Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib

ARQ 197-215 was a randomized placebo-controlled phase II study testing the MET inhibitor tivantinib in second-line hepatocellular carcinoma (HCC) patients. It identified tumor MET as a key biomarker in HCC. Aim of this research was to study the prognostic and predictive value of tumor (MET, the receptor tyrosine kinase encoded by the homonymous MNNG-HOS transforming gene) and circulating (MET, hepatocyte growth factor [HGF], alpha-fetoprotein [AFP], vascular endothelial growth factor [VEGF]) biomarkers in second-line HCC. Tumor MET-High status was centrally assessed by immunohistochemistry. Circulating biomarkers were centrally analyzed on serum samples collected at baseline and every 4-8 weeks, using medians as cut-off to determine High/Low status. Tumor MET, tested in 77 patients, was more frequently High after (82%) versus before (40%) sorafenib. A significant interaction (p = 0.04) between tivantinib and baseline tumor MET in terms of survival was observed. Baseline circulating MET and HGF (102 patients) High status correlated with shorter survival (HR 0.61, p = 0.03, and HR 0.60, p = 0.02, respectively), while the association between AFP (104 patients) or VEGF (103 patients) status and survival was non-significant. Conclusions: Tumor MET levels were higher in patients treated with sorafenib. Circulating biomarkers such as MET and HGF may be prognostic in second-line HCC. These results need to be confirmed in larger randomized clinical trials

Targeting antitumoral proteins to breast cancer by local administration of functional inclusion bodies

Altres ajuts de l'Instituto de Salud Carlos III: PI15/00272, PI1702242FIS i #PI16/01224Two structurally and functionally unrelated proteins, namely Omomyc and p31, are engineered as CD44-targeted inclusion bodies produced in recombinant bacteria. In this unusual particulate form, both types of protein materials selectively penetrate and kill CD44 tumor cells in culture, and upon local administration, promote destruction of tumoral tissue in orthotropic mouse models of human breast cancer. These findings support the concept of bacterial inclusion bodies as versatile protein materials suitable for application in chronic diseases that, like cancer, can benefit from a local slow release of therapeutic protein

Prognostic value of the neutrophil-to-lymphocyte ratio in advanced hepatocellular carcinoma: An exploratory analysis from the ARQ197-215 study

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Quantitative time-resolved analysis reveals intricate, differential regulation of standard- and immuno-proteasomes

Proteasomal protein degradation is a key determinant of protein half-life and hence of cellular processes ranging from basic metabolism to a host of immunological processes. Despite its importance the mechanisms regulating proteasome activity are only incompletely understood. Here we use an iterative and tightly integrated experimental and modelling approach to develop, explore and validate mechanistic models of proteasomal peptide-hydrolysis dynamics. The 20S proteasome is a dynamic enzyme and its activity varies over time because of interactions between substrates and products and the proteolytic and regulatory sites; the locations of these sites and the interactions between them are predicted by the model, and experimentally supported. The analysis suggests that the rate-limiting step of hydrolysis is the transport of the substrates into the proteasome. The transport efficiency varies between human standard- and immuno-proteasomes thereby impinging upon total degradation rate and substrate cleavage-site usage

Arterial spin labelling shows functional depression of non-lesion tissue in chronic Wernicke’s aphasia

Behavioural impairment post-stroke is a consequence of structural damage and altered functional network dynamics. Hypoperfusion of intact neural tissue is frequently observed in acute stroke, indicating reduced functional capacity of regions outside the lesion. However, cerebral blood flow is rarely investigated in chronic stroke. This study investigated cerebral blood flow in individuals with chronic Wernicke’s aphasia and examined the relationship between lesion, cerebral blood flow and neuropsychological impairment. Arterial spin labelling cerebral blood flow imaging and structural MRIs were collected in 12 individuals with chronic Wernicke’s aphasia and 13 age-matched control participants. Joint independent component analysis (jICA) investigated the relationship between structural lesion and hypoperfusion. Partial correlations explored the relationship between lesion, hypoperfusion and language measures. Joint ICA revealed significant differences between the control and WA groups reflecting a large area of structural lesion in the left posterior hemisphere and an associated area of hypoperfusion extending into grey matter surrounding the lesion. Small regions of remote cortical hypoperfusion were observed, ipsilateral and contralateral to the lesion. Significant correlations were observed between the neuropsychological measures (naming, repetition, reading and semantic association) and the jICA component of interest in the WA group. Additional ROI analyses found a relationship between perfusion surrounding the core lesion and the same neuropsychological measures

Comparison of Bayesian Clustering and Edge Detection Methods for Inferring Boundaries in Landscape Genetics

Recently, techniques available for identifying clusters of individuals or boundaries between clusters using genetic data from natural populations have expanded rapidly. Consequently, there is a need to evaluate these different techniques. We used spatially-explicit simulation models to compare three spatial Bayesian clustering programs and two edge detection methods. Spatially-structured populations were simulated where a continuous population was subdivided by barriers. We evaluated the ability of each method to correctly identify boundary locations while varying: (i) time after divergence, (ii) strength of isolation by distance, (iii) level of genetic diversity, and (iv) amount of gene flow across barriers. To further evaluate the methods’ effectiveness to detect genetic clusters in natural populations, we used previously published data on North American pumas and a European shrub. Our results show that with simulated and empirical data, the Bayesian spatial clustering algorithms outperformed direct edge detection methods. All methods incorrectly detected boundaries in the presence of strong patterns of isolation by distance. Based on this finding, we support the application of Bayesian spatial clustering algorithms for boundary detection in empirical datasets, with necessary tests for the influence of isolation by distance

Comparative Epigenomics Reveals that RNA Polymerase II Pausing and Chromatin Domain Organization Control Nematode piRNA Biogenesis.

Piwi-interacting RNAs (piRNAs) are important for genome regulation across metazoans, but their biogenesis evolves rapidly. In Caenorhabditis elegans, piRNA loci are clustered within two 3-Mb regions on chromosome IV. Each piRNA locus possesses an upstream motif that recruits RNA polymerase II to produce an ∼28 nt primary transcript. We used comparative epigenomics across nematodes to gain insight into the origin, evolution, and mechanism of nematode piRNA biogenesis. We show that the piRNA upstream motif is derived from core promoter elements controlling snRNA transcription. We describe two alternative modes of piRNA organization in nematodes: in C. elegans and closely related nematodes, piRNAs are clustered within repressive H3K27me3 chromatin, while in other species, typified by Pristionchus pacificus, piRNAs are found within introns of active genes. Additionally, we discover that piRNA production depends on sequence signals associated with RNA polymerase II pausing. We show that pausing signals synergize with chromatin to control piRNA transcription.Work in the Sarkies laboratory is funded by a grant from the Medical Research Council MC-A652-5PY80. P.S. was funded by an Imperial College Research Fellowship. L.S. was funded by a Bailie-Gifford PhD studentship. We thank the London Institute of Medical Sciences Genomics Facility for sequencing. Some sequencing was carried out at Edinburgh Genomics, which has core support from the NERC Biomolecular Analysis Facility award UKSBS PR18037. Work in the Martínez-Pérez laboratory was funded by a grant from the Medical Research Council MC-A652-5PY60. G.S. was funded by a Newton International Fellowship (Royal Society). J.A. was funded by a Wellcome Senior Research Fellowship (101863). T.Y.B. was funded by a Genetics Society Summer Studentship to the Sarkies lab

Foundations of Translational Ecology

Ecologists who specialize in translational ecology (TE) seek to link ecological knowledge to decision making by integrating ecological science with the full complement of social dimensions that underlie today\u27s complex environmental issues. TE is motivated by a search for outcomes that directly serve the needs of natural resource managers and decision makers. This objective distinguishes it from both basic and applied ecological research and, as a practice, it deliberately extends research beyond theory or opportunistic applications. TE is uniquely positioned to address complex issues through interdisciplinary team approaches and integrated scientist–practitioner partnerships. The creativity and context-specific knowledge of resource managers, practitioners, and decision makers inform and enrich the scientific process and help shape use-driven, actionable science. Moreover, addressing research questions that arise from on-the-ground management issues – as opposed to the top-down or expert-oriented perspectives of traditional science – can foster the high levels of trust and commitment that are critical for long-term, sustained engagement between partners