Nonuniversal Dynamics of Hyperbranched Metallo-Supramolecular Polymer Networks by the Spontaneous Formation of Nanoparticles.

Various transient and permanent bonds are commonly combined in increasingly complex hierarchical structures to achieve biomimetic functions, along with high mechanical properties. However, there is a traditional trade-off between mechanical strength and biological functions like self-healing. To fill this gap, we develop a metallo-supramolecular polymer hydrogel based on the hyperbranched poly(ethylene imine) (PEI) backbone and phenanthroline ligands, which have unexpectedly high plateau modulus at low concentrations. Rheological measurements demonstrate nonuniversal metal-ion-specific dynamics, with significantly larger plateau moduli, longer relaxation times, and stronger temperature dependencies, compared to equivalent networks based on model-type telechelic precursors, which cannot be explained by the theory of linear viscoelasticity. TEM images reveal the in situ mineralization of metal ions, which nucleate by the ligand complexation and grow thanks to the spontaneous reducing effect of the PEI backbone. Evidently, the complex lifetime works against Ostwald ripening, resulting in the formation of thermodynamically stable smaller particles. This trend is followed by time-dependent network buildup measurements and is confirmed by a kinetic model for particle formation and aggregation. The spontaneous formation of particles with complex lifetime-dependent sizes can explain the nonuniversal dynamics through the interaction of polymer segments and particles at the nanoscale. This work describes how the polymer backbone can affect the strength and stability of supramolecular bonds, promising for combining high mechanical properties and self-healing comparable to natural tissues.

Population Pharmacokinetic Modelling of Norepinephrine in Healthy Volunteers Prior to and During General Anesthesia.

BACKGROUND: Intraoperation hypotension (IOH) is commonly observed in patients undergoing surgery under general anesthesia, and even a brief episode of IOH can lead to unfavorable outcomes. To reduce the risk, blood pressure is closely measured during general anesthesia, and norepinephrine (NE) is frequently administered if hypotension is detected. Despite its routine application, information on the dose-exposure-response relationship of NE remains limited. Additionally, quantification of the influence of general anesthesia on the pharmacokinetics (PK) of NE is lacking. OBJECTIVE: In this study, we aimed to describe NE PK in healthy volunteers and the influence of general anesthesia on its PK. METHODS: A single-center, cross-over study was conducted in healthy volunteers. The volunteers received a step-up NE dosing scheme (0.04, 0.08, 0.12, 0.16 and 0.20 mcg-1/kg-1/min-1) first in the awake state and then under general anesthesia. General anesthesia was administered using a propofol/remifentanil Eleveld target-controlled infusion. During general anesthesia, a 30-second electrical stimulus was given as surrogate for surgical incision to the volunteers at each dosage step. Blood samples were drawn before the initial dosing and after each dosing step, and plasma NE, propofol and remifentanil concentrations were subsequently determined. A population PK model was developed using non-linear mixed effects modelling. Simulations were conducted to predict the plasma NE concentration in patients at different measured propofol concentrations. RESULTS: A total of 1219 samples were analyzed from 36 volunteers. A two-compartment model with a first-order elimination best described the data. Weight, age, and session effect (awake vs general anesthesia) were identified as relevant covariates on the clearance (CL) of NE. A 10% decrease in NE CL was observed after general anesthesia induction. This difference between sessions is better explained by the measured concentration of propofol, rather than the anticipated impact of cardiac output. The estimated post-stimulation NE concentration is 0.66 nmol/L-1 (95% CI 0.06-1.20 nmol/L-1) lower than the pre-stimulation NE concentration. Model simulation indicates that patients at a higher measured propofol concentration (e.g., 6 mcg/mL-1) exhibited higher NE concentrations (95% PI 18.10-43.89 nmol/L-1) than patients at a lower measured propofol concentration (e.g., 3 mcg/mL-1) (95% PI 16.81-38.91 nmol L-1). CONCLUSION: The NE PK is well described with a two-compartment model with a first-order elimination. NE CL exhibiting a 10% decrease under general anesthesia, with this difference being attributed to the measured concentration of propofol. The impact of stimulation on NE PK under general anesthesia is very limited. CLINICAL TRIALS REGISTRATION NUMBER: NL9312.

A Staff Educational Intervention to Increase the Time of Skin-to-Skin Care in a Swedish NICU: A Quality Improvement Project.

BACKGROUND: Skin-to-skin contact (SSC) is crucial in neonatal intensive care unit (NICU) care; yet, challenges exist in its implementation. This study addresses a knowledge gap by examining the most effective ways to introduce SSC in the NICU, emphasizing the need to seamlessly integrate this practice for optimal infant and parent care. One way, among many, to implement SSC is to increase staff's knowledge and awareness about SSC. OBJECTIVE: To describe the effect of an educational intervention on SSC time, the number of SSC sessions per day, and the number of infants cared for with SSC within their first day of life. METHODS: A pre- and postinterventional study design was used to determine the effect of an educational intervention on SSC time, the number of SSC sessions per day, and the number of infants cared for with SSC within their first day of life. RESULTS: The prevalence of infants receiving SSC during their first 24 hours of life, the number of SSC sessions per day, and the duration of each SSC session increased after the intervention, and these effects persisted over 2 years. IMPLICATIONS FOR PRACTICE: Our study highlights the impact of staff education and reflective discussions on SSC in the NICU. Integrating these with practical training, parental education, and NICU environment modifications is pivotal for enhancing and sustaining optimal SSC practices, benefiting both infants and parents.

Glucose disturbances in very low-birthweight infants-Results from the prospective LIGHT study.

AIM: To describe glucose homeostasis disturbances (dysglycaemia) in very low-birthweight infants (<1500 g) during the admission period and explore associated risk factors. METHODS: The LIGHT (very low-birthweight infants - glucose and hormonal profile over time) study was a prospective observational cohort study that included 49 very low-birthweight infants admitted to the tertiary neonatal intensive care unit in Umeå, Sweden, during 2016-2019. All glucose concentrations (n = 3515) sampled during the admission period were registered. RESULTS: Hyperglycaemia >10 mmol/L and hypoglycaemia <2.6 mmol/L were registered in 63% and 55% of the infants, respectively. Onset of dysglycaemia occurred almost exclusively in the first postnatal week. Hyperglycaemia followed 15% of corticosteroid doses given; all were preceded by pre-existing hyperglycaemia. Pre-existing hyperglycaemia was found in 66.7% of hyperglycaemic infants who received inotrope treatment. Upon commencement, 72.5% of antimicrobial treatments given were neither preceded nor followed by hyperglycaemia. CONCLUSION: Dysglycaemia was common in very low-birthweight infants. Daily means of glucose concentrations seemed to follow a postmenstrual age-dependent pattern, decreasing towards term age suggesting a postmenstrual age-dependent developmental mechanism. The primary mechanism causing hyperglycaemia was independent of sepsis, and corticosteroid and inotrope treatments. No hypoglycaemia was registered during ongoing insulin treatment.

The impact of an illness perception conversation on open-label placebo response in knee osteoarthritis: A randomised controlled trial.

OBJECTIVE: To compare the effect of an illness perception conversation (IPC), relative to a research participation conversation (RPC), on 2-week changes in knee pain in patients with knee osteoarthritis. METHOD: This was a randomised single-blind trial. Patients were randomised to two matched conversations. An IP conversation concerning the participant's knee pain-related illness perception (IP) or an RPC concerning the participant's motivation for participating in research. Both conversations were followed by an open-label intraarticular saline injection in the most symptomatic knee. The primary outcome was change in knee pain from baseline to 2 weeks follow-up on a 100 mm visual analogue scale (VAS). Key secondary outcomes included the Knee injury and Osteoarthritis Outcome Score (KOOS) subscales: Activities of daily living (ADL) and Quality of life (QoL). Main analyses were based on the intention-to-treat population using repeated measures mixed effects linear models. RESULTS: 103 patients were randomised to the IPC group (n = 52) and the RPC group (n = 51). VAS knee pain scores changed statistically significantly from baseline to end of treatment in both groups, -13.7 (standard error [SE]: 3.2) in the IPC group and -13.0 (SE: 3.1) in the RPC group with an adjusted between-group difference of -0.7 (95% CI: -8.3 to 6.9; P = 0.85). Likewise, no group differences were seen in KOOS ADL and KOOS QoL. CONCLUSION: A conversation concerning knee pain-related IP did not augment the pain-relieving effect of an open-label placebo injection when compared to a similar control conversation concerning motivations for participating in research. TRIAL REGISTRATION: NCT05225480.

Comparative effectiveness of different placebos and comparator groups for hand osteoarthritis exploring the impact of contextual factors: A systematic review and meta-analysis of randomised trials.

OBJECTIVE: To examine the pain relief effects of comparators (placebos and untreated control groups) in hand osteoarthritis trials and the impact of contextual factors. METHODS: We systematically searched PubMed, EMBASE and CENTRAL from inception to December 26, 2021. We included randomised controlled trials of people with hand osteoarthritis with a placebo or an untreated control group. We assessed the Risk of Bias with Cochrane Risk-of-Bias tool version 2. Each comparator was contrasted with a null-arm, imputed as having a zero change from baseline with the same standard deviation as the comparator. We combined the standardised mean differences with a random effects meta-analysis. The contextual factors' effect was explored in meta-regression and stratified models with pain as the dependent variable. RESULTS: 84 trials (7262 participants) were eligible for quantitative synthesis, of which 76 (6462 participants) were eligible for the stratified analyses. Placebos were superior to their matched null-arms in relieving pain with an effect size of -0.51 (95% confidence interval -0.61 to -0.42), while untreated control groups were not. When analysing all comparators, blinded trial designs and low risk of bias were associated with higher pain relief compared to an open-label trial design and some concern or high risk of bias. CONCLUSION: The placebo response on pain for people with hand osteoarthritis was increased by appropriate blinding and a lower risk of bias assessment. Placebos were superior to a null-arm, while untreated control groups were not. Results emphasise the importance of using appropriate comparators in clinical trials. PROSPERO REGISTRATION ID: CRD42022298984.

Carbohydrate distribution via SWEET17 is critical for Arabidopsis inflorescence branching under drought.

Sugars Will Eventually be Exported Transporters (SWEETs) are the most recently discovered family of plant sugar transporters. By acting as uniporters, SWEETs facilitate the diffusion of sugars across cell membranes and play an important role in various physiological processes such as abiotic stress adaptation. AtSWEET17, a vacuolar fructose facilitator, was shown to be involved in the modulation of the root system during drought. In addition, previous studies have shown that overexpression of an apple homolog leads to increased drought tolerance in tomato plants. Therefore, SWEET17 might be a molecular element involved in plant responses to drought. However, the role and function of SWEET17 in above-ground tissues of Arabidopsis under drought stress remain elusive. By combining gene expression analysis and stem architecture with the sugar profiles of different above-ground tissues, we uncovered a putative role for SWEET17 in carbohydrate supply and thus cauline branch elongation, especially during periods of carbon limitation, as occurs under drought stress. Thus, SWEET17 seems to be involved in maintaining efficient plant reproduction under drought stress conditions.

Impact of trial attrition rates on treatment effect estimates in chronic inflammatory diseases: A meta-epidemiological study.

The objective of this meta-epidemiological study was to explore the impact of attrition rates on treatment effect estimates in randomised trials of chronic inflammatory diseases (CID) treated with biological and targeted synthetic disease-modifying drugs. We sampled trials from Cochrane reviews. Attrition rates and primary endpoint results were retrieved from trial publications; Odds ratios (ORs) were calculated from the odds of withdrawing in the experimental intervention compared to the control comparison groups (i.e., differential attrition), as well as the odds of achieving a clinical response (i.e., the trial outcome). Trials were combined using random effects restricted maximum likelihood meta-regression models and associations between estimates of treatment effects and attrition rates were analysed. From 37 meta-analyses, 179 trials were included, and 163 were analysed (301 randomised comparisons; n = 62,220 patients). Overall, the odds of withdrawal were lower in the experimental compared to control groups (random effects summary OR = 0.45, 95% CI, 0.41-0.50). The corresponding overall treatment effects were large (random effects summary OR = 4.43, 95% CI 3.92-4.99) with considerable heterogeneity across interventions and clinical specialties (I2 = 85.7%). The ORs estimating treatment effect showed larger treatment benefits when the differential attrition was more prominent with more attrition in the control group (OR = 0.73, 95% CI 0.55-0.96). Higher attrition rates from the control arm are associated with larger estimated benefits of treatments with biological or targeted synthetic disease-modifying drugs in CID trials; differential attrition may affect estimates of treatment benefit in randomised trials.

Insulin resistance prior to term age in very low birthweight infants: a prospective study.

OBJECTIVE: To explore the glucose-related hormone profile of very low birthweight (VLBW) infants and assess the association between neonatal hyperglycaemia and insulin resistance during the admission period. DESIGN: A prospective observational study-the Very Low Birth Weight Infants, Glucose and Hormonal Profiles over Time study. SETTING: A tertiary neonatal intensive care unit and four neonatal units in county hospitals in Sweden. PATIENTS: 48 infants born <1500 g (VLBW) during 2016-2019. OUTCOME MEASURES: Plasma concentrations of glucose-related hormones and proteins (C-peptide, insulin, ghrelin, glucagon-like peptide 1 (GLP-1), glucagon, leptin, resistin and proinsulin), insulin:C-peptide and proinsulin:insulin ratios, Homoeostatic Model Assessment 2 (HOMA2) and Quantitative Insulin Sensitivity Check (QUICKI) indices, measured on day of life (DOL) 7 and at postmenstrual age 36 weeks. RESULTS: Lower gestational age was significantly associated with higher glucose, C-peptide, insulin, proinsulin, leptin, ghrelin, resistin and GLP-1 concentrations, increased HOMA2 index, and decreased QUICKI index and proinsulin:insulin ratio. Hyperglycaemic infants had significantly higher glucose, C-peptide, insulin, leptin and proinsulin concentrations, and lower QUICKI index, than normoglycaemic infants. Higher glucose and proinsulin concentrations and insulin:C-peptide ratio, and lower QUICKI index on DOL 7 were significantly associated with longer duration of hyperglycaemia during the admission period. CONCLUSIONS: VLBW infants seem to have a hormone profile consistent with insulin resistance. Lower gestational age and hyperglycaemia are associated with higher concentrations of insulin resistance markers.

Implementation of a Bayesian based advisory tool for target-controlled infusion of propofol using qCON as control variable.

This single blinded randomized controlled trial aims to assess whether the application of a Bayesian-adjusted CePROP (effect-site of propofol) advisory tool leads towards a more stringent control of the cerebral drug effect during anaesthesia, using qCON as control variable. 100 patients scheduled for elective surgery were included and randomized into a control or intervention group (1:1 ratio). In the intervention group the advisory screen was made available to the clinician, whereas it was blinded in the control group. The settings of the target-controlled infusion pumps could be adjusted at any time by the clinician. Cerebral drug effect was quantified using processed EEG (CONOX monitor, Fresenius Kabi, Bad Homburg, Germany). The time of qCON between the desired range (35-55) during anaesthesia maintenance was defined as our primary end point. Induction parameters and recovery times were considered secondary end points and coefficient of variance of qCON and CePROP was calculated in order to survey the extent of control towards the mean of the population. The desired range of qCON between 35 and 55 was maintained in 84% vs. 90% (p = 0.15) of the case time in the control versus intervention group, respectively. Secondary endpoints showed similar results in both groups. The coefficient of variation for CePROP was higher in the intervention group. The application of the Bayesian-based CePROP advisory system in this trial did not result in a different time of qCON between 35 and 55 (84 [21] vs. 90 [18] percent of the case time). Significant differences between groups were hard to establish, most likely due to a very high performance level in the control group. More extensive control efforts were found in the intervention group. We believe that this advisory tool could be a useful educational tool for novices to titrate propofol effect-site concentrations.

Exit pathways of therapeutic antibodies from the brain and retention strategies.

Treating brain diseases requires therapeutics to pass the blood-brain barrier (BBB) which is nearly impermeable for large biologics such as antibodies. Several methods now facilitate crossing or circumventing the BBB for antibody therapeutics. Some of these exploit receptor-mediated transcytosis, others use direct delivery bypassing the BBB. However, successful delivery into the brain does not preclude exit back to the systemic circulation. Various mechanisms are implicated in the active and passive export of antibodies from the central nervous system. Here we review findings on active export via transcytosis of therapeutic antibodies - in particular, the role of the neonatal Fc receptor (FcRn) - and discuss a possible contribution of passive efflux pathways such as lymphatic and perivascular drainage. We point out open questions and how to address these experimentally. In addition, we suggest how emerging findings could aid the design of the next generation of therapeutic antibodies for neurologic diseases.

General purpose models for intravenous anesthetics, the next generation for target-controlled infusion and total intravenous anesthesia?

PURPOSE OF REVIEW: There are various pharmacokinetic-dynamic models available, which describe the time course of drug concentration and effect and which can be incorporated into target-controlled infusion (TCI) systems. For anesthesia and sedation, most of these models are derived from narrow patient populations, which restricts applicability for the overall population, including (small) children, elderly, and obese patients. This forces clinicians to select specific models for specific populations. RECENT FINDINGS: Recently, general purpose models have been developed for propofol and remifentanil using data from multiple studies and broad, diverse patient groups. General-purpose models might reduce the risks associated with extrapolation, incorrect usage, and unfamiliarity with a specific TCI-model, as they offer less restrictive boundaries (i.e., the patient "doesn't fit in the selected model") compared with the earlier, simpler models. Extrapolation of a model can lead to delayed recovery or inadequate anesthesia. If multiple models for the same drug are implemented in the pump, it is possible to select the wrong model for that specific case; this can be overcome with one general purpose model implemented in the pump. SUMMARY: This article examines the usability of these general-purpose models in relation to the more traditional models.

Neoadjuvant Intratumoral Immunotherapy with Cowpea Mosaic Virus Induces Local and Systemic Antitumor Efficacy in Canine Mammary Cancer Patients.

The lack of optimal models to evaluate novel agents is delaying the development of effective immunotherapies against human breast cancer (BC). In this prospective open label study, we applied neoadjuvant intratumoral immunotherapy with empty cowpea mosaic virus-like particles (eCPMV) to 11 companion dogs diagnosed with canine mammary cancer (CMC), a spontaneous tumor resembling human BC. We found that two neoadjuvant intratumoral eCPMV injections resulted in tumor reduction in injected tumors in all patients and in noninjected tumors located in the ipsilateral and contralateral mammary chains of injected dogs. Tumor reduction was independent of clinical stage, tumor size, histopathologic grade, and tumor molecular subtype. RNA-seq-based analysis of injected tumors indicated a decrease in DNA replication activity and an increase in activated dendritic cell infiltration in the tumor microenvironment. Immunohistochemistry analysis demonstrated significant intratumoral increases in neutrophils, T and B lymphocytes, and plasma cells. eCPMV intratumoral immunotherapy demonstrated antitumor efficacy without any adverse effects. This novel immunotherapy has the potential for improving outcomes for human BC patients.

HDR-based CRISPR/Cas9-mediated Knockout of PD-L1 in C57BL/6 Mice.

The immune-inhibitory molecule programmed cell death ligand 1 (PD-L1) has been shown to play a role in pathologies such as autoimmunity, infections, and cancer. The expression of PD-L1 not only on cancer cells but also on non-transformed host cells is known to be associated with cancer progression. Generation of PD-L1 deficiency in the murine system enables us to specifically study the role of PD-L1 in physiological processes and diseases. One of the most versatile and easy to use site-specific gene editing tools is the CRISPR/Cas9 system, which is based on an RNA-guided nuclease system. Similar to its predecessors, the Zinc finger nucleases or transcription activator-like effector nucleases (TALENs), CRISPR/Cas9 catalyzes double-strand DNA breaks, which can result in frameshift mutations due to random nucleotide insertions or deletions via non-homologous end joining (NHEJ). Furthermore, although less frequently, CRISPR/Cas9 can lead to insertion of defined sequences due to homology-directed repair (HDR) in the presence of a suitable template. Here, we describe a protocol for the knockout of PD-L1 in the murine C57BL/6 background using CRISPR/Cas9. Targeting of exon 3 coupled with the insertion of a HindIII restriction site leads to a premature stop codon and a loss-of-function phenotype. We describe the targeting strategy as well as founder screening, genotyping, and phenotyping. In comparison to NHEJ-based strategy, the presented approach results in a defined stop codon with comparable efficiency and timelines as NHEJ, generates convenient founder screening and genotyping options, and can be swiftly adapted to other targets.

The NK cell checkpoint NKG2A maintains expansion capacity of human NK cells.

Human natural killer (NK) cells are cytotoxic effector cells that are increasingly harnessed in cancer immunotherapy. NKG2A/CD94 is an inhibitory receptor on NK cells that has established regulatory functions in the direct interaction with target cells when engaged with its ligand, the non-classical HLA class I molecule HLA-E. Here, we confirmed NKG2A as a checkpoint molecule in primary human NK cells and identified a novel role for NKG2A in maintaining NK cell expansion capacity by dampening both proliferative activity and excessive activation-induced cell death. Maintenance of NK cell expansion capacity might contribute to the preferential accumulation of human NKG2A+ NK cells after hematopoietic cell transplantation and enrichment of functionally impaired NK cells in human cancers. Functional silencing of NKG2A for cancer immunotherapy is highly attractive but will need to consider that this might also lead to a reduced survival by driving activation-induced cell death in targeted NK cells.

Basement membrane product, endostatin, as a link between inflammation, coagulation and vascular permeability in COVID-19 and non-COVID-19 acute respiratory distress syndrome.

Background: Immune cell recruitment, endothelial cell barrier disruption, and platelet activation are hallmarks of lung injuries caused by COVID-19 or other insults which can result in acute respiratory distress syndrome (ARDS). Basement membrane (BM) disruption is commonly observed in ARDS, however, the role of newly generated bioactive BM fragments is mostly unknown. Here, we investigate the role of endostatin, a fragment of the BM protein collagen XVIIIα1, on ARDS associated cellular functions such as neutrophil recruitment, endothelial cell barrier integrity, and platelet aggregation in vitro. Methods: In our study we analyzed endostatin in plasma and post-mortem lung specimens of patients with COVID-19 and non-COVID-19 ARDS. Functionally, we investigated the effect of endostatin on neutrophil activation and migration, platelet aggregation, and endothelial barrier function in vitro. Additionally, we performed correlation analysis for endostatin and other critical plasma parameters. Results: We observed increased plasma levels of endostatin in our COVID-19 and non-COVID-19 ARDS cohort. Immunohistochemical staining of ARDS lung sections depicted BM disruption, alongside immunoreactivity for endostatin in proximity to immune cells, endothelial cells, and fibrinous clots. Functionally, endostatin enhanced the activity of neutrophils, and platelets, and the thrombin-induced microvascular barrier disruption. Finally, we showed a positive correlation of endostatin with soluble disease markers VE-Cadherin, c-reactive protein (CRP), fibrinogen, and interleukin (IL)-6 in our COVID-19 cohort. Conclusion: The cumulative effects of endostatin on propagating neutrophil chemotaxis, platelet aggregation, and endothelial cell barrier disruption may suggest endostatin as a link between those cellular events in ARDS pathology.

Characterizing Evolutionary Dynamics Reveals Strategies to Exhaust the Spectrum of Subclonal Resistance in EGFR-Mutant Lung Cancer.

The emergence of resistance to targeted therapies restrains their efficacy. The development of rationally guided drug combinations could overcome this currently insurmountable clinical challenge. However, our limited understanding of the trajectories that drive the outgrowth of resistant clones in cancer cell populations precludes design of drug combinations to forestall resistance. Here, we propose an iterative treatment strategy coupled with genomic profiling and genome-wide CRISPR activation screening to systematically extract and define preexisting resistant subpopulations in an EGFR-driven lung cancer cell line. Integrating these modalities identifies several resistance mechanisms, including activation of YAP/TAZ signaling by WWTR1 amplification, and estimates the associated cellular fitness for mathematical population modeling. These observations led to the development of a combination therapy that eradicated resistant clones in large cancer cell line populations by exhausting the spectrum of genomic resistance mechanisms. However, a small fraction of cancer cells was able to enter a reversible nonproliferative state of drug tolerance. This subpopulation exhibited mesenchymal properties, NRF2 target gene expression, and sensitivity to ferroptotic cell death. Exploiting this induced collateral sensitivity by GPX4 inhibition clears drug-tolerant populations and leads to tumor cell eradication. Overall, this experimental in vitro data and theoretical modeling demonstrate why targeted mono- and dual therapies will likely fail in sufficiently large cancer cell populations to limit long-term efficacy. Our approach is not tied to a particular driver mechanism and can be used to systematically assess and ideally exhaust the resistance landscape for different cancer types to rationally design combination therapies. SIGNIFICANCE: Unraveling the trajectories of preexisting resistant and drug-tolerant persister cells facilitates the rational design of multidrug combination or sequential therapies, presenting an approach to explore for treating EGFR-mutant lung cancer.

The endothelium in lung fibrosis: a core signaling hub in disease pathogenesis?

Pulmonary fibrosis (PF) is a progressive chronic lung disease characterized by excessive deposition of extracellular matrix (ECM) and structural destruction, associated with a severe 5-year mortality rate. The onset of the disease is thought to be triggered by chronic damage to the alveolar epithelium. Since the pulmonary endothelium is an important component of the alveolar-capillary niche, it is also affected by the initial injury. In addition to ensuring proper gas exchange, the endothelium has critical functional properties, including regulation of vascular tone, inflammatory responses, coagulation, and maintenance of vascular homeostasis and integrity. Recent single-cell analyses have shown that shifts in endothelial cell (EC) subtypes occur in PF. Furthermore, the increased vascular remodeling associated with PF leads to deteriorated outcomes for patients, underscoring the importance of the vascular bed in PF. To date, the causes and consequences of endothelial and vascular involvement in lung fibrosis are poorly understood. Therefore, it is of great importance to investigate the involvement of EC and the vascular system in the pathogenesis of the disease. In this review, we will outline the current knowledge on the role of the pulmonary vasculature in PF, in terms of abnormal cellular interactions, hyperinflammation, vascular barrier disorders, and an altered basement membrane composition. Finally, we will summarize recent advances in extensive therapeutic research and discuss the significant value of novel therapies targeting the endothelium.

Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity.

BACKGROUND: Although immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses in a significant fraction of patients. This lack of long-term efficacy may be due to a poor pre-existing network linking innate and adaptive immunity. Here, we present an antisense oligonucleotide (ASO)-based strategy that dually targets toll-like receptor 9 (TLR9) and programmed cell death ligand 1 (PD-L1), aiming to overcome resistance to anti-PD-L1 monoclonal therapy. METHODS: We designed a high-affinity immunomodulatory IM-TLR9:PD-L1-ASO antisense oligonucleotide (hereafter, IM-T9P1-ASO) targeting mouse PD-L1 messenger RNA and activating TLR9. Then, we performed in vitro and in vivo studies to validate the IM-T9P1-ASO activity, efficacy, and biological effects in tumors and draining lymph nodes. We also performed intravital imaging to study IM-T9P1-ASO pharmacokinetics in the tumor. RESULTS: IM-T9P1-ASO therapy, unlike PD-L1 antibody therapy, results in durable antitumor responses in multiple mouse cancer models. Mechanistically, IM-T9P1-ASO activates a state of tumor-associated dendritic cells (DCs), referred to here as DC3s, which have potent antitumor potential but express the PD-L1 checkpoint. IM-T9P1-ASO has two roles: it triggers the expansion of DC3s by engaging with TLR9 and downregulates PD-L1, thereby unleashing the antitumor functions of DC3s. This dual action leads to tumor rejection by T cells. The antitumor efficacy of IM-T9P1-ASO depends on the antitumor cytokine interleukin-12 (IL-12), produced by DC3s, and Batf3, a transcription factor required for DC development. CONCLUSIONS: By simultaneously targeting TLR9 and PD-L1, IM-T9P1-ASO amplifies antitumor responses via DC activation, leading to sustained therapeutic efficacy in mice. By highlighting differences and similarities between mouse and human DCs, this study could serve to develop similar therapeutic strategies for patients with cancer.

A Prospective Investigation of the Impact of Telemedicine and Telemetry on Global Medical Evacuation Rates.

OBJECTIVES: This study examines whether the availability of telemedicine on offshore installations reduces medical evacuation rates. METHODS: This is a prospective cohort study on offshore platforms in the United States, Malaysia, and the United Kingdom. Emergency evacuation rates were compared between locations with telemedicine (United States) and 2 control groups without telemedicine (Malaysia, United Kingdom). RESULTS: Three hundred eighty-four cases in the telemedicine group and 261 cases in the control groups were included. The odds (adjusted and unadjusted) of medical evacuation were significantly higher for assets without telemedicine, contractors, and age older than 60 years. Analysis indicated a shift from emergency evacuation to routine transport for the telemedicine group. CONCLUSIONS: Telemedicine reduces emergency medical evacuations from offshore installations. This reduction is likely due to an increased capacity for transforming emergency care into routine care at the offshore location.