Future challenges in cephalopod research

We thank Anto´nio M. de Frias Martins, past President of the Unitas Malacologica and Peter Marko, President of the American Malacological Society for organizing the 2013 World Congress of Malacology, and the Cephalopod International Advisory Committee for endorsing a symposium held in honour of Malcolm R. Clarke. In particular, we would like to thank the many professional staff from the University of the Azores for their hospitality, organization, troubleshooting and warm welcome to the Azores. We also thank Malcolm Clarke’s widow, Dorothy, his daughter Zoe¨, Jose´ N. Gomes-Pereira and numerous colleagues and friends of Malcolm’s from around the world for joining us at Ponta Delgada. We are grateful to Lyndsey Claro (Princeton University Press) for granting copyright permissions.Peer reviewedPublisher PD

Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials

The clinical utility of serum alpha-fetoprotein (AFP) in patients with hepatocellular carcinoma (HCC) is widely recognised. However, a clear understanding of the mechanisms of AFP overexpression and the molecular traits of patients with AFP-high tumours are not known. We assessed transcriptome data, whole-exome sequencing data and DNA methylome profiling of 520 HCC patients from two independent cohorts to identify distinct molecular traits of patients with AFP-high tumours (serum concentration?>?400?ng/ml), which represents an accepted prognostic cut-off and a predictor of response to ramucirumab. Those AFP-high tumours (18% of resected cases) were characterised by significantly lower AFP promoter methylation (p?<?0.001), significant enrichment of progenitor-cell features (CK19, EPCAM), higher incidence of BAP1 oncogene mutations (8.5% vs 1.6%) and lower mutational rates of CTNNB1 (14% vs 30%). Specifically, AFP-high tumours displayed significant activation of VEGF signalling (p?<?0.001), which might provide the rationale for the reported benefit of ramucirumab in this subgroup of patients

Natural geochemical markers reveal environmental history and population connectivity of common cuttlefish in the Atlantic Ocean and Mediterranean Sea

Natural markers (delta C-13 and delta O-18 stable isotopes) in the cuttlebones of the European common cuttlefish (Sepia officinalis) were determined for individuals collected across a substantial portion of their range in the Northeast Atlantic Ocean (NEAO) and Mediterranean Sea. Cuttlebone delta C-13 and delta O-18 were quantified for core and edge material to characterize geochemical signatures associated with early (juvenile) and recent (sub-adult/adult) life-history periods, respectively. Regional shifts in cuttlebone delta C-13 and delta O-18 values were detected across the 12 sites investigated. Individuals collected from sites in the NEAO displayed more enriched delta C-13 and delta O-18 values relative to sites in the Mediterranean Sea, with the latter also showing salient differences in both markers among western, central and eastern collection areas. Classification success based on cuttlebone delta C-13 and delta O-18 values to four geographical regions (NEAO, western, central and eastern Mediterranean Sea) was relatively high, suggesting that environmental conditions in each region were distinct and produced area-specific geochemical signatures on the cuttlebones ofS. officinalis. A modified delta C-13 and delta O-18 baseline was developed from sites proximal to the Strait of Gibraltar in both the NEAO and Mediterranean Sea to assess potential mixing through this corridor. Nearly, all (95%) of delta C-13 and delta O-18 signatures ofS. officinaliscollected in the area of the NEAO closest to the Strait of Gibraltar (Gulf of Cadiz) matched the signatures of specimens collected in the western Mediterranean, signifying potential movement and mixing of individuals through this passageway. This study extends the current application of these geochemical markers for assessing the natal origin and population connectivity of this species and potentially other taxa that inhabit this geographical area.Portuguese Foundation for Science and Technology: IF/00576/2014info:eu-repo/semantics/publishedVersio

Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003

PURPOSE PNOC003 is a multicenter precision medicine trial for children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG). PATIENTS AND METHODS Patients (3-25 years) were enrolled on the basis of imaging consistent with DIPG. Biopsy tissue was collected for whole-exome and mRNA sequencing. After radiotherapy (RT), patients were assigned up to four FDA-approved drugs based on molecular tumor board recommendations. H3K27M-mutant circulating tumor DNA (ctDNA) was longitudinally measured. Tumor tissue and matched primary cell lines were characterized using whole-genome sequencing and DNA methylation profiling. When applicable, results were verified in an independent cohort from the Children's Brain Tumor Network (CBTN). RESULTS Of 38 patients enrolled, 28 patients (median 6 years, 10 females) were reviewed by the molecular tumor board. Of those, 19 followed treatment recommendations. Median overall survival (OS) was 13.1 months [95% confidence interval (CI), 11.2-18.4] with no difference between patients who followed recommendations and those who did not. H3K27M-mutant ctDNA was detected at baseline in 60% of cases tested and associated with response to RT and survival. Eleven cell lines were established, showing 100% fidelity of key somatic driver gene alterations in the primary tumor. In H3K27-altered DIPGs, TP53 mutations were associated with worse OS (TP53mut 11.1 mo; 95% CI, 8.7-14; TP53wt 13.3 mo; 95% CI, 11.8-NA; P = 3.4e-2), genome instability (P = 3.1e-3), and RT resistance (P = 6.4e-4). The CBTN cohort confirmed an association between TP53 mutation status, genome instability, and clinical outcome. CONCLUSIONS Upfront treatment-naïve biopsy provides insight into clinically relevant molecular alterations and prognostic biomarkers for H3K27-altered DIPGs

Genome skimming elucidates the evolutionary history of Octopoda

11 pages, 5 figures, 3 tables, supplementary data https://doi.org/10.1016/j.ympev.2023.107729Phylogenies for Octopoda have, until now, been based on morphological characters or a few genes. Here we provide the complete mitogenomes and the nuclear 18S and 28S ribosomal genes of twenty Octopoda specimens, comprising 18 species of Cirrata and Incirrata, representing 13 genera and all five putative families of Cirrata (Cirroctopodidae, Cirroteuthidae, Grimpoteuthidae, Opisthoteuthidae and Stauroteuthidae) and six families of Incirrata (Amphitretidae, Argonautidae, Bathypolypodidae, Eledonidae, Enteroctopodidae, and Megaleledonidae) which were assembled using genome skimming. Phylogenetic trees were built using Maximum Likelihood and Bayesian Inference with several alignment matrices. All mitochondrial genomes had the ‘typical’ genome composition and gene order previously reported for octopodiforms, except Bathypolypus ergasticus, which appears to lack ND5, two tRNA genes that flank ND5 and two other tRNA genes. Argonautoidea was revealed as sister to Octopodidae by the mitochondrial protein-coding gene dataset, however, it was recovered as sister to all other incirrate octopods with strong support in an analysis using nuclear rRNA genes. Within Cirrata, our study supports two existing classifications suggesting neither is likely in conflict with the true evolutionary history of the suborder. Genome skimming is useful in the analysis of phylogenetic relationships within Octopoda; inclusion of both mitochondrial and nuclear data may be keyThis work was funded by a Tony Ryan Fellowship and an Irish Research Council postgraduate scholarship (GOIPG/2017/1740) to MT. FÁF-Á was supported by an Irish Research Council–Government of Ireland Postdoctoral Fellowship Award (ref. GOIPD/2019/460) and a JdC-I Postdoctoral Fellowship Grant (ref. IJC2020-043170-I) awarded by MCIN/AEI /10.13039/501100011033 and the European Union NextGenerationEU/PRTR. This research was supported by the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S). We are grateful to two anonymous referees for their thoughtful contributionsPeer reviewe

Therapy-induced tumour secretomes promote resistance and tumour progression.

Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafenib is driven by downregulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and the PI(3)K/AKT/mTOR intracellular signalling pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant human melanoma, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy

Reversing Melanoma Cross-Resistance to BRAF and MEK Inhibitors by Co-Targeting the AKT/mTOR Pathway

The sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAF(V600) mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression. Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors. However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway.The sensitivity to vemurafenib or the MEK inhibitor AZD6244 was tested in sensitive and resistant human melanoma cell lines exploring differences in activation-associated phosphorylation levels of major signaling molecules, leading to the testing of co-inhibition of the AKT/mTOR pathway genetically and pharmacologically. There was a high degree of cross-resistance to vemurafenib and AZD6244, except in two vemurafenib-resistant cell lines that acquired a secondary mutation in NRAS. In other cell lines, acquired resistance to both drugs was associated with persistence or increase in activity of AKT pathway. siRNA-mediated gene silencing and combination therapy with an AKT inhibitor or rapamycin partially or completely reversed the resistance.Primary and acquired resistance to vemurafenib in these in vitro models results in frequent cross resistance to MEK inhibitors, except when the resistance is the result of a secondary NRAS mutation. Resistance to BRAF or MEK inhibitors is associated with the induction or persistence of activity within the AKT pathway in the presence of these drugs. This resistance can be potentially reversed by the combination of a RAF or MEK inhibitor with an AKT or mTOR inhibitor. These combinations should be available for clinical testing in patients progressing on BRAF inhibitors

Measuring personal networks and their relationship with scientific production

The analysis of social networks has remained a crucial and yet understudied aspect of the efforts to measure Triple Helix linkages. The Triple Helix model aims to explain, among other aspects of knowledge-based societies, ¿the current research system in its social context. This paper develops a novel approach to study the research system from the perspective of the individual, through the analysis of the relationships among researchers, and between them and other social actors. We develop a new set of techniques and show how they can be applied to the study of a specific case (a group of academics within a university department). We analyse their informal social networks and show how a relationship exists between the characteristics of an individual¿s network of social links and his or her research output

Cuttlefish conservation: a global review of methods to ameliorate unwanted fishing mortality and other anthropogenic threats to sustainability

Cuttlefish are an important global fisheries resource, and their demand is placing increasing pressure on populations in many areas, necessitating conservation measures. We reviewed evidence from case studies spanning Europe, Africa, Asia, and Australia encompassing diverse intervention methods (fisheries closures, protected areas, habitat restoration, fishing-gear modifications, promoting egg survival, and restocking), and we also discuss the effects of pollution on cuttlefish. We conclude: (1) spatio-temporal closures need to encompass substantial portions of a species’ range and protect at least one major part of their life cycle; (2) fishing-gear modifications have the potential to reduce unwanted cuttlefish capture, but more comprehensive trials are needed; (3) egg survival can be improved by diverting and salvaging from traps; (4) existing lab rearing and restocking may not produce financially viable results; and (5) fisheries management policies should be regularly reviewed in light of rapid changes in cuttlefish stock status. Further, citizen science can provide data to reduce uncertainty in empirical assessments. The information synthesized in this review will guide managers and stakeholders to implement regulations and conservation initiatives that increase the productivity and sustainability of fisheries interacting with cuttlefish, and highlights gaps in knowledge that need to be addressed