The rockefeller university

Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver-and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins alpha(6)beta(4) and alpha(6)beta(1) were associated with lung metastasis, while exosomal integrin alpha(v)beta(5) was linked to liver metastasis. Targeting the integrins alpha(6)beta(4) and alpha(v)beta(5) decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

Tumor-initiating stem cells (SCs) exhibit distinct patterns of transcription factors and gene expression compared to healthy counterparts. Here, we show that dramatic shifts in large open-chromatin domain (super-enhancer) landscapes underlie these differences and reflect tumor microenvironment. By in vivo super-enhancer and transcriptional profiling, we uncover a dynamic cancer-specific epigenetic network selectively enriched for binding motifs of a transcription factor cohort expressed in squamous cell carcinoma SCs (SCC-SCs). Many of their genes, including Ets2 and Elk3, are themselves regulated by SCC-SC super-enhancers suggesting a cooperative feed forward loop. Malignant progression requires these genes, whose knockdown severely impairs tumor growth and prohibits progression from benign papillomas to SCCs. ETS2-deficiency disrupts the SCC-SC super-enhancer landscape and downstream cancer genes while ETS2-overactivation in epidermal-SCs induces hyperproliferation and SCC super-enhancer-associated genes Fos, Junb and Klf5. Together, our findings unearth an essential regulatory network required for the SCC-SC chromatin landscape and unveil its importance in malignant progression.

The primate brain contains a set of face-selective areas, which are thought to extract the rich social information that faces provide, such as emotional state and personal identity. The nature of this information raises a fundamental question about these face-selective areas: Do they respond to a face purely because of its visual attributes, or because the face embodies a larger social agent? Here, we used functional magnetic resonance imaging to determine whether the macaque face patch system exhibits a whole-agent response above and beyond its responses to individually presented faces and bodies. We found a systematic development of whole-agent preference through the face patches, from subadditive integration of face and body responses in posterior face patches to superadditive integration in anterior face patches. Superadditivity was not observed for faces atop nonbody objects, implying categorical specificity of face-body interaction. Furthermore, superadditivity was robust to visual degradation of facial detail, suggesting whole-agent selectivity does not require prior face recognition. In contrast, even the body patches immediately adjacent to anterior face areas did not exhibit superadditivity. This asymmetry between face-and body-processing systems may explain why observers attribute bodies' social signals to faces, and not vice versa. The development of whole-agent selectivity from posterior to anterior face patches, in concert with the recently described development of natural motion selectivity from ventral to dorsal face patches, identifies a single face patch, AF (anterior fundus), as a likely link between the analysis of facial shape and semantic inferences about other agents.

Mouse fmr1 models, and recent cross-sectional human data, suggest that different triple CGG(n) ranges of the fragile X mental retardation 1 (FMR1) gene are associated with variations in ovarian aging and infertility treatment outcomes. The FMR1 mutation affecting reproductive function most negatively in humans is the so-called low mutation, characterized by CGG(n < 26). We here present a first longitudinal study of selected young women with normal functional ovarian reserve (FOR). In a prospective cohort study, we selected among 233 young oocyte donors (mean age 24.8 +/- 3.3 years) as study population of 66 who had more than 1 anti-Mullerian hormone (AMH) level drawn over a 4-year period. AMH curves, as reflection of FOR, were then statistically compared between women with and without low FMR1 alleles. Biallelic low FMR1 (hom-low/low) donors already at initial presentation demonstrated significantly lower FOR than donors with biallelic normal (norm) FMR1 (CGG(n = 26-34); P = 0.001). Although monoallelic low FMR1 at initial presentation was not yet associated with decreased FOR, it over 4 years did demonstrate significantly enhanced declines in FOR (P = 0.046). Including repeat measurements, low/low (P = 0.006) and high/high (CGG(n > 34)) alleles (P < 0.001) demonstrated lower FOR by AMH than norm donors. Even monoallelic low FMR1 alleles are, thus, already at young female ages associated with accelerated declines in FOR. Low FMR1 alleles, therefore, potentially represent a screening tool for women at genetic risk toward premature ovarian senescence, representing in all races circa 10% of the female population.

IgG antibodies are actively produced in response to antigenic challenge or passively administered as an effective form of immunotherapy to confer immunity against foreign antigens. Their protective activity is mediated through their bifunctional nature: a variable Fab domain mediates antigen-binding specificity, whereas the constant Fc domain engages Fc receptors (FcRs) expressed on the surface of leukocytes to mediate effector functions. While traditionally considered the invariant domain of an IgG molecule, the Fc domain displays remarkable structural heterogeneity determined primarily by differences in the amino acid sequence of the various IgG subclasses and by the composition of the complex, Fc-associated biantennary N-linked glycan. These structural determinants regulate the conformational flexibility of the IgG Fc domain and affect its capacity to interact with distinct types of FcRs (type I or type II FcRs). FcR engagement activates diverse downstream immunomodulatory pathways with pleiotropic functional consequences including cytotoxicity and phagocytosis of IgG-coated targets, differentiation and activation of antigen presenting cells, modulation of T-cell activation, plasma cell survival, and regulation of antibody responses. These functions highlight the importance of FcR-mediated pathways in the modulation of adaptive immune responses and suggest a central role for IgG-FcR interactions during active and passive immunization.

The normalized differential cross section for top quark pair (t (t) over bar) production is measured in pp collisions at a centre-of-mass energy of 8 TeV at the CERN LHC using the CMS detector in data corresponding to an integrated luminosity of 19.7 fb(-1). The measurements are performed in the lepton+jets (e/mu+jets) and in the dilepton (e(+)e(-), mu(+)mu(-), and e(+/-)mu(-/+)) decay channels. The t (t) over bar cross section is measured as a function of the kinematic properties of the charged leptons, the jets associated to b quarks, the top quarks, and the t (t) over bar system. The data are compared with several predictions from perturbative quantum chromodynamic up to approximate next-to-next-to-leading-order precision. No significant deviations are observed relative to the standard model predictions.

Microbes living in stagnant water typically rely on chemical diffusion to draw nutrients from their environment. The sulfur-oxidizing bacterium Thiovulum majus and the ciliate Uronemella have independently evolved the ability to form a 'veil', a centimetre-scale mucous sheet on which cells organize to produce a macroscopic flow. This flow pulls nutrients through the community an order of magnitude faster than diffusion. To understand how natural selection led these microbes to evolve this collective behaviour, we connect the physical limitations acting on individual cells to the cell traits. We show how diffusion limitation and viscous dissipation have led individual T. majus and Uronemella cells to display two similar characteristics. Both of these cells exert a force of approximately 40 pN on the water and attach to boundaries by means of a mucous stalk. We show how the diffusion coefficient of oxygen in water and the viscosity of water define the force the cells must exert. We then show how the hydrodynamics of filter-feeding orient a microbe normal to the surface to which it attaches. Finally, we combine these results with new observations of veil formation and a review of veil dynamics to compare the collective dynamics of these microbes. We conclude that this convergent evolution is a reflection of similar physical limitations imposed by diffusion and viscosity acting on individual cells.

Suppression of RAD52 causes synthetic lethality in BRCA-deficient cells. Yet pharmacological inhibition of RAD52, which binds single-strand DNA (ssDNA) and lacks enzymatic activity, has not been demonstrated. Here, we identify the small molecule 6-hydroxy-DL-dopa (6-OH-dopa) as a major allosteric inhibitor of the RAD52 ssDNA binding domain. For example, we find that multiple small molecules bind to and completely transform RAD52 undecamer rings into dimers, which abolishes the ssDNA binding channel observed in crystal structures. 6-OH-Dopa also disrupts RAD52 heptamer and undecamer ring superstructures, and suppresses RAD52 recruitment and recombination activity in cells with negligible effects on other double-strand break repair pathways. Importantly, we show that 6-OH-dopa selectively inhibits the proliferation of BRCA-deficient cancer cells, including those obtained from leukemia patients. Taken together, these data demonstrate small-molecule disruption of RAD52 rings as a promising mechanism for precision medicine in BRCA-deficient cancers.

Background: Alopecia areata (AA) is a common T cell-mediated disorder with limited therapeutics. A molecular profile of cytokine pathways in AA tissues is lacking. Although studies have focused on T(H)1/IFN-gamma responses, several observations support a shared genetic background between AA and atopy. Objective: We sought to define the AA scalp transcriptome and associated biomarkers with comparisons with atopic dermatitis (AD) and psoriasis. Methods: We performed microarray and RT-PCR profiling of 27 lesional and 17 nonlesional scalp samples from patients with AA for comparison with normal scalp samples (n = 6). AA gene expression was also compared with samples from patients with lesional or nonlesional AD and those with psoriasis. A fold change of greater than 1.5 and a false discovery rate of less than 0.05 were used for differentially expressed genes (DEGs). Results: We established the AA transcriptomes (lesional vs nonlesional: 734 DEGs[297 upregulated and 437 downregulated]; lesional vs normal: 4230 DEGs [1980 upregulated and 2250 downregulated]), including many upregulated immune and downregulated hair keratin genes. Equally impressive as upregulation in T(H)1/interferon markers (IFNG and CXCL10/CXCL9) were those noted in T(H)2 (IL13, CCL18, CCL26, thymic stromal lymphopoietin, and periostin), T(H)9/IL-9, IL-23 (p40 and p19), and IL-16 mediators (all P < .05). There were no increases in T(H)17/T(H)22 markers. Hair keratin (KRT) expressions (ie, KRT86 and KRT85) were significantly suppressed in lesional skin. Greater scalp involvement (>25%) was associated with greater immune and keratin dysregulation and larger abnormalities in nonlesional scalp samples (ie, CXCL10 and KRT85). Conclusions: Our data associate the AA signature with T(H)2, T(H)1, IL-23, and IL-9/T(H)9 cytokine activation, suggesting consideration of anti-T(H)2, anti-T(H)1, and anti-IL-23 targeting strategies. Similar to psoriasis and AD, clinical trials with selective antagonists are required to dissect key pathogenic pathways.