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OBJECTIVES: Pulmonary ventilation/perfusion (V/Q) mismatch measured by electrical impedance tomography (EIT) is associated with the outcome of patients with the acute respiratory distress syndrome (ARDS), but the underlying pathophysiological mechanisms have not been fully elucidated. The present study aimed to verify the correlation between relevant pathophysiological markers of ARDS severity and V/Q mismatch. DESIGN: Prospective observational study. SETTING: General ICU of a university-affiliated hospital. PATIENTS: Deeply sedated intubated adult patients with ARDS under controlled mechanical ventilation. INTERVENTIONS: Measures of V/Q mismatch by EIT, respiratory mechanics, gas exchange, lung imaging, and plasma biomarkers. MEASUREMENTS AND MAIN RESULTS: Unmatched V/Q units were assessed by EIT as the fraction of ventilated nonperfused plus perfused nonventilated lung units. At the same time, plasma biomarkers with proven prognostic and mechanistic significance for ARDS (carbonic anhydrase 9 [CA9], hypoxia-inducible factor 1 [HIF1], receptor for advanced glycation endproducts [RAGE], angiopoietin 2 [ANG2], gas exchange, respiratory mechanics, and quantitative chest CT scans were measured. Twenty-five intubated ARDS patients were included with median unmatched V/Q units of 37.1% (29.2–49.2%). Unmatched V/Q units were correlated with plasma levels of CA9 (rho = 0.47; p = 0.01), HIF1 (rho = 0.40; p = 0.05), RAGE (rho = 0.46; p = 0.02), and ANG2 (rho = 0.42; p = 0.03). Additionally, unmatched V/Q units correlated with plateau pressure (r = 0.38; p = 0.05) and with the number of quadrants involved on chest radiograph (r = 0.73; p < 0.01). Regional unmatched V/Q units were correlated with the corresponding fraction of poorly aerated lung tissue (r = 0.62; p = 0.01) and of lung tissue weight (rho: 0.51; p = 0.04) measured by CT scan. CONCLUSIONS: In ARDS patients, unmatched V/Q units are correlated with pathophysiological markers of lung epithelial and endothelial dysfunction, increased lung stress, and lung edema. Unmatched V/Q units could represent a comprehensive marker of ARDS severity, reflecting the complex organ pathophysiology and reinforcing their prognostic significance. [ABSTRACT FROM AUTHOR]

Nociceptive sensitization is accompanied by the upregulation of glycolysis in the central nervous system in neuropathic pain. Growing evidence has demonstrated glycolysis and angiogenesis to be related to the inflammatory processes. This study investigated whether fumagillin inhibits neuropathic pain by regulating glycolysis and angiogenesis. Fumagillin was administered through an intrathecal catheter implanted in rats with chronic constriction injury (CCI) of the sciatic nerve. Nociceptive, behavioral, and immunohistochemical analyses were performed to evaluate the effects of the inhibition of spinal glycolysis-related enzymes and angiogenic factors on CCI-induced neuropathic pain. Fumagillin reduced CCI-induced thermal hyperalgesia and mechanical allodynia from postoperative days (POD) 7 to 14. The expression of angiogenic factors, vascular endothelial growth factor (VEGF) and angiopoietin 2 (ANG2), increased in the ipsilateral lumbar spinal cord dorsal horn (SCDH) following CCI. The glycolysis-related enzymes, pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA) significantly increased in the ipsilateral lumbar SCDH following CCI on POD 7 and 14 compared to those in the control rats. Double immunofluorescence staining indicated that VEGF and PKM2 were predominantly expressed in the astrocytes, whereas ANG2 and LDHA were predominantly expressed in the neurons. Intrathecal infusion of fumagillin significantly reduced the expression of angiogenic factors and glycolytic enzymes upregulated by CCI. The expression of hypoxia-inducible factor-1α (HIF-1α), a crucial transcription factor that regulates angiogenesis and glycolysis, was also upregulated after CCI and inhibited by fumagillin. We concluded that intrathecal fumagillin may reduce the expression of ANG2 and LDHA in neurons and VEGF and PKM2 in the astrocytes of the SCDH, further attenuating spinal angiogenesis in neuropathy-induced nociceptive sensitization. Hence, fumagillin may play a role in the inhibition of peripheral neuropathy-induced neuropathic pain by modulating glycolysis and angiogenesis. [ABSTRACT FROM AUTHOR]

Tumorigenesis embodies the formation of a heterotypic tumour microenvironment (TME) that, among its many functions, enables the evasion of T cell-mediated immune responses. Remarkably, most TME cell types, including cancer cells, fibroblasts, myeloid cells, vascular endothelial cells and pericytes, can be stimulated to deploy immunoregulatory programmes. These programmes involve regulatory inducers (signals-in) and functional effectors (signals-out) that impair CD8 + and CD4 + T cell activity through cytokines, growth factors, immune checkpoints and metabolites. Some signals target specific cell types, whereas others, such as transforming growth factor-β (TGFβ) and prostaglandin E 2 (PGE 2 ), exert broad, pleiotropic effects; as signals-in, they trigger immunosuppressive programmes in most TME cell types, and as signals-out, they directly inhibit T cells and also modulate other cells to reinforce immunosuppression. This functional diversity and redundancy pose a challenge for therapeutic targeting of the immune-evasive TME. Fundamentally, the commonality of regulatory programmes aimed at abrogating T cell activity, along with paracrine signalling between cells of the TME, suggests that many normal cell types are hard-wired with latent functions that can be triggered to prevent inappropriate immune attack. This intrinsic capability is evidently co-opted throughout the TME, enabling tumours to evade immune destruction., Competing Interests: Competing interests: None of the research results reviewed and discussed here reflect bona fide competing interests. In the interest of full disclosure, D.H. currently serves on the scientific advisory boards of Pfizer Oncology, Opna Bio, 4D Molecular Therapeutics and Cellestia, and is a founder of Opna Bio, which has licensed an EPFL patent describing the RNA-binding protein FMRP as a new cancer target. O.M. has served as an adviser for Roche, Novartis, GSK, BMS, MSD, Regeneron, Pierre-Fabre, Merck and Amgen, and is a scientific board member of Cellula Therapeutics. M.J.P. has served as an adviser for AstraZeneca, ImmuneOncia, LegoChem Bio, MaxiVax, Merck, Molecular Partners, Third Rock Ventures, Tidal and Unikum., (© 2024. Springer Nature Limited.)

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors, necessitating innovative therapeutic approaches. Polymer-based nanotechnology has emerged as a promising solution, offering precise drug delivery, enhanced blood-brain barrier (BBB) penetration, and adaptability to the tumor microenvironment (TME). This review explores the diverse applications of polymeric nanoparticles (NPs) in GBM treatment, including delivery of chemotherapeutics, targeted therapeutics, immunotherapeutics, and other agents for radiosensitization and photodynamic therapy. Recent advances in targeted delivery and multifunctional polymer highlight their potential to overcome the challenges that GBM brought, such as heterogeneity of the tumor, BBB limitation, immunosuppressive TME, and consideration of biocompatibility and safety. Meanwhile, the future directions to address these challenges are also proposed. By addressing these obstacles, polymer-based nanotechnology represents a transformative strategy for improving GBM treatment outcomes, paving the way for more effective and patient-specific therapies. [ABSTRACT FROM AUTHOR]

CAR-T cell therapies have risen to prominence over the last decade, and their indications are increasing with several products approved as early as second line in Large B Cell non-Hodgkin Lymphomas. Their major toxicities are the cytokine release syndrome (CRS) and the Immune-effector Cell Associated Neurotoxicity Syndrome (ICANS). These entities involve a hyperinflammatory cascade which is amplified through the mononuclear phagocytic system (MPS). Herein, we review the immune mediated adverse events related to CAR therapy, including their pathophysiologies, and current therapies. In particular, we discuss the emerging role of the MPS in both the toxicity and efficacy of CAR-T therapy, and possible avenues for the modulation of the MPS to optimize efficacy while minimizing toxicity. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats. [ABSTRACT FROM AUTHOR]

Introduction: Non-small cell lung cancer (NSCLC) constitutes approximately 80–85% of cancer-related fatalities globally, and direct and indirect comparisons of various therapies for NSCLC are lacking. In this study, we aimed to compare the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with epidermal growth factor receptor (EGFR)-mutated NSCLC. Methods: The electronic databases were systematically searched from inception until March 18, 2024. Studies comparing two or more treatments involving ICIs in patients with EGFR-mutated NSCLC were included. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were overall response rate (ORR), any grade adverse events (AEs), grade ≥3 AEs, and AEs requiring treatment discontinuation. The R software with the gemtc package was used to compare the outcomes of the different treatments. Results: In 11 eligible studies involving 1462 patients and 5 regimens (chemotherapy [chemo], ICI, ICI+chemo, antiangiogenesis+chemo, and ICI+antiangiogenesis+chemo), ICI+antiangiogenesis+chemo achieved the most favorable OS compared to chemo (HR=0.74, 95% CI 0.41–1.23), ICI+chemo (HR=0.94, 95% CI 0.57–1.46), and ICI (HR=0.58, 95% CI 0.27–1.08) and a nearly equivalent effect to antiangiogenesis+chemo (HR=1.01, 95% CI 0.52–1.92). The PFS and ORR results were similar to those of OS. ICI monotherapy exhibited the lowest toxicity profile. Conclusions: These findings indicate that ICI+antiangiogenesis+chemo may be potentially beneficial for patients with EGFR-mutated NSCLC. However, the observed difference was not significant; thus, more studies are needed to confirm the efficacy and safety of the combined ICI treatment strategy. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD42023424781. [ABSTRACT FROM AUTHOR]

The correlation between serum angiopoietin-2 levels and acute kidney injury (AKI) is a topic of significant clinical interest. This meta-analysis aims to provide a comprehensive evaluation of this relationship. A systematic search was conducted in PubMed, Embase, Web of Science, and Cochrane databases up to October 11, 2023. The included studies were evaluated using the Newcastle-Ottawa Scale (NOS) and Methodological Index for Non-Randomized Studies (MINORS). Weighted mean differences (WMD) and odds ratios (OR) were calculated using random-effects models. Sensitivity analysis, funnel plots, and Egger's test were used to assess the robustness and publication bias of the findings. Subgroup analyses were performed to explore potential variations between adults and children. Eighteen studies encompassing a total of 7,453 participants were included. The analysis revealed a significant elevation in serum angiopoietin-2 levels in patients with AKI compared to those without (WMD: 4.85; 95 % CI: 0.75 to 0.27; I²=93.2 %, p<0.001). Subgroup analysis indicated significantly higher angiopoietin-2 levels in adults with AKI (WMD: 5.17; 95 % CI: 3.51 to 6.83; I²=82.6 %, p<0.001), but not in children. Additionally, high serum angiopoietin-2 levels were associated with an increased risk of AKI (OR: 1.58; 95 % CI: 1.39 to 1.8; I²=89.1 %, p<0.001). Sensitivity analysis validated the robustness of these results, showing no substantial change in the overall effect size upon the exclusion of individual studies. This meta-analysis supports a significant association between elevated serum angiopoietin-2 levels and increased risk of AKI. The observed differential association between adults and children highlights the need for further targeted research to understand these age-specific variations. [ABSTRACT FROM AUTHOR]

Hyperplasia of microvessels in the superficial dermis is the main pathological feature of psoriasis, and is linked to the pathogenesis of psoriasis. Thus, anti-angiogenic therapy may be effective for psoriasis. Angiopoietins (Angs) are crucial angiogenic factors. Ang1 supports a static mature vascular phenotype, while Ang2 is associated with the formation of abnormal vascular structure, vascular leakage and inflammation. The Ang/Tie2 axis and its signal transduction play an important role in regulation of vascular stability, angiogenesis and inflammation. Targeting the Ang/Tie2 signal axis can normalize microvessels in psoriatic lesions. This paper reviews Ang/Tie2 signal axis and its role in angiogenesis of psoriasis, aiming to provide new ideas and strategies for anti-angiogenic therapy of psoriasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)