Tissues and industrial co-products formed during alginate extraction from <i>Laminaria hyperborea</i> provide different metabolite profiles depending on harvest season

The metabolic profiles of different tissues and industrially relevant co-products of alginate extraction from Laminaria hyperborea samples harvested in different seasons were assessed using Hydrophilic Interaction Liquid Chromatography – Mass Spectrometry (HILIC-MS). Positive and negative mode MS data, predicted exact mass data and matching with database and literature searches, allowed the putative identification of 57 major metabolites. The metabolites ranged from known and abundant components (e.g., iodide, mannitol, and various betaines) to components not previously noted in this species and 11 major components which could not be identified. The levels of these components varied between tissues and co-products with some metabolites seemingly specific to certain samples. The components also varied between winter and summer harvested material, perhaps reflecting seasonality in their biosynthesis and accumulation in the tissues and co-products. The approach applied in this work could assess when components of potential specific commercial interest were maximally accumulated and help plan the most efficient exploitation of the harvested biomass. It could also be used to define variation in components in L. hyperborea from different locations or potential biotopes of this species. This initial work extends our ability to understand the phenotype of seaweeds whilst also identifying new components and new commercial opportunities

N-WASP control of LPAR1 trafficking establishes response to self-generated LPA gradients to promote pancreatic cancer cell metastasis

Pancreatic ductal adenocarcinoma is one of the most invasive and metastatic cancers and has a dismal 5-year survival rate. We show that N-WASP drives pancreatic cancer metastasis, with roles in both chemotaxis and matrix remodeling. lysophosphatidic acid, a signaling lipid abundant in blood and ascites fluid, is both a mitogen and chemoattractant for cancer cells. Pancreatic cancer cells break lysophosphatidic acid down as they respond to it, setting up a self-generated gradient driving tumor egress. N-WASP-depleted cells do not recognize lysophosphatidic acid gradients, leading to altered RhoA activation, decreased contractility and traction forces, and reduced metastasis. We describe a signaling loop whereby N-WASP and the endocytic adapter SNX18 promote lysophosphatidic acid-induced RhoA-mediated contractility and force generation by controlling lysophosphatidic acid receptor recycling and preventing degradation. This chemotactic loop drives collagen remodeling, tumor invasion, and metastasis and could be an important target against pancreatic cancer spread

Fam49/CYRI interacts with Rac1 and locally suppresses protrusions

Actin-based protrusions are reinforced through positive feedback, but it is unclear what restricts their size, or limits positive signals when they retract or split. We identify an evolutionarily conserved regulator of actin-based protrusion: CYRI (CYFIP-related Rac interactor) also known as Fam49 (family of unknown function 49). CYRI binds activated Rac1 via a domain of unknown function (DUF1394) shared with CYFIP, defining DUF1394 as a Rac1-binding module. CYRI-depleted cells have broad lamellipodia enriched in Scar/WAVE, but reduced protrusion–retraction dynamics. Pseudopods induced by optogenetic Rac1 activation in CYRI-depleted cells are larger and longer lived. Conversely, CYRI overexpression suppresses recruitment of active Scar/WAVE to the cell edge, resulting in short-lived, unproductive protrusions. CYRI thus focuses protrusion signals and regulates pseudopod complexity by inhibiting Scar/WAVE-induced actin polymerization. It thus behaves like a ‘local inhibitor’ as predicted in widely accepted mathematical models, but not previously identified in cells. CYRI therefore regulates chemotaxis, cell migration and epithelial polarization by controlling the polarity and plasticity of protrusions

Medical management and surgery versus medical management alone for symptomatic cerebral cavernous malformation (CARE):a feasibility study and randomised, open, pragmatic, pilot phase trial

BackgroundThe highest priority uncertainty for people with symptomatic cerebral cavernous malformation is whether to have medical management and surgery or medical management alone. We conducted a pilot phase randomised controlled trial to assess the feasibility of addressing this uncertainty in a definitive trial.MethodsThe CARE pilot trial was a prospective, randomised, open-label, assessor-blinded, parallel-group trial at neuroscience centres in the UK and Ireland. We aimed to recruit 60 people of any age, sex, and ethnicity who had mental capacity, were resident in the UK or Ireland, and had a symptomatic cerebral cavernous malformation. Computerised, web-based randomisation assigned participants (1:1) to medical management and surgery (neurosurgical resection or stereotactic radiosurgery) or medical management alone, stratified by the neurosurgeon's and participant's consensus about the intended type of surgery before randomisation. Assignment was open to investigators, participants, and carers, but not clinical outcome event adjudicators. Feasibility outcomes included site engagement, recruitment, choice of surgical management, retention, adherence, data quality, clinical outcome event rate, and protocol implementation. The primary clinical outcome was symptomatic intracranial haemorrhage or new persistent or progressive non-haemorrhagic focal neurological deficit due to cerebral cavernous malformation or surgery during at least 6 months of follow-up. We analysed data from all randomly assigned participants according to assigned management. This trial is registered with ISRCTN (ISRCTN41647111) and has been completed.FindingsBetween Sept 27, 2021, and April 28, 2023, 28 (70%) of 40 sites took part, at which investigators screened 511 patients, of whom 322 (63%) were eligible, 202 were approached for recruitment, and 96 had collective uncertainty with their neurosurgeon about whether to have surgery for a symptomatic cerebral cavernous malformation. 72 (22%) of 322 eligible patients were randomly assigned (mean recruitment rate 0·2 [SD 0·25] participants per site per month) at a median of 287 (IQR 67–591) days since the most recent symptomatic presentation. Participants’ median age was 50·6 (IQR 38·6–59·2) years, 68 (94%) of 72 participants were adults, 41 (57%) were female, 66 (92%) were White, 56 (78%) had a previous intracranial haemorrhage, and 28 (39%) had a previous epileptic seizure. The intended type of surgery before randomisation was neurosurgical resection for 19 (26%) of 72, stereotactic radiosurgery for 44 (61%), and no preference for nine (13%). Baseline clinical and imaging data were complete for all participants. 36 participants were randomly assigned to medical management and surgery (12 to neurosurgical resection and 24 to stereotactic radiosurgery) and 36 to medical management alone. Three (4%) of 72 participants withdrew, one was lost to follow-up, and one declined face-to-face follow-up, leaving 67 (93%) retained at 6-months’ clinical follow-up. 61 (91%) of 67 participants with follow-up adhered to the assigned management strategy. The primary clinical outcome occurred in two (6%) of 33 participants randomly assigned to medical management and surgery (8·0%, 95% CI 2·0–32·1 per year) and in two (6%) of 34 participants randomly assigned to medical management alone (7·5%, 1·9–30·1 per year). Investigators reported no deaths, no serious adverse events, one protocol violation, and 61 protocol deviations.InterpretationThis pilot phase trial exceeded its recruitment target, but a definitive trial will require extensive international engagement.FundingNational Institute for Health and Care Research

Feasibility of comparing medical management and surgery (with neurosurgery or stereotactic radiosurgery) with medical management alone in people with symptomatic brain cavernoma - protocol for the Cavernomas: A Randomised Effectiveness (CARE) pilot trial

IntroductionThe top research priority for cavernoma, identified by a James Lind Alliance Priority setting partnership was 'Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with a cavernoma?' This pilot randomised controlled trial (RCT) aims to determine the feasibility of answering this question in a main phase RCT.Methods and analysisWe will perform a pilot phase, parallel group, pragmatic RCT involving approximately 60 children or adults with mental capacity, resident in the UK or Ireland, with an unresected symptomatic brain cavernoma. Participants will be randomised by web-based randomisation 1:1 to treatment with medical management and with surgery (neurosurgery or stereotactic radiosurgery) versus medical management alone, stratified by prerandomisation preference for type of surgery. In addition to 13 feasibility outcomes, the primary clinical outcome is symptomatic intracranial haemorrhage or new persistent/progressive focal neurological deficit measured at 6 monthly intervals. An integrated QuinteT Recruitment Intervention (QRI) evaluates screening logs, audio recordings of recruitment discussions, and interviews with recruiters and patients/parents/carers to identify and address barriers to participation. A Patient Advisory Group has codesigned the study and will oversee its progress.Ethics and disseminationThis study was approved by the Yorkshire and The Humber-Leeds East Research Ethics Committee (21/YH/0046). We will submit manuscripts to peer-reviewed journals, describing the findings of the QRI and the Cavernomas: A Randomised Evaluation (CARE) pilot trial. We will present at national specialty meetings. We will disseminate a plain English summary of the findings of the CARE pilot trial to participants and public audiences with input from, and acknowledgement of, the Patient Advisory Group.Trial registration numberISRCTN41647111

Feasibility of comparing medical management and surgery (with neurosurgery or stereotactic radiosurgery) with medical management alone in people with symptomatic brain cavernoma - protocol for the Cavernomas: A Randomised Effectiveness (CARE) pilot trial.

Peer reviewed: TrueAcknowledgements: We thank all members of the Patient, carer and public Advisory Group (PAG) for contributing to the development, design and delivery of this study.INTRODUCTION: The top research priority for cavernoma, identified by a James Lind Alliance Priority setting partnership was 'Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with a cavernoma?' This pilot randomised controlled trial (RCT) aims to determine the feasibility of answering this question in a main phase RCT. METHODS AND ANALYSIS: We will perform a pilot phase, parallel group, pragmatic RCT involving approximately 60 children or adults with mental capacity, resident in the UK or Ireland, with an unresected symptomatic brain cavernoma. Participants will be randomised by web-based randomisation 1:1 to treatment with medical management and with surgery (neurosurgery or stereotactic radiosurgery) versus medical management alone, stratified by prerandomisation preference for type of surgery. In addition to 13 feasibility outcomes, the primary clinical outcome is symptomatic intracranial haemorrhage or new persistent/progressive focal neurological deficit measured at 6 monthly intervals. An integrated QuinteT Recruitment Intervention (QRI) evaluates screening logs, audio recordings of recruitment discussions, and interviews with recruiters and patients/parents/carers to identify and address barriers to participation. A Patient Advisory Group has codesigned the study and will oversee its progress. ETHICS AND DISSEMINATION: This study was approved by the Yorkshire and The Humber-Leeds East Research Ethics Committee (21/YH/0046). We will submit manuscripts to peer-reviewed journals, describing the findings of the QRI and the Cavernomas: A Randomised Evaluation (CARE) pilot trial. We will present at national specialty meetings. We will disseminate a plain English summary of the findings of the CARE pilot trial to participants and public audiences with input from, and acknowledgement of, the Patient Advisory Group. TRIAL REGISTRATION NUMBER: ISRCTN41647111