Search Results (866)

Liver transplantation remains the definitive treatment for end-stage liver disease and acute liver failure, yet a critical and persistent shortage of donor organs results in thousands of preventable deaths annually worldwide. Xenotransplantation has emerged as a potential solution to this structural deficit. This narrative review traces the evolution of liver xenotransplantation, from early non-human primate trials in the 1960s through the application of CRISPR/Cas9-driven multi-gene editing platforms in contemporary porcine donors. The immunological barriers that drove the transition from primate to porcine donors are examined, including hyperacute rejection mediated by anti-α-Gal antibodies, coagulation dysregulation and xenograft thrombotic microangiopathy. The genetic engineering strategies underlying current triple-knockout, ten-gene-edited donor pigs are reviewed alongside the preclinical non-human primate evidence establishing biological feasibility. The three pig-to-human liver xenotransplantation studies published between 2025 and 2026 are then analyzed, encompassing heterotopic auxiliary transplantation in a brain-dead decedent, extracorporeal liver cross-circulation and the first auxiliary liver xenotransplantation in a living recipient with a documented 171-day survival. These cases collectively provide preliminary evidence supporting proof-of-concept for porcine hepatic bridging therapy, with current evidence supporting a role for xenogeneic liver support as a temporary bridge to recovery or allotransplantation rather than definitive organ replacement. Xenograft thrombotic microangiopathy is identified as the principal remaining biological barrier, and the substantial translational challenges, including reproducibility, scalability and regulatory readiness that must be resolved before broader clinical application can be considered. Full article

CRISPR technologies are transforming cardiovascular therapy development by creating an increasingly seamless pipeline from potential target discovery to clinical translation. What began as a genome-editing tool has evolved into a versatile platform that enables researchers to precisely interrogate and modulate cardiac biology with tools such as base- and prime-editors, and CRISPR inhibition and activation. In this review, we follow the use of CRISPR across the stages of biomedical research through to bench-to-bedside application. This review begins by addressing how genome-wide and focused CRISPR screens discover developmental regulators, disease drivers, and drug-response pathways, making the first steps in identifying therapeutic targets. We then explore how CRISPR engineering creates progressively more relevant disease model systems to validate mechanisms of disease and test interventions, helping bridge the translational gaps between the lab and the clinic. Finally, we consider how CRISPR technologies are beginning to enter cardiovascular clinical trials, while highlighting the key challenges that still limit this translation. By linking the latest advances of modern CRISPR platforms to the stages of therapeutic development, this review highlights how CRISPR technology is reshaping the pipeline from molecular insight to clinical innovation in cardiac disease. Full article

Importance: Immune checkpoint inhibitors (ICIs) have expanded downstaging options for hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), enabling bridging to liver transplantation (LT). However, the immunologic consequences of pre-transplant checkpoint blockade, particularly the risk of allograft rejection mediated by persistent T-cell activation, remain insufficiently characterized, creating a critical knowledge gap at the intersection of immuno-oncology and transplant medicine. Objective: To synthesize current evidence on oncologic outcomes, rejection risk, washout intervals, donor-type considerations, and immunosuppression strategies in LT recipients with pre-transplant ICI exposure. Evidence Review: A PRISMA-ScR-guided review was conducted using MEDLINE, Embase, Cochrane Library, and Web of Science from January 2015 through December 2025. Studies reporting outcomes in adult LT recipients with documented pre-transplant ICI exposure for HCC or CCA were included. Methodological quality was descriptively assessed using the Newcastle-Ottawa Scale and JBI tools. Given study heterogeneity, findings were narratively synthesized. Findings: Thirty studies were included. In HCC, neoadjuvant ICI therapy achieved downstaging to Milan criteria in 75.6% of candidates in the largest multicenter cohort (n = 117), with complete pathologic response rates ranging from 23.8% to 40%. Rejection rates ranged from 16.3% to 20.2% in large series but increased to 56.3% with short washout intervals. Washout intervals exceeding 50 days were associated with rejection rates approaching non-ICI controls, while an individual patient meta-analysis of 91 patients estimated each additional week of washout was associated with approximately 8% reduction in rejection risk, suggesting that approximately 94 days may be required to achieve a rejection probability of 20% or less. Rejection occurred at a median of 7–10 days post-transplantation, earlier than typical acute cellular rejection. Three-year overall survival exceeded 85.3% in major cohorts. Donor type was not consistently associated with rejection after adjustment for washout duration. CCA data remain limited. Immune-related adverse events during ICI therapy were associated with increased post-transplant rejection risk. Conclusions: Pre-transplant ICI therapy may expand transplant eligibility in advanced hepatobiliary malignancies but carries time-dependent rejection risk. Current evidence supports a minimum washout interval of at least 50 days, with emerging data favoring 90–94 days when feasible. Prospective multicenter studies, biomarker-guided risk stratification, and standardized immunosuppression protocols are needed to refine patient selection and optimize timing. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) are increasingly used in hepatocellular carcinoma (HCC), but their application around liver transplantation (LT) remains controversial because checkpoint blockade may enhance antitumor immunity while disrupting graft tolerance. We systematically reviewed the available evidence on ICI exposure before LT and ICI therapy after LT for recurrent HCC. Methods: A PRISMA-guided systematic review with qualitative synthesis was performed. PubMed/MEDLINE, Embase, and Web of Science were searched from inception to 15 March 2026. Studies including adult patients with HCC treated with PD-1-, PD-L1-, and/or CTLA-4-targeting ICIs before LT or after LT for recurrent HCC were eligible. Results: Fifty-one studies were included. In the pre-LT setting, 25 studies reported 576 transplanted patients. Acute allograft rejection occurred in approximately 22% and graft loss in 3.8%, and shorter washout intervals were consistently associated with higher rejection risk. In the post-LT setting, 26 studies reported 117 recipients treated with ICIs; at least 22 rejection episodes (18.8%) were described, usually within 2–4 weeks of treatment initiation, with limited and inconsistent antitumor benefit. Conclusions: Pre-LT ICI use appears feasible in selected patients when adequate washout is respected. Post-LT ICI therapy remains high risk and should be reserved for highly selected cases within a multidisciplinary framework. Full article

Background/Objectives: Lung cancer (LC) remains the leading cause of cancer-related death worldwide, despite advances in systemic and targeted therapies. A mechanism of survival of tumor cells is metabolic reprogramming, characterized by increased glucose uptake, aerobic glycolysis, and alterations in mitochondrial function. These adaptations seem to support tumor growth, immune evasion, and therapeutic resistance. In parallel, supportive care and specifically nutritional interventions have become essential components of modern oncology. The interplay between metabolic reprogramming and targeted nutritional strategies represents a promising area of investigation that bridges tumor biology with supportive care, aiming to enhance both therapeutic efficacy and patient quality of life. Methods: This narrative review explores the biological and pathophysiological rationale for the ketogenic diet (KD) as a possible complementary intervention in LC management and summarizes the published preclinical and clinical data supporting this rationale. Results: We discuss key aspects of tumor metabolism, including the Warburg effect, glucose dependency, oxidative stress regulation, fatty acid metabolism, lactate cycling and tumor microenvironment interactions, with particular emphasis on how carbohydrate restriction and ketosis may exacerbate mitochondrial dysfunction in cancer cells and modulate inflammatory pathways. Furthermore, we summarize available preclinical and clinical evidence evaluating the KD in oncology and, more specifically, in LC, focusing on feasibility, safety, metabolic effects, and potential synergy with chemotherapy, radiotherapy, and immunotherapy. Conclusions: While preclinical models suggest enhanced treatment efficacy, clinical data remain limited and heterogeneous, with patient adherence representing a major challenge. Further well-designed longitudinal studies are required to clarify the therapeutic role of the ketogenic diet in lung cancer. Full article

Objectives: The Impella 5.5 (J&J MedTech, USA) is increasingly used for refractory cardiogenic shock (CS), yet early predictors of mortality and recovery remain unclear. This study aimed to evaluate early patient characteristics and device-related parameters in relation to clinical outcomes; to compare outcome-based phenotypic groups (native heart recovery (NHR), heart replacement therapy (HRT), and death on the device (DEC)); and to analyze P-level impact on hemolysis and acute kidney injury. Methods: This retrospective single-center study included 28 CS patients supported with Impella 5.5 between May 2023 and August 2024. Data included intensive care unit (ICU) hemodynamics, vasoactive-inotropic score (VIS), lab markers, and pump parameters. Primary analysis evaluated early (first 24 h) parameters as potential indicators associated with mortality on the device and recovery, while secondary analyses compared hemodynamic and pump performance parameters across outcome groups, evaluated the association between P-level and hemolysis, and assessed the impact of shock etiology on clinical outcomes. Results: Among 28 patients (mean age 56 years, 10.7% female, body mass index (BMI) 27.7 kg/m²), NHR occurred in 39.3% and bridged to HRT in 42.9%. Non-survivors (17.8%) had significantly higher lactate (3.1 vs. NHR: 1.9 vs. HRT: 1.4 mmol/L, p < 0.001) and VIS (307.0 vs. NHR: 18.8 vs. HRT: 12.6, p < 0.001) at implantation. Higher VIS values (>69) were strongly associated with mortality on the device, with 100% sensitivity and 77% specificity (area under the curve (AUC) = 0.86); VIS < 9.9 was related to NHR (AUC = 0.63, 94% sensitivity, 45% specificity). P-levels were not linked to hemolysis index (r = −0.03, p = 0.64) or lactate dehydrogenase (r = −0.06, p = 0.37). Conclusions: Early vasoactive burden was associated with clinical outcomes in Impella 5.5-supported patients. No association between P-levels and the analyzed hemolysis surrogates was detected in this cohort. Distinct phenotypes across recovery outcomes may guide personalized management, but prospective validation of this exploratory and hypothesis-generating analysis is needed. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is molecularly heterogeneous, and approximately 30-50% of patients fail to achieve cure with standard R-CHOP. Genotype-directed first-line therapy may improve outcomes by targeting subtype-specific oncogenic pathways. This study evaluated the feasibility, efficacy, and safety of a molecularly adapted R-CHOP-X strategy with two-year follow-up. Methods: In this single-center, prospective, non-randomized study conducted between September 2023 and the data cut-off (16 September 2025), 43 adults with newly diagnosed DLBCL (excluding high-grade B-cell lymphoma, primary immune-privileged, and primary mediastinal large B-cell lymphomas) underwent tumor genotyping using the LymphGen classification after targeted sequencing: a 19-gene Sanger panel (Cohort 1, n = 35) or an expanded 60-gene panel (Cohort 2, n = 8; proof-of-concept). All patients received one initial cycle of R-CHOP as bridge therapy pending molecular profiling results, followed by five cycles of R-CHOP-X, with the additional agent (vorinostat, acalabrutinib, decitabine, or lenalidomide) selected according to molecular subtype. Response was assessed by PET/CT per Lugano criteria; adverse events were graded per NCI CTCAE v5.0. Results: The overall study population was predominantly high-risk: 72% had an IPI of 3–5, 58% had stage III–IV disease, and 67% exhibited a non-GCB immunophenotype. Expansion from the 19-gene to the 60-gene panel reduced unclassifiable (NOS) cases from 34% to 12%. The overall response rate was 100% (43/43); complete response among patients completing therapy was 100% (35/35). At two years, overall survival was 92% (95% CI 83–100%) and progression-free survival was 94% (95% CI 86–100%). Two early relapses occurred (NOS and N1 subtypes), both resulting in death. Grade 3–4 neutropenia, thrombocytopenia, and anemia occurred in 26%, 12%, and 7% of patients, respectively; no dose reductions or treatment discontinuations were recorded. Conclusions: Molecularly adapted R-CHOP-X is feasible and associated with high response rates and favorable two-year survival in newly diagnosed DLBCL, comparing favorably with historical R-CHOP outcomes in high-risk populations. Expanded genomic panels substantially improve molecular classifiability. These findings warrant validation in larger, multicenter, randomized clinical trials. Full article

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) remains a high-risk entity despite advances in tyrosine kinase inhibitors (TKIs), immunotherapy, and cellular therapies. Relapse driven by clonal evolution, central nervous system (CNS) sanctuary disease, and TKI resistance, particularly T315I mutations, continues to limit durable disease control. Asciminib, a first-in-class allosteric BCR::ABL1 (STAMP) inhibitor, has demonstrated efficacy and favorable tolerability in chronic myeloid leukemia, but its optimal role in Ph+ ALL remains to be defined. We report a three-patient case series of Ph+ acute leukemia treated with asciminib across diverse high-risk clinical settings, including multiply relapsed disease, CNS involvement, T315I-mutated leukemia, post-CAR-T-cell relapses, and transplant bridging. Clinical outcomes are contextualized through a comprehensive review of emerging clinical trial data, real-world cohorts, and mechanistic studies evaluating asciminib in Ph+ ALL. Across all cases, asciminib was incorporated as part of combination or consolidation strategies rather than as monotherapy in active disease. Asciminib contributed to molecular disease control, CNS leukemia clearance, and successful bridging to allogeneic transplantation or cellular therapy, with acceptable tolerability and no major vascular toxicity. Integration of published evidence demonstrates that asciminib exhibits consistent biological activity in Ph+ ALL, with improved durability when used in rational combinations, particularly with immunotherapy or ATP-competitive TKIs. Preclinical data further support asciminib’s compatibility with antibody-based and cellular therapies through preservation of immune effector function. Asciminib represents a versatile but context-dependent therapeutic option in Ph+ ALL. Its greatest clinical value appears to lie in rational combination regimens, maintenance strategies, and bridging to definitive therapies rather than single-agent salvage. Emerging structural biomarkers and ongoing clinical trials are expected to further refine patient selection, sequencing, and optimal integration of asciminib, particularly in CNS-involved disease and post-CAR-T cell relapse. Full article

Periodontal disease represents a major global health burden, beginning with gingivitis and progressing to periodontitis, which causes connective tissue breakdown, alveolar bone resorption, and eventual tooth loss. Beyond local pathology, periodontitis is a chronic inflammatory condition with systemic associations, including cardiovascular disease, diabetes, and metabolic disorders. Mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs) have emerged as promising candidates for periodontal regeneration. This review aimed to map the current evidence on MSC-derived EVs (MSC-EVs) in periodontal regeneration, focusing on their mechanisms of action, therapeutic potential, and translational challenges. A comprehensive literature search was conducted across a major biomedical database (PubMed) to identify preclinical and clinical studies investigating MSC-EVs in the context of periodontitis. Data were charted on EV cargo composition, biological functions, regenerative outcomes, and reported limitations. Evidence indicates that MSC-EVs encapsulate bioactive molecules—including antimicrobial peptides, proteins, lipids, and microRNAs—that modulate immune responses, suppress pro-inflammatory signaling, and promote angiogenesis and tissue repair. In periodontal models, MSC-EVs attenuate osteoclast activity, enhance fibroblast proliferation, and stimulate extracellular matrix remodeling, supporting regeneration of periodontal ligament and alveolar bone. Exosome-based approaches demonstrate advantages such as reduced immunogenicity, improved safety, and feasibility for storage and standardization. However, most findings remain preclinical, with limited human data available. To bridge the translational gap, well-designed clinical trials are needed to confirm efficacy and safety while addressing regulatory challenges, GMP standards, and outcome measures. Harnessing their regenerative capacity while mitigating side effects may guide precision-targeted therapies, and continued mechanistic studies with standardized production will be key to advancing MSC-EVs into clinical practice. Full article

Purinergic signaling plays a critical role in several inflammatory diseases, including acute lung injury, inflammatory bowel disease, coronary artery diseases, and various cancers. Purine and its derivatives, specifically adenosine and ATP, exhibit a critical regulatory axis that bridges platelet activation, vascular thrombosis, and sterile inflammation. Myocardial infarction (MI) initiates a complex pathophysiological cascade characterized by profound hypoxia, inflammation response, reduced coronary blood flow, and increased oxidative stress, which leads to myocardial cell death and apoptosis. Reperfusion therapy remains a primary strategy for restoring coronary blood flow and maximally limiting infarct size; increased infarct size further exacerbates ischemic injury, making it myocardial ischemic/reperfusion injury (MIRI). In this review, we delineate the mechanistic “triad axis”, comprising adenosine signaling, hypoxia-inducible factor (HIF) stabilization, and reactive oxygen species (ROS) homeostasis; this axis serves as a pivotal determinant of cardiomyocyte death during MIRI. We further examine the cell-specific roles of adenosine signaling in modulating immune cell infiltration and function within the ischemic milieu. Finally, we highlight the emerging role of mitochondrial ROS (mtROS) and HIF-dependent signaling in circadian regulation, suggesting that the chronotherapeutic approaches targeting these pathways may offer transformative opportunities for the treatment of ischemic heart disease (IHD). Full article

Hepatocellular carcinoma (HCC) remains a major contributor to global cancer mortality, with many patients presenting beyond the bounds of upfront curative therapy (resection/transplant). Locoregional therapies, particularly transarterial chemoembolization (TACE), transarterial embolization (TAE), and transarterial radioembolization (TARE), therefore play an essential role in bridging and downstaging strategies designed to enable curative intent in otherwise ineligible patients. Bridging therapy aims to maintain transplant eligibility and reduce waitlist dropout, whereas downstaging seeks to reduce tumor burden to meet accepted criteria for resection or transplantation. This review synthesizes current evidence on TACE, TAE, and TARE for bridging to resection and transplantation, as well as for downstaging to surgical eligibility, drawing from systematic reviews and cohort studies in the recent literature. We examine modality-specific outcomes, contextualized by tumor biology, liver function, and treatment selection criteria. Comparative effectiveness and the need for standardized outcome measures will be highlighted, reflecting heterogeneity in study endpoints and patient populations. Finally, future directions in personalized locoregional therapy, integration with systemic therapies, and refined conversion strategies will be discussed, with emphasis on the need for consensus in defining treatment success. By integrating evolving clinical evidence with practical application, this review will help clarify the expanding role of locoregional therapies in enabling curative-intent strategies for HCC. Full article

In an era marked by rising stress-related disorders and cardiovascular morbidity, understanding how the brain and heart adapt to environmental, physiological, and social stressors has become an urgent biomedical priority. This review advances an integrative framework centered on sociostasis, defined as the dynamic regulation of physiological state through social interaction, and its intersection with hormesis, a biphasic adaptive response to controlled stress that enhances resilience. We focus on four evolutionarily conserved neuropeptides, vasopressin, oxytocin, corticotropin-releasing hormone, and the urocortins, which serve as molecular bridges linking social behavior, neuroendocrine signaling, autonomic regulation, and cardiovascular function. Operating within an organized autonomic architecture, these systems calibrate responses to acute and chronic stress. Their context-dependent synergy enables adaptive flexibility under manageable challenge but may promote maladaptive cardiovascular remodeling when chronically dysregulated. Genetic vulnerability, developmental adversity, and persistent psychosocial stress can shift neuroendocrine–autonomic set points, increasing susceptibility to hypertension, endothelial dysfunction, and stress-induced cardiomyopathy. Conditioning and preconditioning paradigms illustrate how repeated exposure to subthreshold stressors primes cardiovascular tissues for future insults, enhancing ischemic tolerance and adaptive gene expression. We propose that cardiovascular hormesis depends not only on stimulus intensity but also on the integrity of neuroautonomic regulatory mechanisms that support recovery and flexibility. Vagal efficiency, a dynamic index of cardioinhibitory regulation, is discussed as a potential translational metric of adaptive capacity. By integrating molecular, physiological, and psychosocial perspectives, this framework conceptualizes cardiovascular resilience as an emergent property of coordinated hormetic signaling, neuropeptidergic modulation, autonomic regulation, and social buffering. Translational implications include peptide-based therapies, autonomic biofeedback, and behavioral interventions designed to enhance stress adaptability. Full article

Endoscopic bariatric and metabolic therapies (EBMTs) offer minimally invasive treatment options for obesity and related metabolic disorders such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD). These therapies are broadly categorized into gastric and small bowel interventions. Gastric EBMTs, including intragastric balloons and endoscopic sleeve gastroplasty, promote weight loss primarily through mechanical restriction and delayed gastric emptying, thereby improving metabolic outcomes. Small bowel therapies target the proximal intestine to modulate nutrient-sensing and hormonal pathways, providing metabolic benefits that may occur independently of weight loss. Techniques such as duodenal mucosal resurfacing, electroporation-based re-cellularization, and duodenal-jejunal bypass liners demonstrate promising effects on glycemic control, insulin sensitivity, and liver health. Emerging technologies utilizing thermal, vapor, and laser ablation further expand therapeutic possibilities. While these interventions show favorable safety profiles and potential as standalone or adjunctive treatments, further long-term studies and randomized trials are necessary to optimize patient selection and procedural protocols. Collectively, EBMTs represent an evolving paradigm in the management of obesity and metabolic diseases, bridging the gap between conservative medical therapies and bariatric surgery. Full article

Background: Single-target Alzheimer’s disease (AD) therapies have repeatedly failed to modify disease progression, highlighting a critical mismatch between multifactorial pathology and reductionist pharmacology. Methods: We developed a representation learning framework using Knowledge-guided Pre-trained Graph Transformers (KPGT) to enable rational multi-target drug discovery, analyzing 2446 molecules across APP, PSEN1, and VCP. Results: KPGT captured target-specific mechanistic signatures with 99.35% classification accuracy. Geometric midpoint analysis identified 15 bridging candidates with mean pIC₅₀ 8.09. We discovered two orthogonal molecular feature signatures, structural features driving multi-target breadth versus chemical features determining single-target potency, with zero descriptor overlap. Chemical orthogonality (d = 3.86) outperformed functional similarity for predicting synergistic pairs, with 95% overlap between multi-target molecules and synergistic combinations. Conclusions: This framework operationalizes systems-level AD drug discovery through interpretable representation learning. Full article

Sequestosome 1 (SQSTM1, also known as p62) has emerged as a multifunctional signaling adaptor that bridges autophagy, proteostasis, and inflammation. In this review, we discuss the molecular mechanisms by which SQSTM1 regulates selective autophagy and immune signaling pathways, and how its dynamic modulation shapes host responses during sepsis. We highlight the tissue-specific roles of SQSTM1 in sepsis-associated injury across major organs—including the liver, kidney, heart, lung, brain, and skeletal muscle—and explore its function as a damage-associated molecular pattern (DAMP) in the extracellular milieu. Recent studies implicate extracellular SQSTM1 in metabolic reprogramming and pro-inflammatory cytokine production via INSR signaling, supporting its classification as a novel DAMP and potential therapeutic target. We conclude a stage- and compartment-specific model for SQSTM1 during sepsis: its transition from a protective intracellular autophagy mediator in the early stage to a pathological extracellular DAMP in late stage. Furthermore, we discuss the translational relevance of pharmacological agents that modulate SQSTM1 levels or activity to restore immune balance and organ homeostasis. A better understanding of SQSTM1’s dual roles in immune activation and resolution could open new avenues for precision therapies in sepsis. Full article