Search Results (151)

Sickle cell disease (SCD) is a monogenic disorder responsible for recurrent vaso-occlusive crises, progressive organ damage, and shortened life expectancy. For decades, allogeneic hematopoietic stem cell transplantation from a matched sibling donor has been the only established cure, but its reach remains limited by donor availability and transplant-related toxicity. The approval of two autologous gene therapy products in 2023, exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel), marked a turning point for the SCD population and the gene therapy field in general. This review proposes a molecular rationale for fetal hemoglobin reactivation and β-globin gene addition, describes the engineering of lentiviral and CRISPR-based platforms, and highlights the clinical evidence accumulated to date that demonstrated durable disease modification with acceptable short-term toxicity. We then assess the clinical positioning of gene therapy within the broader spectrum of curative options compared to current available treatments and address the financial, ethical and psychosocial barriers that limit access to gene therapy both within high-income countries and globally. Critical research priorities include long-term safety surveillance, comparative effectiveness studies, pediatric trials below 12 years, and validated patient-reported outcome instruments. Base editing, non-genotoxic conditioning, and in vivo delivery represent the most promising avenues to broaden access and reduce treatment burden. Full article

Critical size bone defects (CSBD) remain a major challenge in orthopedic surgery. Autologous bone grafting is considered the gold standard but is limited by restricted availability and significant donor-site morbidity. Synthetic bone substitutes offer an alternative; however, these materials are avital and lack osteoinductive properties. This study evaluated whether intraoperative bioactivation of bone substitutes using a surgical suction handle can safely enhance their regenerative potential. Fifty patients with CSBD, non-unions, or high-risk defects were enrolled, and calcium phosphate-based ceramics were intraoperatively coated with autologous tissue via a surgical suction handle and implanted into the defects. Clinical outcomes—including pain, range of motion, and wound healing—were scored using a standardized system, with all patients achieving results in the “excellent” range (10–13 points). Radiographic follow-up showed progressive cortical and extracortical bone formation in all patients. Surgeons reported high ease-of-use for the device, and no device-related complications occurred. Although biomaterial resorption was incomplete in some cases (36% with <75% resorption at six months), no patient required revision surgery. Our data indicate that intraoperative bioactivation of bone substitutes using a surgical suction handle is safe, feasible, and promotes local bone regeneration, providing a minimally invasive and practical approach to enhance the performance of synthetic grafts in challenging defects. Full article

S-methylmethionine (SMM, also known as vitamin U) is a sulfur-containing vitamin-like compound that has been investigated since the 1940s for its gastroprotective and cytoprotective properties. Historically derived from observations of antiulcer activity in plant-derived foods, SMM has been studied in preclinical models and limited clinical settings for its multilevel pharmacological effects. This narrative review critically evaluates the available evidence on SMM’s pharmacological actions across organ systems, with explicit differentiation between preclinical and clinical data. It covers the most consistently reported gastroprotective and antiulcer effects, as well as antioxidant, anti-inflammatory, cytoprotective, and regenerative activities observed predominantly in preclinical studies. Particular attention is paid to organ-specific protection in the nervous system, liver, kidneys, lungs, skin, eyes, and oral tissues, although human evidence remains scarce. Proposed mechanisms are mediated primarily through suppression of oxidative stress, modulation of inflammatory and immune responses, maintenance of glutathione homeostasis, activation of ERK/NF-κB and Nrf2/Keap1 pathways, and regulation of methylation processes. Building on recent descriptive reviews, this work provides a structured critical synthesis that grades evidence quality, compares SMM with the structurally related methyl donor S-adenosylmethionine (SAMe), and analyses the translational and regulatory barriers that have prevented Western drug registration despite over 70 years of investigation. Despite a substantial preclinical evidence base and historical clinical observations, the level of evidence for many indications remains limited. Well-designed Phase II randomized controlled trials and innovative pharmaceutical formulations (especially topical and mucosal delivery systems) are urgently needed to translate preclinical promise into clinical benefits. Full article

Deposition of three key 4-alkyl branched-chain fatty acids (KBCFA), including 4-methyloctanoic acid (MOA), 4-ethyloctanoic acid (EOA), and 4-methylnonanoic acid (MNA), causes the gamey flavor in sheep meat. This study integrated metagenomics and metabolomics to evaluate how Allium mongolicum Regel (AMR) supplementation (15 g/d) and rumen fluid transplantation (RFT) modulate rumen microbiota and hepatic metabolism to reduce KBCFA in lamb longissimus thoracis muscle. The experiment consisted of two phases. In Phase I, twelve 3-month-old male Dorper × Small Tailed Han sheep (25 ± 1 kg) were selected as the rumen donor group. These sheep were supplemented with 15 g/d/head of AMR powder in their basal diet until the end of the experiment. In Phase II, thirty 3-month-old male Dorper × Small Tailed Han sheep (23 ± 2 kg) were randomly assigned to one of three groups (n = 10 per group): the control group (STG), which was fed the basal diet and received a physiological saline transplant; the AMR group, which was fed the basal diet supplemented with 15 g/d/head of AMR powder and received a physiological saline transplant; and the rumen fluid transplant group (RTG), which was fed the basal diet and received a rumen fluid transplant from the donor group. Compared to the STG, results showed that the MOA, EOA, and MNA in the AMG decreased by 64.51%, 54.72%, and 49.34%, respectively. Similarly, the MOA, EOA, and MNA in the RTG were reduced by 63.13%, 56.17%, and 49.60%, respectively (p < 0.001). For the rumen metagenome, AMR enriched the genus Prevotella, while RFT increased Butyrivibrio. Hepatic metabolomics revealed a distinct shift where AMR elevated amino acid derivatives and RFT enhanced carnitine-related metabolites. These alterations indicate a potential metabolic shift associated with amino acid metabolism and mitochondrial β-oxidation, rather than lipid elongation. We postulate that this coordinated regulation across the rumen–liver–muscle axis may alter the availability of lipogenic precursors for KBCFA synthesis, ultimately contributing to improved meat flavor. Full article

Chronic wounds are ulcers unable to heal due to vascular insufficiency, diabetes, or obesity. Adipose-derived stromal cells (ASCs) are promising candidates for regenerative therapies owing to their pro-healing and angiogenic properties. Compared with autologous approaches, allogeneic ASC therapies offer the opportunity for off-the-shelf use, enabling immediate availability, standardized qualification, and consistent potency. Gelatin sponges have been shown to reprogram ASCs toward a highly angiogenic phenotype. However, because this activation also modulates some immune-related genes, including MHC, its impact on immunogenicity is unknown and could be critical for allogeneic applications. This study evaluated whether ASCs embedded in a gelatin sponge could be used in an allogeneic setting for ischemic wound repair. To mimic clinical allogeneic conditions, a controlled MHC mismatch was introduced in a rat ischemic wound model: donor ASCs carrying RT1^n or RT1^l haplotypes were implanted into outbred RT1^a recipients. Embedding ASCs within the gelatin sponge upregulated MHC class I but not class II expression, without inducing systemic or local alloreactivity. Serum acute-phase proteins remained unchanged, and no CD3⁺ T-cell infiltration was detected. Histology confirmed efficacy on ischemic wounds, with increased granulation tissue thickness, red blood cell infiltration, and enhanced vessel density versus controls. Allogeneic ASCs activated by a gelatin scaffold promote wound revascularization without eliciting immune rejection, supporting their development as standardized, off-the-shelf therapies for chronic ischemic wounds. Full article

Background/Objectives: Tuberculosis remains one of the preventable causes of mortality among liver transplant recipients. The prevalence of tuberculosis in solid organ transplant recipients is higher than in the general population. The aim of this study was to evaluate the incidence of latent tuberculosis infection (LTBI) and active tuberculosis after liver transplantation. Methods: This is a retrospective, single-center, case–control study. Adult liver transplant candidates who were evaluated between 1 January 2016 and 31 December 2022 were retrospectively assessed. Patients with pre-transplant tuberculin skin test (TST) and/or interferon-gamma release assay (IGRA) results who underwent transplantation were included in this study. Results: A total of 111 liver transplant recipients with available IGRA and/or TST results were included; 70 were men (63.1%) and 41 were women (36.9%), with a mean age of 53.5 ± 11.3 years. Demographic, clinical, and laboratory characteristics were evaluated. The most common indication for liver transplantation was viral hepatitis (33.3%), followed by cryptogenic cirrhosis (19.8%) and hepatocellular carcinoma (10.8%). All patients had a Bacillus Calmette–Guérin (BCG) vaccination scar. Ten patients received grafts from deceased donors, while 101 underwent living-donor liver transplantation. No patient received LTBI treatment before transplantation, whereas LTBI treatment was initiated in four patients after transplantation. None of the patients had a diagnosis of active tuberculosis prior to transplantation. Thoracic computed tomography revealed findings compatible with tuberculosis sequelae in 11 patients (9.9%). During a median follow-up period of 49 [27–64] months after transplantation, no cases of active tuberculosis were observed among patients with positive TST and/or IGRA results. Patients were divided into two groups according to their TST and IGRA results. Group 1 consisted of patients with IGRA positivity and/or a TST ≥ 5 mm, while Group 2 included patients with a TST < 5 mm and negative IGRA results. The only statistically significant difference between the groups was the administration of LTBI treatment (p = 0.027); four patients in Group 1 received LTBI therapy. None of these patients were able to continue prophylaxis due to treatment-related adverse effects. Conclusions: Prophylaxis with hepatotoxic agents poses a substantial risk in liver transplant candidates. Since the hepatotoxicity may cause early cessation of LTBI treatment, the risk–benefit ratio of post-transplant LTBI therapy should be carefully assessed. In situations where LTBI treatment is deferred, close clinical monitoring is strongly recommended. Full article

Lysine propionylation (Kpr) is a metabolically coupled lysine acylation that links propionyl-CoA availability to the molecular regulation of gene expression and protein function. Although lysine acetylation (Kac) is the most extensively characterized, recent proteomic and metabolic studies suggest that Kpr is more frequent than previously appreciated, occurs at defined lysine sites, and displays tissue-resolved and context-dependent patterns. Kpr often co-varies with other short-chain acylations such as Kac and lysine butyrylation (Kbu); however, emerging genomic-scale evidence indicates mark-biased genomic distributions and functional associations, suggesting that Kpr is not simply an extension or alternative to Kac. Notably, propionyl-CoA, the direct acyl donor for Kpr, can be influenced by microbiome-derived short-chain fatty acids (SCFAs), implying that interventions modulating SCFA availability (e.g., dietary manipulation) may provide an actionable route to tune Kpr and related acylations. Here, we summarize recent advances in propionyl-CoA sources and compartmentalization, the enzymatic writers/erasers/readers, the molecular mechanisms underlying Kpr, and the functional consequences of Kpr in physiology and disease. Full article

Background: In countries lacking donor registries, related donors, including haploidentical ones, often serve as the main option. This research aimed to examine the feasibility of locating donors for allogeneic hematopoietic stem cell transplants and to assess the outcomes associated with various donor types. Methods: Between 2019 and 2024, a retrospective observational study was carried out, involving 520 patients and 824 potential stem cell donors. Of these patients, 155 successfully identified a suitable donor and underwent allogeneic stem cell transplantation using mobilized peripheral blood stem cells. The study tracked overall and event-free survival over a five-year period to assess outcomes based on different donor types. Results: With alternative related donors (ARDs), 91% of patients were able to find at least one suitable donor for transplantation. The chances of identifying an appropriate donor increase with a larger pool of potential donors. Transplantation outcomes using ARDs, such as siblings, children, or parents, were similar to those with matched sibling donors. Other relatives could be considered as potential haploidentical donors, but the results with these donors were less favorable compared to those of others. Conclusions: The use of ARDs has significantly expanded the availability of related donors, with promising outcomes. Full article

Background/Objectives Sports-related musculoskeletal injuries remain a major challenge in physically active populations, with substantial interindividual variability in susceptibility and recovery that cannot be fully explained by biomechanics or genetics alone. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, provide a dynamic interface through which mechanical loading, inflammation, and metabolic signals regulate gene expression during tissue adaptation and repair. This narrative review synthesizes current evidence on “epigenetically active” dietary supplements and their potential relevance to sports injuries, focusing on methyl donors, polyphenols, omega-3 fatty acids, vitamin D, and redox-active nutrients. Methods Targeted searches of PubMed, Scopus, and Web of Science (2000–2026) were performed using epigenetics-, injury-, exercise-, and supplementation-related terms, prioritizing mechanistic and translational evidence. Results Available data indicate that these compounds can influence molecular mechanisms implicated in musculoskeletal recovery. However, human evidence is largely derived from peripheral tissues and indirect molecular markers, with limited clear linkage to clinically significant injury outcomes such as injury incidence, severity, or return-to-play timelines. Accordingly, these nutrients are best viewed as modulators of recovery-related biology rather than as direct therapeutic agents. Conclusions This review highlights a notable translational gap between mechanistic plausibility and clinical evidence and discusses practical implications for sports nutrition from a personalized perspective. Future research priorities include tissue-relevant epigenetic assessments, integration of multi-omics approaches, and longitudinal trials incorporating injury endpoints. Nutritional epigenomics, therefore, represents a promising avenue to support musculoskeletal health while underscoring the need for rigorous clinical validation. Full article

Background and Objectives: Recurrence of lupus nephritis (LN) after kidney transplantation is a major clinical concern in patients with systemic lupus erythematosus (SLE) who progress to end-stage renal disease (ESRD). Reported rates of post-transplant LN recurrence vary widely and are influenced by patient characteristics, immunosuppressive regimens, and indications for allograft biopsy. Patients and Methods: Medical records of adult LN patients treated at the University Hospital in Kraków, Poland, during the years 2012–2022 were retrospectively reviewed to identify individuals who progressed to ESRD and received a kidney transplant. Data collected included patient demographics as well as clinical, laboratory, transplant-related, and dialysis-related information. Results: Among 1039 patients with SLE, LN was diagnosed in 351 (33.8%), and 28 (8.0%) progressed to ESRD, of whom n = 9 (32.1%) underwent kidney transplantation. All patients received deceased-donor grafts, with a median time from ESRD to transplantation of 3 years (range 1–8) and a median post-transplant follow-up of 6 years (3–20). Maintenance immunosuppression consisted predominantly of glucocorticosteroids, mycophenolate mofetil, and tacrolimus in 77.8% of patients, with basiliximab induction was used in 2 of 2 patients with available data. Biopsy-proven LN recurrence occurred in 22.2% (2/9) of recipients. Graft loss was observed in 22.2% (2/9), while overall mortality reached 33.3% (3/9), including one peri-transplant death and one death due to infectious complications. Hematological manifestations were present in 100% of patients, hypercholesterolemia in 100%, and arterial hypertension in 88.9%, while anti-dsDNA antibodies were detected in 77.8%. LN relapse occurred despite standard immunosuppressive therapy and in the absence of consistent clinical or immunological predictors. Conclusions: LN recurrence occurred in 2 of 9 patients (22.2%). Patients with LN after kidney transplantation require careful long-term monitoring and individualized immunosuppressive management, considering baseline risk profile and relevant clinical with immunological factors. Full article

Introduction: Chronic lymphocytic leukemia (CLL) is a common adult leukemia often treated with fludarabine, cyclophosphamide, and rituximab (FCR). While effective, FCR can lead to therapy-related myeloid neoplasms (t-MN), including aggressive therapy-related acute myeloid leukemia (t-AML). Stem cell transplantation offers the best chance for long-term remission in these cases. Here, we report a rare case of t-AML with plasmacytoid dendritic cells (pDC-AML) developing after FCR treatment for CLL that was successfully treated with haplotransplantation. Case Presentation: A 57-year-old woman with CLL-B was treated with six cycles of FCR, achieving a complete response. Six years later, at age 63, she developed t-AML with a rare morphophenotypic subtype: acute myelomonocytic leukemia with plasmacytoid dendritic cells (pDC-AML) and monosomy 8. Diagnostic challenges included distinguishing this subtype from blastic plasmacytoid dendritic cell neoplasm (BPDCN). She was treated with high-dose cytarabine followed by haploidentical stem cell transplantation from her son. Haploidentical transplantation was prioritized due to the urgent clinical need in a patient with high-risk acute leukemia (therapy-related leukemia secondary to prior chemoimmunotherapy and failure to achieve complete remission following the standard 3 + 7 induction protocol). In this critical setting, the patient’s son was immediately available as an HLA-haploidentical donor. Prior to the performance of the haploidentical stem cell transplant from her son, no HLA-matched unrelated donor (MUD) could be identified. Another viable alternative would have been the utilization of umbilical cord blood-derived stem cells harvested from the patient’s twin granddaughters. She was closely monitored post-transplant for potential complications, including graft-versus-host disease (GVHD), post-transplant lymphoproliferative disorder, and thyroid dysfunction, all of which were ruled out during follow-up. The patient remains in complete remission 15 years after her initial CLL diagnosis and 8 years after the t-AML diagnosis and haplotransplantation. Notably, no residual CLL clone was detected at the time of t-AML development, and a benign polyclonal lymphocytosis observed between 2018 and 2020 spontaneously resolved without intervention. Conclusions: This case illustrates the potential for long-term survival in high-risk patients with therapy-related AML developed after cytotoxic treatment for lymphoid malignancies. Haplotransplantation from a semi-identical Human Leukocyte Antigen (HLA) donor proved to be a viable and effective treatment option despite the patient’s age and dual hematologic malignancies. Full article

β-thalassemia and sickle cell disease are two inherited hematological diseases due to defective hemoglobin synthesis or to the production of hemoglobin with altered properties. These two conditions have prolonged survival with modern support therapies, albeit life-long, complex, expensive and resource-consuming. Studies carried out in the last three decades have shown that allogeneic hematopoietic stem cell transplantation (allo-HSCT) and gene therapy may offer a curative approach for these diseases. Allo-HSCT should be performed early in life to reduce disease-related complications like irreversible tissue damage due to iron overload in patients with transfusion-dependent β-thalassemia (TDT) and systemic vasculopathy in patients with sickle cell disease (SCD). HSCTs from a matched-sibling donor or a matched-unrelated donor represent the best therapeutic option; however, haploidentical HSCT in both TDT and SCD is now increasingly performed as a valuable and viable option for a larger number of these patients. An alternative curative strategy is based on gene therapy. These curative approaches, particularly those of gene therapy, are available only in a part of the world. Gene therapy diffusion is strongly limited by its high technological and infrastructure requirements and its very high cost. Criteria must be defined for the optimal selection of TDT and SCD patients for allo-HSCT or gene therapy. Full article

Hepatitis A (HAV) and E (HEV) are clinically indistinguishable diseases. This study aimed to determine the seroprevalence of both viruses among 469 blood donor candidates at HEMOBA, Salvador, Brazil. The seroprevalence of anti-HAV IgG was determined by chemiluminescence (Abbott Diagnostics, Chicago, IL, USA) and that of anti-HEV (IgG/IgM) was determined by ELISA (Wantai-Biopharm, Beijing, China). The ineligibility rate was 16.8% (79/469), mostly temporary. There were no statistically significant demographic differences between ineligible and eligible donor candidates. The participants were predominantly male (52.7%), with the skin color Brown/Black (83.2%), and had completed secondary education or started/completed higher education (89.6%). The seroprevalence of anti-HAV IgG was 53.5% (193/361; 95%CI: 48.2–58.7%) among unvaccinated participants; the seroprevalence of anti-HEV IgG was 7.0% (33/469; 95%CI: 4.9–9.7%), and no case of anti-HEV IgM was found. In univariate analysis, HAV was associated with work with livestock and eating fresh fish; HEV was related to low incomes and eating game meat. However, only aging and being born in the interior of the state retained statistical significance in the final model. In conclusion, despite the availability of the HAV vaccine, this study revealed a higher burden of HAV when compared to HEV. Future studies must prioritize risk factor investigations of both viruses in non-metropolitan and rural areas. Full article

Age-related osteoporosis is driven in part by senescence-associated rewiring of bone marrow mesenchymal stem cells (MSCs) from osteogenic toward adipogenic fates. Accumulating evidence indicates that epigenetic drift and reduced autophagy are not isolated lesions but are mechanistically coupled through a bidirectional DNA methylation and autophagy axis. Here, we summarize how promoter hypermethylation of genes involved in autophagy and osteogenesis suppresses autophagic flux and osteoblast lineage transcriptional programs. Conversely, autophagy insufficiency reshapes the methylome by limiting methyl donor availability, most notably S-adenosylmethionine (SAM), and by reducing the turnover of key epigenetic regulators, including DNA methyltransferases (DNMTs), ten-eleven translocation (TET) dioxygenases, and histone deacetylases (HDACs). This self-reinforcing circuitry exacerbates mitochondrial dysfunction, oxidative stress, and inflammation driven by the senescence-associated secretory phenotype (SASP), thereby stabilizing adipogenic bias and progressively impairing marrow niche homeostasis and bone remodeling. We further discuss therapeutic strategies to restore balance within this axis, including selective modulation of epigenetic enzymes; activation of AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) signaling with downstream engagement of Unc-51-like autophagy-activating kinase 1 (ULK1) and transcription factor EB (TFEB); targeting sirtuin pathways; mitochondria- and autophagy-supportive natural compounds; and bone-targeted delivery approaches or rational combination regimens. Full article

Fecal microbiota transplantation (FMT) is a therapeutic strategy designed to modify and enrich the recipient’s gut microbiota by administering processed donor stool, with the goal of treating dysbiosis and related conditions. In 2013, the United States Food and Drug Administration (FDA) approved FMT for recurrent Clostridioides difficile infection (rCDI). Since then, its use has been proposed and investigated in several other disorders characterized by gut microbiota imbalance and altered host–microbiota interactions, including inflammatory bowel disease (IBD), immune checkpoint inhibitor-induced colitis (ICI-iC), and gastrointestinal graft-versus-host disease (GI-GVHD). This review aims to highlight the commonalities among these conditions, the pathophysiological mechanisms that support the rationale for FMT, and emerging evidence from clinical studies. Although available studies are heterogeneous, FMT is a rapidly evolving field of research with promising potential to treat IBD and improve outcomes following oncological immunotherapy and allogenic stem cell transplantation. With further validation, FMT could become an important approach in managing immune-mediated gastrointestinal diseases. Full article