Search Results (287)

Transthyretin amyloidosis (ATTR) is a disease caused by the deposition of transthyretin-derived fibrils in the body. Despite extensive research conducted over the years, there are currently only four drugs available in clinical use to treat this condition, two of which are repurposed drugs used off-label. However, these treatments present several limitations; therefore, there is an urgent need for new therapeutic options. In this context, dietary supplements containing natural compounds capable of stabilizing the transthyretin (TTR) protein could represent a promising approach to contrast the disease progression, potentially supporting the therapeutic effects of the aforementioned drugs. In light of this, the present review highlights and analyzes the natural compounds that have most recently been reported in the literature as TTR stabilizers. In particular, the studies elucidating the potential of these compounds in the treatment of ATTR, along with the available crystallographic data explaining their binding mode to TTR, are reported. Overall, although the use of natural compounds as supplements shows promise in managing ATTR, further research is still needed to explore its feasibility and confirm its effectiveness. Hopefully, this work will help shed light on these issues and serve as a useful starting point for the development of new strategies to treat this disease. Full article

This story began half a century ago with the discovery of an unusually high presence of tryptophan (Trp, W) in transthyretin (TTR), one of the three carrier proteins of thyroid hormones. With the Trp-rich retinol-binding protein (RBP), TTR forms a plasma complex implicated in the delivery of retinoid compounds to body tissues. W has the lowest concentration among all AAs involved in the sequencing of human body proteins. The present review proposes molecular maps focusing on the ratio of W/AA residues found in the sequence of proteins involved in immune events, allowing us to ascribe the guidance of inflammatory processes as fully under the influence of W. Under the control of cytokine stimulation, plasma biomarkers of protein nutritional status work in concert with major acute-phase reactants (APRs) and with carrier proteins to release, in a free and active form, their W and hormonal ligands, interacting to generate hot spots affecting the course of acute stress disorders. The prognostic inflammatory and nutritional index (PINI) scoring formula contributes to identifying the respective roles played by each of the components prevailing during the progression of the disease. Glucagon demonstrates ambivalent properties, remaining passive under steady-state conditions while displaying stronger effects after cytokine activation. In developing countries, inappropriate weaning periods lead to toddlers eating W-deficient cereals as a staple, causing a dramatic reduction in the levels of W-rich biomarkers in plasma, constituting a novel nutritional deficiency at the global scale. Appropriate counseling should be set up using W implementations to cover the weaning period and extended until school age. In adult and elderly subjects, the helpful immune protections provided by W may be hindered by the surge in harmful catabolites with the occurrence of chronic complications, which can have a significant public health impact but lack the uncontrolled surges in PINI observed in young infants and teenagers. Biomarkers of neurodegenerative and neoplastic disorders measured in elderly patients indicate the slow-moving elevation of APRs due to rampant degradation processes. Full article

Purpose: To investigate if radiomics signatures generated from longitudinal CT scans could predict IRE treatment effectiveness and outcomes in patients with locally advanced pancreatic cancer (LAPC). Methods: A cohort of 50 (60% male, mean [SD] age 60.7 [8.7] years) LAPC patients treated with IRE were retrospectively selected. Preoperative and 12-week follow-up CT scans were reviewed by two radiologists for tumor segmentation. A total of 2078 features were extracted: shape (n = 16), texture (n = 68), filter (n = 1892), intensity (n = 18), and local texture (n = 84). Principal component analysis (PCA) was applied to develop composite radiomics features. Composite signatures and clinically relevant radiomics features were correlated with time to recurrence (TTR), time to local recurrence (TTLR), time to distant recurrence (TTDR), recurrence-free survival (RFS) and overall survival (OS). Risk stratification performance was evaluated using hazard ratios (HRs), and significance was evaluated using the log-rank test. Results: Statistically significant separation between high and low patient TTR risk groups was observed in the following: gray-level co-occurrence matrix (HR = 2.65, p < 0.01, median survival difference = 6.6 mo); composite radiomics features derived from the following feature groups: all radiomics features (HR = 2.27, p = 0.01, median survival difference = 6.4 mo), intensity features (HR = 3.13, p < 0.01, median survival difference = 14.0 mo), and filter features (HR = 2.27, p = 0.01, median survival difference = 6.4 mo). Conclusions: Pre-treatment radiomics signatures were significantly associated with LAPC patient outcomes. The observed correlations used pre-treatment CT scans, implying that the features predict the individual risk of disease recurrence. Full article

Per- and polyfluoroalkyl substances (PFAS) are of concern because of their potential thyroid hormone system disruption by binding to human transthyretin (hTTR). However, the amount of experimental data is scarce. In this work, new classification and regression QSARs were developed to predict the hTTR disruption based on experimental data measured for 134 PFAS. Bootstrapping, randomization procedures, and external validation were used to check for overfitting, to avoid random correlations, and to evaluate the predictivity of the QSARs, respectively. The best QSARs were characterized by good performances (e.g., training and test accuracies in classification of 0.89 and 0.85, respectively; R², Q²_loo, and Q²_F3 in regression of 0.81, 0.77, and 0.82, respectively) and significantly broader domains compared to the few existing similar models. The application of QSARs application to the OECD List of PFAS allowed for the identification of structural categories of major concern, such as per- and polyfluoroalkyl ether-based, perfluoroalkyl carbonyl, and perfluoroalkane sulfonyl compounds. Forty-nine PFAS showed a stronger binding affinity to hTTR than the natural ligand T4. Uncertainty quantification for each model and prediction further enhanced the reliability assessment of predictions. The implementation of the new QSARs in non-commercial software facilitates their application to support future research efforts and regulatory actions. Full article

Transthyretin-related (ATTR) amyloidosis is a progressive, multisystem disease caused by the extracellular deposition of misfolded transthyretin (TTR) monomers as insoluble amyloid fibrils. Clinical manifestations vary widely and may include cardiomyopathy (ATTR-CM), polyneuropathy (ATTR-PN), or mixed phenotypes. The condition is increasingly recognized as an underdiagnosed contributor to heart failure, particularly in elderly patients. ATTR amyloidosis exists in two major forms: hereditary (ATTRv), resulting from mutations in the TTR gene, and wild-type (ATTRwt), typically affecting men over 70 years of age. Advances in disease understanding have led to a paradigm shift in management, with the introduction of targeted therapies that slow disease progression and improve prognosis. First-generation therapies such as tafamidis have demonstrated survival benefits in ATTR-CM. More recently, second-generation agents—such as the TTR stabilizer acoramidis and RNA silencers including vutrisiran and eplontersen—have shown promising efficacy in clinical trials. Additional strategies under investigation include gene editing and monoclonal antibodies targeting TTR amyloid deposits. This review outlines current diagnostic strategies and therapeutic options for ATTR amyloidosis, emphasizing the need for early detection and individualized treatment approaches. The expanding therapeutic landscape highlights the importance of accurate phenotyping and timely intervention to optimize clinical outcomes. Full article

Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant disorder caused by pathogenic variants in the TTR gene. The destabilized mutant form of the transport protein transthyretin (TTR) leads to the extracellular deposition of amyloid fibrils. Materials and Methods: A 65-year-old female patient with suspected clinical diagnosis of ATTR was referred for genetic testing for pathogenic variants in the TTR gene after physical, neurological and cardiac testing. Results: The patient had had cardiac dysfunction, atrial fibrillation and supraventricular tachycardia for around 10 years before the suspected and confirmed cardiac amyloidosis. The molecular genetic testing showed a heterozygous pathogenic variant in exon 3 of the TTR gene NM_000371.4(TTR): c.258A>C, p.(Glu86Asp). This variant in the TTR gene is classified as pathogenic in accordance with ACMG/AMP for the interpretation of variants. Conclusions: The presented case of a very rare pathogenic variant in the TTR gene displays the valuable role of genetic testing on the way to clarifying a diagnosis. Full article

Transthyretin (TTR) variant (V30M) polyneuropathy (ATTRv-PN) is a progressive systemic amyloidosis caused by transthyretin aggregation, leading to a variety of debilitating manifestations, including neuropathy and cardiomyopathy. We investigated the plasma proteome of heterozygotic V30M TTR asymptomatic carriers and heterozygotic V30M ATTRv-PN patients (before and after tafamidis treatment) versus WT TTR healthy control plasma using an organic solvent-induced shift in solubility assay to identify biosignatures for disease progression and therapeutic response. We identified many proteins, including TTR, apolipoproteins, ceruloplasmin, and proteins with functions in innate immunity that displayed changes in either their abundances or their sensitivity to precipitation. Elevated oxidative modifications of TTR and APOE in ATTRv-PN patients suggest a role for oxidative stress in disease pathogenesis/progression. Tafamidis treatment mitigated these pathology-associated changes, suggesting that alleviating proteotoxic stress impacts these other pathways. Although our study was limited to a Portuguese cohort, these findings nevertheless provide a comprehensive plasma proteomic profile of V30M ATTRv-PN patients, V30M TTR carriers, and tafamidis-treated ATTRv-PN patients over up to 60 months; provide insights into ATTRv-PN pathophysiology; identify potential biomarkers for disease progression and therapeutic response; and highlight the utility of proteomics in advancing personalized treatments for amyloidosis. Full article

Background: Adjuvant chemotherapy (ACT) can improve survival outcomes for patients with early-stage non-small cell lung cancer (NSCLC), but its benefit varies significantly across individuals. Identifying patients who are likely to benefit from ACT remains a critical challenge in precision oncology. Methods: We constructed a meta-database from two publicly available NSCLC gene expression datasets (GSE37745 and GSE29013) to address population heterogeneity. Feature selection was performed using Cox-based univariate screening with leave-one-out cross-validation. We then developed and compared three survival modeling frameworks: bagging with elastic net penalized Cox regression, Random Survival Forests (RSF), and DeepSurv neural survival networks. All models incorporated clinical covariates and selected genomic features to predict survival and recommend ACT versus observation (OBS). Results: Across 155 patients, RSF achieved the highest predictive performance, with a test concordance index (C-index) of0.885. Model-based recommendations were associated with improved survival in both training and test datasets, as confirmed by Kaplan–Meier analysis. Key genomic features identified included TTR, MTURN, and ETV3, suggesting their potential relevance in treatment response stratification. DeepSurv demonstrated strong predictive accuracy (C-index = 0.982) but less distinct survival curve separation compared to RSF. Conclusions: Our findings demonstrate that machine learning-driven survival models, particularly RSF, can effectively identify NSCLC patients who may benefit from ACT. This approach supports data-driven, individualized chemotherapy decision-making and contributes to advancing personalized treatment strategies in early-stage NSCLC. Full article

Background: Bisphosphonate scintigraphy (BS) is a recognized tool for diagnosing amyloid transthyretin cardiomyopathy (ATTR-CA). However, its sensitivity for rare transthyretin (TTR) variants, like Glu54Gln, remains underexplored. Methods: This was a retrospective descriptive study including all known patients with the Glu54Gln variant diagnosed between 2017 and 2023 in Romania, aiming to evaluate the diagnostic performance of BS in Glu54Gln ATTR–CA. Results: All symptomatic patients (n = 22) with histologically confirmed ATTR-CA had positive BS results (100% sensitivity). No false negatives were observed in asymptomatic carriers (n = 4). The Perugini visual score correlated with disease severity, with grade 3 scores associated with advanced cardiac involvement. We proposed a new parameter, heart-to-liver-uptake (H/L) ratio, which proved a strong positive correlation with both the heart-to-contralateral-uptake (H/CL) ratio (R² = 0.768, p < 0.001) and interventricular septum thickness (R² = 0.584, p < 0.001) and a weak correlation with the global longitudinal strain (R² = 0.212, p = 0.023). Conclusions: BS demonstrates high diagnostic accuracy for Glu54GlnATTR-CA, underscoring its utility in early diagnosis and clinical management. The H/L ratio presents a novel approach to semiquantitative analysis of bisphosphonate uptake in cardiac amyloidosis, potentially addressing key limitations of the traditional H/CL ratio. Full article

Background/Objectives: Cardiac amyloidosis (CA) is an underdiagnosed and potentially life-threatening infiltrative cardiomyopathy characterized by the extracellular deposition of misfolded amyloid fibrils in cardiac tissue. It is most commonly associated with light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis, either hereditary or wild-type. The disease often presents with non-specific symptoms, leading to delayed diagnosis and treatment. This study aims to provide a comprehensive overview of the pathophysiology, diagnostic strategies, and current therapeutic approaches for cardiac amyloidosis, with a focus on improving early detection and clinical outcomes. Methods: A narrative review was conducted using databases such as PubMed and Scopus, covering the period from September 2016 to March 2025. Keywords such as “cardiac amyloidosis”, “cardiac amyloidosis from transthyretin”, “cardiomyopathy”, “transthyretin”, “immunoglobulin light-chain amyloidosis”, and “familial amyloidosis” were used. Relevant clinical trials and guideline-based management recommendations were also included. Results: This review highlights that non-invasive imaging modalities and serum biomarker analyses are key to reducing diagnostic delays. New therapeutic developments, including gene-editing technologies and RNA-based therapies, show promise in early trials. Multidisciplinary management and increased awareness are crucial for timely diagnosis and treatment optimization. Conclusions: The early recognition of cardiac amyloidosis remains a major clinical challenge. Advances in non-invasive diagnostics and emerging disease-modifying therapies are transforming the prognosis of affected patients. Continued research and heightened clinical suspicion are essential to improve outcomes in this complex and heterogeneous disease. Full article

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive disease that has emerged as a significant cause of heart failure. Advances in the understanding of ATTR-CM pathophysiology have revolutionised its therapeutic landscape over the past decade, with the development of targeted therapies that are able to improve survival and quality of life. TTR stabilizers, such as tafamidis and acoramidis, can reduce TTR instability and subsequent amyloid fibril formation. Clinical trials have demonstrated their efficacy both in improving survival and quality of life in patients with ATTR-CM. Gene-silencing therapies using small interfering RNAs (siRNAs), such as patisiran and vutrisiran, or antisense oligonucleotide inhibitors (ASOs), such as inotersen and eplontersen, serve as powerful therapeutic options by decreasing TTR production; trials on patients with ATTR-CM have been recently published or are ongoing. Novel, emerging therapies aim to enhance fibril clearance using monoclonal antibodies, such as NI006, that target amyloid deposits in the myocardium, promoting their depletion, plausibly with regression of the structural and functional impairments caused by the disease. Concurrently, advancements in diagnostic modalities have facilitated earlier detection of this disease, allowing the timely initiation of treatment with a more significant impact on patients’ survival and quality of life. Despite these strides, challenges remain, including the high cost of disease-modifying therapy and the need for response criteria to monitor treatment’s efficacy. Future directions will involve improving patients’ screening to achieve earlier diagnoses, optimising patients’ selection for disease-modifying therapy and identifying criteria for the treatment’s response or lack thereof to possibly consider therapy switch or associations. In this review, we will explore the more recent therapeutic advancements in ATTR-CM, starting from traditional heart failure therapies and moving to disease-modifying therapies with a detailed evaluation of the registration trials to explore the strengths and shortcomings of each treatment. Full article

Over 150 transthyretin (TTR) mutations have been identified in hereditary transthyretin (ATTRv) amyloidosis, and new TTR variants have recently emerged. However, the pathogenicity of several new variants remains unclear, making it important to elucidate the differences between amyloidogenic and wild-type TTR. In this study, we report a novel TTR variant (V121A) identified in two unrelated amyloidosis patients aged > 60 years who developed cardiomyopathy. We evaluated the detailed biochemical features of this TTR variant to confirm its amyloidogenicity using plasma samples from these patients and recombinant TTR proteins. While the V121A TTR variant has a similar ability to assemble into a tetramer as wild-type TTR, it aggregates more readily over a wide potential hydrogen range than wild-type TTR. Additionally, the V121A variant is highly prone to dissociation and resistant to binding with known TTR tetramer stabilizers. Clinical and biochemical data suggest that this novel variant is clearly pathogenic, is highly prone to dissociation and aggregation, and is associated with the development of late-onset amyloid cardiomyopathy. Interestingly, amyloid fibril formation due to this variant may not be affected by known TTR stabilizers. Full article

The tetrameric protein transthyretin (TTR) transports the hormone thyroxine in plasma and cerebrospinal fluid. Certain point mutations of TTR, including the Val122Ile mutation investigated here, destabilize the tetramer leading to its dissociation, misfolding, aggregation, and the eventual buildup of amyloid fibrils in the myocardium. Cioffi et al. reported the design and synthesis of a novel TTR kinetic stabilizing ligand, referred to here as TKS14, that inhibited TTR dissociation and amyloid fibril formation. In this study, molecular dynamics simulations were used to investigate the binding of TKS14 and eight TSK14 derivatives to the Val122Ile TTR mutant. For each complex, the ligand’s solvent accessible surface area (SASA), ligand–receptor hydrogen-bonding interactions, and the free energy of ligand-binding to TTR were investigated. The goal of this study was to identify the TSK14 functional groups that contributed to TTR stabilization. TKS14 was found to form a stable, two-point interaction with TTR by hydrogen bonding to Ser-117 residues in the inner receptor binding pocket and interacting through hydrogen bonds and electrostatically with Lys-15 residues near the receptor’s surface. The free energy of TKS14-TTR binding was −18.0 kcal mol⁻¹ and the ligand’s average SASA value decreased by over 80% upon binding to the receptor. The thermodynamic favorability of TTR binding decreased when TKS14 derivatives contained either methyl ester, amide, tetrazole, or N-methyl functional groups that disrupted the above two-point interaction. One derivative in which a tetrazole ring was added to TKS14 was found to form hydrogen bonds with Thr-106, Thr-119, Ser-117, and Lys-15 residues. This derivative had a free energy of TTR binding of −21.4 kcal mol⁻¹. Overall, the molecular dynamics simulations showed that the functional groups within the TKS14 structural template can be tuned to optimize the thermodynamic favorability of ligand binding. Full article

Severe immune effector cell-associated neurotoxicity syndrome (ICANS) occurs in about 30% of all patients with large B-cell lymphoma (LBCL) who are treated with axicabtagene ciloleucel (axi-cel). There are currently limited treatment strategies other than the standard corticosteroids, and it is essential to find additional therapies to manage severe ICANS. We conducted a retrospective study of neurologic outcomes among patients who received axi-cel for LBCL from May 2015 to February 2019. We identified patients who developed severe ICANS and were treated with glucocorticoids followed by intravenous immunoglobulin (IVIG) (n  =  9) or glucocorticoids alone (n  =  10). There was no statistically significant difference in the time to resolution (TTR) of severe ICANS between groups; however, patients in the IVIG had more severe grades of ICANS with a lower performance status at baseline. The cumulative steroid days were 11.2 in the IVIG arm and 13.5 in the glucocorticoids-only arm. The use of IVIG for severe ICANS after axi-cel therapy was tolerable and safe and is generally recommended in the CAR-T setting in patients with hypogammaglobinemia. The use of IVIG as a potential therapeutic agent for severe ICANS can be further explored in future prospective studies. Full article

A major aspect of transition of care is the patient handover, during which miscommunication can significantly cause medical error and harm in patient care. Few medical schools in the U.S. offer formalized instructions on patient handovers, with most medical students learning from interns and residents through unstructured teaching. The aim of this study was to assess the effectiveness of a patient handover curriculum we developed for fourth-year medical students to increase their confidence and skills. Graduating fourth-year medical students (N = 98) enrolled in a two-week Transition to Residency (TTR) course attended an interactive session on patient handovers. During this session, students were presented with the I-PASS (illness severity, patient summary, action items, situation awareness and contingency planning, synthesis by receiver) mnemonic, went over case vignettes, and practiced giving and receiving handovers with a partner using the I-PASS template. At the end of TTR, students participated in an OSCE (Objective Structured Clinical Exam) activity that consisted of two standardized patient cases on blood transfusion and informed consent. Overall, our students did well with including important information in their Patient Summary (P: Case Scenario 1 Mean Score 56%; Case Scenario 2 Mean Score: 68%) and Action List (A: Case Scenario 2 Mean Score; 78%; Case Scenario 2 Mean Score: 87%) in their simulated patient case scenario. Pre-and-post survey results also indicated a significant improvement on student level of confidence (agreed or strongly agreed) in giving a patient handover (Pre: 53.1%; Post: 93.6%, p < 0.001), in receiving a patient handover (Pre: 58.2%; Post: 92.5%, p < 0.001), and in knowing what pertinent information to include in a patient handover (Pre: 62.2%; Post: 89.4%, p < 0.001). This study underscores the importance of systematic and repeated patient handover education throughout medical school training. Full article