A unidirectional transition from migratory to perivascular macrophage is required for tumor cell intravasation

Summary: Tumor-associated macrophages (TAMs) are critical for tumor metastasis. Two TAM subsets support cancer cell intravasation: migratory macrophages guide cancer cells toward blood vessels, where sessile perivascular macrophages assist their entry into the blood. However, little is known about the inter-relationship between these functionally distinct TAMs or their possible inter-conversion. We show that motile, streaming TAMs are newly arrived monocytes, recruited via CCR2 signaling, that then differentiate into the sessile perivascular macrophages. This unidirectional process is regulated by CXCL12 and CXCR4. Cancer cells induce TGF-β-dependent upregulation of CXCR4 in monocytes, while CXCL12 expressed by perivascular fibroblasts attracts these motile TAMs toward the blood vessels, bringing motile cancer cells with them. Once on the blood vessel, the migratory TAMs differentiate into perivascular macrophages, promoting vascular leakiness and intravasation. : Tumor-associated macrophages (TAMs) are essential for metastasis. Arwert et al. show that, following extravasation, monocytes initially become motile TAMs. Tumor-derived TGF-β then induces CXCR4 on TAMs, stimulating them to migrate toward CXCL12-expressing perivascular fibroblasts. Once adjacent to blood vessels, TAMs differentiate into metastasis-assisting perivascular TAMs. Keywords: tumor associated macrophages, TAMs, TGF beta, breast cancer, metastasis, CXCR4, CCR2, TMEM, Men

Development and preliminary effectiveness of an innovative treatment for binge eating in racially diverse adolescent girls

Binge and loss of control (LOC) eating are significant concerns among many adolescents and are associated with poor physical, social, and psychological functioning. Black girls appear to be particularly vulnerable to binge and LOC eating. Yet, empirically validated, culturally sensitive treatments for these disordered eating behaviors are not well established. This investigation examined satisfaction, feasibility, and preliminary outcomes of a binge eating intervention for ethnically diverse adolescent girls

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Author Correction: The Anglo-Saxon migration and the formation of the early English gene pool.

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The Anglo-Saxon migration and the formation of the early English gene pool.

The history of the British Isles and Ireland is characterized by multiple periods of major cultural change, including the influential transformation after the end of Roman rule, which precipitated shifts in language, settlement patterns and material culture1. The extent to which migration from continental Europe mediated these transitions is a matter of long-standing debate2-4. Here we study genome-wide ancient DNA from 460 medieval northwestern Europeans-including 278 individuals from England-alongside archaeological data, to infer contemporary population dynamics. We identify a substantial increase of continental northern European ancestry in early medieval England, which is closely related to the early medieval and present-day inhabitants of Germany and Denmark, implying large-scale substantial migration across the North Sea into Britain during the Early Middle Ages. As a result, the individuals who we analysed from eastern England derived up to 76% of their ancestry from the continental North Sea zone, albeit with substantial regional variation and heterogeneity within sites. We show that women with immigrant ancestry were more often furnished with grave goods than women with local ancestry, whereas men with weapons were as likely not to be of immigrant ancestry. A comparison with present-day Britain indicates that subsequent demographic events reduced the fraction of continental northern European ancestry while introducing further ancestry components into the English gene pool, including substantial southwestern European ancestry most closely related to that seen in Iron Age France5,6

The Anglo-Saxon migration and the formation of the early English gene pool

The history of the British Isles and Ireland is characterized by multiple periods of major cultural change, including the influential transformation after the end of Roman rule, which precipitated shifts in language, settlement patterns and material culture1. The extent to which migration from continental Europe mediated these transitions is a matter of long-standing debate2,3,4. Here we study genome-wide ancient DNA from 460 medieval northwestern Europeans—including 278 individuals from England—alongside archaeological data, to infer contemporary population dynamics. We identify a substantial increase of continental northern European ancestry in early medieval England, which is closely related to the early medieval and present-day inhabitants of Germany and Denmark, implying large-scale substantial migration across the North Sea into Britain during the Early Middle Ages. As a result, the individuals who we analysed from eastern England derived up to 76% of their ancestry from the continental North Sea zone, albeit with substantial regional variation and heterogeneity within sites. We show that women with immigrant ancestry were more often furnished with grave goods than women with local ancestry, whereas men with weapons were as likely not to be of immigrant ancestry. A comparison with present-day Britain indicates that subsequent demographic events reduced the fraction of continental northern European ancestry while introducing further ancestry components into the English gene pool, including substantial southwestern European ancestry most closely related to that seen in Iron Age France5,6

THE EFFECTS OF ALCOHOL CONSUMPTION ON MEASURES OF ANAEROBIC PERFORMANCE

Although alcohol is widely researched for its psychological and physiological effects on performance, past research has focused on aerobic modes. Therefore, we aimed to determine the effects of acute alcohol ingestion on tests of anaerobic performance. Twenty five subjects (13 female, 12 male, 22 ± 3 yrs, 173 ± 12 cm, 70 ± 17 kg, VO2 max 45 ± 8 ml/kg/min) were tested in a randomized crossover design, once consuming a placebo (6.4 ml/kg orange juice for females and 7.9 ml /kg for males) and once consuming 80 proof alcohol (2.6 ml/kg alcohol + 5.3 ml/kg orange juice for males and 2.1 ml/kg alcohol + 4.3 ml/kg juice for females) to achieve a 0.06% blood alcohol content as measured with a breathalyzer. Drinks were administered at 0, 15, and 30 minutes. Tests included a one repetition maximum (RM) bench press, vertical jump, two-minute crunches, and 30 second Wingate. Results indicated a significant decrease with alcohol consumption vs. placebo in average mean power (539 ± 168 vs. 556 ± 179 watts, alcohol and placebo, respectively, p\u3c0.01) as well as average minimum power (384 ± 129 and 405 ± 131 watts, alcohol and placebo, respectively, p\u3c0.01) during the Wingate. There was no difference between trials in the bench press, vertical jump, crunches, or Wingate peak power. These data suggest short duration (\u3c15 seconds) or low intensity (i.e. crunches) activities are less influenced by alcohol than sustained high intensity activities. Further research is needed to elucidate the effect of alcohol on sustained anaerobic power

Targeted Inactivation of Snail Family EMT Regulatory Factors by a Co(III)-Ebox Conjugate

<div><p>Snail family proteins are core EMT (epithelial-mesenchymal transition) regulatory factors that play essential roles in both development and disease processes and have been associated with metastasis in carcinomas. Snail factors are required for the formation of neural crest stem cells in most vertebrate embryos, as well as for the migratory invasive behavior of these cells. Snail factors have recently been linked to the formation of cancer stem cells, and expression of Snail proteins may be associated with tumor recurrence and resistance to chemotherapy and radiotherapy. We report that Co(III)-Ebox is a potent inhibitor of Snail- mediated transcriptional repression in breast cancer cells and in the neural crest of <em>Xenopus</em>. We further show that the activity of Co(III)-Ebox can be modulated by temperature, increasing the utility of this conjugate as a Snail inhibitor in model organisms. We exploit this feature to further delineate the requirements for Snail function during neural crest development, showing that in addition to the roles that Snail factors play in neural crest precursor formation and neural crest EMT/migration, inhibition of Snail function after the onset of neural crest migration leads to a loss of neural crest derived melanocytes. Co(III)-Ebox-mediated inhibition therefore provides a powerful tool for analysing the function of these core EMT factors with unparalleled temporal resolution. Moreover, the potency of Co(III)-Ebox as a Snail inhibitor in breast cancer cells suggests its potential as a therapeutic inhibitor of tumor progression and metastasis.</p> </div