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Sepsis is a life-threatening condition characterized by endothelial dysfunction. The peptide hormone adrenomedullin (ADM) plays a key role in sepsis owing to its potent vasodilatory effects, ability to maintain vascular integrity, and critical role in modulating immune responses and reducing inflammation. To gain its biological activity, the inactive ADM precursor (ADM-Gly) is converted into its active form (bio-ADM) by peptidylglycine α-amidating monooxygenase (PAM). Here, we present hourly resolved kinetics of ADM activation during early sepsis onset in a porcine model and analyze the AdrenOSS-1 human cohort data to assess biomarker changes in advanced sepsis progression. The porcine model data showed that both bio-ADM and ADM-Gly mean concentrations rose within the first two hours post-induction, preceding measurable sepsis onset, with a greater increase in ADM-Gly (260.8 ± 92.0 pg/mL) compared to bio-ADM (28.0 ± 12.9 pg/mL). PAM activity increased at 6 h (39.3 ± 10.5 Units), accompanied by a rise in the bio-ADM/ADM-Gly ratio. AdrenOSS-1 study revealed that ICU sepsis patients had higher ADM-Gly (121.5 pg/mL [IQR: 44.4–284.1]) and PAM activity (23.5 Units [IQR: 17.7–32.7]) than controls. Elevated ADM-Gly (> 730 pg/mL) and PAM activity (> 35.1 Units) were associated with increased 28-day mortality, with non-survivors exhibiting higher ADM-Gly (603.5 pg/mL [IQR: 131.1–1443]) and PAM activity (28.3 Units [IQR: 19.0–45.1]) than survivors. This study provides novel insights into the dynamics of adrenomedullin (ADM) homeostasis during sepsis progression, highlighting the critical interplay between its glycine-extended precursor (ADM-Gly), fully active form (bio-ADM), and the amidating enzyme PAM. The findings demonstrate that early and significant elevations in ADM-Gly, accompanied by delayed PAM activity, result in incomplete ADM amidation, compromising endothelial barrier function. Elevated ADM-Gly and PAM activity were associated with increased sepsis severity and 28-day mortality, while a higher bio-ADM/ADM-Gly ratio was linked to improved survival. These results underscore the potential of ADM-Gly, bio-ADM, and PAM as biomarkers for sepsis severity and prognosis, and support therapeutic strategies aimed at enhancing PAM activity to restore endothelial integrity and improve patient outcomes in sepsis.

Background Renal replacement therapy (RRT) remains the key rescue therapy for critically ill patients with severe acute kidney injury (AKI). However, there are currently no tools available to predict successful liberation from RRT. Biomarkers may allow for risk stratification and individualization of treatment strategies. Proenkephalin A 119–159 (penKid) has been suggested as a promising marker of kidney function in the context of AKI, but has not yet been evaluated for RRT liberation in critically ill patients with AKI. Methods This post hoc analysis included 210 patients from the randomized clinical ELAIN trial and penKid levels were measured in the blood of these patients. Competing risk time-to-event analyses were performed for pre-RRT penKid at initiation of RRT and in a landmark analysis at day 3 after initiation of RRT. Competing risk endpoints were successful liberation from RRT or death without prior liberation from RRT. Results Low pre-RRT penKid levels (penKid ≤ 89 pmol/l) at RRT initiation were associated with early and successful liberation from RRT compared to patients with high pre-RRT penKid levels (subdistribution hazard ratio (sHR) 1.83, 95%CI 1.26–2.67, p  = 0.002, estimated 28d-cumulative incidence function (28d-CIF) of successful liberation from RRT 61% vs. 45%, p  = 0.022). This association persisted in the landmark analysis on day 3 of RRT (sHR 1.78, 95%CI 1.17–2.71, p  = 0.007, 28d-CIF of successful liberation from RRT 67% vs. 47%, p  = 0.018). For both time points, no difference in the competing event of death was detected. Conclusions In critically ill patients with RRT-dependent AKI, plasma penKid appears to be a useful biomarker for the prediction of shorter duration and successful liberation from RRT and may allow an individualized approach to guide strategies of RRT liberation in critically ill patients with RRT-dependent AKI. Trial registration: The ELAIN trial was prospectively registered at the German Clinical Trial Registry (Identifier: DRKS00004367) on 28th of May 2013. Graphical Abstract

Cytokine-mediated systemic inflammation after open thoracoabdominal aortic aneurysm (TAAA) repairs plays a pivotal role in disrupting circulatory homeostasis, potentially leading to organ dysfunction. The bioactive form of adrenomedullin (bio-ADM) is a peptide hormone with immunomodulatory and vasomotor effects, making it a potential diagnostic agent in these cases. This retrospective, bicentric study, conducted between January 2019 and December 2022, recruited 36 elective open TAAA repair patients in two German centres. Serum and plasma samples were collected at multiple time points to measure bio-ADM levels. The primary objective was to evaluate the association of bio-ADM levels with the onset of acute respiratory distress syndrome (ARDS), with secondary endpoints focusing on mortality and SIRS-related morbidity. Results showed a significant association between postoperative bio-ADM levels (12–48 h after surgery) and the onset of ARDS ( p  < .001), prolonged ventilation ( p  = .015 at 12h after surgery), atrial fibrillation ( p  < .001), and mortality ( p  = .05 at 24h). The biomarker was also strongly associated with sepsis ( p  = .01 at 12 h) and multi-organ dysfunction syndrome (MODS) ( p  = .02 at 24 h after surgery). The study underscores the potential utility of bio-ADM as a diagnostic tool for identifying patients at risk of postoperative complications following open TAAA repairs.

An early and reliable prediction of outcomes after stroke is important for early effective stroke management and the adequate optimal planning of post-stroke rehabilitation and long-term care. Bioactive adrenomedullin (bio-ADM) is a 52-amino acid peptide that is an important peptide hormone in nervous system diseases. The aim of this study was to investigate the prognostic value of bio-ADM on outcomes after rehabilitation in patients with stroke. A total of 557 consecutive patients with a primary diagnosis of ischemic or hemorrhagic stroke (age 69.6–12.9 years, male 51.3%, ischemic stroke 72.5%), who were admitted to an in-patient early rehabilitation center directly after discharge from acute stroke hospital care, were enrolled in this prospective observational study. Plasma concentrations of bio-ADM were determined by using a chemiluminescence immunoassay (functional assay sensitivity 8 pg/ml). The early rehabilitation barthel index (ERBI) was used for the neurological assessment of the patients. The plasma bio-ADM level was analyzed in association with 6-month all-cause mortality as well as a composite outcome of all-cause mortality, unscheduled re-hospitalization, or transfer to a long-term care facility in a vegetative or minimally conscious state. Bio-ADM levels significantly increased in patients with ischemic stroke who died compared to surviving patients (40.4 pg/ml vs. 23.8 pg/ml, p < 0.001) or in those with composite outcomes compared to those with no events (36.9 pg/ml vs. 23.5 pg/ml, p < 0.001). Six-month all-cause mortality was higher in all patients with bio-ADM levels > 70 pg/ml (HR 4.83 [CI 2.28–10.2]). Patients with bio-ADM levels > 70 pg/ml also had higher rates of 6-month composite outcomes (HR 3.82 [CI 2.08–7.01]). Bio-ADM was an independent predictor of all-cause mortality and 6-month composite outcomes after adjusting for age, gender, and ERBI (adjusted OR 1.5; 95% CI 1.0–2.1; p = 0.047 and adjusted OR 1.48; 95% CI 1.1–2.0; p = 0.01, respectively). Bio-ADM may be a suitable novel biomarker to assess the outcomes of patients in rehabilitation after acute stroke. Elevated bio-ADM concentrations may have prognostic value for fatal and nonfatal events in patients with ischemic stroke during early rehabilitation.

Background Sepsis is a leading cause of death worldwide and a major challenge for physicians to predict and manage. Proenkephalin A 119–159 (penKid) is a reliable surrogate marker for the more unstable endogenous opioid peptide enkephalin, which has previously been shown to predict both acute and chronic kidney disease. The aim of this prospective observational study was to assess penKid as a predictor of acute kidney injury (AKI), multi-organ failure and mortality in sepsis among unselected sepsis patients presenting to the emergency department (ED). Method We enrolled 644 patients consecutively during office-hours (6 AM-6 PM) between December 1, 2013 and February 1, 2015. Fifty-six patients were excluded due to incomplete data. We measured penKid in 588 adult patients (patients under 18 years of age were excluded) with sepsis (≥2SIRS criteria + suspected infection) upon admission to the ED at Skåne University Hospital, Malmö, Sweden. Logistic regression analysis was used to relate levels of penKid at presentation to AKI, multi-organ failure, 28-day mortality and progression of renal SOFA subscore. Odds ratios are presented as the number of standard deviations from the mean of log-transformed penKid. Results In age and sex adjusted models, penKid predicted AKI within 48 h and 7 days, but these associations were attenuated after additional adjustment for estimated creatinine-based glomerular filtration rate (eGFR). In models adjusted for age, sex and eGFR, penKid significantly predicted progression from rSOFA = 0 and ≤ 1 to higher rSOFA scores as well as multi-organ failure and mortality. In contrast, eGFR did not predict 28-day mortality. Conclusion PenKid is an effective predictor of renal injury, severe multi-organ failure and mortality in unselected sepsis patients presenting to the emergency department.

The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome‐mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9‐engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours. Synopsis The study reveals that squamous tumours are dependent on the expression of the deubiquitylase USP28. Inhibition of USP28 destabilises ΔNp63 protein abundance and enables therapeutic targeting of squamous tumours of various origins, such as head and neck, lung, cervix and pancreas. USP28 protein was upregulated in squamous tumours. USP28 modulated the expression of essential squamous genes by regulating ΔNp63 protein abundance. Pharmacologic inhibition of USP28 activity was well tolerated in vivo and negatively affected squamous tumour growth. Graphical Abstract The study reveals that squamous tumours are dependent on the expression of the deubiquitylase USP28. Inhibition of USP28 destabilises ΔNp63 protein abundance and enables therapeutic targeting of squamous tumours of various origins, such as head and neck, lung, cervix and pancreas.

Background Dipeptidyl peptidase-3 (DPP3) is a metallopeptidase which cleaves bioactive peptides, notably angiotensin II, and is involved in inflammation regulation. DPP3 has been proposed to be a myocardial depressant factor and to be involved in circulatory failure in acute illnesses, possibly due to angiotensin II cleavage. In this study, we evaluated the association between plasmatic DPP3 level and outcome (mortality and hemodynamic failure) in severely ill burn patients. Methods In this biomarker analysis of a prospective cohort study, we included severely ill adult burn patients in two tertiary burn intensive care units. DPP3 was measured at admission (DPP3 admin ) and 3 days after. The primary endpoint was 90-day mortality. Secondary endpoints were hemodynamic failure and acute kidney injury (AKI). Results One hundred and eleven consecutive patients were enrolled. The median age was 48 (32.5–63) years, with a median total body surface area burned of 35% (25–53.5) and Abbreviated Burn Severity Index (ABSI) of 8 (7–11). Ninety-day mortality was 32%. The median DPP3 admin was significantly higher in non-survivors versus survivors (53.3 ng/mL [IQR 28.8–103.5] versus 27.1 ng/mL [IQR 19.4–38.9]; p  < 0.0001). Patients with a sustained elevated DPP3 had an increased risk of death compared to patients with high DPP3 admin but decreased levels on day 3. Patients with circulatory failure had higher DPP3 admin (39.2 ng/mL [IQR 25.9–76.1] versus 28.4 ng/mL [IQR 19.8–39.6]; p  = 0.001) as well as patients with AKI (49.7 ng/mL [IQR 30.3–87.3] versus 27.6 ng/mL [IQR 19.4–41.4]; p  = 0.001). DPP3 admin added prognostic value on top of ABSI (added chi 2 12.2, p  = 0.0005), Sequential Organ Failure Assessment (SOFA) score at admission (added chi 2 4.9, p  = 0.0268), and plasma lactate at admission (added chi 2 6.9, p  = 0.0086) to predict circulatory failure within the first 48 h. Conclusions Plasma DPP3 concentration at admission was associated with an increased risk of death, circulatory failure, and AKI in severely burned patients. Whether DPP3 plasma levels could identify patients who would respond to alternative hemodynamic support strategies, such as intravenous angiotensin II, should be explored.

Molecular understanding of osteogenic differentiation (OD) of human bone marrow-derived mesenchymal stem cells (hBMSCs) is important for regenerative medicine and has direct implications for cancer. We report that the RNF4 ubiquitin ligase is essential for OD of hBMSCs, and that RNF4-deficient hBMSCs remain as stalled progenitors. Remarkably, incubation of RNF4-deficient hBMSCs in conditioned media of differentiating hBMSCs restored OD. Transcriptional analysis of RNF4-dependent gene signatures identified two secreted factors that act downstream of RNF4 promoting OD: (1) BMP6 and (2) the BMP6 co-receptor, RGMb (Dragon). Indeed, knockdown of either RGMb or BMP6 in hBMSCs halted OD, while only the combined co-addition of purified RGMb and BMP6 proteins to RNF4-deficient hBMSCs fully restored OD. Moreover, we found that the RNF4-RGMb-BMP6 axis is essential for survival and tumorigenicity of osteosarcoma and therapy-resistant melanoma cells. Importantly, patient-derived sarcomas such as osteosarcoma, Ewing sarcoma, liposarcomas, and leiomyosarcomas exhibit high levels of RNF4 and BMP6, which are associated with reduced patient survival. Overall, we discovered that the RNF4~BMP6~RGMb axis is required for both OD and tumorigenesis.

The two p53 homologues p63 and p73 regulate transcriptional programs in epithelial tissues and several cell types in these tissues express both proteins. All members of the p53 family form tetramers in their active state through a dedicated oligomerization domain that structurally assembles as a dimer of dimers. The oligomerization domain of p63 and p73 share a high sequence identity, but the p53 oligomerization domain is more divergent and it lacks a functionally important C-terminal helix present in the other two family members. Based on these structural differences, p53 does not hetero-oligomerize with p63 or p73. In contrast, p63 and p73 form hetero-oligomers of all possible stoichiometries, with the hetero-tetramer built from a p63 dimer and a p73 dimer being thermodynamically more stable than the two homo-tetramers. This predicts that in cells expressing both proteins a p63 2 /p73 2 hetero-tetramer is formed. So far, the tools to investigate the biological function of this hetero-tetramer have been missing. Here we report the generation and characterization of Designed Ankyrin Repeat Proteins (DARPins) that bind with high affinity and selectivity to the p63 2 /p73 2 hetero-tetramer. Using these DARPins we were able to confirm experimentally the existence of this hetero-tetramer in epithelial mouse and human tissues and show that its level increases in squamous cell carcinoma.