Search Results (17)

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumours, driven by late diagnosis, early metastatic dissemination, and profound resistance to systemic therapies. Increasing evidence indicates that these hallmarks are not solely tumour cell intrinsic but are critically orchestrated by a complex and highly dynamic tumour microenvironment (TME) composed of pancreatic stellate cells (PSCs), cancer-associated fibroblast (CAF) subtypes, immune cells, endothelial and neuronal elements, and a dense extracellular matrix (ECM). This review provides an integrated overview of the cellular and acellular components of the PDAC TME and delineates how their reciprocal crosstalk drives desmoplasia, immune suppression, metabolic reprogramming, epithelial–mesenchymal transition (EMT), pre-metastatic niche formation, and metastatic outgrowth. Particular emphasis is placed on the context-dependent roles of stromal and immune niches in modulating drug delivery, chemoresistance, and failure of immunotherapy, highlighting why indiscriminate stromal depletion has yielded paradoxical outcomes. Building on these mechanistic insights, the review critically examines emerging therapeutic strategies targeting PSCs, CAF subsets, ECM components, myeloid and lymphoid populations, and key signalling pathways, including approaches that normalize stroma, reprogram immunity, or exploit nanocarrier-based delivery systems. Finally, a structured framework is proposed for rational TME-targeted combination regimens that integrate cytotoxic, targeted, and immunotherapeutic agents to overcome current therapeutic barriers in PDAC. Full article

Background/Objectives: Post-COVID-19 pulmonary fibrosis (PCPF) and idiopathic pulmonary fibrosis (IPF) exhibit significant clinical and pathophysiological overlap, suggesting convergent molecular pathways driving fibrosis. This prospective longitudinal study investigates the sustained dysregulation of matrix metalloproteinases (MMP)-2 and MMP-9 and its relationship with evolving systemic inflammation and endothelial dysfunction in convalescent COVID-19 patients, with comparative analysis to IPF. Methods: We conducted a prospective observational study of 86 patients at 6 and 12 months post-SARS-CoV-2 infection, stratified by high-resolution CT evidence of PCPF (FB+ group, n = 32) or absence of fibrosis (FB− group, n = 54). Gene expression of MMP-2 and MMP-9 in peripheral blood leukocytes and circulating levels of MMP-2, MMP-9, pro-inflammatory cytokines (TNF-α, IL-6), and endothelial dysfunction markers (Endothelin-1 [ET-1], adhesion molecules) were quantified via qRT-PCR and ELISA. A pre-pandemic healthy control group (HD, n = 20) and an IPF patient group (n = 10) served as comparators. Results: A significant, sustained elevation of MMP-2 and MMP-9 was observed in all post-COVID-19 patients versus HDs, most pronounced in the FB+ group and qualitatively similar to IPF. A critical divergence emerged: FB− patients showed resolution of systemic inflammation (reduced TNF-α, IL-6), whereas FB+ patients exhibited persistent cytokine elevation. Critically, a delayed, severe endothelial dysfunction, characterized by a profound surge in ET-1 and elevated adhesion molecules, manifested exclusively in the FB+ cohort at 12 months. Positive correlations linked plasma MMP-2/9 levels with ET-1 (r_s = 0.65, p = 0.004; r_s = 0.49, p = 0.009) and ET-1 with sICAM-1 (r_s = 0.68, p = 0.01). Conclusions: The development of PCPF is associated with a distinct pathogenic triad: sustained MMP dysregulation, failure to resolve inflammation, and severe late-phase endothelial dysfunction. The correlative links between these components suggest a self-reinforcing loop. This systemic signature mirrors patterns in IPF, underscoring shared final pathways in fibrotic lung disease and identifying the MMP–inflammation–endothelial axis as a promising target for biomarker development and therapeutic intervention. Full article

Background/Objective: Early hemodynamic instability in sepsis arises from endothelial dysfunction and vasoplegia before capillary leakage and organ failure occur. Albumin administration guided by serum concentration or shock criteria has not improved outcomes. This review synthesized evidence supporting an early, physiology-guided framework for albumin and norepinephrine use in pre-δ vasoplegic sepsis. Methods: A narrative synthesis of experimental and clinical studies examined endothelial injury, sepsis phenotypes, hemodynamic monitoring, biochemical markers, and intravascular albumin mass. Evidence from phenotype cohorts was integrated to construct a physiology-based therapeutic framework. Results: The δ phenotype consistently emerged as a vasoplegic, hyperinflammatory endotype with hypoalbuminemia, elevated lactate, and the highest mortality. Studies showed 20–25% of patients with community-acquired sepsis exhibit early vasoplegia, with low systemic vascular resistance and high cardiac output. Mass-balance analyses showed intravascular albumin mass declines early in sepsis, correlate inversely with fluid balance, and predict mortality. These findings suggest early low-dose norepinephrine may stabilize perfusion pressure, while albumin use should follow intravascular albumin mass trajectories. A dynamic exclusion concept proposes withholding albumin during capillary leak and reintroducing it when intravascular albumin mass stabilizes. Conclusions: Albumin therapy in sepsis should shift from late concentration-based to early physiology-guided endothelial protection. Monitoring intravascular albumin mass, lactate, and fluid balance may guide targeted norepinephrine and albumin use before δ-type endothelial failure occurs. This framework needs phenotype-stratified validation. Full article

Background: Mushroom penetrating keratoplasty (MPK) is an alternative to traditional penetrating keratoplasty (PK) that offers improved graft survival and reduced immunological rejection. However, MPK grafts may still experience endothelial failure over time. This study evaluates the outcomes of non-Descemet Stripping Automated Endothelial Keratoplasty (nDSAEK) as a surgical approach for endothelial decompensation following MPK. Methods: A monocentric, retrospective study was conducted at the Ophthalmology Department of Sant’Orsola-Malpighi Hospital, including patients who underwent nDSAEK for endothelial failure after MPK between 2022 and 2024. Pre- and postoperative best-corrected visual acuity (BCVA), central corneal thickness (CCT), and endothelial cell density (ECD) were assessed. Results: Eighteen eyes from 18 patients (mean age: 39.94 years) were included. Primary MPK indications were post-keratitis leucoma (77.7%), traumatic scarring (16.7%), and keratoconus (5.6%). At one year, mean BCVA improved significantly from 1.40 ± 0.42 logMAR to 0.46 ± 0.19 logMAR (p < 0.05), and mean CCT decreased from 721 ± 70.12 µm to 616 ± 52.80 µm (p < 0.05). The mean postoperative ECD was 1748 ± 100 cells/mm², with lower eye values requiring re-bubbling. No immunological rejection or graft failures were reported. Conclusions: nDSAEK is a promising treatment for MPK endothelial failure, demonstrating good visual and anatomical outcomes. Full article

Renal artery stenosis (RAS) is a vascular condition characterized by narrowing of one or both renal arteries, leading to reduced blood flow to the kidneys, activation of the renin–angiotensin–aldosterone system (RAAS), and subsequent renovascular hypertension. Overactivation of the same cascade potentiates the production of angiotensin II, which induces systemic vasoconstriction, increases sodium and water retention via aldosterone, and activates the sympathetic nervous system. Angiotensin II is also implicated in endothelial dysfunction, oxidative stress, and chronic inflammation, thus impairing vascular remodeling and arterial stiffness, all of which serve to accelerate cardiovascular complications, such as left ventricular hypertrophy, heart failure, and myocardial infarction. RAS is usually due in at least 90% of cases to atherosclerosis, which typically affects older people with diabetes and smoking as risk factors. There are two types of RAS: unilateral and bilateral. Bilateral RAS is commonly associated with flash pulmonary edema, a life-threatening emergency condition in which alveolar space flooding can occur within minutes. RAS typically remains asymptomatic until the late stage with complications of hypertension, ischemic nephropathy, or chronic kidney disease. FMD tends to create structural abnormalities of the artery, whereas atherosclerosis causes plaque formation and endothelial dysfunction of the artery. Epidemiological surveys have revealed that the prevalence of RAS ranges from 4% to 53% and is especially high among patients with hypertension, cardiovascular disease, or CKD. Diagnosis is based on clinical suspicion and supported by imaging studies, including Doppler ultrasound, computed tomography angiography, and magnetic resonance angiography. Early detection also relies on certain laboratory biomarkers, especially in identifying high-risk patients. These markers would include increased plasma renin activity, elevated aldosterone-renin ratio, and inflammatory markers, including C-reactive protein and endothelin-1. Treatment would also involve pharmacological approaches, including RAAS inhibitors, beta-blockers, and statins, and interventional treatments, including angioplasty and stenting in patients with severe forms of the disease. However, the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) Trial showed that most patients would likely require medical therapy, and that intervention should be reserved for those with uncontrolled hypertension, progressive renal dysfunction, or recurrent episodes of pulmonary edema. Other emerging therapies include drug-eluting balloons, bioresorbable stents, and gene-editing techniques, all of which have shown great promise in the few studies that have been conducted, although further evaluation is needed. Despite these advances, there are still gaps in knowledge regarding patient stratification, biomarker validation, and the development of personalized treatment strategies. This article reviews the complexities of RAAS and its systemic impact on cardiovascular and renal health. Future research can therefore focus on improving early diagnosis, optimizing patient selection for intervention, and developing new therapies to slow disease progression and mitigate complications. Full article

Objective: The aim of this study was to evaluate the effect of a surgical technique for managing post-penetrating keratoplasty (PK) ectasia complicated by late endothelial failure (LEF). Methods: A single-center pilot case series was conducted regarding consecutive patients affected by post-PK ectasia with late graft failure. Using a microkeratome, a single donor cornea was dissected to prepare a two-piece graft, comprising a larger anterior lamella made up of anterior stroma and a smaller posterior lamella made up of posterior stroma, Descemet’s membrane, and endothelium. The two lamellae were then positioned on the appropriately prepared recipient cornea. The technique was applied to 15 patients between 2022 and 2023, and data were retrospectively collected from preoperative evaluations and at 1, 6, and 12 months, post-operatively. At each visit, patients underwent standard clinical evaluation, corneal topography, and endothelial cell density evaluation, and visual acuity was measured using a LogMAR chart. Results: The technique restored normal corneal curvature and achieved a clear graft in all patients, leading to the resolution of preoperative ectasia and improved corneal pachymetry. At the one-year follow-up, the average K was reduced from 51.1 ± 4.5 D to 43.5 ± 1.1 D; the best corrected visual acuity (BCVA) was improved from 1.1 ± 0.4 to 0.3 ± 0.2 LogMAR; the central corneal thickness was reduced from 629 ± 39 μm to 532 ± 45 µm; and the endothelial cell density was 1926 ± 199 cells/mm². None of the patients developed severe complications. Conclusions: The two-piece manual mushroom PK may represent an effective technique for managing complex post-PK ectasia cases combined with endothelial decompensation. Full article

Mesenchymal-epithelial transition (MET) is a widely spread and evolutionarily conserved process across species during development. In Ciona embryogenesis, the notochord cells undergo the transition from the non-polarized mesenchymal state into the polarized endothelial-like state to initiate the lumen formation between adjacent cells. Based on previously screened MET-related transcription factors by ATAC-seq and Smart-Seq of notochord cells, Ciona robusta Snail (Ci-Snail) was selected for its high-level expression during this period. Our current knockout results demonstrated that Ci-Snail was required for notochord cell MET. Importantly, overexpression of the transcription factor Brachyury in notochord cells resulted in a similar phenotype with failure of lumen formation and MET. More interestingly, expression of Ci-Snail in the notochord cells at the late tailbud stage could partially rescue the MET defect caused by Brachyury-overexpression. These results indicated an inverse relationship between Ci-Snail and Brachyury during notochord cell MET, which was verified by RT-qPCR analysis. Moreover, the overexpression of Ci-Snail could significantly inhibit the transcription of Brachyury, and the CUT&Tag-qPCR analysis demonstrated that Ci-Snail is directly bound to the upstream region of Brachyury. In summary, we revealed that Ci-Snail promoted the notochord cell MET and was essential for lumen formation via transcriptionally repressing Brachyury. Full article

Diabetic patients have a two- to four-fold increase in the risk of heart failure (HF), and the co-existence of diabetes and HF is associated with poor prognosis. In randomized clinical trials (RCTs), compelling evidence has demonstrated the beneficial effects of sodium-glucose co-transporter-2 inhibitors on HF. The mechanism includes increased glucosuria, restored tubular glomerular feedback with attenuated renin–angiotensin II–aldosterone activation, improved energy utilization, decreased sympathetic tone, improved mitochondria calcium homeostasis, enhanced autophagy, and reduced cardiac inflammation, oxidative stress, and fibrosis. The RCTs demonstrated a neutral effect of the glucagon-like peptide receptor agonist on HF despite its weight-reducing effect, probably due to it possibly increasing the heart rate via increasing cyclic adenosine monophosphate (cAMP). Observational studies supported the markedly beneficial effects of bariatric and metabolic surgery on HF despite no current supporting evidence from RCTs. Bromocriptine can be used to treat peripartum cardiomyopathy by reducing the harmful cleaved prolactin fragments during late pregnancy. Preclinical studies suggest the possible beneficial effect of imeglimin on HF through improving mitochondrial function, but further clinical evidence is needed. Although abundant preclinical and observational studies support the beneficial effects of metformin on HF, there is limited evidence from RCTs. Thiazolidinediones increase the risk of hospitalized HF through increasing renal tubular sodium reabsorption mediated via both the genomic and non-genomic action of PPARγ. RCTs suggest that dipeptidyl peptidase-4 inhibitors, including saxagliptin and possibly alogliptin, may increase the risk of hospitalized HF, probably owing to increased circulating vasoactive peptides, which impair endothelial function, activate sympathetic tones, and cause cardiac remodeling. Observational studies and RCTs have demonstrated the neutral effects of insulin, sulfonylureas, an alpha-glucosidase inhibitor, and lifestyle interventions on HF in diabetic patients. Full article

Anthracycline-induced cardiotoxicity (AIC) poses a clinical challenge in the management of cancer patients. AIC is characterized by myocardial systolic dysfunction and remodeling, caused by cardiomyocyte DNA damage, oxidative stress, mitochondrial dysfunction, or renin-angiotensin-aldosterone system (RAAS) dysregulation. In the past decade, after positive results of a PARADIGM-HF trial, a new class of drugs, namely angiotensin receptor/neprilysin inhibitors (ARNi), was incorporated into the management of patients with heart failure with reduced ejection fraction. As demonstrated in a variety of preclinical studies of cardiovascular diseases, the cardioprotective effects of ARNi administration are associated with decreased oxidative stress levels, the inhibition of myocardial inflammatory response, protection against mitochondrial damage and endothelial dysfunction, and improvement in the RAAS imbalance. However, data on ARNi’s effectiveness in the prevention of AIC remains limited. Several reports of ARNi administration in animal models of AIC have shown promising results, as ARNi prevented ventricular systolic dysfunction and electrocardiographic changes and ameliorated oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and the inflammatory response associated with anthracyclines. There is currently an ongoing PRADAII trial aimed to assess the efficacy of ARNi in patients receiving breast cancer treatment, which is expected to be completed by late 2025. Full article

Purpose: this study aimed to assess the frequency of complications related to corneal grafts, including epithelialization disorders, wound dehiscence, infectious keratitis, recurrence of herpetic keratitis, graft rejection, late graft failure, and infectious and noninfectious corneal melting, while also considering risk factors, particularly indications. Methods: this retrospective analysis of corneal graft failure included a chart review of the hospital records of patients who underwent penetrating keratoplasty (PK) between January 2016 and December 2020 at the Department of Ophthalmology of the District Railway Hospital, Katowice, Poland. Results: Between 2016 and 2020, a total of 758 PK procedures were carried out at the ophthalmology department. Bullous keratopathy (20.58%), keratoconus (18.07%), and corneal perforation (13.32%) were the primary indications for keratoplasty. Secondary glaucoma was diagnosed in 99 patients (13.06%). The success rate of PK was 72.43% (494). The most frequent treatment complication was secondary glaucoma (13.06%), followed by late endothelial failure, perforation (4.1%), and bacterial keratitis (3.23%). Patients in the high-risk group were 4.65 times more likely to develop complications than those in the low-risk group. Multivariate regression analysis showed that concomitant ophthalmic diseases (odds ratio (OR): 3.12, confidence interval (CI): 1.60–6.08, p = 0.00) and connective tissue diseases (OR: 7.76, CI: 2.40–25.05, p = 0.00) were significant factors associated with the occurrence of complications. Diabetes, dermatological diseases, primary glaucoma, and sex were not associated with corneal graft failure (p > 0.05). Conclusion: Chronic loss of the endothelium was the primary cause of graft failure in individuals who underwent PK. The high-risk transplant has up to 4.65 times higher risk of complications compared to the indications with a good prognosis. Full article

BACKGROUND: Corneal transplantation in keratoconus (KC) patients is generally considered to be successful with a high grade of patient satisfaction. Long-term studies suggest a 6% to 11% probability of KC recurrence manifested by keratometric instability and progressive corneal ectasia. METHODS: We propose to review the frequency, risk factors for the development, and the surgical options for the correction of high irregular astigmatism due to late graft ectasia following penetrating keratoplasty (PK). RESULTS: Post-keratoplasty ectasia is characterized by increasing corneal steepening with myopic shift and high irregular astigmatism, developing years or decades after PK, mostly occurring in KC patients. Contact lenses may adequately improve the visual acuity; however, because these patients are often elderly and intolerant to hard contact lenses, ultimately a surgical correction is proposed to the patient. Compressive suture and corneal wedge resection may improve corneal astigmatism, but the outcomes are unpredictable and often temporary. For this reason, a larger PK graft is often proposed for surgical rehabilitation with the consequence of removing more of the recipient’s healthy endothelium and exposing the patient to a renewed immunogenic stimulus and short-term graft failure for endothelial decompensation. More recently, lamellar keratoplasty using various techniques has been proposed as an alternative to PK in order to maximize the visual outcomes and minimize the complications. CONCLUSIONS: Management of advanced corneal ectasia is a significant challenge for corneal surgeons. Many surgical approaches have been developed, so there is a large arsenal of surgical operations to correct post-PK ectasia. Among them, large-diameter anterior lamellar keratoplasty may be a viable, safer, and effective alternative to PK for the correction of post-keratoplasty ectasia. Full article

Predictive scores assessing the risk of respiratory failure in COVID-19 mostly focused on the prediction of early intubation. A combined assessment of clinical parameters and biomarkers of endotheliopathy could allow to predict late worsening of acute respiratory failure (ARF), subsequently warranting intubation in COVID-19. Retrospective single-center derivation (n = 92 subjects) and validation cohorts (n = 59 subjects), including severe COVID-19 patients with non-invasive respiratory support, were assessed for at least 48 h following intensive care unit (ICU) admission. We used stepwise regression to construct the COVID endothelial and respiratory failure (CERES) score in a derivation cohort, and secondly assessed its accuracy for the prediction of late ARF worsening, requiring intubation within 15 days following ICU admission in an independent validation cohort. Platelet count, fraction of inspired oxygen, and endocan measured on ICU admission were identified as the top three predictive variables for late ARF worsening and subsequently included in the CERES score. The area under the ROC curve of the CERES score to predict late ARF worsening was calculated in the derivation and validation cohorts at 0.834 and 0.780, respectively. The CERES score is a simple tool with good performances to predict respiratory failure worsening, leading to secondary intubation, in COVID-19 patients. Full article

Convalescent plasma therapy (CPT) has gained significant attention since the onset of the coronavirus disease 2019 (COVID-19) pandemic. However, clinical trials designed to study the efficacy of CPT based on antibody concentrations were inconclusive. Lymphatic transport is at the interplay between the immune response and the resolution of inflammation from peripheral tissues, including the artery wall. As vascular complications are a key pathogenic mechanism in COVID-19, leading to inflammation and multiple organ failure, we believe that sustaining lymphatic vessel function should be considered to define optimal CPT. We herein sought to determine what specific COVID-19 convalescent plasma (CCP) characteristics should be considered to limit inflammation-driven lymphatic endothelial cells (LEC) dysfunction. CCP donated 16 to 100 days after the last day of symptoms was characterized and incubated on inflammation-elicited adult human dermal LEC (aHDLEC). Plasma analysis revealed that late donation correlates with higher concentration of circulating pro-inflammatory cytokines. Conversely, extracellular vesicles (EVs) derived from LEC are more abundant in early donated plasma (r = −0.413, p = 0.004). Thus, secretion of LEC-EVs by an impaired endothelium could be an alarm signal that instigate the self-defense of peripheral lymphatic vessels against an excessive inflammation. Indeed, in vitro experiments suggest that CCP obtained rapidly following the onset of symptoms does not damage the aHDLEC junctions as much as late-donated plasma. We identified a particular signature of CCP that would counteract the effects of an excessive inflammation on the lymphatic endothelium. Accordingly, an easy and efficient selection of convalescent plasma based on time of donation would be essential to promote the preservation of the lymphatic and immune system of infected patients. Full article

Sepsis is a sustained systemic inflammatory condition involving multiple organ failures caused by dysregulated immune response to infections. Sepsis induces substantial changes in energy demands at the cellular level leading to metabolic reprogramming in immune cells and stromal cells. Although sepsis-associated organ dysfunction and mortality have been partly attributed to the initial acute hyperinflammation and immunosuppression precipitated by a dysfunction in innate and adaptive immune responses, the late mortality due to metabolic dysfunction and immune paralysis currently represent the major problem in clinics. It is becoming increasingly recognized that intertissue and/or intercellular metabolic crosstalk via endocrine factors modulates maintenance of homeostasis, and pathological events in sepsis and other inflammatory diseases. Exosomes have emerged as a novel means of intercellular communication in the regulation of cellular metabolism, owing to their capacity to transfer bioactive payloads such as proteins, lipids, and nucleic acids to their target cells. Recent evidence demonstrates transfer of intact metabolic intermediates from cancer-associated fibroblasts via exosomes to modify metabolic signaling in recipient cells and promote cancer progression. Here, we review the metabolic regulation of endothelial cells and immune cells in sepsis and highlight the role of exosomes as mediators of cellular metabolic signaling in sepsis. Full article

Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, in late December 2019. Since then, COVID-19 has spread rapidly worldwide and was declared a global pandemic on 20 March 2020. Cardiovascular complications are rapidly emerging as a major peril in COVID-19 in addition to respiratory disease. The mechanisms underlying the excessive effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with cardiovascular comorbidities remain only partly understood. SARS-CoV-2 infection is caused by binding of the viral surface spike (S) protein to the human angiotensin-converting enzyme 2 (ACE2), followed by the activation of the S protein by transmembrane protease serine 2 (TMPRSS2). ACE2 is expressed in the lung (mainly in type II alveolar cells), heart, blood vessels, small intestine, etc., and appears to be the predominant portal to the cellular entry of the virus. Based on current information, most people infected with SARS-CoV-2 virus have a good prognosis, while a few patients reach critical condition, especially the elderly and those with chronic underlying diseases. The “cytokine storm” observed in patients with severe COVID-19 contributes to the destruction of the endothelium, leading to “acute respiratory distress syndrome” (ARDS), multiorgan failure, and death. At the origin of the general proinflammatory state may be the SARS-CoV-2-mediated redox status in endothelial cells via the upregulation of ACE/Ang II/AT1 receptors pathway or the increased mitochondrial reactive oxygen species (mtROS) production. Furthermore, this vicious circle between oxidative stress (OS) and inflammation induces endothelial dysfunction, endothelial senescence, high risk of thrombosis and coagulopathy. The microvascular dysfunction and the formation of microthrombi in a way differentiate the SARS-CoV-2 infection from the other respiratory diseases and bring it closer to cardiovascular diseases like myocardial infarction and stroke. Due the role played by OS in the evolution of viral infection and in the development of COVID-19 complications, the use of antioxidants as adjuvant therapy seems appropriate in this new pathology. Alpha-lipoic acid (ALA) could be a promising candidate that, through its wide tissue distribution and versatile antioxidant properties, interferes with several signaling pathways. Thus, ALA improves endothelial function by restoring the endothelial nitric oxide synthase activity and presents an anti-inflammatory effect dependent or independent of its antioxidant properties. By improving mitochondrial function, it can sustain the tissues’ homeostasis in critical situation and by enhancing the reduced glutathione it could indirectly strengthen the immune system. This complex analysis could open a new therapeutic perspective for ALA in COVID-19 infection. Full article