Influence of wiring cost on the large-scale architecture of human cortical connectivity

In the past two decades some fundamental properties of cortical connectivity have been discovered: small-world structure, pronounced hierarchical and modular organisation, and strong core and rich-club structures. A common assumption when interpreting results of this kind is that the observed structural properties are present to enable the brain's function. However, the brain is also embedded into the limited space of the skull and its wiring has associated developmental and metabolic costs. These basic physical and economic aspects place separate, often conflicting, constraints on the brain's connectivity, which must be characterized in order to understand the true relationship between brain structure and function. To address this challenge, here we ask which, and to what extent, aspects of the structural organisation of the brain are conserved if we preserve specific spatial and topological properties of the brain but otherwise randomise its connectivity. We perform a comparative analysis of a connectivity map of the cortical connectome both on high- and low-resolutions utilising three different types of surrogate networks: spatially unconstrained (‘random’), connection length preserving (‘spatial’), and connection length optimised (‘reduced’) surrogates. We find that unconstrained randomisation markedly diminishes all investigated architectural properties of cortical connectivity. By contrast, spatial and reduced surrogates largely preserve most properties and, interestingly, often more so in the reduced surrogates. Specifically, our results suggest that the cortical network is less tightly integrated than its spatial constraints would allow, but more strongly segregated than its spatial constraints would necessitate. We additionally find that hierarchical organisation and rich-club structure of the cortical connectivity are largely preserved in spatial and reduced surrogates and hence may be partially attributable to cortical wiring constraints. In contrast, the high modularity and strong s-core of the high-resolution cortical network are significantly stronger than in the surrogates, underlining their potential functional relevance in the brain

Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia

Although angiogenesis is a prerequisite for the growth of most human solid tumours, alternative mechanisms of vascularisation can be adopted. We have previously described a non-angiogenic growth pattern in liver metastases of colorectal adenocarcinomas (CRC) in which tumour cells replace hepatocytes at the tumour-liver interface, preserving the liver architecture and co-opting the sinusoidal blood vessels. The aim of this study was to determine whether this replacement pattern occurs during liver metastasis of breast adenocarcinomas (BC) and whether the lack of an angiogenic switch in such metastases is due to the absence of hypoxia and subsequent vascular fibrinogen leakage. The growth pattern of 45 BC liver metastases and 28 CRC liver metastases (73 consecutive patients) was assessed on haematoxylin- and eosin-stained tissue sections. The majority of the BC liver metastases had a replacement growth pattern (96%), in contrast to only 32% of the CRC metastases (P<0.0001). The median carbonic anhydrase 9 (CA9) expression (M75 antibody), as a marker of hypoxia, (intensity x % of stained tumour cells) was 0 in the BC metastases and 53 in the CRC metastases (P<0.0001). There was CA9 expression at the tumour-liver interface in only 16% of the BC liver metastases vs 54% of the CRC metastases (P=0.002). There was fibrin (T2G1 antibody) at the tumour-liver interface in only 21% of the BC metastases vs 56% of the CRC metastases (P=0.04). The median macrophage count (Chalkley morphometry; KP-1 anti-CD68 antibody) at the interface was 4.3 and 7.5, respectively (P<0.0001). Carbonic anhydrase 9 score and macrophage count were positively correlated (r=0.42; P=0.002) in all metastases. Glandular differentiation was less in the BC liver metastases: 80% had less than 10% gland formation vs only 7% of the CRC metastases (P<0.0001). The liver is a densely vascularised organ and can host metastases that exploit this environment by replacing the hepatocytes and co-opting the vasculature. Our findings confirm that a non-angiogenic pattern of liver metastasis indeed occurs in BC, that this pattern of replacement growth is even more prevalent than in CRC, and that the process induces neither hypoxia nor vascular leakage

Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry.

Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients

A Mechanistic Basis for the Coordinated Regulation of Pharyngeal Morphogenesis in Caenorhabditis elegans by LIN-35/Rb and UBC-18–ARI-1

Genetic redundancy, whereby two genes carry out seemingly overlapping functions, may in large part be attributable to the intricacy and robustness of genetic networks that control many developmental processes. We have previously described a complex set of genetic interactions underlying foregut development in the nematode Caenorhabditis elegans. Specifically, LIN-35/Rb, a tumor suppressor ortholog, in conjunction with UBC-18–ARI-1, a conserved E2/E3 complex, and PHA-1, a novel protein, coordinately regulates an early step of pharyngeal morphogenesis involving cellular re-orientation. Functional redundancy is indicated by the observation that lin-35; ubc-18 double mutants, as well as certain allelic combinations of pha-1 with either lin-35 or ubc-18, display defects in pharyngeal development, whereas single mutants do not. Using a combination of genetic and molecular analyses, we show that sup-35, a strong recessive suppressor of pha-1–associated lethality, also reverts the synthetic lethality of lin-35; ubc-18, lin-35; pha-1, and ubc-18 pha-1 double mutants. SUP-35, which contains C2H2-type Zn-finger domains as well as a conserved RMD-like motif, showed a dynamic pattern of subcellular localization during embryogenesis. We find that mutations in sup-35 specifically suppress hypomorphic alleles of pha-1 and that SUP-35, acting genetically upstream of SUP-36 and SUP-37, negatively regulates pha-1 transcription. We further demonstrate that LIN-35, a transcriptional repressor, and UBC-18–ARI-1, a complex involved in ubiquitin-mediated proteolysis, negatively regulate SUP-35 abundance through distinct mechanisms. We also show that HCF-1, a C. elegans homolog of host cell factor 1, functionally antagonizes LIN-35 in the regulation of sup-35. Our cumulative findings piece together the components of a novel regulatory network that includes LIN-35/Rb, which functions to control organ morphogenesis. Our results also shed light on general mechanisms that may underlie developmental genetic redundancies as well as principles that may govern complex disease traits

A New Measure of Centrality for Brain Networks

Recent developments in network theory have allowed for the study of the structure and function of the human brain in terms of a network of interconnected components. Among the many nodes that form a network, some play a crucial role and are said to be central within the network structure. Central nodes may be identified via centrality metrics, with degree, betweenness, and eigenvector centrality being three of the most popular measures. Degree identifies the most connected nodes, whereas betweenness centrality identifies those located on the most traveled paths. Eigenvector centrality considers nodes connected to other high degree nodes as highly central. In the work presented here, we propose a new centrality metric called leverage centrality that considers the extent of connectivity of a node relative to the connectivity of its neighbors. The leverage centrality of a node in a network is determined by the extent to which its immediate neighbors rely on that node for information. Although similar in concept, there are essential differences between eigenvector and leverage centrality that are discussed in this manuscript. Degree, betweenness, eigenvector, and leverage centrality were compared using functional brain networks generated from healthy volunteers. Functional cartography was also used to identify neighborhood hubs (nodes with high degree within a network neighborhood). Provincial hubs provide structure within the local community, and connector hubs mediate connections between multiple communities. Leverage proved to yield information that was not captured by degree, betweenness, or eigenvector centrality and was more accurate at identifying neighborhood hubs. We propose that this metric may be able to identify critical nodes that are highly influential within the network

Altered regulation of Prox1-gene-expression in liver tumors

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

An Amphioxus Gli Gene Reveals Conservation of Midline Patterning and the Evolution of Hedgehog Signalling Diversity in Chordates

Background. Hedgehog signalling, interpreted in receiving cells by Gli transcription factors, plays a central role in the development of vertebrate and Drosphila embryos. Many aspects of the signalling pathway are conserved between these lineages, however vertebrates have diverged in at least one key aspect: they have evolved multiple Gli genes encoding functionally-distinct proteins, increasing the complexity of the hedgehog-dependent transcriptional response. Amphioxus is one of the closest living relatives of the vertebrates, having split from the vertebrate lineage prior to the widespread gene duplication prominent in early vertebrate evolution. Principal findings. We show that amphioxus has a single Gli gene, which is deployed in tissues adjacent to sources of hedgehog signalling derived from the midline and anterior endoderm. This shows the duplication and divergence of the Gli family, and hence the origin of vertebrate Gli functional diversity, was specific to the vertebrate lineage. However we also show that the single amphioxus Gli gene produces two distinct transcripts encoding different proteins. We utilise three tests of Gli function to examine the transcription regulatory capacities of these different proteins, demonstrating one has activating activity similar to Gli2, while the other acts as a weak repressor, similar to Gli3. Conclusions. These data show that the vertebrates and amphioxus have evolved functionally-similar repertoires of Gli proteins using parallel molecular routes; vertebrates via gene duplication and divergence, and amphioxus via alternate splicing of a single gene. Our results demonstrate that similar functional complexity of intercellular signalling can be achieved via different evolutionary pathways

Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis—a review

This review deals with podocyte proteins that play a significant role in the structure and function of the glomerular filter. Genetic linkage studies has identified several genes involved in the development of nephrotic syndrome and contributed to the understanding of the pathophysiology of glomerular proteinuria and/or focal segmental glomerulosclerosis. Here, we describe already well-characterized genetic diseases due to mutations in nephrin, podocin, CD2AP, alpha-actinin-4, WT1, and laminin β2 chain, as well as more recently identified genetic abnormalities in TRPC6, phospholipase C epsilon, and the proteins encoded by the mitochondrial genome. In addition, the role of the proteins which have shown to be important for the structure and functions by gene knockout studies in mice, are also discussed. Furthermore, some rare syndromes with glomerular involvement, in which molecular defects have been recently identified, are briefly described. In summary, this review updates the current knowledge of genetic causes of congenital and childhood nephrotic syndrome and provides new insights into mechanisms of glomerular dysfunction