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Inflammation is a hallmark of cancer1. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities2–5. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXbibr2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXbibr2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXbibr2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11b+HLA-DRloCD15+CD14− myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.A translational study demonstrates the role of myeloid inflammatory cells in driving disease progression and treatment resistance in prostate cancer and shows that these cells can be targeted therapeutically. [ABSTRACT FROM AUTHOR]

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Given that the condition of 'mortal liveness' was a greater cause for perplexity in Beckett's writing than the notion of an afterlife, this essay considers evocations of a post-mortal state in The Unnamable and the three works of the later trilogy, Nohow On , as a continuum from the pre-natal state he claims to recall. The paintings of Jack B. Yeats, an acknowledged influence on Beckett, exhibit significant parallels in the evocation of figures whose tenuous presence in the landscape erases the boundary between shades and mortal beings. Résumé: La condition d' une vie mortelle étant dans l' œuvre de Beckett une notion plus importante que celle de vie future, cet essai se concentre sur les évocations d' un état post mortem dans L' innommable et dans les trois textes de la deuxième trilogie, Nohow On , se situant dans le prolongement de l' état prénatal dont Beckett prétend se souvenir. Les peintures de Jack B. Yeats, dont on connaît l' influence sur Beckett, montrent des parallèles importants dans l' évocation de figures sont la présence hésitante dans le paysage efface la frontière entre les ombres et les être mortels. [ABSTRACT FROM AUTHOR]

Disease and other health hazards pose serious threats to the persistence of wild ape populations. The total chimpanzee population at Gombe National Park, Tanzania, has declined from an estimated 120 to 150 individuals in the 1960's to around 100 individuals by the end of 2013, with death associated with observable signs of disease as the leading cause of mortality. In 2004, we began a non‐invasive health‐monitoring program in the two habituated communities in the park (Kasekela and Mitumba) with the aim of understanding the prevalence of health issues in the population, and identifying the presence and impacts of various pathogens. Here we present prospectively collected data on clinical signs (observable changes in health) in the chimpanzees of the Kasekela (n = 81) and Mitumba (n = 32) communities over an 8‐year period (2005–2012). First, we take a population approach and analyze prevalence of clinical signs in five different categories: gastrointestinal system (diarrhea), body condition (estimated weight loss), respiratory system (coughing, sneezing etc.), wounds/lameness, and dermatologic issues by year, month, and community membership. Mean monthly prevalence of each clinical sign per community varied, but typically affected <10% of observed individuals. Secondly, we analyze the presence of clinical signs in these categories as they relate to individual demographic and social factors (age, sex, and dominance rank) and simian immunodeficiency virus (SIVcpz) infection status. Adults have higher odds of being observed with diarrhea, loss of body condition, and wounds or lameness when compared to immatures, while males have a higher probability of being observed with wounds or lameness than females. In contrast, signs of respiratory illness appear not to be related to chimpanzee‐specific factors and skin abnormalities are very rare. For a subset of known‐rank individuals, dominance rank predicts the probability of wounding/lameness in adult males, but does not predict any adverse clinical signs in adult females. Instead, adult females with SIVcpz infection are more likely to be observed with diarrhea, a finding that warrants further investigation. Comparable data are needed from other sites to determine whether the prevalence of clinical signs we observe are relatively high or low, as well as to more fully understand the factors influencing health of wild apes at both the population and individual level. Am. J. Primatol. 80:e22562, 2018. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Dectin-1/CLEC7A is a pattern recognition receptor that recognizes β-1,3 glucans, and its stimulation initiates signaling events characterized by the production of inflammatory cytokines from human dendritic cells (DCs) required for antifungal immunity. β-glucans differ greatly in size, structure, and ability to activate effector immune responses from DC; as such, small particulate β-glucans are thought to be poor activators of innate immunity. We show that β-glucan particle size is a critical factor contributing to the secretion of cytokines from human DC; large β-glucan-stimulated DC generate significantly more IL-1β, IL-6, and IL-23 compared to those stimulated with the smaller β-glucans. In marked contrast, the secretion of TSLP and CCL22 were found to be insensitive to β-glucan particle size. Furthermore, we show that the capacity to induce phagocytosis, and the relative IL-1β production determined by β-glucan size, regulates the composition of the cytokine milieu generated from DC. This suggests that β-glucan particle size is critically important in orchestrating the nature of the immune response to fungi. [ABSTRACT FROM AUTHOR]

The innate immune system is a critical component of host defence against microbial pathogens, but effective responses require an ability to distinguish between infectious and non-infectious insult to prevent inappropriate inflammation. Using the important obligate intracellular human pathogen Chlamydia trachomatis; an organism that causes significant immunopathology, we sought to determine critical host and pathogen factors that contribute to the induction of inflammasome activation. We assayed inflammasome activation by immunoblotting and ELISA to detect IL-1β processing and LDH release to determine pyroptosis. Using primary murine bone marrow derived macrophages or human monocyte derived dendritic cells, infected with live or attenuated Chlamydia trachomatis we report that the live organism activates both canonical and non-canonical inflammasomes, but only canonical inflammasomes controlled IL-1β processing which preceded pyroptosis. NADPH oxidase deficient macrophages were permissive to Chlamydia trachomatis replication and displayed elevated type-1 interferon and inflammasome activation. Conversely, attenuated, non-replicating Chlamydia trachomatis, primed but did not activate inflammasomes and stimulated reduced type-1 interferon responses. This suggested bacterial replication or metabolism as important factors that determine interferon responses and inflammasome activation. We identified STING but not cGAS as a central mediator of interferon regulated inflammasome activation. Interestingly, exogenous delivery of a Chlamydia trachomatis metabolite and STING ligand—cyclic di-AMP, recovered inflammasome activation to attenuated bacteria in a STING dependent manner thus indicating that a bacterial metabolite is a key factor initiating inflammasome activation through STING, independent of cGAS. These data suggest a potential mechanism of how the innate immune system can distinguish between infectious and non-infectious insult and instigate appropriate immune responses that could be therapeutically targeted. [ABSTRACT FROM AUTHOR]

For all his readiness to allow ghosts into his narratives, Beckett was no super-naturalist. Yet in his later plays, the voice of consciousness ranges across the human life span, from pre-natal to post-mortem states. This latitude in the way he dramatizes anxieties of incarnation harks back to his analysis with Wilfred Bion, with whom Beckett explored his own intrauterine memories. Bion's view of 'birth' and 'death' as indeterminate boundaries may have enduring resonances in Beckett's work. [ABSTRACT FROM AUTHOR]

FOXP3+ regulatory T (Treg) cells are indispensable for immune homeostasis, but their study in humans is complicated by heterogeneity within Treg, the difficulty in purifying Tregs using surface marker expression (e.g. CD25) and the transient expression of FOXP3 by activated effector cells. Here, we report that expression of CD39 and CD45RO distinguishes three sub‐populations within human CD4+CD25hi T cells. Initial phenotypic and functional analysis demonstrated that CD4+CD25hiCD39+CD45RO+ cells had properties consistent with effector Treg, CD4+CD25hiCD39−CD45RO− cells were naïve Treg and CD4+CD25hiCD39−CD45RO+ cells were predominantly non‐Treg with effector T‐cell function. Differences in these two newly identified Treg subsets were corroborated by studies of gene expression and TCR analysis. To apply this approach, we studied these two newly identified Treg subsets in ankylosing spondylitis, and showed impairment in both effector and naïve Treg. This work highlights the importance of discriminating Treg subsets to enable proper comparisons of immune regulatory capacity in healthy individuals and those with inflammatory disease. [ABSTRACT FROM AUTHOR]

Thymic stromal lymphopoietin (TSLP) produced by epithelial cells acts on dendritic cells (DCs) to drive differentiation of TH2-cells, and is therefore important in allergic disease pathogenesis. However, DCs themselves make significant amounts of TSLP in response to microbial products, but little is known about the key downstream signals that induce and modulate this TSLP secretion from human DCs. We show that human monocyte derived DC (mDC) secretion of TSLP in response to Candida albicans and β-glucans requires dectin-1, Syk, NF-κB, and p38 MAPK signaling. In addition, TSLP production by mDCs is greatly enhanced by IL-1β, but not TNF-α, in contrast to epithelial cells. Furthermore, TSLP secretion is significantly increased by signals emanating from the endoplasmic reticulum (ER) stress response, specifically the unfolded protein response sensors, inositol-requiring transmembrane kinase/endonuclease 1 and protein kinase R-like ER kinase, which are activated by dectin-1 stimulation. Thus, TSLP production by mDCs requires the integration of signals from dectin-1, the IL-1 receptor, and ER stress signaling pathways. Autocrine TSLP production is likely to play a role in mDC-controlled immune responses at sites removed from epithelial cell production of the cytokine, such as lymphoid tissue. [ABSTRACT FROM AUTHOR]

The article discusses a study focusing on plasma androgen receptor (AR) and abiraterone-resistant prostate cancer. Topics discussed include the targeted next-generation sequencing used in the study, the treatment of castration-resistant prostate cancer patients using abiraterone, and the lack of change in AR copy number from before treatment to progression. Also mentioned are the mutant AR alleles.

In many mammals, early social experience is critical to developing species-appropriate adult behaviors. Although mother-infant interactions play an undeniably significant role in social development, other individuals in the social milieu may also influence infant outcomes. Additionally, the social skills necessary for adult success may differ between the sexes. In chimpanzees (Pan troglodytes), adult males are more gregarious than females and rely on a suite of competitive and cooperative relationships to obtain access to females. In fission-fusion species, including humans and chimpanzees, subgroup composition is labile and individuals can vary the number of individuals with whom they associate. Thus, mothers in these species have a variety of social options. In this study, we investigated whether wild chimpanzee maternal subgrouping patterns differed based on infant sex. Our results show that mothers of sons were more gregarious than mothers of daughters; differences were especially pronounced during the first 6 mo of life, when infant behavior is unlikely to influence maternal subgrouping. Furthermore, mothers with sons spent significantly more time in parties containing males during the first 6 mo. These early differences foreshadow the well-documented sex differences in adult social behavior, and maternal gregariousness may provide sons with important observational learning experiences and social exposure early in life. The presence of these patterns in chimpanzees raises questions concerning the evolutionary history of differential social exposure and its role in shaping sex-typical behavior in humans. [ABSTRACT FROM AUTHOR]

Parental investment theory predicts that maternal resources are finite and allocated among offspring based on factors including maternal age and condition, and offspring sex and parity. Among humans, firstborn children are often considered to have an advantage and receive greater investment than their younger siblings. However, conflicting evidence for this "firstborn advantage" between modern and hunter-gatherer societies raises questions about the evolutionary history of differential parental investment and birth order. In contrast to humans, most nonhuman primate firstborns belong to young, inexperienced mothers and exhibit higher mortality than laterborns. In this study, we investigated differences in maternal investment and offspring outcomes based on birth order (firstborn vs. laterborn) among wild chimpanzees (Pan troglodyte schweinfurthii). During the critical first year of life, primiparous mothers nursed, groomed, and played with their infants more than did multiparous mothers. Furthermore, this pattern of increased investment in firstborns appeared to be compensatory, as probability of survival did not differ by birth order. Our study did not find evidence for a firstborn advantage as observed in modern humans but does suggest that unlike many other primates, differences in maternal behavior help afford chimpanzee firstborns an equal chance of survival. [ABSTRACT FROM AUTHOR]

The blood system is sustained by a pool of haematopoietic stem cells (HSCs) that are long-lived due to their capacity for self-renewal. A consequence of longevity is exposure to stress stimuli including reactive oxygen species (ROS), nutrient fluctuation and DNA damage. Damage that occurs within stressed HSCs must be tightly controlled to prevent either loss of function or the clonal persistence of oncogenic mutations that increase the risk of leukaemogenesis. Despite the importance of maintaining cell integrity throughout life, how the HSC pool achieves this and how individual HSCs respond to stress remain poorly understood. Many sources of stress cause misfolded protein accumulation in the endoplasmic reticulum (ER), and subsequent activation of the unfolded protein response (UPR) enables the cell to either resolve stress or initiate apoptosis. Here we show that human HSCs are predisposed to apoptosis through strong activation of the PERK branch of the UPR after ER stress, whereas closely related progenitors exhibit an adaptive response leading to their survival. Enhanced ER protein folding by overexpression of the co-chaperone ERDJ4 (also called DNAJB9) increases HSC repopulation capacity in xenograft assays, linking the UPR to HSC function. Because the UPR is a focal point where different sources of stress converge, our study provides a framework for understanding how stress signalling is coordinated within tissue hierarchies and integrated with stemness. Broadly, these findings reveal that the HSC pool maintains clonal integrity by clearance of individual HSCs after stress to prevent propagation of damaged stem cells. [ABSTRACT FROM AUTHOR]

The role of biological and social influences on sex differences in human child development is a persistent topic of discussion and debate. Given their many similarities to humans, chimpanzees are an important study species for understanding the biological and evolutionary roots of sex differences in human development. In this study, we present the most detailed analyses of wild chimpanzee infant development to date, encompassing data from 40 infants from the long-term study of chimpanzees at Gombe National Park, Tanzania. Our goal was to characterize age-related changes, from birth to five years of age, in the percent of observation time spent performing behaviors that represent important benchmarks in nutritional, motor, and social development, and to determine whether and in which behaviors sex differences occur. Sex differences were found for indicators of social behavior, motor development and spatial independence with males being more physically precocious and peaking in play earlier than females. These results demonstrate early sex differentiation that may reflect adult reproductive strategies. Our findings also resemble those found in humans, which suggests that biologically-based sex differences may have been present in the common ancestor and operated independently from the influences of modern sex-biased parental behavior and gender socialization. [ABSTRACT FROM AUTHOR]

Coalitionary aggression occurs when at least two individuals jointly direct aggression at one or more conspecific targets. Scientists have long argued that this common form of cooperation has positive fitness consequences. Nevertheless, despite evidence that social bond strength (which is thought to promote coalition formation) is correlated with fitness in primates, cetaceans, and ungulates, few studies have directly examined whether coalitionary aggression improves reproductive success. We tested the hypothesis that among free-ranging chimpanzees ( Pan troglodytes schweinfurthii), participation in coalitionary aggression increases reproductive output. Using 14 years of genetic and behavioral data from Gombe National Park, Tanzania, we found that coalitionary aggression increased a male's chances of (A) siring offspring, compared to other males of similar dominance rank, and (B) ascending in rank, a correlate of future reproductive output. Because male chimpanzees form coalitions with many others within a complex network, we used social network analysis to identify the types of connections correlated with these fitness benefits. The beneficiaries of coalitionary aggression were males with the highest 'betweenness'-that is, those who tended to have coalition partners who themselves did not form coalitions with each other. This suggests that beyond simply recognizing third-party relationships, chimpanzees may use this knowledge to choose coalition partners. If so, this is a significant step forward in our knowledge of the adaptive value of social intelligence. Regardless of mechanism, however, this is the first evidence of genetic benefits of coalitionary aggression in this species, and therefore has important implications for understanding the evolution of cooperation. [ABSTRACT FROM AUTHOR]

Chimpanzees exhibit cultural variation, yet examples of successful cultural transmission between wild communities are lacking. Here we provide the first account of tool-assisted predation ("ant fishing") on Camponotus ants by the Kasekela and Mitumba communities of Gombe National Park. We then consider three hypotheses for the appearance and spread of this behavior in Kasekela: (1) changes in prey availability or other environmental factors, (2) innovation, sod (3) introduction. Ant fishing was recognized as habitual in the Mitumba community by 1992, soon after their habituation began. Apart from one session in 1978, Camponotus predation (typically with tools) was documented in the Kasekela community beginning only in 1994, despite decades of prior observation. By February 2010, ant fishing was customary in Kasekela and with one exception was practiced exclusively by chimpanzees born after 1981 and immigrant females. We hypothesize that changes insect prey availability over time and/or the characteristics of one popular ant-fishing site may have influenced the establishment of ant fishing. Though innovation cannot be completely ruled out, the circumstantial evidence suggests that a Mitumba immigrant introduced ant fishing to Kasekela. We submit that this report represents the first documented case of successful transmission of a novel cultural behavior between wild chimpanzee communities. [ABSTRACT FROM AUTHOR]