Dynamic regulation of tissue fluidity controls skin repair during wound healing.

During wound healing, different pools of stem cells (SCs) contribute to skin repair. However, how SCs become activated and drive the tissue remodeling essential for skin repair is still poorly understood. Here, by developing a mouse model allowing lineage tracing and basal cell lineage ablation, we monitor SC fate and tissue dynamics during regeneration using confocal and intravital imaging. Analysis of basal cell rearrangements shows dynamic transitions from a solid-like homeostatic state to a fluid-like state allowing tissue remodeling during repair, as predicted by a minimal mathematical modeling of the spatiotemporal dynamics and fate behavior of basal cells. The basal cell layer progressively returns to a solid-like state with re-epithelialization. Bulk, single-cell RNA, and epigenetic profiling of SCs, together with functional experiments, uncover a common regenerative state regulated by the EGFR/AP1 axis activated during tissue fluidization that is essential for skin SC activation and tissue repair.

The extracellular matrix dictates regional competence for tumour initiation.

The skin epidermis is constantly renewed throughout life1,2. Disruption of the balance between renewal and differentiation can lead to uncontrolled growth and tumour initiation3. However, the ways in which oncogenic mutations affect the balance between renewal and differentiation and lead to clonal expansion, cell competition, tissue colonization and tumour development are unknown. Here, through multidisciplinary approaches that combine in vivo clonal analysis using intravital microscopy, single-cell analysis and functional analysis, we show how SmoM2-a constitutively active oncogenic mutant version of Smoothened (SMO) that induces the development of basal cell carcinoma-affects clonal competition and tumour initiation in real time. We found that expressing SmoM2 in the ear epidermis of mice induced clonal expansion together with tumour initiation and invasion. By contrast, expressing SmoM2 in the back-skin epidermis led to a clonal expansion that induced lateral cell competition without dermal invasion and tumour formation. Single-cell analysis showed that oncogene expression was associated with a cellular reprogramming of adult interfollicular cells into an embryonic hair follicle progenitor (EHFP) state in the ear but not in the back skin. Comparisons between the ear and the back skin revealed that the dermis has a very different composition in these two skin types, with increased stiffness and a denser collagen I network in the back skin. Decreasing the expression of collagen I in the back skin through treatment with collagenase, chronic UV exposure or natural ageing overcame the natural resistance of back-skin basal cells to undergoing EHFP reprogramming and tumour initiation after SmoM2 expression. Altogether, our study shows that the composition of the extracellular matrix regulates how susceptible different regions of the body are to tumour initiation and invasion.

Efficacy and safety of therapeutic alpha-1-microglobulin RMC-035 in reducing kidney injury after cardiac surgery: a multicentre, randomised, double-blind, parallel group, phase 2a trial.

Background: Cardiac surgery invariably triggers acute kidney stress causing adverse renal outcomes. The AKITA study evaluated the efficacy and safety of RMC-035, a novel analogue of alpha-1-microglobulin, for reducing cardiac surgery-associated kidney injury. Methods: In this randomised double-blind placebo-controlled phase 2a study, we randomly assigned (1:1) adult hospitalised patients undergoing open-chest cardiac surgery at high risk for acute kidney injury (AKI) at 21 sites in North America and Europe to receive either RMC-035 (1.3 or 0.65 mg/kg) or placebo (1:1) for 2 days (5 intravenous infusions), stratified by region and renal function. Eligible patients had at least one pre-defined AKI risk factor. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) were excluded. The co-primary efficacy and safety endpoints were AKI (Kidney Disease: Improving Global Outcomes definition) within 72 h after surgery and nature, frequency, and severity of treatment-emergent adverse events (TEAEs). Secondary endpoints included eGFR and Major Adverse Kidney Events (MAKE) up to Day 90. Randomised patients who had received at least one dose of study drug were analysed for primary and safety analyses. Participants, investigators and sponsor were masked to treatment allocation. This study is registered at ClinicalTrials.gov (NCT05126303) and EudraCT (2021-004040-19). Findings: Patient enrolment was stopped at interim analysis due to futility. Between March 31, 2022 and July 12, 2023, 177 patients (RMC-035: 89, placebo: 88) were randomised and treated. AKI rate for RMC-035 vs placebo was 50.6% (n = 45) and 39.8% (n = 35) (relative risk [RR]: 1.30, 90% confidence interval [90% CI]: 0.99, 1.71; p = 0.12). A short-lived creatinine increase was observed with the higher RMC-035 dose. Treatment with RMC-035 was associated with improved secondary renal outcomes at Day 90: placebo-adjusted eGFR change from baseline 4.3 mL/min/1.73 m2, 90% CI 0.51-8.12, p = 0.06; and MAKE 6.7% (n = 6) vs 15.9% (n = 14); RR: 0.41, 90% CI: 0.19, 0.88, p = 0.05. The most frequently reported TEAEs for RMC-035 were chills (30.3%), nausea (21.3%), anaemia (20.2%); and atrial fibrillation (29.5%), anaemia (20.5%), hypervolemia (14.8%) for placebo. The majority of TEAEs in both treatment groups were mild or moderate in severity. In the RMC-035 group, 26 (29.2%) patients experienced at least one severe or life-threatening TEAE and in the placebo group 16 (18.2%) patients. There were 4 deaths per treatment arm (one treatment-related, in placebo group). Interpretation: In this proof-of-concept study, RMC-035 did not reduce AKI 72 h after cardiac surgery. Evaluations may have been confounded by a drug-induced transient creatinine increase in a subgroup of patients. RMC-035 was associated with improved secondary renal outcomes. These results merit further investigation and should be interpreted with caution, as the study was not powered for these outcomes. Funding: Guard Therapeutics.

Optic neuritis in lung adenocarcinoma: A challenging diagnosis.

Optic neuritis with CRMP-5 IgG is a paraneoplastic inflammation of the optic nerve associated with lung cancer, mostly small-cell lung cancer. We present the case of a patient with lung adenocarcinoma who developed progressive bilateral visual loss a few months after immune-chemotherapy with pembrolizumab and after Covid-19 vaccination. Positive CRMP-5 IgG were detected in blood sample and complete work-up - including brain MRI - did not show any progression. High dose systemic corticoids were administered with transient improving, followed by intravenous immunoglobulins, methotrexate and rituximab but despite negativization of CRMP-5 IgG, the patient had a progressive visual loss.

Metastatic breast cancer and pseudocirrhosis: an unknown clinical entity.

PURPOSE: Pseudocirrhosis is a radiological term used to describe rapid changes in the contour of liver invaded by metastases and treated with chemotherapy. Our primary objectives were to analyse the clinical and biological characteristics of those patients with breast cancer and to assess the prevalence of complications generally associated with decompensated cirrhosis. We have also assessed associated treatments and response. METHODS: This retrospective study included all women with metastatic breast cancer to the liver who had imaging protocols describing diffuse liver contour abnormalities during systemic treatment between 2003 and 2018 in our centre. The following were identified: neoplastic characteristics, complications presented, treatments administered and response. RESULTS: 48 patients were included. There was a trend towards an increased proportion of luminal cancers (88.2%, n=30, p=0052) when compared with our hospital cancer registry. Most patients (97.9%, n=47) had a widespread liver invasion, 58.3% (n=28) had ascites on physical examination; 90% (n=18) of ascites were classified as transudate. Nearly 23% (n=11) of patients had oesophageal varices and 6.5% (n=3) had an episode of variceal rupture. At the time of the appearance of liver contour abnormalities, the most frequently used molecules were: 5-fluorouracil (22.9%; n=11) and cisplatin (18.8%; n=9). A partial response was observed in 52.1% (n=25) of patients. CONCLUSION: This is the largest reported series of patients with pseudocirrhosis. Many patients developed complications related to portal hypertension and liver failure, similar to those observed in decompensated cirrhosis. Luminal subtypes could be over-represented. In our series, pseudocirrhosis appears to develop at the expense of extensive liver disease burden and most often under 5-fluorouracil, or its derivatives, with or without cisplatin, possibly following a response to treatment.

Survey of Contemporary Cardiac Surgery Intensive Care Unit Models in the United States.

BACKGROUND: Intensive care unit (ICU) structure and intensive care physician staffing (IPS) models are thought to influence outcomes after cardiac surgery. Given limited information on staffing in the cardiothoracic ICU, The Society of Thoracic Surgeons Workforce on Critical Care undertook a survey to describe current IPS models. We hypothesized that variability would exist throughout the United States. METHODS: A survey was sent to The Society of Thoracic Surgeons centers in the United States. Center case volume, ICU census, procedure profiles, and the primary specialties of consultants were queried. Definitions of IPS models were open (managed by cardiac surgeons), closed (all decisions made by dedicated intensivists 7 days a week), or semiopen (intensivist attends 5-7 days a week with surgeons cosharing management). Experience level of bedside providers and after-hours provider coverage were also assessed. RESULTS: Of the 965 centers contacted, 148 (15.3%) completed surveys. Approximately 41% of reporting centers used a dedicated cardiothoracic ICU for immediate postoperative management. The most common IPS model was open (47%), followed by semiopen (41%) and closed (12%). The primary specialties of intensivists varied, with pulmonary medicine/critical care being predominant (67%). Physician assistants were the most common after-hours provider (44%). More than one-third of responding centers described having no house staff, other than bedside nurses, for nighttime coverage. CONCLUSIONS: Cardiothoracic ICU models vary widely in the United States, with almost half being open, often with no in-house coverage. In-house nighttime coverage was (1) not driven by case complexity and (2) most commonly provided by a physician assistant. Clinical outcomes associated with different ISPS models require further evaluation.