Regenerative NanoMedicine

Data are needed on the effect of oxygen delivered through a high-flow nasal cannula, as compared with standard oxygen therapy, on intubation and mortality in patients with acute hypoxemic respiratory failure. In this multicenter, open-label trial, we randomly assigned patients who had acute hypoxemic respiratory failure to receive high-flow-oxygen or standard-oxygen therapy. All the patients had a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 200 or less, a respiratory rate of more than 25 breaths per minute, and pulmonary infiltrate on chest imaging. The primary outcome was death by day 28. A total of 1116 patients underwent randomization. Of these patients, 1110 (556 in the high-flow-oxygen group and 554 in the standard-oxygen group) were included in the analysis. Mortality at day 28 was 14.6% (in 81 of 556 patients) in the high-flow-oxygen group and 14.6% (in 81 of 554 patients) in the standard-oxygen group (difference, -0.05 percentage points; 95% confidence interval [CI], -4.21 to 4.10; P = 0.98). The incidence of intubation by day 28 was 42.4% (in 236 of 556 patients) in the high-flow-oxygen group and 48.4% (in 268 of 554 patients) in the standard-oxygen group (difference, -5.93 percentage points; 95% CI, -11.78 to -0.08). Serious adverse events (cardiac arrest or pneumothorax) occurred during spontaneous breathing in 13 patients (2.3%) in the high-flow-oxygen group and in 6 patients (1.1%) in the standard-oxygen group. Among patients with acute hypoxemic respiratory failure, the use of oxygen delivered through a high-flow nasal cannula did not significantly reduce mortality at day 28. (Funded by the French Ministry of Health and Fisher and Paykel Healthcare; SOHO ClinicalTrials.gov number, NCT04468126.).

PC is the second most common malignancy in men, and progression to metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT) remains incurable. Current treatments for mCRPC include chemotherapy, immunotherapy, radiopharmaceuticals, and second-line androgen receptor signaling inhibitors (ARSIs) such as Abiraterone. PARP inhibitors (PARPis) have recently shown clinical benefits in tumors with homologous recombination repair (HRR) deficiencies, particularly BRCA1/2 mutations. Combining PARPi with ARSIs has improved progression-free (PFS) and overall survival (OS), especially in ARSI-naïve patients, but limited data exist for resistant disease. This work focuses on intrinsically hormone-insensitive, AR-negative, BRCA-wildtype models, representing a clinically distinct population with limited therapeutic options. We thus investigated the therapeutic potential of combining Abiraterone with PARPis (Niraparib or Olaparib) in Abiraterone-resistant prostate cancer. Resistant PC3 and DU145 cell lines were analyzed using 2D and 3D cultures and cell-derived xenograft (CDX) mouse models. Cytotoxicity assays revealed significantly reduced cell viability with combination therapy compared to single agents. These findings were supported by RT-qPCR, Western blot, and immunofluorescence analyses of xenograft tumors, demonstrating enhanced antitumor activity with the combination. Overall, the results indicate that maintaining Abiraterone treatment in combination with PARPis after resistance develops provides superior therapeutic efficacy compared to PARP inhibition alone, offering a promising strategy for managing Abiraterone-resistant prostate cancer. Combining Abiraterone with PARPis enhances therapeutic efficacy and overcomes the acquired insensitivity in mCRPC with BRCA1/2 or HRR mutations. These results support continued use of PARPis with Abiraterone to improve clinical outcomes.

Extracorporeal membrane oxygenation (ECMO) is a critical rescue therapy for severe respiratory or cardiac failure. However, current blood pumps generate high shear stresses that can damage blood components, leading to hemolysis, loss of von Willebrand factor multimers, and increased risks of bleeding, thrombosis, and organ injury. We developed novel magnetostaltic pumps that use magnetic liquid interfaces instead of solid walls to transport blood, aiming to reduce mechanical stress on blood cells. Four magnetostaltic pump designs were tested in ex vivo ECMO circuits using human donor blood at clinically relevant flow rates and compared with standard centrifugal and peristaltic pumps. Across all flow rates, magnetostaltic pumps produced less hemolysis than conventional pumps. Under pediatric flow conditions (1 L/min for 48 h), the large-scale magnetostaltic pump (QR3) reduced hemolysis by approximately one-third compared with commercial centrifugal pumps and preserved high-molecular-weight von Willebrand factor multimers. Platelet function was unaffected. Small amounts of nanoparticle leakage from the magnetic fluid were detected but remained well below toxic thresholds. Magnetostaltic pumping offers a promising alternative to current ECMO pumps by reducing blood damage. These results support further testing in animal models to evaluate the potential for clinical translation.

Sepsis is now considered a dysregulated host response in which inflammation, coagulation, and endothelial injury converge to create a self-amplifying network of thromboinflammation. This definition reflects maladaptive immunothrombosis-a defense mechanism that becomes pathogenic when excessive, rather than an isolated inflammatory process. This review integrates recent mechanistic advances linking damage-associated molecular patterns (DAMPs), endothelial dysfunction, and intravascular coagulation. Endogenous alarmins, such as high-mobility group box 1, histones, and mitochondrial DNA, engage in pattern recognition (Toll-like receptors, receptor for advanced glycation end products) to propagate leukocyte activation, platelet aggregation, and endothelial disruption. The resulting loss of critical endothelial anticoagulant molecules (thrombomodulin, endothelial cell protein C receptor, antithrombin) and glycocalyx degradation convert the vascular endothelium into a procoagulant interface. Complement activation and protease-activated receptor signaling reinforce this loop, producing microvascular thrombosis, capillary leakage, and organ ischemia. Platelet-leukocyte aggregates and neutrophil extracellular traps (NETs) serve as intravascular scaffolds for fibrin deposition, thereby propagating disseminated intravascular coagulation (DIC). Targeted interventions, including recombinant thrombomodulin, antithrombin supplementation, neutralization of NETs and DAMPs, complement blockade, and endothelial-protective strategies, seek to restore vascular homeostasis. A multidomain biomarker approach integrating DAMPs, endothelial markers, and coagulation indices, combined with machine learning-based phenotyping, may enable precision stratification of sepsis endotypes. The convergence of DAMP signaling, immune activation, and coagulation underlies the pathophysiologic continuum from sepsis-induced coagulopathy to DIC. Therapeutically interrupting this axis represents the most promising avenue toward personalized, mechanism-driven treatment in sepsis.

Demonstrating the efficacy of new treatments in any condition may be a challenging endeavor, and is particularly the case in sepsis. In the early 21st century, recombinant activated protein C showed a survival benefit in severe sepsis; however, subsequent studies could not replicate these results, leading to the discontinuation of this agent. Several potential reasons have been proposed for the unfavorable results of trials, including choosing an inappropriate outcome target. Concerning anticoagulant therapies, some studies have targeted sepsis with disseminated intravascular coagulation (DIC) and demonstrated clinical benefits, while other studies have focused on severe sepsis or septic shock independent of whether patients had DIC. The timing for treatment initiation, dosage, and duration of anticoagulant agents could be significant factors contributing to the limitations faced in these trials. Moreover, relying solely on 28-day mortality as the primary endpoint for sepsis trials may not be appropriate, as it can be influenced by various factors beyond anticoagulant therapies, and discernment in a shorter period might be more pertinent. Success in clinical trials is more likely if these issues are addressed and improvements are made. Recent clinical trials concentrating on anticoagulants are increasingly targeting sepsis or septic shock with coagulopathy, and adopting composite endpoints, including DIC resolution, is anticipated to overcome some of these challenges.

IntroductionMesenchymal stem cells (MSCs) participate in the dynamic remodeling of the extracellular matrix during wound healing, natural bleeding processes or cancer progression. Pericellular proteolysis is a key mechanism mediating the aforementioned processes.AimThis study primarily aimed to define mechanistic pathways of plasmin formation and its consequences on MSC phenotype and functioning. We have also investigated the regulatory mechanisms mediated by PAI-1 and the ability of MSCs to shed microvesicles bearing the proteolytic machinery.MethodsHuman MSCs were derived from bone marrow or umbilical cord donors. Cells thus obtained were seeded in multi-well plates and treated with different concentrations of plasminogen and pro-urokinase in the presence or absence of variable amounts of tranexamic acid. We measured MVs formation and phenotypical changes occurring on MSCs. The amount of plasmin formed was quantified by western blot along with the plasmin activity detected by photometry.ResultsWe demonstrate that vesiculation is the early response of plasmin formation at the membrane of MSCs followed by cell retraction and detachment. We measured the effect of TXA on plasmin formation and its consequences on cell behavior. Our findings provide the first demonstration that TXA efficiently inhibits MSC-driven plasmin generation by competitively blocking plasminogen binding to the uPA•uPAR complex at the cell plasma membrane.DiscussionWe propose that plasmin formation on MSCs may be involved in pathological processes such as endometrial hemorrhage (metrorrhagia and Post-Partum Hemorrhage), autoimmune and ischaemic diseases, as well as cancer. By advancing our understanding of these mechanisms, we open new avenues for the development of biomarkers and targeted treatments.