacity to deliver reproducible results. Here, we present a new protocol to transdifferentiate human circulating monocytes into neuronal-like cells in 20 days and without the need for viral insertion or reprograming. We have thoroughly characterized these monocyte-derived-neuronal-like cells (MDNCs) through various approaches including immunofluorescence (IF), flow cytometry, qRT-PCR, single cell mRNA sequencing, electrophysiology and pharmacological techniques. These MDNCs resembled human neurons early in development, expressed a variety of neuroprogenitor and neuronal genes as well as several neuroprogenitor and neuronal proteins and also presented electrical activity. In addition, when these neuronal-like cells were exposed to either dopamine or colchicine, they responded similarly to neurons by retracting their neuronal arborizations. More importantly, MDNCs exhibited reproducible differentiation rates, arborizations and expression of dopamine 1 receptors (DR1) on separate sequential samples from the same individual. Differentiation efficiency measured by cell morphology was on average 11.9 ± 1.4% (mean, SEM, n = 38,819 cells from 15 donors). To provide context and help researchers decide which in vitro model of neuronal development is best suited to address their scientific question,we compared our results with those of other in vitro models currently available and exposed advantages and disadvantages of each paradigm

Submarine record of volcanic island construction and collapse in the Lesser Antilles arc: First scientific drilling of submarine volcanic island landslides by IODP Expedition 340

IODP Expedition 340 successfully drilled a series of sites offshore Montserrat, Martinique and Dominica in the Lesser Antilles from March to April 2012. These are among the few drill sites gathered around volcanic islands, and the first scientific drilling of large and likely tsunamigenic volcanic island-arc landslide deposits. These cores provide evidence and tests of previous hypotheses for the composition and origin of those deposits. Sites U1394, U1399, and U1400 that penetrated landslide deposits recovered exclusively seafloor-sediment, comprising mainly turbidites and hemipelagic deposits, and lacked debris avalanche deposits. This supports the concepts that i/ volcanic debris avalanches tend to stop at the slope break, and ii/ widespread and voluminous failures of pre-existing low-gradient seafloor sediment can be triggered by initial emplacement of material from the volcano. Offshore Martinique (U1399 and 1400), the landslide deposits comprised blocks of parallel strata that were tilted or micro-faulted, sometimes separated by intervals of homogenized sediment (intense shearing), while Site U1394 offshore Montserrat penetrated a flat-lying block of intact strata. The most likely mechanism for generating these large-scale seafloor-sediment failures appears to be propagation of a decollement from proximal areas loaded and incised by a volcanic debris avalanche. These results have implications for the magnitude of tsunami generation. Under some conditions, volcanic island landslide deposits comprised of mainly seafloor sediment will tend to form smaller magnitude tsunamis than equivalent volumes of subaerial block-rich mass flows rapidly entering water. Expedition 340 also successfully drilled sites to access the undisturbed record of eruption fallout layers intercalated with marine sediment which provide an outstanding high-resolution dataset to analyze eruption and landslides cycles, improve understanding of magmatic evolution as well as offshore sedimentation processes. This article is protected by copyright. All rights reserved

The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8α+ dendritic cells

Human BDCA3+ dendritic cells (DCs) were suggested to be homologous to mouse CD8α+ DCs. We demonstrate that human BDCA3+ DCs are more efficient than their BDCA1+ counterparts or plasmacytoid DCs (pDCs) in cross-presenting antigen and activating CD8+ T cells, which is similar to mouse CD8α+ DCs as compared with CD11b+ DCs or pDCs, although with more moderate differences between human DC subsets. Yet, no specific marker was known to be shared between homologous DC subsets across species. We found that XC chemokine receptor 1 (XCR1) is specifically expressed and active in mouse CD8α+, human BDCA3+, and sheep CD26+ DCs and is conserved across species. The mRNA encoding the XCR1 ligand chemokine (C motif) ligand 1 (XCL1) is selectively expressed in natural killer (NK) and CD8+ T lymphocytes at steady-state and is enhanced upon activation. Moreover, the Xcl1 mRNA is selectively expressed at high levels in central memory compared with naive CD8+ T lymphocytes. Finally, XCR1−/− mice have decreased early CD8+ T cell responses to Listeria monocytogenes infection, which is associated with higher bacterial loads early in infection. Therefore, XCR1 constitutes the first conserved specific marker for cell subsets homologous to mouse CD8α+ DCs in higher vertebrates and promotes their ability to activate early CD8+ T cell defenses against an intracellular pathogenic bacteria

Weighing stars from birth to death: mass determination methods across the HRD

The mass of a star is the most fundamental parameter for its structure, evolution, and final fate. It is particularly important for any kind of stellar archaeology and characterization of exoplanets. There exists a variety of methods in astronomy to estimate or determine it. In this review we present a significant number of such methods, beginning with the most direct and model-independent approach using detached eclipsing binaries. We then move to more indirect and model-dependent methods, such as the quite commonly used isochrone or stellar track fitting. The arrival of quantitative asteroseismology has opened a completely new approach to determine stellar masses and to complement and improve the accuracy of other methods. We include methods for different evolutionary stages, from the pre-main sequence to evolved (super)giants and final remnants. For all methods uncertainties and restrictions will be discussed. We provide lists of altogether more than 200 benchmark stars with relative mass accuracies between $[0.3,2]\%$ for the covered mass range of M\in [0.1,16]\,\msun, $75\%$ of which are stars burning hydrogen in their core and the other $25\%$ covering all other evolved stages. We close with a recommendation how to combine various methods to arrive at a "mass-ladder" for stars.Comment: Invited review article for The Astronomy and Astrophysics Review. 146 pages, 16 figures, 11 tables. Accepted version by the Journal. It includes summary figure of accuracy/precision of methods for mass ranges and summary table for individual method

Weighing stars from birth to death : mass determination methods across the HRD

Funding: C.A., J.S.G.M., and M.G.P. received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 670519: MAMSIE). N.B. gratefully acknowledge financial support from the Royal Society (University Research Fellowships) and from the European Research Council (ERC-CoG-646928, Multi-Pop).The mass of a star is the most fundamental parameter for its structure, evolution, and final fate. It is particularly important for any kind of stellar archaeology and characterization of exoplanets. There exist a variety of methods in astronomy to estimate or determine it. In this review we present a significant number of such methods, beginning with the most direct and model-independent approach using detached eclipsing binaries. We then move to more indirect and model-dependent methods, such as the quite commonly used isochrone or stellar track fitting. The arrival of quantitative asteroseismology has opened a completely new approach to determine stellar masses and to complement and improve the accuracy of other methods. We include methods for different evolutionary stages, from the pre-main sequence to evolved (super)giants and final remnants. For all methods uncertainties and restrictions will be discussed. We provide lists of altogether more than 200 benchmark stars with relative mass accuracies between [0.3 ,2 ]% for the covered mass range of M ∈[0.1 ,16 ] M⊙ , 75 % of which are stars burning hydrogen in their core and the other 25 % covering all other evolved stages. We close with a recommendation how to combine various methods to arrive at a "mass-ladder" for stars.PostprintPeer reviewe

Dendritic Cells Crosspresent Antigens from Live B16 Cells More Efficiently than from Apoptotic Cells and Protect from Melanoma in a Therapeutic Model

Dendritic cells (DC) are able to elicit anti-tumoral CD8+ T cell responses by cross-presenting exogenous antigens in association with major histocompatibility complex (MHC) class I molecules. Therefore they are crucial actors in cell-based cancer immunotherapy. Although apoptotic cells are usually considered to be the best source of antigens, live cells are also able to provide antigens for cross-presentation by DC. We have recently shown that prophylactic immunotherapy by DC after capture of antigens from live B16 melanoma cells induced strong CD8+ T-cell responses and protection against a lethal tumor challenge in vivo in C57Bl/6 mice. Here, we showed that DC cross-presenting antigens from live B16 cells can also inhibit melanoma lung dissemination in a therapeutic protocol in mice. DC were first incubated with live tumor cells for antigen uptake and processing, then purified and irradiated for safety prior to injection. This treatment induced stronger tumor-specific CD8+ T-cell responses than treatment by DC cross-presenting antigens from apoptotic cells. Apoptotic B16 cells induced more IL-10 secretion by DC than live B16 cells. They underwent strong native antigen degradation and led to the expression of fewer MHC class I/epitope complexes on the surface of DC than live cells. Therefore, the possibility to use live cells as sources of tumor antigens must be taken into account to improve the efficiency of cancer immunotherapy

ERK1 Regulates the Hematopoietic Stem Cell Niches

The mitogen-activated protein kinases (MAPK) ERK1 and ERK2 are among the major signal transduction molecules but little is known about their specific functions in vivo. ERK activity is provided by two isoforms, ERK1 and ERK2, which are ubiquitously expressed and share activators and substrates. However, there are not in vivo studies which have reported a role for ERK1 or ERK2 in HSCs and the bone marrow microenvironment. The present study shows that the ERK1-deficient mice present a mild osteopetrosis phenotype. The lodging and the homing abilities of the ERK1−/− HSC are impaired, suggesting that the ERK1−/−-defective environment may affect the engrafment of HSCs. Serial transplantations demonstrate that ERK1 is involved in the maintenance of an appropriate medullar microenvironment, but that the intrinsic properties of HSCs are not altered by the ERK1−/− defective microenvironment. Deletion of ERK1 impaired in vitro and in vivo osteoclastogenesis while osteoblasts were unaffected. As osteoclasts derive from precursors of the monocyte/macrophage lineage, investigation of the monocytic compartment was performed. In vivo analysis of the myeloid lineage progenitors revealed that the frequency of CMPs increased by approximately 1.3-fold, while the frequency of GMPs significantly decreased by almost 2-fold, compared with the respective WT compartments. The overall mononuclear-phagocyte lineage development was compromised in these mice due to a reduced expression of the M-CSF receptor on myeloid progenitors. These results show that the cellular targets of ERK1 are M-CSFR-responsive cells, upstream to osteoclasts. While ERK1 is well known to be activated by M-CSF, the present results are the first to point out an ERK1-dependent M-CSFR regulation on hematopoietic progenitors. This study reinforces the hypothesis of an active cross-talk between HSCs, their progeny and bone cells in the maintenance of the homeostasis of these compartments