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20 pages, 1094 KiB  
Article
Aims and Rationale of a National Registry Integrating Clinical, Echocardiographic, and Multi-Omics Profiling to Promote Precision Medicine in Peripartum Cardiomyopathy
by Alessia Palmentieri, Ciro Battaglia, Dario D’Alconzo, Luigi Anastasia, Luca Bardi, Giuseppe Bifulco, Maria Calanducci, Martina Carotenuto, Paolo Ivo Cavoretto, Federica Carusone, Emilio Di Lorenzo, MariaFrancesca Di Santo, Attilio Di Spiezio Sardo, Federica Ilardi, Danila Ioele, Francesca Lanni, Marco Licciardi, Francesco Loffredo, Rachele Manzo, Daniele Masarone, Nicolò Montali, Roberta Paolillo, Vanessa Peano, Giovanni Peretto, Enrica Pezzullo, Pina Polese, Gabriele Saccone, Alaide Chieffo, Giovanni Esposito and Cinzia Perrinoadd Show full author list remove Hide full author list
Biomedicines 2025, 13(8), 2026; https://doi.org/10.3390/biomedicines13082026 - 20 Aug 2025
Abstract
Background. Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening condition typically presenting as heart failure with reduced ejection fraction in the last month of pregnancy or in the first five months following delivery in women without other known causes of heart failure. [...] Read more.
Background. Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening condition typically presenting as heart failure with reduced ejection fraction in the last month of pregnancy or in the first five months following delivery in women without other known causes of heart failure. PPCM incidence and prevalence are highly variable in different populations and geographical areas. The etiology of PPCM is likely multifactorial, with genetic predisposition, autoimmune conditions, nutritional deficiencies, hormonal and metabolic changes, myocardial inflammation, enhanced oxidative stress, vascular dysfunction, and angiogenic imbalance all listed as possible contributing factors. Objectives. The complexity and multifactorial nature of PPCM can be explored by large-scale “omics” investigations, and their integration has the potential to identify key drivers and pathways that have the largest contribution to the disease. The scarcity of relevant knowledge and experience with most rare diseases raises the unique need for cooperation and networking. Methods and results. In the context of PPCM, we hypothesize that the creation of prospective patient registries could represent an answer to this criticality. Therefore, we created a multicenter national registry of PPCM in different geographical areas in Italy. Conclusions. We expect that the integration of clinical, imaging and omics-based data might provide novel insights into PPCM pathophysiology and allow in the future early detection, risk assessment, and patient-specific therapeutic interventions, thereby offering new perspectives in precision medicine. Full article
(This article belongs to the Special Issue Heart Failure: New Diagnostic and Therapeutic Approaches)
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11 pages, 857 KiB  
Article
Assessment of Azathioprine-Associated Lymphopenia Incidence Rates in Polish Children with Inflammatory Bowel Disease and Autoimmune Hepatitis: A Retrospective Study
by Katarzyna Bąk-Drabik, Anna Kaput, Anna Jarzumbek, Katarzyna Górowska-Kowolik, Agnieszka Szymlak, Agnieszka Krzywicka, Piotr Adamczyk and Jarosław Kwiecień
Children 2025, 12(8), 1093; https://doi.org/10.3390/children12081093 - 20 Aug 2025
Abstract
Background and objective: Thiopurines (azathioprine (AZA) and 6-mercaptopurine (6-MP)), used to maintain remission in inflammatory bowel diseases (Crohn’s disease (CD), ulcerative colitis (CU)) and autoimmune hepatitis (AIH), are responsible for a number of adverse effects. One is leukopenia, mainly due to neutropenia and [...] Read more.
Background and objective: Thiopurines (azathioprine (AZA) and 6-mercaptopurine (6-MP)), used to maintain remission in inflammatory bowel diseases (Crohn’s disease (CD), ulcerative colitis (CU)) and autoimmune hepatitis (AIH), are responsible for a number of adverse effects. One is leukopenia, mainly due to neutropenia and less known lymphopenia. This study aimed to assess the incidence rate of lymphopenia in pediatric patients with CD, CU, and AIH treated with azathioprine (AZA) and to evaluate the impact of lymphopenia on the occurrence of opportunistic infections and its relationship with disease activity, treatment, and nutritional status. Materials and methods: A retrospective analysis was carried out in ninety-eight (98) paediatric patients, suffering from CD, CU, or AIH and treated with AZA, in order to assay blood cell count and thiopurine metabolite levels, assess the mean AZA dose, measure the anthropometric parameters, evaluate disease activity vs. the treatment administered, and to find out concomitant infections. Results: Lymphopenia was diagnosed in twenty-two (22) children and evaluated as severe in two (2) cases, which were associated with treatment discontinuation. The percentage of patients with lymphopenia in the CD group (34.5%) was significantly higher vs. the CU (3.7%) and AIH (7.7%) groups. The prevalence rates of the patients with low and moderate-to-high disease activity were 13.9% and 46.1%, respectively. The patients with lymphopenia demonstrated higher prevalence rates of mild respiratory tract and skin infections (identified in 32%). No cases of opportunistic infections were reported. Conclusions: Lymphopenia affected approximately one-quarter of the patients observed, the condition being transient in most cases and not demanding any therapy modifications. In no case was it associated with the occurrence of any opportunistic infections. It was significantly more common in the patients with Crohn’s disease and the subgroup with a more intense course of the disease, obviously suggesting a need for more frequent follow-up of the patients in those subgroups. The AZA therapy did not seem to be associated with lymphopenia occurrence in any significant way. Full article
(This article belongs to the Section Pediatric Gastroenterology and Nutrition)
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17 pages, 1424 KiB  
Article
MiRNA-186 as a Biomarker of Disease Exacerbation in Rheumatoid Arthritis: Insights from Clinical Data and Molecular Marker Analysis
by Marek Cieśla, Dorota Darmochwał-Kolarz, Hubert Kubis and Bogdan Kolarz
Int. J. Mol. Sci. 2025, 26(16), 8039; https://doi.org/10.3390/ijms26168039 (registering DOI) - 20 Aug 2025
Abstract
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by inflammation of the synovial tissue, leading to joint destruction, pain, stiffness, and progressive impairment of motor functions. Despite significant advances in diagnosis and treatment, RA remains a major clinical and social challenge, [...] Read more.
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by inflammation of the synovial tissue, leading to joint destruction, pain, stiffness, and progressive impairment of motor functions. Despite significant advances in diagnosis and treatment, RA remains a major clinical and social challenge, negatively impacting patients’ quality of life. The aim of this study was to assess the relationship between the expression of selected microRNAs (miRNAs) and the activity of the disease. A total of 46 RA patients and 20 healthy controls (HCs) were enrolled in the study. A quantitative real-time polymerase chain reaction was used to evaluate the expression of miRNAs in whole blood. MiRNA-186 exhibited decreased concentrations in RA patients compared to HCs (p = 0.03). Patients with an active form of the disease (DAS28 > 3.2) exhibited lower expression of miRNA-186 than HCs (p = 0.04). Additionally, ACPA-negative patients also demonstrated reduced miRNA-186 expression compared to controls. AUC analysis confirmed that the combination of miRNA-186, the erythrocyte sedimentation rate (ESR), and Visual Analog Scale—Patient Global Assessment (VAS PGA) may be effective in identifying RA exacerbation. The combination of classical laboratory markers, clinical data, and molecular markers enhances the ability to assess RA exacerbation. MiRNA-186 may be considered a potential marker of disease activity in RA. Full article
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18 pages, 540 KiB  
Review
The Renin–Angiotensin–Aldosterone System (RAAS): Beyond Cardiovascular Regulation
by Agnese Valentini, Romy M. Heilmann, Anna Kühne, Lucia Biagini, Danilo De Bellis and Giacomo Rossi
Vet. Sci. 2025, 12(8), 777; https://doi.org/10.3390/vetsci12080777 (registering DOI) - 20 Aug 2025
Abstract
The renin–angiotensin–aldosterone system (RAAS) plays a pivotal role in regulating cardiovascular function, fluid balance, and blood pressure. Recent research has revealed the RAAS’s influence extends beyond cardiovascular physiology, encompassing key roles in inflammation, fibrosis, immune regulation, cancer progression, and organ-specific disease mechanisms. This [...] Read more.
The renin–angiotensin–aldosterone system (RAAS) plays a pivotal role in regulating cardiovascular function, fluid balance, and blood pressure. Recent research has revealed the RAAS’s influence extends beyond cardiovascular physiology, encompassing key roles in inflammation, fibrosis, immune regulation, cancer progression, and organ-specific disease mechanisms. This review provides a comprehensive overview of classical and alternative RAAS pathways, focusing on the dual roles of angiotensin II (Ang II) and angiotensin-(1–7) (Ang 1–7), mediated through AT1R, AT2R, MasR, and MrgD receptors. We discuss molecular signaling cascades, including mitochondrial, nuclear, and caveolae-mediated mechanisms, and explore the impact of RAAS modulation on hepatic fibrosis, vascular remodeling, and autoimmune inflammation. Genetic models and emerging pharmacologic strategies illustrate tissue-specific RAAS actions, emphasizing the therapeutic potential of enhancing the ACE2/Ang 1–7/Mas axis while inhibiting the deleterious ACE/Ang II/AT1R signaling. Furthermore, we highlight implications for veterinary medicine, particularly in canine chronic inflammatory enteropathies, where RAAS dysfunction may contribute to treatment resistance. Understanding RAAS complexity and inter-receptor crosstalk is essential for developing new therapeutic strategies targeting cardiovascular, hepatic, and inflammatory diseases in both human and veterinary contexts. Full article
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12 pages, 1075 KiB  
Case Report
Primary Hepatic Mucosa-Associated B-Cell Lymphoma in a Patient with Primary Sclerosing Cholangitis—A Case Ultimately Requiring Liver Transplantation
by Jerica Novak, Mihajlo Đokić, Miha Petrič, Diana Vozlič, Milanka Živanović, Branislava Ranković and Blaž Trotovšek
Diagnostics 2025, 15(16), 2082; https://doi.org/10.3390/diagnostics15162082 - 19 Aug 2025
Abstract
Background: Primary hepatic extranodal marginal zone lymphoma of mucosa-associated type (MALT) is an extremely rare liver neoplasm. The lesions are often misdiagnosed for the most common primary hepatic malignancy, such as hepatocellular carcinoma and cholangiocarcinoma. As the diagnosis is most often made after [...] Read more.
Background: Primary hepatic extranodal marginal zone lymphoma of mucosa-associated type (MALT) is an extremely rare liver neoplasm. The lesions are often misdiagnosed for the most common primary hepatic malignancy, such as hepatocellular carcinoma and cholangiocarcinoma. As the diagnosis is most often made after the resection, there are still no clear guidelines for the optimal treatment of these patients. Case Presentation: A 30-year-old male patient with known primary sclerosing cholangitis (PSC) was treated at the Department of Abdominal Surgery Ljubljana due to a mass in the right liver, believed to be an intrahepatic cholangiocarcinoma. Due to the extent of the disease, extended right hepatectomy with the resection of the hepatocholedochus, lymphadenectomy, and hepaticojejunal anastomosis were performed. After the surgery, the patient developed a small-for-size syndrome and therefore necessitated a liver transplantation (LT) that was afterwards successfully performed. Discussion: This case highlights the diagnostic challenges of differentiating primary hepatic MALT lymphoma from cholangiocarcinoma on imaging, especially in patients with underlying liver disease. Preoperative confirmation of the malignant disease could potentially change treatment course in our patient. Therefore, a serious surgical complication with development of small-for-size syndrome after major hepatectomy could potentially be prevented. Regarding the underlying liver disease, the patient could probably be a candidate for LT with the bridging chemotherapy. Conclusion: Primary hepatic MALT lymphoma is an extremely rare liver lesion but remains a valid option in a differential diagnosis of liver lesions in patients with chronic viral infection or autoimmune disease, especially in settings of cirrhosis. Moreover, a high level of suspicion must be raised in young patients with solitary liver mass and autoimmune liver disease. Surgical resection is the best way to achieve elimination of the disease. Full article
23 pages, 522 KiB  
Article
Disseminated Varicella-Zoster Virus Infection with Internal Organ Involvement: A Scoping Review of 156 Cases
by Aleksandar Timotijevic, Pratyusha Kodela, Vladislav Glušac, Sara Bokonjic, Bojan Joksimovic, Juan Vera Gomez, David Ladin and Igor Dumic
Viruses 2025, 17(8), 1135; https://doi.org/10.3390/v17081135 - 19 Aug 2025
Abstract
Visceral disseminated varicella-zoster virus infection (VD-VZV) involves the hematogenous spread of VZV from the skin to the internal organs. Though rare, it is potentially life-threatening, predominantly affecting immunocompromised individuals. Diagnosis is often delayed due to nonspecific symptoms mimicking other viral illnesses. While the [...] Read more.
Visceral disseminated varicella-zoster virus infection (VD-VZV) involves the hematogenous spread of VZV from the skin to the internal organs. Though rare, it is potentially life-threatening, predominantly affecting immunocompromised individuals. Diagnosis is often delayed due to nonspecific symptoms mimicking other viral illnesses. While the vesicular rash is a hallmark sign, it is absent in approximately 5% of cases. Visceral involvement may precede cutaneous lesions, complicate early recognition, and increase the risk of severe complications. This scoping review screened 594 articles of which 153 met the inclusion criteria, yielding 156 individual cases. Patients were predominantly male (53.8%), with a mean age of 42.3 years. The overall mortality rate was 25.0%. Multiple organs were involved in 46.1% of cases. The most frequently affected were the lungs (56%), liver (44%), heart (16%), kidneys (11%), pancreas (11%), stomach (10%), and esophagus (6%). Antivirals were administered in 89.1% of cases, while corticosteroids were used in 22.4%, with no significant impact on outcomes. Early diagnosis, achieved in 65.4% of patients, was significantly associated with survival (p = 0.043). Mortality was significantly associated with underlying comorbidities (p = 0.004), especially autoimmune diseases requiring immunosuppression (p = 0.048). Septic shock or multi-organ dysfunction (MODS), hepatitis, acute kidney injury, and acute liver failure were linked to higher mortality in univariate analysis. Multivariate analysis identified comorbidities (p < 0.001), septic shock/MODS (p = 0.008), and acute liver failure (p = 0.039) as independent predictors of mortality. Patients with septic shock/MODS had over twice the risk of death (OR = 2.24; p = 0.008). This review underscores the diagnostic challenges and high mortality of VD-VZV. Early recognition and timely administration of antiviral treatment appear critical for survival. Greater clinical awareness and further research are needed to guide management. Full article
(This article belongs to the Special Issue Herpesviruses and Associated Diseases)
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28 pages, 1786 KiB  
Systematic Review
Trends and Future Directions in Mitigating Silica Exposure in Construction: A Systematic Review
by Roohollah Kalatehjari, Funmilayo Ebun Rotimi, Rajitha Sachinthaka and Taofeeq Durojaye Moshood
Buildings 2025, 15(16), 2924; https://doi.org/10.3390/buildings15162924 - 18 Aug 2025
Abstract
Respirable crystalline silica is a well-established occupational hazard in construction work. Despite increased awareness, consistent exposure control remains a challenge, particularly in dynamic and resource-constrained environments. Respirable crystalline silica exposure in construction environments challenges the achievement of the United Nations Sustainable Development Goals [...] Read more.
Respirable crystalline silica is a well-established occupational hazard in construction work. Despite increased awareness, consistent exposure control remains a challenge, particularly in dynamic and resource-constrained environments. Respirable crystalline silica exposure in construction environments challenges the achievement of the United Nations Sustainable Development Goals (SDGs), particularly SDG 3 (Good Health and Well-Being) and SDG 8 (Decent Work and Economic Growth). Respirable crystalline silica particles cause severe health complications, including silicosis, lung cancer, cardiovascular diseases, and autoimmune disorders, representing a significant barrier to achieving SDG 3.9’s target of reducing deaths and illnesses from hazardous chemical exposures by 2030. This systematic review evaluates two decades of advancements (2004–2024) in respirable crystalline silica identification, characterisation, and mitigation within construction, synthesising evidence from 143 studies to assess progress toward sustainable occupational health management. This review documents a paradigmatic shift from traditional exposure assessment toward sophisticated monitoring approaches incorporating real-time detection systems, virtual reality–Computational Fluid Dynamics simulations, and wearable sensor technologies. Engineering controls, including local exhaust ventilation, wet suppression methods, and modified tool designs, have achieved exposure reductions exceeding 90%, directly supporting SDG 8.8’s commitment to safe working environments for all workers, including migrants and those in precarious employment. However, substantial barriers persist, including prohibitive costs, inadequate infrastructure, and regional regulatory disparities that particularly disadvantage lower-resourced countries, contradicting the Sustainable Development Goals’ principles of leaving no one behind. The findings advocate holistic approaches integrating technological innovation with context-specific regulations, enhanced international cooperation, and culturally adapted worker education to achieve equitable occupational health protection supporting multiple Sustainable Development Goals’ objectives by 2030 and also highlighting potential areas for future research. Full article
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11 pages, 987 KiB  
Case Report
Acute Myocarditis Following Zoledronic Acid Infusion: Cardiac MRI Diagnosis of a Rare Cardiotoxic Event with Contextual Literature Review
by Ismaell Massalha, Reem Zabit, Aryeh Shalev and Gal Bin-Arie
Diagnostics 2025, 15(16), 2064; https://doi.org/10.3390/diagnostics15162064 - 18 Aug 2025
Abstract
Background and Clinical Significance: Zoledronic acid (ZA) is a widely used bisphosphonate for the prevention of skeletal-related events in patients with metastatic bone disease. While it is generally well tolerated, rare immune-mediated complications may be underrecognized. To date, myocarditis has not been reported [...] Read more.
Background and Clinical Significance: Zoledronic acid (ZA) is a widely used bisphosphonate for the prevention of skeletal-related events in patients with metastatic bone disease. While it is generally well tolerated, rare immune-mediated complications may be underrecognized. To date, myocarditis has not been reported in association with ZA. Case Presentation: A 35-year-old woman with metastatic pheochromocytoma developed acute, non-exertional chest pain approximately 36 h after receiving her first intravenous ZA infusion. Laboratory testing revealed elevated high-sensitivity troponin T, peaking at 1182 ng/L. Cardiac magnetic resonance imaging (CMR) demonstrated myocardial edema and subepicardial late gadolinium enhancement, consistent with acute myocarditis per the 2018 revised Lake Louise criteria. An extensive diagnostic workup excluded infectious, autoimmune, and ischemic causes. Symptoms and troponin levels improved following ZA discontinuation and supportive care. In the absence of alternative etiologies, and given the close temporal association with ZA administration, the diagnosis of presumed ZA-associated myocarditis was supported by clinical presentation, biochemical markers, and CMR findings, recognizing that histopathological confirmation is rarely pursued in clinically stable patients. Conclusions: To our knowledge, this is the first reported case of presumed zoledronic acid–associated myocarditis confirmed by cardiac MRI. This report highlights the diagnostic utility of CMR in suspected drug-related cardiac inflammation and the importance of considering myocarditis in patients presenting with unexplained chest pain following ZA infusion, particularly when other causes have been excluded. Full article
(This article belongs to the Section Clinical Diagnosis and Prognosis)
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18 pages, 7739 KiB  
Article
Construction and Analysis of Immune Infiltration and Competing Endogenous RNA Network in Moyamoya Disease
by Wenhao Liu, Hanhui Fu, Shiyuan Fang, Jun Ni and Bin Peng
Int. J. Mol. Sci. 2025, 26(16), 7957; https://doi.org/10.3390/ijms26167957 - 18 Aug 2025
Abstract
Moyamoya disease (MMD) is a cerebrovascular condition characterized by progressive stenosis of intracranial arteries, leading to stroke. While MMD was long considered a genetic disorder, emerging evidence suggests autoimmune mechanisms may contribute to its pathogenesis. The role of non-coding RNAs (ncRNAs) in the [...] Read more.
Moyamoya disease (MMD) is a cerebrovascular condition characterized by progressive stenosis of intracranial arteries, leading to stroke. While MMD was long considered a genetic disorder, emerging evidence suggests autoimmune mechanisms may contribute to its pathogenesis. The role of non-coding RNAs (ncRNAs) in the pathogenesis of MMD is under heated discussion, and a competitive endogenous RNA (ceRNA) network involving MMD-related ncRNAs has not been constructed. In this study, we integrated multiple bioinformatic analyses on transcriptomic data from the middle cerebral arteries of MMD patients and controls. Our analysis revealed a significant enrichment of innate immune system pathways, including antigen processing and macrophage activation, in MMD tissue. We constructed a robust ceRNA network centered on the long non-coding RNA MALAT1, identifying 15 core mRNA targets. A classifier built from these MALAT1-related genes accurately distinguished MMD patients from controls, with an area under the curve of 0.869 in independent validation. Furthermore, immune deconvolution analysis showed a marked increase in microvascular endothelial cells and a decrease in CD4+ memory T cells and regulatory T cells in MMD arteries. The expression of the MALAT1 network genes strongly correlated with these shifts in cellular composition, positively with endothelial cells and negatively with T cells. Our findings uncover a MALAT1-driven ceRNA network that links immune dysregulation to vascular changes in MMD, highlighting MALAT1 as a potential biomarker and therapeutic target. Full article
(This article belongs to the Section Molecular Immunology)
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12 pages, 239 KiB  
Review
Promising Molecular Therapeutic Targets for Drug Development in Rheumatoid Arthritis
by Sang Wan Chung
J. Clin. Med. 2025, 14(16), 5827; https://doi.org/10.3390/jcm14165827 - 18 Aug 2025
Abstract
Rheumatic diseases encompass various autoimmune and inflammatory conditions affecting the joints, muscles, and connective tissues. Recent studies have advanced our understanding of the molecular pathogenesis of rheumatic diseases and have led to the identification of several promising therapeutic targets, paving the way for [...] Read more.
Rheumatic diseases encompass various autoimmune and inflammatory conditions affecting the joints, muscles, and connective tissues. Recent studies have advanced our understanding of the molecular pathogenesis of rheumatic diseases and have led to the identification of several promising therapeutic targets, paving the way for the development of novel drug interventions. This review highlights the latest molecular advances in rheumatoid arthritis, with a particular focus on innovative therapeutic strategies, and presents new perspectives on their management, including cytokines, intracellular signaling pathways, immune checkpoints, and novel cell-based therapies. A better understanding of these targets is essential for developing effective and personalized treatments. Full article
(This article belongs to the Section Immunology)
18 pages, 7939 KiB  
Article
Peripheral Nerve Decellularisation Protocol for Allogeneic Transplantation: From Tissue Procurement to Banking
by Marco Govoni, Leonardo Vivarelli, Nicola Fazio, Federico Bolognesi, Viscardo Paolo Fabbri, Alessandra Maso, Elisa Storni, Giulia Querzoli, Deyanira Contartese, Stefania Pagani, Luca Cavazza, Marta Pluchino, Lucia De Franceschi, Gianluca Giavaresi and Dante Dallari
Int. J. Mol. Sci. 2025, 26(16), 7937; https://doi.org/10.3390/ijms26167937 - 17 Aug 2025
Viewed by 132
Abstract
Peripheral nerve injuries affect over one million individuals annually worldwide due to various causes such as trauma, metabolic disorders, and autoimmune diseases. While autologous nerve grafting remains the gold standard for treating large-gap nerve injuries, its limitations, including limited tissue availability, donor site [...] Read more.
Peripheral nerve injuries affect over one million individuals annually worldwide due to various causes such as trauma, metabolic disorders, and autoimmune diseases. While autologous nerve grafting remains the gold standard for treating large-gap nerve injuries, its limitations, including limited tissue availability, donor site morbidity, infection risk, and suboptimal functional recovery, have spurred interest in alternative approaches. Among these, allogeneic nerve grafting has emerged as a promising option, offering structural and functional advantages due to the native architecture of donor nerves. However, immune rejection due to histocompatibility antigens remains a significant challenge. Decellularisation protocols utilising mild detergents have shown the most promise in preserving the extracellular matrix’s structural and regenerative properties while mitigating immunogenicity. The study aimed to adapt and validate a decellularisation protocol for human nerves within our tissue bank, adhering to European and national regulatory guidelines. The protocol, based on the cleanroom-compliant method previously developed by our group, was optimised to reduce tissue handling time and ensure regulatory compliance. Decellularised sural nerves were assessed for extracellular matrix preservation and sterility using European (EU) Pharmacopoeia and European Directorate for the Quality of Medicines & HealthCare (EDQM) guidelines. The results demonstrated the feasibility of producing high-quality acellular nerve allografts (ANAs) that are suitable for peripheral nerve repair, paving the way for cost-effective and widely accessible grafting solutions. Full article
(This article belongs to the Special Issue Advances in Peripheral Nerve Regeneration)
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13 pages, 1294 KiB  
Review
VEXAS Syndrome: Genetics, Gender Differences, Clinical Insights, Diagnostic Pitfalls, and Emerging Therapies
by Salvatore Corrao, Marta Moschetti, Salvatore Scibetta, Luigi Calvo, Annarita Giardina, Ignazio Cangemi, Carmela Zizzo, Paolo Colomba and Giovanni Duro
Int. J. Mol. Sci. 2025, 26(16), 7931; https://doi.org/10.3390/ijms26167931 - 17 Aug 2025
Viewed by 183
Abstract
VEXAS syndrome (Vacuoles, E1-enzyme, X-linked, Autoinflammation, and Somatic) is a recently identified late-onset autoinflammatory disorder characterized by a unique interplay between hematological and inflammatory manifestations. It results from somatic mutations in the UBA1 gene, located on the short arm of the X chromosome. [...] Read more.
VEXAS syndrome (Vacuoles, E1-enzyme, X-linked, Autoinflammation, and Somatic) is a recently identified late-onset autoinflammatory disorder characterized by a unique interplay between hematological and inflammatory manifestations. It results from somatic mutations in the UBA1 gene, located on the short arm of the X chromosome. Initially, females were considered mere carriers, with the syndrome primarily affecting males over 50. However, recent evidence indicates that heterozygous females can exhibit symptoms as severe as those seen in hemizygous males. The disease manifests as systemic inflammation, macrocytic anemia, thrombocytopenia, chondritis, neutrophilic dermatoses, and steroid-dependent inflammatory symptoms. Due to its overlap with autoimmune and hematologic disorders such as relapsing polychondritis, Still’s disease, and myelodysplastic syndromes, misdiagnosis is common. At the molecular level, VEXAS syndrome is driven by impaired ubiquitination pathways, resulting in dysregulated immune responses and clonal hematopoiesis. A key diagnostic marker is the presence of cytoplasmic vacuoles in myeloid and erythroid precursors, though definitive diagnosis requires genetic testing for UBA1 mutations. Traditional immunosuppressants and TNF inhibitors are generally ineffective, while JAK inhibitors and IL-6 blockade provide partial symptom control. Azacitidine and decitabine have shown promise in reducing disease burden, but hematopoietic stem cell transplantation (HSCT) remains the only curative treatment, albeit with significant risks. This review provides a comprehensive analysis of VEXAS syndrome, examining its clinical features, differential diagnoses, diagnostic challenges, and treatment approaches, including both pharmacological and non-pharmacological strategies. By enhancing clinical awareness and optimizing therapeutic interventions, this article aims to bridge emerging genetic insights with practical patient management, ultimately improving outcomes for those affected by this complex and often life-threatening disease. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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10 pages, 453 KiB  
Article
Clinicopathological Features and Pathogenesis of Thymoma Complicated with Alopecia Areata: A Multicenter, Matched Case Analysis
by Xin Du, Xuehan Gao, Jian Cui, Xintao Yu, Cheng Huang, Yeye Chen, Chao Guo, Ye Zhang, Chao Gao, Xiayao Diao, Lei Yu and Shanqing Li
Cancers 2025, 17(16), 2672; https://doi.org/10.3390/cancers17162672 - 16 Aug 2025
Viewed by 190
Abstract
Background: Thymoma is a malignant tumor originating from the thymic epithelium and can be associated with over 100 paraneoplastic syndromes (PNSs). Due to the low incidence of thymoma and the relative rarity of alopecia areata (AA) as an associated autoimmune disease, patients with [...] Read more.
Background: Thymoma is a malignant tumor originating from the thymic epithelium and can be associated with over 100 paraneoplastic syndromes (PNSs). Due to the low incidence of thymoma and the relative rarity of alopecia areata (AA) as an associated autoimmune disease, patients with thymoma combined with AA are relatively uncommon in clinical practice. As a result, the clinicopathological features and pathogenesis of such patients have been rarely investigated. Methods: This study retrospectively analyzed the clinical records of thymoma patients who underwent surgical treatment at Peking Union Medical College Hospital and Beijing Tongren Hospital from August 2014 to July 2019, with a focus on the clinicopathological features of thymoma patients with AA. Propensity score matching (PSM) was employed to create a 1:5 matched comparison group with thymoma patients without AA. Results: A total of 428 thymoma patients were included, among which 9 had AA. Using PSM, we matched 45 control patients without AA based on age and gender. The analysis revealed that thymoma patients with AA had a significantly higher proportion of myasthenia gravis (MG) [100.00% (9/9) vs. 66.67% (30/45), p = 0.049], although there were no significant differences between the AChR antibodies, Titin antibodies, MG severity, and the incidence of postoperative myasthenic crisis. However, the proportion of thymoma patients with AA who also had other PNSs besides MG was significantly higher [88.89% (8/9) vs. 6.67% (3/45), p < 0.001]. Additionally, CD4+/CD8+ T-cell inversion in the serum was observed at a much higher rate in thymoma patients with AA [100.00% (9/9) vs. 24.44% (11/45), p < 0.001]. Conclusions: We hypothesize that the pathogenesis of thymoma with AA differs from that of thymoma with MG, though there may be a correlation. The etiology of thymoma with AA may be attributed to abnormal autoimmune CD8+ T lymphocytes produced by the thymoma, which can also lead to other cytotoxic T-cell-mediated autoimmune diseases. Full article
(This article belongs to the Section Cancer Pathophysiology)
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19 pages, 1412 KiB  
Review
Primary Biliary Cholangitis: Immunopathogenesis and the Role of Bile Acid Metabolism in Disease Progression
by María Del Barrio, Álvaro Díaz-González and Marta Alonso-Peña
Int. J. Mol. Sci. 2025, 26(16), 7905; https://doi.org/10.3390/ijms26167905 - 16 Aug 2025
Viewed by 267
Abstract
Primary biliary cholangitis (PBC) is a chronic, immune-mediated liver disease characterized by progressive destruction of the small intrahepatic bile ducts, leading to cholestasis, inflammation, and ultimately fibrosis and cirrhosis. This review emphasizes the central role of bile acids in PBC pathogenesis, exploring how [...] Read more.
Primary biliary cholangitis (PBC) is a chronic, immune-mediated liver disease characterized by progressive destruction of the small intrahepatic bile ducts, leading to cholestasis, inflammation, and ultimately fibrosis and cirrhosis. This review emphasizes the central role of bile acids in PBC pathogenesis, exploring how disruptions in their synthesis, transport, and detoxification contribute to cholangiocyte damage and disease progression. In addition to discussing the autoimmune features of PBC, including the presence of specific autoantibodies and cellular immune responses, we examine how bile acid dysregulation exacerbates cholestasis and promotes lipid metabolic disturbances. Particular attention is given to the “bicarbonate umbrella” hypothesis, which describes a protective mechanism by which cholangiocytes resist bile acid–induced injury—an essential factor disrupted in PBC. The aim of this review is to summarize current knowledge gaps in the pathophysiology of PBC, with a focus on the role of bile acids not only as key drivers of disease mechanisms, but also as potential biomarkers of disease progression and treatment response. Full article
(This article belongs to the Special Issue Bile Acids and Bile Acid Modifications in Health and Disease)
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Multilayered Insights into Poorly Differentiated, BRAFV600E-Positive, Thyroid Carcinoma in a Rapidly Developing Goiter with Retrosternal Extension: From En “Y” Cervicotomy to SPECT/CT-Positive Lung Metastases
by Oana-Claudia Sima, Anca-Pati Cucu, Dana Terzea, Claudiu Nistor, Florina Vasilescu, Lucian-George Eftimie, Mihai-Lucian Ciobica, Mihai Costachescu and Mara Carsote
Diagnostics 2025, 15(16), 2049; https://doi.org/10.3390/diagnostics15162049 - 15 Aug 2025
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Abstract
Poorly differentiated thyroid malignancy, a rare histological type of aggressive thyroid malignancy with associated difficulties and gaps in its histological and molecular characterization, might lead to challenging clinical presentations that require a prompt multimodal approach. This case study involved a 56-year-old, non-smoking male [...] Read more.
Poorly differentiated thyroid malignancy, a rare histological type of aggressive thyroid malignancy with associated difficulties and gaps in its histological and molecular characterization, might lead to challenging clinical presentations that require a prompt multimodal approach. This case study involved a 56-year-old, non-smoking male with a rapidly developing goiter (within 2–3 months) in association with mild, non-specific neck compressive symptoms. His medical history was irrelevant. A voluminous goiter with substernal and posterior extension up to the vertebral bodies was detected using an ultrasound and computed tomography (CT) scan and required emergency thyroidectomy. He had normal thyroid function, as well as negative thyroid autoimmunity and serum calcitonin. The surgery was successful upon “Y” incision, which was used to give better access to the retrosternal component in order to avoid a sternotomy. Post-operatively, the subject developed hypoparathyroidism-related hypocalcemia and showed a very high serum thyroglobulin level (>550 ng/mL). The pathological report confirmed poorly differentiated, multifocal thyroid carcinoma (with an insular, solid, and trabecular pattern) against a background of papillary carcinoma (pT3b, pN0, and pM1; L1; V2; Pn0; R1; and stage IVB). The subject received 200 mCi of radioiodine therapy for 6 weeks following the thoracic surgery. Whole-body scintigraphy was performed before radioiodine therapy and showed increased radiotracer uptake at the thyroid remnants and pre-tracheal levels. Additionally, single-photon emission computed tomography combined with CT (SPECT/CT) was performed, and confirmed the areas of intense uptake, in addition to a moderate uptake in the right and left pulmonary parenchyma, suggesting lung metastasis. To conclude, an overall low level of statistical evidence exists regarding poorly differentiated malignancy in substernal goiters, and the data also remains scarce regarding the impact of genetic and molecular configurations, such as the BRAF-positive profile, in this specific instance. Furthermore, multimodal management includes additional diagnosis methods such as SPECT/CT, while long-term multilayered therapy includes tyrosine kinase inhibitors if the outcome shows an iodine-resistant profile with a poor prognosis. Awareness remains a key factor in cases of a poorly differentiated carcinoma presenting as a rapidly growing goiter with substernal extension in an apparently healthy adult. A surgical approach, while varying with the surgeon’s skills, represents a mandatory step to ensure a better prognosis. In addition to a meticulous histological characterization, genetic/molecular features provide valuable information regarding the outcome and can further help with the decision to use new anti-cancer drugs if tumor response upon radioiodine therapy is no longer achieved; such a development is expected in this disease stage in association with a BRAF-positive configuration. Full article
(This article belongs to the Special Issue Thyroid Cancer: Types, Symptoms, Diagnosis and Management)
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