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Sea stars use adhesive secretions to attach their numerous tube feet strongly and temporarily to diverse surfaces. After detachment of the tube feet, the adhesive material stays bound to the substrate as so-called ‘footprints’. In the common sea star species Asterias rubens , the adhesive material has been studied extensively and the first sea star footprint protein (Sfp1) has been characterized. We identified Sfp1-like sequences in 17 additional sea star species, representing different taxa and tube foot morphologies, and analysed the evolutionary conservation of this protein. In A. rubens , we confirmed the expression of 34 footprint proteins in the tube foot adhesive epidermis, with 22 being exclusively expressed in secretory cells of the adhesive epidermis and 12 showing an additional expression in the stem epidermis. The sequences were used for BLAST searches in seven asteroid transcriptomes providing a first insight in the conservation of footprint proteins among sea stars. Our results highlighted a high conservation of the large proteins making up the structural core of the footprints, whereas smaller, potential surface-binding proteins might be more variable among sea star species. This article is part of the theme issue ‘Transdisciplinary approaches to the study of adhesion and adhesives in biological systems’.

Sea stars can adhere to various underwater substrata using an adhesive secretion of which Sfp1 is a major component. Sfp1 is a multimodular protein composed of four subunits (Sfp1 Alpha, Beta, Delta, and Gamma) displaying different functional domains. We recombinantly produced two fragments of Sfp1 comprising most of its functional domains: the C-terminal part of the Beta subunit (rSfp1 Beta C-term) and the Delta subunit (rSfp1 Delta). Surface plasmon resonance analyses of protein adsorption onto different model surfaces showed that rSfp1 Beta C-term exhibits a significantly higher adsorption than the fibrinogen control on hydrophobic, hydrophilic protein-resistant, and charged self-assembled monolayers, while rSfp1 Delta adsorbed more on negatively charged and on protein-resistant surfaces compared to fibrinogen. Truncated recombinant rSfp1 Beta C-term proteins were produced in order to investigate the role of the different functional domains in the adsorption of this protein. The analysis of their adsorption capacities on glass showed that two mechanisms are involved in rSfp1 Beta C-term adsorption: (1) one mediated by the EGF-like domain and involving Ca2+ and Mg2+ ions, and (2) one mediated by the sequence of Sfp1 Beta with no homology with known functional domain in databases, in the presence of Na+, Ca2+ and Mg2+ ions.

Background: Marine biological adhesives are a promising source of inspiration for biomedical and industrial applications. Nevertheless, natural adhesives and especially temporary adhesion systems are mostly unexplored. Sea stars are able to repeatedly attach and detach their hydraulic tube feet. This ability is based on a duo-gland system and, upon detachment, the adhesive material stays behind on the substrate as a 'footprint'. In recent years, characterization of sea star temporary adhesion has been focussed on the forcipulatid species Asterias rubens . Results: We investigated the temporary adhesion system in the distantly related valvatid species Asterina gibbosa . The morphology of tube feet was described using histological sections, transmission-, and scanning electron microscopy. Ultrastructural investigations revealed two adhesive gland cell types that both form electron-dense secretory granules with a more lucid outer rim and one de-adhesive gland cell type with homogenous granules. The footprints comprised a meshwork on top of a thin layer. This topography was consistently observed using various methods like scanning electron microscopy, 3D confocal interference microscopy, atomic force microscopy, and light microscopy with crystal violet staining. Additionally, we tested 24 commercially available lectins and two antibodies for their ability to label the adhesive epidermis and footprints. Out of 15 lectins labelling structures in the area of the duo-gland adhesive system, only one also labelled footprints indicating the presence of glycoconjugates with α-linked mannose in the secreted material. Conclusion: Despite the distant relationship between the two sea star species, the morphology of tube feet and topography of footprints in A. gibbosa shared many features with the previously described findings in A. rubens . These similarities might be due to the adaptation to a benthic life on rocky intertidal areas. Lectin- and immuno-labelling indicated similarities but also some differences in adhesive composition between the two species. Further research on the temporary adhesive of A. gibbosa will allow the identification of conserved motifs in sea star adhesion and might facilitate the development of biomimetic, reversible glues.

Sea stars use adhesive secretions to attach their numerous tube feet strongly and temporarily to diverse surfaces. After detachment of the tube feet, the adhesive material stays bound to the substrate as so-called 'footprints'. In the common sea star species Asterias rubens, the adhesive material has been studied extensively and the first sea star footprint protein (Sfp1) has been characterized. We identified Sfp1-like sequences in 17 additional sea star species, representing different taxa and tube foot morphologies, and analysed the evolutionary conservation of this protein. In A. rubens, we confirmed the expression of 34 footprint proteins in the tube foot adhesive epidermis, with 22 being exclusively expressed in secretory cells of the adhesive epidermis and 12 showing an additional expression in the stem epidermis. The sequences were used for BLAST searches in seven asteroid transcriptomes providing a first insight in the conservation of footprint proteins among sea stars. Our results highlighted a high conservation of the large proteins making up the structural core of the footprints, whereas smaller, potential surface-binding proteins might be more variable among sea star species. This article is part of the theme issue 'Transdisciplinary approaches to the study of adhesion and adhesives in biological systems'.

Increased preoperative delay in patients with hip fractures may be responsible for increased morbidity and mortality. We hypothesized that a strategy of reversal of vitamin K antagonist (VKA) by prothrombin complexes concentrates (PCCs), as compared to vitamin K, is safe and reduces preoperative delay and hospital length of stay (LOS). In this pilot study, we reviewed the records of patients admitted to a university-affiliated hospital for hip fracture between Jan. 1, 2012, and Dec. 31, 2016, who were taking VKA. Patients were stratified according to reversal strategy (vitamin K v. PCC). Adverse effects, time to surgery, LOS and mortality were collected from the electronic medical record and were compared between the 2 study groups and a control group not treated with VKA. A total of 141 patients were included in the study: 65 in the vitamin K group, 26 in the PCC group and 50 in the control group. The median preoperative delay in the PCC group (20 h [interquartile range (IQR)] 13–25 h]) and the control group (20 h [IQR 15–33 h]) was lower than that in the vitamin K group (45 h [IQR 31–52 h]) (p < 0.001). Patients in the PCC group had a shorter median hospital LOS than those in the vitamin K group (6 d [IQR 4–9 d] v. 8 d [IQR 6–11 d], p < 0.05). No difference was observed in the proportion of patients who received a red blood cell transfusion, or had thrombotic or hemorrhagic complications. No difference in mortality at 12 months was observed between the groups. In patients with hip fracture, the use of PCCs as compared to vitamin K to reverse the effect of VKA significantly reduced preoperative delay and hospital LOS, and was not associated with an increase in the rates of thrombotic or hemorrhagic complications. Prospective studies involving a greater number of patients are required to confirm these promising results. L’allongement du délai préopératoire chez les patients atteints d’une fracture de la hanche pourrait expliquer l’augmentation de la morbidité et de la mortalité. Selon notre hypothèse, une stratégie d’inversion des antagonistes de la vitamine K (AVK) au moyen de concentrés de complexes prothrombiques (CCP), plutôt que de vitamine K, est sécuritaire et réduit le délai préopératoire et la durée du séjour hospitalier. Pendant cette étude pilote, nous avons passé en revue les dossiers de patients sous AVK admis dans un centre universitaire pour fracture de la hanche entre le 1er janvier 2012 et le 31 décembre 2016. Les patients ont été stratifiés selon la stratégie d’inversion choisie (vitamine K c. CCP). Les effets indésirables, le délai préopératoire, la durée du séjour hospitalier et la mortalité ont été recueillis à partir des dossiers médicaux électroniques et ont été comparés entre les 2 groupes de l’étude et un groupe témoin non sous AVK. En tout, 141 patients ont été inclus dans l’étude, 65 dans le groupe sous vitamine K, 26 dans le groupe sous CCP et 50 dans le groupe témoin. Le délai préopératoire médian pour le groupe sous CCP (20 h [éventail interquartile (ÉIQ)] 13–25 h]) et le groupe témoin (20 h [ÉIQ 15–33 h]) a été plus bref que pour le groupe sous vitamine K (45 h [ÉIQ 31–52 h]) (p < 0,001). Les patients du groupe sous CCP ont eu un séjour hospitalier médian plus bref que les patients du groupe sous vitamine K (6 j [ÉIQ 4–9 j] c. 8 j [ÉIQ 6–11 j]) (p < 0,05). Aucune différence n’a été observée quant à la proportion de patients ayant reçu une transfusion de culot globulaire ou ayant manifesté des complications thrombotiques ou hémorragiques. Aucune différence quant à la mortalité à 12 mois n’a été observée entre les groupes. Chez les patients atteints d’une fracture de la hanche, l’utilisation des CCP plutôt que de la vitamine K pour inverser l’effet des AVK a significativement abrégé le délai préopératoire et la durée du séjour hospitalier, et n’a pas été associée à une augmentation des taux de complications thrombotiques ou hémorragiques. Des études prospectives sur un plus grand nombre de patients sont nécessaires pour confirmer ces résultats prometteurs.

This open-label, non-comparative, 2:1 randomized, phase II trial (NCT03275506) in women with stage IIIC/IV high-grade serous carcinoma (HGSC) for whom upfront complete resection was unachievable assessed whether adding pembrolizumab (200 mg every 3 weeks) to standard-of-care carboplatin plus paclitaxel yielded a complete resection rate (CRR) of at least 50%. Postoperatively patients continued assigned treatment for a maximum of 2 years. Postoperative bevacizumab was optional. The primary endpoint was independently assessed CRR at interval debulking surgery. Secondary endpoints were Completeness of Cytoreduction Index (CCI) and peritoneal cancer index (PCI) scores, objective and best response rates, progression-free survival, overall survival, safety, postoperative morbidity, and pathological complete response. The CRR in 61 pembrolizumab-treated patients was 74% (one-sided 95% CI = 63%), exceeding the prespecified ≥50% threshold and meeting the primary objective. The CRR without pembrolizumab was 70% (one-sided 95% CI = 54%). In the remaining patients CCI scores were ≥3 in 27% of the standard-of-care group and 18% of the investigational group and CC1 in 3% of the investigational group. PCI score decreased by a mean of 9.6 in the standard-of-care group and 10.2 in the investigational group. Objective response rates were 60% and 72%, respectively, and best overall response rates were 83% and 90%, respectively. Progression-free survival was similar with the two regimens (median 20.8 versus 19.4 months in the standard-of-care versus investigational arms, respectively) but overall survival favored pembrolizumab-containing therapy (median 35.3 versus 49.8 months, respectively). The most common grade ≥3 adverse events with pembrolizumab-containing therapy were anemia during neoadjuvant therapy and infection/fever postoperatively. Pembrolizumab was discontinued prematurely because of adverse events in 23% of pembrolizumab-treated patients. Combining pembrolizumab with neoadjuvant chemotherapy is feasible for HGSC considered not completely resectable; observed activity in some subgroups justifies further evaluation to improve understanding of the role of immunotherapy in HGSC. Immune checkpoint blockade could improve the complete cytoreduction rate with standard-of-care neoadjuvant chemotherapy (NACT) in patients with ovarian cancer. Here the authors report the results of a randomized phase II trial of NACT alone or in combination with pembrolizumab (anti-PD1) in patients with advanced high-grade serous carcinoma.

This study showed that there were mutations in ARMC5, a putative tumor-suppressor gene, in a substantial proportion of patients with corticotropin-independent macronodular adrenal hyperplasia, a finding that may be helpful in the diagnosis and management of this disease. Corticotropin-independent macronodular adrenal hyperplasia can lead to excess cortisol secretion and Cushing's syndrome. 1 , 2 Adrenocortical nodules in corticotropin-independent macronodular adrenal hyperplasia are, by definition, larger than 10 mm in diameter and frequently reach 30 to 40 mm in diameter. The condition is typically diagnosed in patients with Cushing's syndrome who are between 40 and 60 years of age and who have suppressed levels of circulating corticotropin. Tumor growth and cortisol dysregulation appear to progress slowly in cases of corticotropin-independent macronodular adrenal hyperplasia, and the diagnosis is often made only after several years or decades of disease progression. 3 Milder forms are . . .

Background Multiplex polymerase chain reaction (mPCR) enables recovery of viruses from airways of patients with community-acquired pneumonia (CAP), although their clinical impact remains uncertain. Methods Among consecutive adult patients who had undergone a mPCR within 72 hours following their admission to one intensive care unit (ICU), we retrospectively included those with a final diagnosis of CAP. Four etiology groups were clustered: bacterial, viral, mixed (viral-bacterial) and no etiology. A composite criterion of complicated course (hospital death or mechanical ventilation > 7 days) was used. A subgroup analysis compared patients with bacterial and viral-bacterial CAP matched on the bacterial pathogens. Results Among 174 patients (132 men [76 %], age 63 [53–75] years, SAPSII 38 [27;55], median PSI score 106 [78;130]), bacterial, viral, mixed and no etiology groups gathered 46 (26 %), 53 (31 %), 45 (26 %) and 30 (17 %) patients, respectively. Virus-infected patients displayed a high creatine kinase serum level, a low platelet count, and a trend toward more frequent alveolar-interstitial infiltrates. A complicated course was more frequent in the mixed group (31/45, 69 %), as compared to bacterial (18/46, 39 %), viral (15/53, 28 %) and no etiology (12/30, 40 %) groups ( p  < 0.01). In multivariate analysis, the mixed (viral-bacterial) infection was independently associated with complicated course (reference: bacterial pneumonia; OR, 3.58; CI 95 %, 1.16–11; p  = 0.03). The subgroup analysis of bacteria-matched patients confirmed these findings. Conclusions Viral-bacterial coinfection during severe CAP in adults is associated with an impaired presentation and a complicated course.

Only a minority of patients derive long-term clinical benefit from anti-PD1/PD-L1 monoclonal antibodies. The presence of tertiary lymphoid structures (TLS) has been associated with improved survival in several tumor types. Here, using a large-scale retrospective analysis of three independent cohorts of cancer patients treated with anti-PD1/PD-L1 antibodies, we showed that the presence of mature TLS was associated with improved objective response rate, progression-free survival, and overall survival independently of PD-L1 expression status and CD8+ T-cell density. These results pave the way for using TLS detection to select patients who are more likely to benefit from immune checkpoint blockade.

The implantation of metallic orthopedic prostheses is increasingly common due to an aging population and accidents. There is a real societal need to implement new metal implants that combine durability, good mechanical properties, excellent biocompatibility, as well as affordable costs. Since the functionalization of low-cost 316L stainless steel substrates through the successive electrodeposition of a polypyrrole film (PPy) and a calcium phosphate deposit doped with silicon was previously carried out by our labs, we have also developed a bio-functional coating by electrodepositing or oxidating of fibronectin (Fn) coating. Fn is an extracellular matrix glycoprotein involved in cell adhesion and differentiation. Impacts of either electrodeposition or oxidation on the structure and functionality of Fn were first studied. Thus, electrodeposition is the technique that permits the highest deposition of fibronectin, compared to adsorption or oxidation. Furthermore, electrodeposition seems to strongly modify Fn conformation by the formation of intermingled long fibers, resulting in changes to the accessibility of the molecular probes tested (antibodies directed against Fn whole molecule and Fn cell-binding domain). Then, the effects of either electrodeposited Fn or oxidized Fn were validated by the resulting pre-osteoblast behavior. Electrodeposition reduced pre-osteoblasts’ ability to remodel Fn coating on supports because of a partial modification of Fn conformation, which reduced accessibility to the cell-binding domain. Electrodeposited Fn also diminished α5 integrin secretion and clustering along the plasma membrane. However, the N-terminal extremity of Fn was not modified by electrodeposition as demonstrated by Staphylococcus aureus attachment after 3 h of culture on a specific domain localized in this region. Moreover, the number of pre-osteoblasts remains stable after 3 h culture on either adsorbed, oxidized, or electrodeposited Fn deposits. In contrast, mitochondrial activity and cell proliferation were significantly higher on adsorbed Fn compared with electrodeposited Fn after 48 h culture. Hence, electro-deposited Fn seems more favorable to pre-osteoblast early-stage behavior than during a longer culture of 24 h and 48 h. The electrodeposition of matrix proteins could be improved to maintain their bio-activity and to develop this promising, fast technique to bio-functionalize metallic implants.