Search

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of receptors that recognize sialoglycans – sialic acid containing glycans that are abundantly present on cell membranes. Siglecs are expressed on most immune cells and can modulate their activity and function. The majority of Siglecs contains immune inhibitory motifs comparable to the immune checkpoint receptor PD-1. In the tumor microenvironment (TME), signaling through the Siglec-sialoglycan axis appears to be enhanced through multiple mechanisms favoring tumor immune evasion similar to the PD-1/PD-L1 signaling pathway. Siglec expression on tumor-infiltrating immune cells appears increased in the immune suppressive microenvironment. At the same time, enhanced Siglec ligand expression has been reported for several tumor types as a result of aberrant glycosylation, glycan modifications, and the increased expression of sialoglycans on proteins and lipids. Siglec signaling has been identified as important regulator of anti-tumor immunity in the TME, but the key factors contributing to Siglec activation by tumor-associated sialoglycans are diverse and poorly defined. Among others, Siglec activation and signaling are co-determined by their expression levels, cell surface distribution, and their binding preferences for cis- and trans-ligands in the TME. Siglec binding preference are co-determined by the nature of the proteins/lipids to which the sialoglycans are attached and the multivalency of the interaction. Here, we review the current understanding and emerging conditions and factors involved in Siglec signaling in the TME and identify current knowledge gaps that exist in the field.

Research about the development of the graphomotor side of writing is very scarce. The goal of this study was to gain a better understanding of what constitutes graphic complexity of written material by determining the impact of graphic characteristics on handwriting production. In this end, the pen stroke of cursive handwriting was precisely described through an algorithm of detection of seven graphic characteristics: the number of angles, turn backs, curves in X and Y, pen-ups and modified links. Twenty typically developing children in grade 2 completed a single-word dictation task, composed of 48 items, on a digital writing tablet. All 48 words were regular words, highly frequent for second graders, and varied in terms of their graphic structure. Their handwriting production for each word was assessed in terms of both legibility and speed. A general linear mixed model was run to determine the impact of each graphic characteristic on handwriting performance. In agreement with our hypothesis, the results showed that words have different levels of graphic complexity. The following characteristics, in order of importance, significantly influenced negatively handwriting legibility: modified links, angles, curves, pen-ups and length. Regarding speed, the angles were the only characteristic that made children slow down while handwriting. These findings represent novelty in the field of research on writing. Unlike the usual approaches, it focused on investigating the graphic complexity at the word-level. It offers for the first time a universal classification of the graphic characteristics of words and it enables the quantification of the graphic complexity of words. [This work was presented at the SIG Writing International Conference 2016 (Liverpool, UK).]

The fully assembled influenza A virus (IAV) has on its surface the highest density of a single membrane protein found in nature—the glycoprotein hemagglutinin (HA) that mediates viral binding, entry, and assembly. HA clusters at the plasma membrane of infected cells, and the HA density (number of molecules per unit area) of these clusters correlates with the infectivity of the virus. Dense HA clusters are considered to mark the assembly site and ultimately lead to the budding of infectious IAV. The mechanism of spontaneous HA clustering, which occurs with or without other viral components, has not been elucidated. Using super-resolution fluorescence photoactivation localization microscopy (FPALM), we have previously shown that these HA clusters are interdependent on phosphatidylinositol 4,5-biphosphate (PIP2). Here, we show that the IAV matrix protein M1 co-clusters with PIP2, visualized using the pleckstrin homology domain. We find that cetylpyridinium chloride (CPC), which is a positively charged quaternary ammonium compound known for its antibacterial and antiviral properties at millimolar concentrations, disrupts M1 clustering and M1-PIP2 co-clustering at micromolar concentrations well below the critical micelle concentration (CMC). CPC also disrupts the co-clustering of M1 with HA at the plasma membrane, suggesting the role of host cell PIP2 clusters as scaffolds for gathering and concentrating M1 and HA to achieve their unusually high cluster densities in the IAV envelope.

BackgroundCurrently, children’s dietary intake patterns do not meet prescribed dietary guidelines. Consequently, childhood obesity is one of the most serious health concerns. Therefore, innovative methods need to be developed and tested in order to effectively improve the dietary intake of children. Teaching children how to cope with the overwhelming number of unhealthy food cues could be conducted effectively by serious health games. ObjectiveThe main aim of this study was to examine the effect of a serious health computer game on young children’s eating behavior and attitudes toward healthy and unhealthy foods. MethodsA cluster-randomized controlled trial with a between-group design was conducted (n=157; 8-12 years), wherein children played a game that promoted a healthy lifestyle or attended regular classes and did not play a game (control). The game was designed in collaboration with researchers and pilot-tested among a group of children repeatedly before conducting the experiment. After 1 week of playing, attitudes toward food snacks and actual intake (children could eat ad libitum from fruits or energy-dense snacks) was assessed. ResultsThe results showed that playing a serious health game did not have an effect on attitude toward fruits or energy-dense snacks or on the intake of fruits or less energy-dense snacks. Additional Bayesian analyses supported these findings. ConclusionsSerious health games are increasingly considered to be a potential effective intervention when it comes to behavior change. The results of the current study stress the importance of tailoring serious health games in order to be effective, because no effect was found on attitude or eating behavior. Trial RegistrationClinicalTrials.gov NCT05025995; https://tinyurl.com/mdd7wrjd

Nuclear power plants (NPP) installed on a river bank use once-through or recirculating wet cooling systems. While the quantitative assessment of mainly local evaporation of river water by a recirculating cooling system (RC) does not involve any major difficulty, the same cannot be said for the once-through cooling system (OTC) for which evaporation (called forced evaporation) occurs in the downstream aquatic environment. Our study applies an energy-balance temperature model to the Rhône River downstream from Lake Geneva. Our results show the approximate figure of 1.5 m3/MWh of forced evaporation per electricity produced (put forward in 2002 by EPRI and widely used in the literature) is debatable for setting a freshwater balance in a watershed because it does not consider the saltiness of the river downstream. The retention time of water bodies in the downstream freshwater stretch, the cross-section shape and regional weather characteristics appear to be key factors to take into account. In particular, for the three NPP with OTC systems installed along the French Rhône, we find an average forced evaporation between 0.3 and 0.7 m3/MWh of net electricity generated in the freshwater river stretch through to Arles between 1994 and 2015. These values are between three to eight times lower than those obtained for the evaporation generated by the plants with RC system installed along the river stretch.

Background and Aims: Surgery for pheochromocytoma (PCC) can cause excessive catecholamine release with severe hypertension. Alpha blockade is the mainstay of preoperative management. The aim of this study was to evaluate the efficacy and tolerance of intra-venous (IV) urapidil, a competitive short acting α1 receptor antagonist, in the prevention of peri-operative hemodynamic instability of patients with PCC. Material and Methods: This retrospective observational study included 75 patients (79 PCC) for PCC removal surgery from 2001 to 2017 at the Bordeaux University Hospital. They received, 3 days before surgery, continuous intravenous infusion of urapidil with stepwise increase to the maximum tolerated dose. Urapidil was maintained during the procedure and stopped after clamping the adrenal vein. Plasma catecholamine concentrations were measured during surgery. Hypertensive peaks (SAP >160 mmHg) and tachycardia >100 beats/min were treated with boluses of nicardipine 2 mg and esmolol 0.5 mg/kg. Results: We recorded 20/79 (25%) cases with systolic arterial pressure (SAP) >180 mmHg. Only 11/79 (14%) had hypotension with SAP

• Abetalipoproteinemia (ABL) is a rare monogenic familial hypobetalipoproteinemia caused by bi-allelic variants in MTTP gene. • We identified four French-Canadian patients homozygous for the same MTTP variant. • The ABL carrier frequency in Saguenay-Lac-Saint-Jean is estimated at 1:203. • This represents the 2nd highest worldwide carrier estimates for ABL. • Screening for ABL should be considered in this population. Abetalipoproteinemia (ABL) is a rare recessive genetic disease caused by bi-allelic pathogenic variants in the microsomal triglyceride transfer protein (MTTP) gene. This disease is characterized by a deficiency in the secretion of apolipoprotein B-containing lipoproteins. Patients with ABL present with neurological, hematological, and gastrointestinal symptoms due to fat malabsorption and a deficiency in liposoluble vitamins. In this report, we present a total of four ABL cases, including three new cases, all originating from the same French-Canadian founder population in Saguenay-Lac-Saint-Jean, Québec, Canada. These individuals are homozygous for the same pathogenic variant in the MTTP gene (c.419dup, p.Asn140Lysfs*2). We found that this variant is more common than anticipated in this population, with an estimated carrier frequency of 1:203. Early diagnosis is essential to initiate treatment known to prevent complications associated with ABL. Population carrier screening or newborn screening for ABL should be considered in this French-Canadian founder population. [ABSTRACT FROM AUTHOR]

Abstract Immunotherapy with checkpoint inhibitors demonstrates impressive improvements in the treatment of several types of cancer. Unfortunately, not all patients respond to therapy while severe immune-related adverse effects are prevalent. Currently, patient stratification is based on immunotherapy marker expression through immunohistochemical analysis on biopsied material. However, expression can be heterogeneous within and between tumor lesions, amplifying the sampling limitations of biopsies. Analysis of immunotherapy target expression by non-invasive quantitative molecular imaging with PET or SPECT may overcome this issue. In this review, an overview of tracers that have been developed for preclinical and clinical imaging of key immunotherapy targets, such as programmed cell death-1, programmed cell death ligand-1, IDO1 and cytotoxic T lymphocyte-associated antigen-4 is presented. We discuss important aspects to consider when developing such tracers and outline the future perspectives of molecular imaging of immunotherapy markers. Graphical abstract Current techniques in immune checkpoint imaging and its potential for future applications

Le premier psautier davidique correspond à une réaffirmation du Messie davidique et par la même occasion celle du Pauvre postexilique exploité auquel David est identifié par les titres des psaumes. La prise en compte du Pauvre est conforme à l’influence du livre des Proverbes et plus spécialement Proverbes 30,1-14 sur le premier livre du Psautier. La référence à l’Arche de Yahvé que David a fait monter à Jérusalem explique le rôle du Psaume 68 dans le premier livre du Psautier et au-delà celle du livre des Nombres. The first Book of the Davidic Psalms corresponds to a reaffirmation of the Davidic Messiah. Similarly, they correspond to exploitation of the postexilic poor in which David is identified in the titles of the psalms. By taking into account the poor in the first book of the Psalter, the first book reveals the influence of the Book of Proverbs, especially Prov 30,1-14. The reference to the Ark of Yahweh that David moved to Jerusalem, explains the role Psalm 68 played in the first book of the Psalms as well as in the Book of Numbers.

The mid-Pliocene is a valuable time interval for investigating equilibrium climate at current atmospheric CO2 concentrations because atmospheric CO2 concentrations are thought to have been comparable to the current day and yet the climate and distribution of ecosystems were quite different. One intriguing, but not fully understood, feature of the early to mid-Pliocene climate is the amplified Arctic temperature response and its impact on Arctic ecosystems. Only the most recent models appear to correctly estimate the degree of warming in the Pliocene Arctic and validation of the currently proposed feedbacks is limited by scarce terrestrial records of climate and environment. Here we reconstruct the summer temperature and fire regime from a subfossil fen-peat deposit on west–central Ellesmere Island, Canada, that has been chronologically constrained using cosmogenic nuclide burial dating to 3.9+1.5/-0.5 Ma. The estimate for average mean summer temperature is 15.4±0.8 ∘C using specific bacterial membrane lipids, i.e., branched glycerol dialkyl glycerol tetraethers. This is above the proposed threshold that predicts a substantial increase in wildfire in the modern high latitudes. Macro-charcoal was present in all samples from this Pliocene section with notably higher charcoal concentration in the upper part of the sequence. This change in charcoal was synchronous with a change in vegetation that included an increase in abundance of fire-promoting Pinus and Picea. Paleo-vegetation reconstructions are consistent with warm summer temperatures, relatively low summer precipitation and an incidence of fire comparable to fire-adapted boreal forests of North America and central Siberia. To our knowledge, this site provides the northernmost evidence of fire during the Pliocene. It suggests that ecosystem productivity was greater than in the present day, providing fuel for wildfires, and that the climate was conducive to the ignition of fire during this period. The results reveal that interactions between paleo-vegetation and paleoclimate were mediated by fire in the High Arctic during the Pliocene, even though CO2 concentrations were similar to modern values.

Abstract The nematode Caenorhabditis elegans has been central to the understanding of metazoan biology. However, C. elegans is but one species among millions and the significance of this important model organism will only be fully revealed if it is placed in a rich evolutionary context. Global sampling efforts have led to the discovery of over 50 putative species from the genus Caenorhabditis, many of which await formal species description. Here, we present species descriptions for 10 new Caenorhabditis species. We also present draft genome sequences for nine of these new species, along with a transcriptome assembly for one. We exploit these whole‐genome data to reconstruct the Caenorhabditis phylogeny and use this phylogenetic tree to dissect the evolution of morphology in the genus. We reveal extensive variation in genome size and investigate the molecular processes that underlie this variation. We show unexpected complexity in the evolutionary history of key developmental pathway genes. These new species and the associated genomic resources will be essential in our attempts to understand the evolutionary origins of the C. elegans model.

Aim: Longitudinal studies are rare in the field of writing research, and little is known about the concurrent development of the two transcription skills: spelling and handwriting. This study was designed to provide a comprehensive picture of the development and the longitudinal relations between spelling, handwriting speed, and handwriting quality at the word level.Method: Over a period of 3 years (coh1: Grades 2–4; coh2: Grades 3–5), 117 French-speaking children were assessed on a single-word dictation task. At each testing time, measures of spelling accuracy, handwriting speed, and handwriting quality were collected on 40 words. Words varied in both orthographic and graphic complexity, making it possible to investigate the influence of these levels of complexity on transcription abilities.Results: Linear growth analyses using cross-classified Bayesian structural equation modeling (CC-BSEM) revealed that spelling and speed continued to improve until Grade 5, while handwriting quality reached an early plateau in Grade 2. In the younger cohort, graphic complexity had a significant influence on the pace of development of handwriting speed and on spelling and handwriting quality performance in Grade 2. In the older cohort, a positive relation between spelling and speed and a negative relation between handwriting speed and handwriting quality were found, indicating that fast handwriting is associated with high spelling ability and that fast handwriting is detrimental to handwriting quality. By providing a better understanding of writing development, this study yields innovative findings not only regarding the development of transcription skills but also regarding how spelling, handwriting speed, and handwriting quality can influence each other's performance throughout primary school.

The rapidly spreading COVID-19 pandemic demanded immediate organizational pivots in departments of laboratory medicine and pathology, including development and implementation of severe acute respiratory syndrome coronavirus 2 diagnostics in the face of unprecedented supply chain shortages. Laboratory medicine and pathology educational programs were affected in numerous ways. Here, we overview the effects of COVID-19 on the large, academic Department of Laboratory Medicine and Pathology educational practice at Mayo Clinic, highlighting lessons learned for the post-pandemic era and planning for the possibility of a future pandemic.

In situ tumor ablation techniques, like radiotherapy, cryo- and heat-based thermal ablation are successfully applied in oncology for local destruction of tumor masses. Although diverse in technology and mechanism of inducing cell death, ablative techniques share one key feature: they generate tumor debris which remains in situ. This tumor debris functions as an unbiased source of tumor antigens available to the immune system and has led to the concept of in situ cancer vaccination. Most studies, however, report generally modest tumor-directed immune responses following local tumor ablation as stand-alone treatment. Tumors have evolved mechanisms to create an immunosuppressive tumor microenvironment (TME), parts of which may admix with the antigen depot. Provision of immune stimuli, as well as approaches that counteract the immunosuppressive TME, have shown to be key to boost ablation-induced anti-tumor immunity. Recent advances in protein engineering have yielded novel multifunctional antibody formats. These multifunctional antibodies can provide a combination of distinct effector functions or allow for delivery of immunomodulators specifically to the relevant locations, thereby mitigating potential toxic side effects. This review provides an update on immune activation strategies that have been tested to act in concert with tumor debris to achieve in situ cancer vaccination. We further provide a rationale for multifunctional antibody formats to be applied together with in situ ablation to boost anti-tumor immunity for local and systemic tumor control.

Vaccination is one of the most efficient public healthcare measures to fight infectious diseases. Nevertheless, the immune mechanisms induced in vivo by vaccination are still unclear. The route of administration, an important vaccination parameter, can substantially modify the quality of the response. How the route of administration affects the generation and profile of immune responses is of major interest. Here, we aimed to extensively characterize the profiles of the innate and adaptive response to vaccination induced after intradermal, subcutaneous, or intramuscular administration with a modified vaccinia virus Ankara model vaccine in non-human primates. The adaptive response following subcutaneous immunization was clearly different from that following intradermal or intramuscular immunization. The subcutaneous route induced a higher level of neutralizing antibodies than the intradermal and intramuscular vaccination routes. In contrast, polyfunctional CD8+ T-cell responses were preferentially induced after intradermal or intramuscular injection. We observed the same dichotomy when analyzing the early molecular and cellular immune events, highlighting the recruitment of cell populations, such as CD8+ T lymphocytes and myeloid-derived suppressive cells, and the activation of key immunomodulatory gene pathways. These results demonstrate that the quality of the vaccine response induced by an attenuated vaccine is shaped by early and subtle modifications of the innate immune response. In this immunization context, the route of administration must be tailored to the desired type of protective immune response. This will be achieved through systems vaccinology and mathematical modeling, which will be critical for predicting the efficacy of the vaccination route for personalized medicine.

During the last years, preclinical and clinical studies have emerged supporting the rationale to integrate radiotherapy and immunotherapy. Radiotherapy may enhance the effects of immunotherapy by improving tumor antigen release, antigen presentation, and T-cell infiltration. Recently, magnetic resonance guided radiotherapy (MRgRT) has become clinically available. Compared to conventional radiotherapy techniques, MRgRT firstly allows for daily on-table treatment adaptation, which enables both dose escalation for increasing tumor response and superior sparing of radiosensitive organs-at-risk for reducing toxicity. The current review focuses on the potential of combining MR-guided adaptive radiotherapy with immunotherapy by providing an overview on the current status of MRgRT, latest developments in preclinical and clinical radio-immunotherapy, and the unique opportunities and challenges for MR-guided radio-immunotherapy. MRgRT might especially assist in answering open questions in radio-immunotherapy regarding optimal radiation dose, fractionation, timing of immunotherapy, appropriate irradiation volumes, and response prediction.

AimsThe objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM).Methods and resultsASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction).ConclusionThis pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without DM.

This paper demonstrates the potential of combining an Appreciative Inquiry (AI) methodological framework with arts-informed research methods, particularly in applying comics to the AI process where children are active participants in research. Included in this article is a review of each methodological framework and a critical exploration of the literature. It is the position of the authors that arts-informed methods applied within an AI framework offers unexplored potential for generating new ways of knowing by valuing and relying on the voices of child participants to gain different perspectives. These perspectives are crucial for research that directly impacts the child population.

The Messianic reaffirmation of Ps 18 must be understood in the context of the influence of the book of Proverbs, more specifically the influence of Prov 30:1–14, upon the Psalter. However, it is not only the influence of Proverbs that is important. It goes further; for example; the psalm also responds to the denunciation of the fate of the poor at the return from the exile. These responses indicate some relations to late redactions of the Book of the Twelve, Jonah, Zephaniah (see Zechariah), Habakkuk, the Prayer of Hannah in 1 Sam 2:1–10 (which frames the books of Samuel together with 2 Sam 22 = Ps 18), or from the book of Job and some passages depending on Judges 5:4, later found in Ps 68, Dt 33:2 or Is 34 and 63:1–6. https://doi.org/10.17159/2312-3621/2020/v33n3a12

Background Myeloid-derived suppressor cells (MDSC) are a functional myeloid cell subset that includes myeloid cells with immune suppressive properties. The presence of MDSC has been reported in the peripheral blood of patients with several malignant and non-malignant diseases. So far, direct comparison of MDSC across different diseases and Centers is hindered by technical pitfalls and a lack of standardized methodology. To overcome this issue, we formed a network through the COST Action Mye-EUNITER (www.mye-euniter.eu) with the goal to standardize and facilitate the comparative analysis of human circulating MDSC in cancer, inflammation and infection. In this manuscript, we present the results of the multicenter study Mye-EUNITER MDSC Monitoring Initiative, that involved 13 laboratories and compared circulating MDSC subsets across multiple diseases, using a common protocol for the isolation, identification and characterization of these cells.Methods We developed, tested, executed and optimized a standard operating procedure for the isolation and immunophenotyping of MDSC using blood from healthy donors. We applied this procedure to the blood of almost 400 patients and controls with different solid tumors and non-malignant diseases. The latter included viral infections such as HIV and hepatitis B virus, but also psoriasis and cardiovascular disorders.Results We observed that the frequency of MDSC in healthy donors varied substantially between centers and was influenced by technical aspects such as the anticoagulant and separation method used. Expansion of polymorphonuclear (PMN)-MDSC exceeded the expansion of monocytic MDSC (M-MDSC) in five out of six solid tumors. PMN-MDSC expansion was more pronounced in cancer compared with infection and inflammation. Programmed death-ligand 1 was primarily expressed in M-MDSC and e-MDSC and was not upregulated as a consequence of disease. LOX-1 expression was confined to PMN-MDSC.Conclusions This study provides improved technical protocols and workflows for the multi-center analysis of circulating human MDSC subsets. Application of these workflows revealed a predominant expansion of PMN-MDSC in solid tumors that exceeds expansion in chronic infection and inflammation.

Background Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME) in non-medullary thyroid carcinoma (TC) and neuroblastoma (NB), being associated with a poor prognosis for patients. However, little is known about how tumors steer the specific metabolic phenotype and function of TAMs.Methods In a human coculture model, transcriptome, metabolome and lipidome analysis were performed on TC-induced and NB-induced macrophages. The metabolic shift was correlated to functional readouts, such as cytokine production and reactive oxygen species (ROS) production, including pharmacological inhibition of metabolic pathways.Results Based on transcriptome and metabolome analysis, we observed a strong upregulation of lipid biosynthesis pathways in TAMs. Subsequently, lipidome analysis revealed that tumor-induced macrophages have an increased total lipid content and enriched levels of intracellular lipids, especially phosphoglycerides and sphingomyelins. Strikingly, this metabolic shift in lipid synthesis contributes to their protumoral functional characteristics: blocking key enzymes of lipid biosynthesis in the tumor-induced macrophages reversed the increased inflammatory cytokines and the capacity to produce ROS, two well-known protumoral factors in the TME.Conclusions Taken together, our data show that tumor cells can stimulate lipid biosynthesis in macrophages to induce protumoral cytokine and ROS responses and advocate lipid biosynthesis as a potential therapeutic target to reprogram the TME.

Abstract In the last decade, organoid technology has developed as a primary research tool in basic biological and clinical research. The reliance on poorly defined animal‐derived extracellular matrix, however, severely limits its application in regenerative and translational medicine. Here, a well‐defined, synthetic biomimetic matrix based on polyisocyanide (PIC) hydrogels that support efficient and reproducible formation of mammary gland organoids (MGOs) in vitro is presented. Only decorated with the adhesive peptide RGD for cell binding, PIC hydrogels allow MGO formation from mammary fragments or from purified single mammary epithelial cells. The cystic organoids maintain their capacity to branch for over two months, which is a fundamental and complex feature during mammary gland development. It is found that small variations in the 3D matrix give rise to large changes in the MGO: the ratio of the main cell types in the MGO is controlled by the cell–gel interactions via the cell binding peptide density, whereas gel stiffness controls colony formation efficiency, which is indicative of the progenitor density. Simple hydrogel modifications will allow for future introduction and customization of new biophysical and biochemical parameters, making the PIC platform an ideal matrix for in depth studies into organ development and for application in disease models.

Whether arterial stiffness is a surrogate end-point for cardiovascular and renal disease has never been directly demonstrated by a controlled clinical trial. Our main hypothesis is a better prevention of outcomes in high risk hypertensives with PWV normalization driven strategy than with usual blood pressure driven therapeutic strategy based on European Society of Hypertension–European Society of Cardiology (ESH–ESC) guidelines. The strategy for preventing cardiovascular and renal events based on arterial stiffness study is a multicenter open-label randomized controlled trial with blinded endpoint evaluation comparing a therapeutic strategy targeting the normalisation of Pulse Wave Velocity (PWV group) versus a classical therapeutic strategy only implementing the ESH–ESC Guidelines (conventional group), for reducing cardiovascular and renal events. Patients with primary hypertension, aged 55–75 years, and at medium-to-very high cardiovascular risk will be included and followed-up for 4 years. In the PWV group, treatment will be adjusted to carotid-femoral PWV measured every 6 months. In the conventional group, PWV will be measured at baseline and every 2 years, but its value will be blinded to the investigator in charge of the patient. In the PWV group, the therapeutic strategy will preferably use a combination of Angiotensin-converting Enzyme Inhibitor (ACEI) [or Angiotensin Receptor Blockers (ARB)] and calcium channel blockers, as well as maximal recommended doses of ACEIs and ARBs. The primary combined endpoint includes stroke and coronary events (myocardial infarction, angioplasty, bypass), fatal or not, peripheral artery disease (angioplasty, bypass, amputation), hospitalization for heart failure, aortic dissection, chronic kidney disease (doubling of creatinine, dialysis), and sudden death. Twenty-five research centers will include a total of 1500 patients, in order to show a 20% reduction in the primary combined endpoint - the incidence of which is estimated at 10% per year - in the PWV group compared to the conventional group.

Background Tumor ablation techniques, like cryoablation, are successfully used in the clinic to treat tumors. The tumor debris remaining in situ after ablation is a major antigen depot, including neoantigens, which are presented by dendritic cells (DCs) in the draining lymph nodes to induce tumor-specific CD8+ T cells. We have previously shown that co-administration of adjuvants is essential to evoke strong in vivo antitumor immunity and the induction of long-term memory. However, which adjuvants most effectively combine with in situ tumor ablation remains unclear.Methods and results Here, we show that simultaneous administration of cytidyl guanosyl (CpG) with saponin-based adjuvants following cryoablation affects multifunctional T-cell numbers and interleukin (IL)-1 induced polymorphonuclear neutrophil recruitment in the tumor draining lymph nodes, relative to either adjuvant alone. The combination of CpG and saponin-based adjuvants induces potent DC maturation (mainly CpG-mediated), antigen cross-presentation (mainly saponin-based adjuvant mediated), while excretion of IL-1β by DCs in vitro depends on the presence of both adjuvants. Most strikingly, CpG/saponin-based adjuvant exposed DCs potentiate antigen-specific T-cell proliferation resulting in multipotent T cells with increased capacity to produce interferon (IFN)γ, IL-2 and tumor necrosis factor-α in vitro. Also in vivo the CpG/saponin-based adjuvant combination plus cryoablation increased the numbers of tumor-specific CD8+ T cells showing enhanced IFNγ production as compared with single adjuvant treatments.Conclusions Collectively, these data indicate that co-injection of CpG with saponin-based adjuvants after cryoablation induces an increased amount of tumor-specific multifunctional T cells. The combination of saponin-based adjuvants with toll-like receptor 9 adjuvant CpG in a cryoablative setting therefore represents a promising in situ vaccination strategy.

Background As part of the scale-up of the Patient Care Collaborative (PCC) at our institution, we explored staff perceptions and patient outcomes at different levels of model implementation in three general internal medicine units.Methods We conducted a mixed-methods embedded experimental healthcare improvement initiative. In the qualitative strand, we conducted five focus group discussions. In the quantitative strand, we used hospital administrative data to compare outcomes (falls per 1000, median length of stay in days and resource use measured as resource intensity weights (RIW), before and after the implementation of the PCC, using χ2 tests, Wilcoxon’s rank sum tests and interrupted time series analyses.Results Staff showed considerable knowledge and acceptance of the PCC but expressed mixed feelings with regards to patient safety, workload, communication and teamwork. Staff perceptions varied by level of implementation of the PCC. A number of falls (overall) in the full implementation phase were not significantly different from the preimplementation phase (227 per 1000 vs 200 per 1000; p=0.449), but the number of moderate to severe falls dropped (12 vs 2 per 1000); p