Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.

Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects

CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation

Recruitment of monocytic myeloid-derived suppressor cells (MDSCs) and differentiation of tumor-associated macrophages (TAMs) are the major factors contributing to tumor progression and metastasis. We demonstrated that differentiation of TAMs in tumor site from monocytic precursors was controlled by downregulation of the activity of the transcription factor STAT3. Decreased STAT3 activity was caused by hypoxia and affected all myeloid cells but was not observed in tumor cells. Upregulation of CD45 tyrosine phosphatase activity in MDSCs exposed to hypoxia in tumor site was responsible for downregulation of STAT3. This effect was mediated by the disruption of CD45 protein dimerization regulated by sialic acid. Thus, STAT3 has a unique function in the tumor environment in controlling the differentiation of MDSC into TAM, and its regulatory pathway could be a potential target for therapy

ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R–mediated apoptosis

Myeloid-derived suppressor cells (MDSCs) dampen the immune response thorough inhibition of T cell activation and proliferation and often are expanded in pathological conditions. Here, we studied the fate of MDSCs in cancer. Unexpectedly, MDSCs had lower viability and a shorter half-life in tumor-bearing mice compared with neutrophils and monocytes. The reduction of MDSC viability was due to increased apoptosis, which was mediated by increased expression of TNF-related apoptosis–induced ligand receptors (TRAIL-Rs) in these cells. Targeting TRAIL-Rs in naive mice did not affect myeloid cell populations, but it dramatically reduced the presence of MDSCs and improved immune responses in tumor-bearing mice. Treatment of myeloid cells with proinflammatory cytokines did not affect TRAIL-R expression; however, induction of ER stress in myeloid cells recapitulated changes in TRAIL-R expression observed in tumor-bearing hosts. The ER stress response was detected in MDSCs isolated from cancer patients and tumor-bearing mice, but not in control neutrophils or monocytes, and blockade of ER stress abrogated tumor-associated changes in TRAIL-Rs. Together, these data indicate that MDSC pathophysiology is linked to ER stress, which shortens the lifespan of these cells in the periphery and promotes expansion in BM. Furthermore, TRAIL-Rs can be considered as potential targets for selectively inhibiting MDSCs

An improved method to identify BAC clones using pooled overgos

Hybridization using overgo probes is an established approach for screening arrayed bacterial artificial chromosome (BAC) libraries. We have improved the use of overgos by increasing the yield of positive clones using reduced levels of radioisotopes and enzyme. The strategy involves labeling with all four radiolabeled nucleotides in a hot pulse followed by a cold nucleotide chase and then extending the exposure time to compensate for reduced specific activity of the probes. The resulting cost savings and reduced human exposure to radiation make the use of highly pooled overgo probes a more attractive approach for screening of BAC libraries from organisms with large genomes

The Speed of Sound in Methane under Conditions of the Thermal Boundary Layer of Uranus

We present the first direct observations of acoustic waves in warm dense matter. We analyze wavenumber- and energy-resolved X-ray spectra taken from warm dense methane created by laser-heating a cryogenic liquid jet. X-ray diffraction and inelastic free electron scattering yield sample conditions of 0.3$\pm$0.1 eV and 0.8$\pm$0.1 g/cm$^3$, corresponding to a pressure of $\sim$13 GPa and matching the conditions predicted in the thermal boundary layer between the inner and outer envelope of Uranus. Inelastic X-ray scattering was used to observe the collective oscillations of the ions. With a highly improved energy resolution of $\sim$50 meV, we could clearly distinguish the Brillouin peaks from the quasi-elastic Rayleigh feature. Data at different wavenumbers were used to obtain a sound speed of 5.9$\pm$0.5 km/s, which enabled us to validate the use of Birch's law in this new parameter regime.Comment: 7 pages, 4 figures with supplementary informatio

Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17-producing CD4(+) T cells

Evidence links chronic inflammation with cancer, but cellular mechanisms involved in this process remain unclear. We have demonstrated that in humans, inflammatory conditions that predispose to development of skin and colon tumors are associated with accumulation in tissues of CD33(+)S100A9(+) cells, the phenotype typical for myeloid-derived suppressor cells in cancer or immature myeloid cells (IMCs) in tumor-free hosts. To identify the direct role of these cells in tumor development, we used S100A9 transgenic mice to create the conditions for topical accumulation of these cells in the skin in the absence of infection or tissue damage. These mice demonstrated accumulation of granulocytic IMCs in the skin upon topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in a dramatic increase in the formation of papillomas during epidermal carcinogenesis. The effect of IMCs on tumorigenesis was not associated with immune suppression, but with CCL4 (chemokine [C-C motif] ligand 4)-mediated recruitment of IL-17–producing CD4(+) T cells. This chemokine was released by activated IMCs. Elimination of CD4(+) T cells or blockade of CCL4 or IL-17 abrogated the increase in tumor formation caused by myeloid cells. Thus, this study implicates accumulation of IMCs as an initial step in facilitation of tumor formation, followed by the recruitment of CD4(+) T cells

Scientific drilling projects in ancient lakes: integrating geological and biological histories

Sedimentary sequences in ancient or long-lived lakes can reach several thousands of meters in thickness and often provide an unrivalled perspective of the lake's regional climatic, environmental, and biological history. Over the last few years, deep drilling projects in ancient lakes became increasingly multi- and interdisciplinary, as, among others, seismological, sedimentological, biogeochemical, climatic, environmental, paleontological, and evolutionary information can be obtained from sediment cores. However, these multi- and interdisciplinary projects pose several challenges. The scientists involved typically approach problems from different scientific perspectives and backgrounds, and setting up the program requires clear communication and the alignment of interests. One of the most challenging tasks, besides the actual drilling operation, is to link diverse datasets with varying resolution, data quality, and age uncertainties to answer interdisciplinary questions synthetically and coherently. These problems are especially relevant when secondary data, i.e., datasets obtained independently of the drilling operation, are incorporated in analyses. Nonetheless, the inclusion of secondary information, such as isotopic data from fossils found in outcrops or genetic data from extant species, may help to achieve synthetic answers. Recent technological and methodological advances in paleolimnology are likely to increase the possibilities of integrating secondary information, e.g., through molecular dating of molecular phylogenies. Some of the new approaches have started to revolutionize scientific drilling in ancient lakes, but at the same time, they also add a new layer of complexity to the generation and analysis of sediment core data. The enhanced opportunities presented by new scientific approaches to study the paleolimnological history of these lakes, therefore, come at the expense of higher logistic, communication, and analytical efforts. Here we review types of data that can be obtained in ancient lake drilling projects and the analytical approaches that can be applied to empirically and statistically link diverse datasets for creating an integrative perspective on geological and biological data. In doing so, we highlight strengths and potential weaknesses of new methods and analyses, and provide recommendations for future interdisciplinary deep drilling projects

Gene expression studies in a hydrozoan (Clytia hemisphaerica) and a scyphozoan (Aurelia aurita) provide insights on key evolutionary innovations composing their medusa stages

Trois des cinq classes de cnidaires présentent des méduses pélagiques, classiquement tenues pour homologues, issues de l'acquisition d'un stade planctonique chez l’ancêtre des médusozoaires. Des différences anatomiques fondamentales opposent pourtant les hydroméduses aux cubo- et scyphoméduses, concernant leurs systèmes nerveux locomoteurs, leurs organes sensoriels, leur ontogenèse. Y aurait-il eu plusieurs acquisitions convergentes d’un stade méduse ? Les présents travaux s’appuient sur l’étude comparative de caractères d’une hydroméduse (Clytia hemisphaerica) et d’une scyphoméduse (Aurelia aurita), via des phylogénies de gènes et le suivi de l’expression de gènes par RNA-seq, hybridation in situ, et qPCR. Ils ont visé (i) une meilleure caractérisation du système tentaculaire de Clytia ; et la comparaison entre ces deux méduses (ii) du déploiement d’acteurs clés du développement et de la morphogenèse chez les animaux, et (iii) de protéines associées aux muscles striés (absents chez les polypes et convergents avec ceux des bilatériens). La comparaison de l'expression des Wnt soutient une conservation chez les cnidaires des rôles de voies de signalisation en aval de ces ligands dans l’organisation de l'axe oral-aboral et d’éléments du système nerveux, et une possible absence d'homologie des tentacules et de la symétrie tétraradiaire entre hydro- et scyphoméduses. Les recrutements indépendants de formes de tropomyosine spécifiques des muscles striés plaident en faveur d’acquisitions convergentes du muscle strié, donc de la locomotion pélagique, entre hydro- et scyphoméduses. Ces données remettent en question le scénario d'acquisition unique de la méduse chez les cnidaires.Three of the five classes of cnidarians possess pelagic medusae. The latter are classically considered homologous, i.e. inherited from a planktonic stage acquired in the ancestor of all medusozoans. However, an impressive array of fundamental differences opposes hydromedusae to cubomedusae/scyphomedusae, e.g. concerning their locomotory nervous systems, sensory organs, and ontogeny. Could there have been several convergent acquisitions of a medusa stage? The research presented here is based on comparative study of a hydromedusa (Clytia hemisphaerica) and a scyphomedusa (Aurelia aurita), involving gene phylogenies, and gene expression surveys using RNA-seq, in situ hybridisation, and qPCR. The main objectives were (i) an improved characterisation of the Clytia tentacle system; and comparisons between these two medusae, of (ii) the deployment of key actors in animal development and morphogenesis, and of (iii) some proteins associated with striated muscles which are absent in polyps and convergent with those of bilaterians. Comparison of Wnt expressions supports conservation among cnidarians of the roles held by several signalling pathways downstream of the Wnt ligands, in the organisation of the oral-aboral polarity and of some elements of the nervous system, and suggests that tentacles and tetraradial symmetry may not be homologous between hydro- and scyphomedusae. Independent recruitments of tropomyosin forms specific to the striated muscles strongly advocate convergent origins of striated muscles and thereby of pelagic locomotion between hydro- and scyphomedusae. These findings challenge the classical scenario of a single medusa acquisition during cnidarian evolution